Pharmacology Ain Shams 123 - Compress 1

Lecture Notes
PHARMACOLOGY
General
Autonomic
Autacoids
Pharmacology Department
Faculty of Medicine
Ain Shams University
2019/2020
\
Lecture Notes
PHARMACOLOGY
Volume 1
General
Autonomic
Autacoids
Faculty of Medicine
2019/2020
Preface
Pharmacology is an ever-changing medical science. The recent, rapid

advances in molecular biology and biotechnology have added relevant
information to drug therapy. This edition of "Lecture Notes on Pharmacology"
provides the most recent advances in drugtherapy within a concise framework.
This work is the result of the combined effort of the Professors of
Pharmacology Department; Ain Shams University. "Each of us is unique in their
own way. We have something to learn from everyone". Colleagues and students
are encouraged to communicate their suggestions. Authors will be pleased to
receive comments concerning this edition
Head of Pharmacology Department

Professor Dr. Lobna Bassyouni
2019-2020
Professors of Pharmacology Department
Head of Department
Prof. Dr. Lobna Bassyouni
Prof. Dr. Ahmed Nour Eldin
Prof. Dr. SaharKamal
Editorial Board: Prof. Dr. Ahmed Abdel-Salam - Prof. Dr. Olfat Hassan
Authors
Prof. Dr. Zeinab Labib
Prof. Dr. Ahmed Abdel-Salam
Prof. Dr. Olfat Hassan
Prof. Dr. Hoda Sallam Prof. Dr. Mohamed Abdel-Bary

Prof. Dr. Mona Hassan Prof. Dr. Ahmed Abedel Tawab
Prof. Dr. Dr. Sonia Saleeb Prof. Dr. Sawsan Abou el Fetouh
Prof. Dr. Osama El Serafy Prof. Dr. MayHamza
Prof. Dr. Ahmed Khalil Ass Prof. Amany Helmy
Deep appreciation for the valuable contribution of

Prof. Dr. Yousria Wahba Prof. Dr Sayed Kamel
Prof. Dr. Samira Mahmoud Prof. Dr. Somia Massoud
Prof. Dr. Adel el Bakry Prof. Dr Atef EL-Esawy.
Prof. Dr. Mahdy Salama Prof. Dr. Ahmed Badawy
Computer graphics &designs: Dr. Essam Ghazaly - Dr. Mohamed Bahr
ii
CONTENTS
1. General pharmacology 1 - 44
2. Adrenergic Pharmacology 45- 71
3. Cholinergic Pharmacology 72 - 89
4. Autacoids Pharmacology 90- 105
in
General Pharmacology
Intended Learning Outcomes (ILOs)
Pharmacodynamics: By the end ofthis chapter, the student should be able to:
• Define basic terms in pharmacology: e.g., pharmacodynamics, pharmacokinetics
bioavailability, first-pass effect, tolerance, intolerance, side effect, hypersensitivity
idiosyncrasy, pharmacogenetics, mutagenicity, carcinogenicity, teratogenesis, iatrogenic
disease, drug abuse.
• Describe the major animal & clinical studies carried out in clinical development.
• Describe the different signaling mechanisms for drug receptorinteraction.
• Compare efficacy & potency of 2 drugs on the basis of their dose response curves.
• Predict efficacy of a partial agonist in presence & in absence of a pureagonist.
• Specify the types of antagonists used in pharmacology basedon theireffects on the dose
response curves of their agonists.
• Describe 2 mechanisms of receptorregulation.
Pharmacokinetics: By the end of this chapter, the student should be able to:
• Realize theclinical importance of pka of a drug & pH of medium, in drug ionization,
lipid solubility& subsequent absorption or excretion.
• List the major phase 1 & phase 2 metabolic reactions.
• List drugs with enzyme inducing or inhibiting properties giving examples of subsequent
clinically important drug interactions.
• Calculate the half-life of a drug based on its clearance & volume of distribution.
• Calculate the loading & maintenance dosage regimen for oral or intravenous
administration of a drug when provided with minimum therapeutic concentration,
bioavailability, clearance& volume of distribution.
• Explain why drugs with saturation kinetics exhibit increased risk of toxicity.
• Calculate the dosage adjustment required for a patient with renal impairment.
• List important mechanisms of drug interactions and their clinical significance.
GENERAL PHARMACOLOGY
Pharmacology (Greek: pharmacon= drug, logos= discource in)
• It is the science that deals with drugs, their nature, pharmacodynamics,
pharmacokinetics, therapeutic uses, preparations and administration.
• The 2 main divisions of pharmacology are pharmacodynamics and
pharmacokinetics.
Target Site Therapeutic effect
Pharmacodynamics
Other Sites Adverse effect
Absorption Distribution Metabolism
d
Pharmacokinetics
Excretion
Fate of the drug in the body
Pharmacodynamics (Greek: dynamics= power)

• What the drug does to the organism. This includes the biological and
therapeutic effects of drugs and their mechanism of action.
Pharmacokinetics (Greek: kinesis= movement)

• What the body does to the drug. This refers to the movement and alterations
of the drug by the body. It includes Absorption, Distribution, Metabolism and
Excretion of drugs (ADME) and their mathematical relationship.
• . . General Pharmacology
Drug_(French: drug= dry herb)
• It is achemical substance that alters body functions and can be used for diagnosis,
prevention or treatment ofdisease and is recognized in apharmacopeia.
Drug Nomenclature
1. Chemical name: itdescribes the drug chemically but is not suitable for use in
prescribing. The drug may be given acode name (e.g., RO-15-1788) for
simplicity before the approved name is coined.
2. Nonproprietary: official or approved name.
3. Proprietary name: commercial property of adrug company "Brand name"
Examples ofnonproprietary /brand nam*.*? HiWpam/ Valium - Sildenafil/
Viagra, - Paracetamol (Acetaminophen)/ Panadol or Tylenol
Essential medicines (drugs^
• These are drugs that satisfy the priority health care needs of the
population. Their choice depends on their safety, efficacy and low cost.
• They should be available at all times in adequate amounts, suitable dosage
forms and low cost.
• WHO releases a list of essential medicines and national lists for individual
countries (including Egypt) are also available. These allow improved
availability ofmedicines, cost saving and more rational use ofdrugs.
Examples of essential drugs: aspirin, paracetamol, warfarin
Orphan drugs
• These are drugs or biological products for diagnosis/ treatment/prevention

of a rare disease or condition, or a common disease endemic only in poor
countries for which the cost of developing and marketing is not expected
to be recovered from the sales of that drug.
• Governments offer drug companies incentives e.g. tax benefits for

development of orphan drugs.
EVALUATION OF NEW DRUGS
I. Evaluation in Animals
• It is conducted on experimental animals (at least 2 species, one of which is
rodents):
A. Safety Tests which include:
• Acute, subacute andchronic toxicity studies.
• Effects on reproductive function.
• Carcinogenic and mutagenic potential.
• Addiction liability.
B. Pharmacologic Profile
• It includes studying the effects of drugs on different body systems:
CNS,GIT,CVS...
II. Evaluation in Humans
• Begun after acute & subacute animal toxicity studies have been
completed:
A. Phase I
• Done on small number of healthy volunteers.

• Trials are non-blind; both investigator & subject know what is being
given.
• Compares human to animal responses & determines the clinical dose
range.
• Pharmacokinetic measurements are often done in phase I.

B. Phase II
• Done on small number of patients to determine safety and efficacy.

• A single-blind design is often used.
• Involves comparison with an older active drug.
C. Phase III
• Done on large number of patients.

• Double-blind and cross-over techniques are frequently employed.
3
• After completion of Phase III, the drug company files a "new drug
application" to the regulatory body.
D. Phase IV "Pharmacovigilance"
• Done to monitor the efficacy and safety of the new drug under actual
conditions of use in large number of patients.
• It also involves "post-marketing surveillance" & post-licensing studies to
determine additional efficacy &toxicity after general marketing.
Placebo
• The term "placebo" is Latin for "I shall please" referring to an inert
substance given just to please the patient.
Placebo Effects
• The reactions unrelated to the pharmacologic effects ofadministered drug.

Placebo Responders
• People who respond excessively to placebo.
Uses of Placebo
1. In therapeutics: in psychotherapy, sometimes a placebo does as much

good (and less harm) as a potent drug with serious toxic effects.
2. In evaluation of new drugs to avoid false conclusions:
• To distinguish the pharmacodynamic effects of a drug from the
psychological effects of the act of medication.
• To distinguish drug effects from fluctuations in severity of disease.
Double-Blind Technique
• This technique was developed to prevent the effect of bias of both doctor and
patient on results.
• The patient (the first "blind" man) does not know whether he is receiving the
active drug or a placebo.
• The investigator (the second "blind" man) is ignorant of whether he is
prescribing a placebo or an active drug.
NB: In single-blind studies, only the patient is ignorant.
4
Cross-Over Trial
• It is conducted to protect against errors ofinterpretation caused by fluctuation
in severity of disease.
• It consists of alternating periods of administration of test drug, placebo and
standard drug control (to which the drug is compared).
• Each patient receives the three types ofmedications in a random sequence.
PHARMACOKINETICS
• The term pharmacokinetics denotes the quantitative studying of drug

Absorption, Distribution, Metabolism and Excretion (ADME) and their
mathematical relationship.
• Studying the mathematical aspect of these items leads to calculation of
pharmacokinetic parameters specific for each drug (e.g. bioavailability,
volume of distribution, half life, clearance ...etc.). These parameters can
help the physician in adjusting dosage schedules of the drug for each
individual patient based on its body characteristics.
•i' '••-/•/.•'••.'j
ABSORPTION OF DRUGS
• Absorption is thepassage of drug from the site of administration to the blood.
Lipid Diffusion1
• It is the most important means by which drugs enter the body and are
distributed within it. It is dependent on the drug being lipid-soluble i.e.
exists mainly in the non-ionized form.
• Ionization ofthe drug depends on the relation between its pKa and the pH
of the surrounding medium:
• When the pH of the medium = pKa of the drug; 50% of the drug
molecules exist in the ionized form & 50% in the non ionized form.
• Ionization of weak acids decreases at pH < pKa e.g. aspirin (pKa = 3.5)
exists mainly in the non ionized (lipid soluble) form at gastric pH (1.5-2.5)
• Ionization of weak bases decreases at pH > pKa e.g. theophylline (pKa =
8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
Clinical Significance of nK„

l.GIT
Aspirin is mostly non-ionized in the empty stomach —^crosses the cell

membrane of the gastric mucosal cells to be trapped inside these cells
(aspirin trap) —• death of the cells inducing "peptic ulceration".
2. Kidney
In drug poisoning, renal drug elimination can be enhanced by changing
urinary pH. This increases drug ionization and inhibits tubular reabsorption:
• Alkalization of urine (to f urine pH above drug pKa) is useful in acidic drug
poisoning e.g. aspirin & phenobarbital. Acidification of urine (to J, urine pH
below drug pKa) is used in basic drug poisoning, e.g. amphetamine.
1Absorption of drugs is mostly by simple diffusion through lipid membranes. Ionized form
of drug is water soluble & can not pass lipid membranes except through water filled
pores (too narrow to allow large molecules). Non-ionized form is lipophilic & can easily
cross lipid membranes.
Bioavailability (Biological Availability)

• It is the percentage of drug released from a formulation that reaches the
systemic circulation and becomes available for biological effect.
• It is calculated by dividing the Area Under the blood concentration-time
Curve (AUG) after any route ofadministration by that after IVI.
Bioequivelance & Therapeutic equivalence:

• Two dosage forms are bio-equivalent ifthey have the same bioavailability
& same time to achieve peak. They are therapeutically equivalent if they
are bioequivalent &they have similar efficacy &toxicity profiles.
Factors Affecting Bioavailability:

• Factors affecting bioavailability include: I. Factors affecting drug absorption
from GIT - II. First -Pass Effect
Fragments
£ '
®
Disintegration Dissolution Crossing the
0• • absorptive surface
Tablet Particles Molecules
Factors affecting Absorption

I. Factors affecting drug absorption from GIT

1. Factor related to dosage form e.g. synthesis techniques &exipients added
during preparation can affect disintegration ofthe dosage form into particles.
2. Factor related to drug: molecular weight, & solubility coefficient of the
drug can affect the dissolution ofthe drug particles into molecules.
3. Factor affecting drug stability in gut contents: GIT secretions can result
in drug destruction; food &coadministered drugs interact with drugs.
4. Gut pH &drug's pKa affect ionization ofdrug molecules into ions.
5. Factor related to the absorptive system e.g. GIT motility, surface area
available for absorption2, presence of GIT disease can modify the rate of
crossing of the absorptive surface.
Drugs with variable bioavailability among different dosage forms
Dieoxin -Phenvtoin.
P. First-Pass Effect fFirst-Pass Metbolism: Presvstemic Elimination)

• It is the metabolism ofsome drugs in a single passage through the liver, gut
wall or the lungs before reaching the systemic circulation.
A. Hepatic first-pass effect: drugs absorbed from the GIT are carried first
in the portal circulation to the liver. Some drugs are extensively
metabolized in their first-pass e.g. nitroglycerin & propranolol.
Factors reducing Hepatic 1st pass metabolism
• Reduction in portal blood flow: portal hypertension, propranolol.

• Inhibition of hepatic enzymes: liver failure - enzyme inhibitors; erythromycin.
B. Intestinal 1st -pass: due to intestinal mucosal metabolism (estrogen).
C. Pulmonary metabolism: after aerosol inhalation (nicotine).
Routes Bypassing the First-pass Effect
Sublingual - Parenteral - Rectal (to some extent)
2The intestineis the largest absorptive surface (200 m2); the lung comes next (70 m2).
8
DISTRIBUTION OF DRUGS
After adrug is absorbed, it is distributed between blood and tissues. The drug
passes through body compartments (plasma, interstitial, intracellular) which
are separated by capillary walls and cell membranes.
Volume of Distribution (Vd)

Drug distribution is interpreted mathematically as the apparent volume of
distribution (Vd)3.
It is defined as the volume that would accommodate the entire amount ofdrug
in body ifits concentration throughout body was the same as that in plasma.
Vd = Amount of drug inthe body/Plasma concentration
Factors affecting distribution of drugs:
•Drug distribution depends on: perfusion- diffusion- plasma protein binding-

binding to tissue constituents- capillary permeability.
1. Perfusion: the amount of the drug which is delivered to a particular organ

depends on the blood flow to that organ: t blood flow -»• t distribution.
2. Diffusion: the ability of the drug to diffuse across the cell membranes is
governed by its liopphilicty: t lipophilicity -*• | distribution.
Significance of lipophilicity
Lipophilicity facilitates drug absorption.

Lipophilicity increases Vd, (lipophilic drugs can penetrate into most tissues e.g.
CNS & placenta or enter the cells).
Lipophilicity -»t hepatic elimination (lipophilic drugs can enter hepatocytes).
Lipophilicity —>J renal excretion (due to f tubular re-absorption).
3It is called apparent volume since it not a real volume

9
3. Binding to plasma proteins:
Drug in blood exists in 2 forms: free form & plasma protein4 bound
form:
• Bound fraction is inactive, nondiffusible, cannot be metabolized or excreted.

• Free fraction is active, diffusible and can be metabolized and excreted.
• The two forms exist in equilibrium; when the free form is metabolized
and/or excreted, another part is released from plasma proteins.
Significance of Binding to Plasma Proteins

Binding facilitates drug absorption by decreasing its free
concentration in plasma.
The binding of drug to plasma proteins limits its tissue penetration &
decreases its Vd.
The bound drug can not be eliminated and provides a reservoir which
continuously releases the free part. This prolongs the t» ofthe drug.
The concentration ofthe active or free part ofhighly protein-bound
drugs may be too low to be effective against dangerous infections.
Drugs which bind to the acidic binding site ofalbumin (low capacity
binding site) can displace each other leading to clinically-significant
drug interactions e.g. displacement ofwarfarin by aspirin -^bleeding.
4. Binding to cell and tissue constituents:
It is due to an affinity to some cellular constituents. Examples:

• Chloroquine is concentrated in the liver.
• Tetracyclines deposit in bone and teeth as they chelate Ca2+.
• Iodides are concentrated in thyroid and salivary glands.
4Plasma proteins responsible for drug binding: albumin (mainly) for acidic, neutral & basic drugs,
globulins & ai-acid glycoprotein (rarely) for basic drugs.
10
Importance of Vd
1. It is anestimate of the extent of tissue uptake of drugs:
• Small Vd (e.g. frusemide) indicates that tissue uptake is limited.
• Large Vd (e.g. digoxin) indicates extensive tissue distribution.
2. In cases of drug toxicity:
• Dialysis is not useful for high Vd drugs (most ofdrug is in the tissues).
• Dialysis is useful for low Vd drugs (most ofdrug is in blood and ECF).
• Vd can be used to calculate the loading dose (LD):
LD = Vd x Steady state plasma concentration (Css)
Passage of Drugs to CNS
1. Lipid-soluble drugs pass freely through BBB, e.g. general anesthetics and
other CNS depressants.
2.2ry &3^ amines can pass while 4^ NH4+ compounds (ionized) cannot.
3. Dopamine cannot penetrate readily into CSF, so in parkinsonism we give
levodopa, which can cross BBB and is decarboxylated to dopamine in brain.
4. Penicillins pass slightly through the normal barrier, but they penetrate readily
in acute meningitis.
5. In tuberculous meningitis, INH, rifampin and pyrazinamide are effective as
they can pass readily, but streptomycin cannot.
Passage of Drugs to the Fetus
Many drugs cross placental barrier by simple diffusion (depending on their

lipid solubility & their degree of ionization) and can harm the fetus:
1. Drugs given in 3rd to 10th week of pregnancy -> teratogenicity
2. Morphine —> respiratory depression (asphyxia neonatorum).
3. Oral anticoagulants —»• fatal hemorrhage in the newborn.
4. Oral hypoglycemics (sulfonylureas) —*• prolonged neonatal hypoglycemia.
5. Antithyroid drugs —*• neonatal goiter & hypothyroidism.
6. Aminoglycosides —• 8th cranial nerve damage.
11
BIOTRANSFORMATION
(Metabolism)
• These are the changes that occur to drugs after absorption until excretion.
• Drug metabolism occurs mainly in the liver, though also in other organs, e.g.
intestinal lumen or wall, lung, plasma, skin and kidney.
Consequences of Drug Metabolism
• The aim of drug metabolism is the conversion of the drug to a more polar
(ionized) metabolite which is easily excreted. This may modify the activity of
the drug in one ofthe following ways:
-Abolishing the activity (occurs with most drugs).
-Converting inactive prodrugs into active drugs, e.g. enalapril (to enalaprilat)
&prednisone (to prednisolone).
-Converting an active drug to another active one, e.g. codeine to morphine.
-Converting drugs to atoxic metabolite e.g. paracetamol -> toxic epoxide
which isthen conjugated with glutathione.
Types of Biotransformation Reactions
Phase I (Non-Synthetic)
• Phase I reactions include: oxidation - reduction - hydrolysis.
• The most important reaction is oxidation by cytochrome P450 enzyme
system (mixed-function oxidases).
• Phase I reactions result in unmasking of a polar group (-OH, -SH, or -
NH2) -• conversion of the drug to an ionizedmetabolite that can be easily
excreted.
Phase II (Synthetic)
• An endogenous substrate, (e.g. glucuronic acid, glycine, glutathione, sulfate
or acetic acid) is conjugated with the functional group of the drug or its
metabolite (if the metabolite is still insufficiently polar). This results in the
formation of non toxic highly polar, rapidly eliminated conjugates.
12
Types of Metabolizing Enzyme Systems

1. Microsomal enzymes e.g. cytochrome P450 oxidases for oxidation and
glucuronyl transferase for conjugation
Cytochrome P450 oxidases or simply "CYP". CYP is the most important
metabolizing enzyme system. This enzyme system is further classified by
family, subfamily & gene into many isozymes. The name of each one is
designated by the term CYP followed by 3characters e.g. CYP 3A4, which is
responsible for metabolism of more than 35% of clinically important drugs5.
2. Non-microsomal enzymes e.g. dehydrogenase & esterases.
Non-microsomal Enzyme Microsomal Enzyme
Plasma Enzyme Cytoplasmic Enzyme
e.g. Cyt. P460 oxidase

for oxidation
eg ich
e.g. xanthine
este a s e
oxidase
e.g. glucuronyl transferase

for conjugation
Factors Affecting Biotransformation
I.Physiological changes in metabolizing activity due to age & sex.

2. Pathological factors which affect hepatic activity e.g. liver cell failure.
3. Pharmacogenetic variations in metabolizing enzymes e.g. slow & fast
acetylators (see pharmacogenetics).
4. Enzyme induction6 & enzyme inhibition.
' The first Arabic numeral represents the family, the alphabetic letter represents the subfamily.
the second Arabic numeral represents the individual gene within the subfamily.
6Enzyme induction is nota phenomenon related to drugs only but can also occur with many
chemical substrates and a useful mechanism for adaptation to environmental pollution .
13
Enzyme Induction:
• Certain drugs stimulate the microsomal enzyme systems leading to an

increase in their activity ->
• Increase metabolism of the inducing drugs (this leads to tolerance e.g.
phenobarbitone).
• Increase the metabolism ofother drugs metabolized by these enzymes (this
leads to drug interactions e.g. rifampicin -»| warfarin metabolism).
• Increase the metabolism ofendogenous substrates (e.g. phenobarbitone may
be used to enhance the elimination ofbilirubin in case ofneonatal jaundice)
• Enzyme induction is reversible. It occurs over a few days and passes offover
2-3 weeks after withdrawal of the inducer.
Examples of Enzyme Inducers

Phenytoin - carbamazepine - phenobarbitone - rifampicin - nicotine.
Enzyme Inhibition:
• Certain drugs inhibit the microsomal enzyme systems leading to a decrease

in theiractivity. This can lead to significant drug interactions.
• It occurs faster than enzyme induction.
Examples of Enzyme Inhibitors

Chloramphenicol - erythromycin - ciprofloxacin - ketoconazole.
14
EXCRETION OF DRUGS
• The kidney is the most important route ofexcretion. Excretion occurs through:
1. Glomerular filtration: molecules whose size are < the glomerular pores.
Factors affecting glomerular filtration

Glomerular filtration rate (GFR)
Plasma protein binding (PPB) -> prevents filtration
Drug Lipophilicity (affected by pH of urine & pKa of the drug)
-> enhances reabsorption of the drug after being filterated.
2. Active tubular secretion: either through acid carrier e.g. for penicillins,
probenecid, salicylic acid, or basic carrier e.g. for amphetamine, quinine.
Other sites for excretion
• Lungs e.g. volatile anesthetics

• Saliva: e.g. iodides
• Bile: e.g. rifampicin
• Milk: this isimportant for lactating mothers 7
Drugs Contraindicated During Breast Feeding
1. Antibiotics: chloramphenicol, tetracyclines, sulfonamides.

2. CNS drugs: narcotics, benzodiazepines, alcohol, nicotine.
3. Laxatives as cascara and senna.
4. Corticosteroids (suppress fetal growth).

5. Bromocriptine & sex hormones (suppress lactation).
N.B.: To jrisk to infants, lactating mothers should take drugs

immediately after nursing and/or 3-4 hrs before the next feeding.
7pH of milk is more acidic than that of plasma -> basic drugs accumulate in milk. Milk contains
more fat -> retention of lipid soluble drugs e.g. cytotoxics, metronidazole, morphine, laxatives.
15
PARAMETERS OF ELIMINATION
1. Kinetic orders
A. First order kinetics B. Zero order Kinetics
• A constant fraction of drug is eliminated • A constantamount of drug is
per unit time, e.g. 50%/ h. eliminated perunit time, e.g. 50 mg/h.
• Rate of elimination varies & is • Rate of elimination is constant, even if
proportional to drug concentration as drug concentration changes, since
metabolizing enzymes have high metabolizing enzymes have limited
capacity. capacity.
Constant t</2. • b/, is not constant
• On repeated dosing; a steadystate • No Css is reached; repeated dosing

concentration8 (Css) is reached. result in overshooting of drug
• Css oc dose. concentration.
• Tss (time to reach Css) » 4-5 11/29

Cone
Cone.
r4
k^kkk
Css
M Time
C w v^y *j w C3 Time
t=? ^P C^> <^> <tT5 C^>
t dose —> t Css
Modest changes in dose or bioavailability Modest changes in dose or

-âre usually tolerated. bioavailability -> toxicity.
Drug metabolites do not vary with dose. Drug metabolites may vary with dose 10
Examples: Most drugs. Famous example: ethanol11.
8Repeated dosing —»t drugconcentration & accordingly the rate of elimination increases till the rate of
administrationbecomes equal to the rate of elimination. At this point the Css is reached
9 After 4 tv,; > 95% of the Css is attained
10 Increasing dose of drug —> depletion of metabolizing enzymes with diversion of drug to other
metabolic routes giving different metabolites
11 Most zero order kinetic drugs areexcluded from the market for safety concerns.
16
C. Saturation kinetics
• The drug follows first order kinetics if it is eliminated by very active or

non restricted mechanism e.g. glomerular filtration or metabolism with
very active enzyme. If the elimination mechanism has very limited
activity; the drug follows zero order kinetics.
• Sometimes the elimination mechanism is in between; in such case the
drug follows first order kinetics at small dose & zero order kinetics at
large doses.The elimination mechanism is said to be saturated and this
type of kinetics istermed saturation kinetics.
Significance of saturation kinetics;

• Modest changes in dose or bioavailability ofdrugs -*• unexpected toxicity.
• Drug interactions are more common.
Drugs with Saturation kinetics
Phenytoin.
Theophylline
17
2. Elimination half life (tm)

Definition
• It is the time required to reduce the plasma concentration of drug to half the
initial concentration:
ti/2= 0.693 Vd/CLs12

Cone.
1/2 C
Time
l1/2
Value of elimination tv.
1. It determines the dosage interval (t).

• If t = \v2 -^ body stores twice the dose (for most drugs, this is an
accepted choice 13).
• If t < ty, -> more drug accumulation occurs.
• If t > tv, -> decrease in drug concentration occurs between doses.
2. It indicates Tss (time required to attain Css ): about 4- 5 t>/2.
Factors affecting elimination tv,
1. The state of the eliminating organs i.e. liver & kidney functions
2. The delivery of the drug to the eliminating organs e.g.:
a. Plasma protein binding limits renal filtration.
b. Drugs with very high Vd may escape from elimination in the tissues.
12 Elimination half-life = In Vi /Ke; ln'/i =0.693 &Ke isthe elimination rate constant = Cls/Vd/
where Cls is the systemic clearance.
13 For drugs with too short ti/2; we may resort to IV infusion or slow release (SR) oral
preparations.
18
3. Extraction ratio (E) & Hepatic clearance (CI liver)
Extraction ratio (E)
• It is the fraction of the drug eliminated by the liver.

E=(Arterial drug cone.) - (Venous drug cone.) / (Arterial drug cone.)
"^
Amount extracted Q x (CA -cv)
Extraction Ratio '
Amount entered
Amount entered Amount exit Amount extracted
QiC, Qx(CA-Cv)
r,Q = blood flow

C» = arterial concentration
Cv= venous concentration
J
a When E is > 0.7 -> clearance is nearlyflow-dependent, e.g. propranolol,

a When E is < 0.2 -> clearance is nearly enzyme-dependent, e.g. warfarin
• When E is 0.2-0.7 -> clearance is both flow and enzyme dependent, e.g.
acetaminophen, chloramphenicol
Hepatic clearance (CI uver)

• It is the volume of blood cleared by the liver per unit time:
CI Uver = Extraction ratio (E) x Hepatic blood flow (Q)
19
4. Systemic clearance (CLs)

Definition
• Itthe volume ofa fluid cleared from the drug per unit time.
CLs = Rate of elimination/Drug concentration
• The systemic clearance is equal to the sum ofindividual organs clearances

i.e. the clearnce by the liver, kidney, lung, ....etc.
Cls =renal clearance (Clr) +non-renal clearance (Clnr)
Factors affecting drug clearance

1. Blood flow to the clearing organ (directly proportional).
2. Binding ofthe drug to plasma proteins (inversely proportional).
3. Activity ofprocesses responsible for drug removal as hepatic enzymes,
glomerular filtration rate and secretory processes (directly proportional).
Significance of clearance
1. Calculation of the maintenance dose (MD):

MD = CLs x Steady state plasma concentration (Css)
2. The dosing regimen of drugs eliminated by glomerular filtration can be
guided by creatinine clearance e.g. dosing of gentamicin
• If Kidney function is normal (Cr Cl=120 ml/min): 80 mg 3 times /day
• If the kidney function is impaired you can reduce the dose or increase the
dose interval according to the level of Cr CI:
o If CrCl = 60 ml/min: give half the usual dose (i.e. 40 mg three
times/day) or give the usual 80 mg dose every 16 hours
o If CrCl = 30 ml/min: give one quarter the usual dose (i.e. 20 mg
three times/day) or give the usual 80 mg dose every 32 hours
20
iPHARMACODYNAMICSl
Mechanism (Mode) of Action of Drugs

• Drugs can induce a tissue response, initially through:
I. Receptor-mediated mechanisms involving interactions with particular
receptors at specialized sites within the body.
II. Non-receptor-mediated mechanisms.
1. Receptor-Mediated Mechanisms
• Receptors14 are specific cellular macromolecules (usually proteins) that
interact with a ligand (binding) to produce a response.
Ligands binding
Types of ligands
1. Full Agonist
Interacts with the receptor (affinity) activating it (efficacy) -> pharmacologic
effect, i.e. it has affinity and efficacy, e.g. acetylcholine (Ach) activates
nicotinic receptors —• depolarization —• skeletal muscle contraction.
2. Partial Agonist (Agonist-Antagonist)

• In absence of the agonist, it activates the empty receptor, but with lower
efficacy than that of a full agonist.
• In the presence of the agonist, it acts as an antagonist.
Example: Buprenorphine is a partial agonist for opioid receptors. In the
absence of a pure agonist e.g. morphine, it exhibits analgesic effects. In the
presence of morphine it acts as an antagonist reducing its analgesic effect.
14 The pharmacological actions mediated by the receptors are characterized by sensitivity (i.e.
very small cone, of ligand is enough toelicit the action), selectivity (i.e. each receptor has the
type of ligand that can interact with it) & specificity (i.e. they elicit the same response each
timethey interact with ligand).
21
. General Pharmacology
3. Inverse agonist
• Stabilizes receptoraway from the constitutional conformation15.

• Produces a response opposite to the pharmacological effect ofthe agonist.
Example: some anti-histamines16
4. Antagonist
•Interacts with the receptor without activation (affinity without efficacy),

e.g. curare blocks nicotinic receptors -> prevents depolarization by Ach
—• relaxation. There are 2 types ofreceptor antagonists:
• Competitive antagonists: compete with agonists for the same recognition
site ofthe receptors —»the agonist behaves as ifit were less potent.
• Noncompetitive antagonists: prevent binding of the agonist or prevent
activation of the receptorby the agonist.
o
to
c
o
Q.
to
&
Constitutive Antagonist
activity
Inverse agonist
Log Dose
15 The three-state model ofreceptor activation suggests that receptors exist in 3 conformational
states, inactive, active& constitutional statesthat are in a reversible equilibrium. The constitutional
state has some activity even in absence of ligand binding. In the presence of an agonist, the
receptors are in the active state, and in presence of the antagonists, they become in the inactive
conformational state. The inverse agonist shifts equilibrium away from theconstitutional state.
16 Other inverse agonists include beta carboline
22
Comparison between Competitive &Noncompetitive Antagonists
Competitive Antagonist Noncompetitive Antagonist

• Antagonist competes with the • Antagonist binds irreversibly to the
agonist for the same recognition recognition site of the receptor or
site of the receptor. bind to an allosteric site.
• Duration of antagonism depends on Duration of antagonism depends on

the relative plasma concentrations the rate of turnover of the receptor
of agonist and antagonist. molecules.
Causes parallel shift to theright in Causes downward shift iri log dose-
the log dose-response curve with response curve with decrease in
increase in the EC50 but no change Emax (maximum response) but no
in Emax (maximumresponse). change in EC50.
Competitive antagonism Non-competitive antagonism

Emax Emu
Log Dose Log Dose
• Examples: • Example:
Curare (Nm blocker). Phenoxybenzamine (a blocker).
23
N.B.:
The action ofa ligand can also be reversed by non-receptor antagonists e.g.:
• Chemical antagonists: interact chemically with the agonist away from
receptor, e.g. negative charges on heparin are neutralized by positive
charges on protamine sulfate (heparin antidote).
• Physiological antagonists: one drug antagonizes the effect of another

by acting on a different receptor to induce the opposite action e.g. p2-
bronchodilator and alpha vasoconstrictor effects of epinephrine
antagonize Hi-bronchconstrictor and vasodilator effects of histamine.
Receptor Cycling or Turnover
The number of receptors is not constant but the receptors are cycling
(old receptors are internalized inside the cell and the new ones are
externalized to the outside) and their number is continuously changing
depending on the rate of recycling.
Binding of the agonist -> increases receptor internalization -> i number
of recruited receptors [down regulation] while binding of the
antagonist -^ T the number ofrecruited receptors [up regulation].
24
SIGNALING MECHANISMS
The most important signal transduction systems are:

1. Ion Channels (for fast neurotransmitters)
• Receptors are ion-selective channels in the plasma membrane.

Binding ofagonist to the receptor —•opening ofthe channel —• alteration
in membrane potential or change in intracellular ion concentration, both
resulting in change in cell activity, e.g. nicotinic Ach receptors
(combined NaVK' channels) - GABAa receptors (CI" channels).
1
Slgnal-Q ** a ®* * *
a a lon*^
molecule v
. (ligand) ^ Plasma
membrane
I -A.- ^ Change In Ion

concentration
Ion-channel /
mombrana
polonllal triggers cellular
protein Cuosot
changes responses
2. Receptors linked to Tyrosine Kinase (RTKs)

• The receptor is formed of two domains:
a. An extracellular domain, to which the agonist (e.g. insulin) binds.
b. An intracellular domain, which is a tyrosine kinase enzyme (effector).
• Binding of insulin causes 2 single tyrosine-kinases receptors to aggregate
into a dimmer with subsequent autophosphorylation. Then, the activated-
phosphorylated dimmer binds to relay proteins, activating them. These relay
proteins trigger the cellular response through either production of a second
messenger or turning on gene expression.
Signal-molecule Signal moloculos
binding site Activated relay
a Hell • in the
membrane protein*
Cellular
fcOO
rosponso
Inactive relay proteins

74^
ÂTPTADP Cellular
response
Activated ty'roslne-klnaso
Tyrosine-kinase receptor receptor (phoephorylatad
proteins (Inactive monomera) dimor)
(a) Inactive tyroslne-klnsso receptor systom (b) Activatod systom
25
3- G protein-Coupled Receptors (for slow neurotransmitters)

• Receptors are linked to G proteins. The G protein is a trimer (a, p and y).
• Agonist binding —> dissociation of a subunit which regulates activity of
several effectors.
Signal-binding site
EXTRACELLULAR
FLUID
XXJOQ
Plasma
&&4
36363^
membrane
• 1 > 1 ' < I 1 1 1 • 1 . . ( : ,
Cytosol —{; s
Segment that
interacts with
G proteins
•4
G protein
GTP GDP
Examples of G Proteins
a. Gs (stimulatory) linked to p-receptors resulting in increased cAMP.

b. Gi (inhibitory) linked to 0:2 and M2 receptors resulting in decreased cAMP.
c. G,| linked to cti and Mi & M3 receptors liberating DAG and IP3.
Effectors Regulated by G proteins
1. Adenvlvl cyclase, which forms the second messenger cAMP which activates
protein kinase A (PKA) with subsequent phosphorylation cascade.
2. Phosnholinase C. which liberates the second messengers: diacyl-.glycerol
(DAG) and inositol triphosphate (IP.i):
• DAG activates protein kinase C (PKC) -» phosphorylation cascade.
• LP3 stimulates Ca2+ release from sarcoplasmic reticulum —>change in cell
activity.
3. Channels: M2 receptors coupled to Gi —• K outflux -> hyperpolarization
26
4. Receptors Regulating Transcription (very slow)

• Steroid hormones, estrogen, progesterone, thyroid hormones and vitamin D
enter the target cell and combine with intracellular receptor proteins
associated with nuclear chromatin (DNA) to activate or inhibit transcription
of the nearby gene. This will modify protein production and cause changes
in the structure or function of the target tissue.
MMUUM
Steroid
hormono
Receptor
proWIn
fflHNA_
&<
Plasma
membrane
of target
CELL
pyfOHAW
5. Nitric Oxide (NO) Receptors:
• NO receptors are protein receptors inside the cell. Binding of NO triggers

an allosteric change in the protein, which in turn, triggers the formation
of a "second messenger" within the cell. The most common protein
receptor for NO seems to be soluble guanylyl cyclase enzyme that
generates the second messenger cyclic GMP (cGMP).
• NO receptors are activated by many drugs that increase NO level e.g.
nitrovasodilators (nitrites, nitrates as nitroglycerine & sodium
nitroprusside) & muscarinic Mi-agonists (release endothelial NO)'. The
action can also be mimicked by the phosphodiesterase inhibitors (e.g.
sildenafil), which increase the level of the second messenger c-GMP.
27
II. Nonreceptor-Mediated Mechanisms
1. Drugs Acting on Enzymes
• Drugs may inhibit or activate enzyme systems.

• Examples of drugs acting via enzyme inhibition:
- Monoamine oxidase inhibitors (MAOIs) —> inhibit MAO enzyme
preventing destruction of biogenic amines (e.g. norepinephrine).
- Choline esterase inhibitors (ChEIs) —> inhibit ChE preserving Ach.
- Aspirin inhibits cyclooxygyenase -> decreases prostaglandin synthesis.
2. Drugs Acting on Plasmatic Membranes

Drugs may affect permeability, carrier systems, transport processes or
enzyme systems in the plasmatic membrane. Examples:
• Cardiac glycosides inhibit membrane-bound ATPase.
Phenytoin activates Na+ pump.
Polyene antifungal drugs increase permeability of fungal plasmatic
membrane.
3. Drugs Acting on Subcellular Structures

Mitochondria: salicylates uncouple oxidative phosphorylation.
Microtubules: Colchicine disrupts microtubules inhibiting mitosis.
4. Drugs Acting on the Genetic Apparatus
• Antibiotics (e.g. aminoglycosides, chloramphenicol & tetracyclines)

' inhibit bacterial protein synthesis.
• Anticancer drugs affect DNA synthesis or function, e.g. antimetabolites
and alkylating agents.
5. Drugs Acting bv Physical Means
• Demulcents (soothing): bismuth salts coat intestinal mucosa.

• Adsorbents: charcoal adsorbs gases and toxins in intestine.
• Lubricants: liquid paraffin is used in constipation.
• Osmosis: osmotic diuretics.
28
6. Drugs Acting bv Chemical Action

a. Antacids neutralize HCL in peptic ulcer.
b. Citrates interact with calcium to inhibit blood coagulation.
c. Protamine neutralizes heparin byits positive charge intreatment of heparin
overdose.
d. Chelation; isthe capacity of organic compounds to form complexes with

metals (chelates). The chelate may become more water-soluble and easily
excreted. It is useful in treatment ofheavymetal poisoning:
Examples of Chelators
1. Ethylene diamine tetra acetic acid (EDTA) chelates lead &calcium.

2. Dimercaprol (BAL) chelates arsenic, gold & copper.
3. Penicillamine chelates copper in Wilson's disease.
4. Desferrioxamine chelates iron and is used in iron toxicity.
29
Dose-response Relationship
Dose-response curves
• The dose-response relationship can be represented graphically by 2 types of

curves: the quantitative (graded) dose-response curve and the qualitative
(All/None) dose-response curve:
I. Graded dose-response curve is obtained if the degree of response is depicted

against log the dose e.g. decreases of blood glucose against the dose.
Response
Emax (efficacy)
Log (Dose)
Parameters that can be obtained from the graded dose-response curve:

1. Efficacy (Emax): is the maximal effect produced by the drug (= the
maximum valueofthe dose-response curve)
2. Potency of the drug is assessed from 2 parameters:

a. EDso: it is dose that produces 50% of the maximal response and is
estimated similar to the "All or none curve". The lower the ED50 the more
potentthe drug is.,7
b. Slope of the middle portion of the curve (it reflects the effect of the drug
produced by one unit of the dose. The steeper the curve (i.e. the higher the
slope) the more potent the drug is.
17: It should be noted thatlow EDJ0 means a more potent drug but it does not essentially mean
a more effective drug; efficacyof the drug is assessed by the Emaxand not the ED50.
30
n. All/None dose-response curve is obtained if the percentage of patients who

respond to the drug is depicted against log the dose e.g. the %of patients
in whom the arrhythmia is terminated by different doses of an
antiarrhythmic drug
Responders <fe
100%
Log (Dose)
EDso (or LDso)
Parameters that can be obtained from the All/None curve;
1. ED50: It is the dose that cures 50% of cases. It is used for comparison between
drugs e.g. drug with a lower ED50 is > potent than that with a higher ED50.
2. LDso: If we draw the relation between the % mortality in animals treated by
the drug (rather than the % responders) and the log of the dose, we will
obtain the LD50 (the dose that kills 50% of animals) instead of ED50. LD50
gives an idea about the absolute toxicity of the drug i.e. the drug with lower
LD50 is considered more toxic than the drug with higher LD50. The dose used
should not exceed 10% of the estimated LD50.
3. Therapeutic index (TI):
• It is the ratio between ED50 & LD50 —> TI = LD50/ED50.
• It gives an idea about the safety of the drug: if the TI is large, i.e. the
LDso is much higherthan the ED50 •> the drug is safer.
Drugs with narrow therapeutic index:

• Aminoglycosides, anticoagulants, antiepileptics, hypoglycemic agents,
lithium, quinidine, theophylline and tricyclic antidepressants.
31
Factors Modifying Dose-Response Relationship

• The dose is the main factor modifying drug action. Other factors include:
[1] Age:
• Younger patients can not tolerate the adult dose; accordingly the dose of the
drug for the children should be reduced.
• Various methods & formulas are used for calculating thechild dose:
a. Surface area method:
The childdose = Adult dose X Surface area(m2)/ 1.73

b. Age method:
The child dose =-Adult dose X Age (years) / age + 12
c. Weight method:
Thechild dose = Adult dose X Weight (Kgs) / 70
d. Percentage method:
The dose is calculated as a percent of adult dose:
1month (12.5%) 2 month (15%) 1year (25%)
2 years (33%) 7 years (50%) 12years (75%)
[2] Sex:
• Certain drugs act specifically in the female organs e.g. sex hormone (estrogen
& progesterone), ergot alkaloids & oxytocin
• In pregnant female: -> some drugs can cause teratogenicity e.g. thalidomide &
antithyroid drugs.
• In lactating female: some drugs can pass to the fetus in milk e.g. ephedrine &
phenobarbitone.
[3] Pathological States:

• The presence of certain disease may make the patient more sensitive to
certain drugs e.g.
• In bronchial asthma: B-blockers —> asthmatic attack.
• In myasthenia gravis: competitive skeletal muscle relaxants and quinine

-> myasthenic attack
32
[4] Tolerance:
• It is reduced responsiveness to the drug on repeated administration so that

higher doses areneeded to produce thesame effect.
Pharmacokinetic tolerance: is tolerance due to decreased drug level at the site
of action. For example: enzyme induction increases the liver capacity to
metabolise the dmg (e.g. with the anti-epileptic drugs phenytoin and
phenobarbitone) which may lead to decrease intheir effects.
, Pharmacodynamictolerance: is tolerance without decreased drug level e.g.
• Decreased sensitivity ofthe receptors e.g. opiates
• Decreased number of receptors [down regulation] e.g. 62-agonists
• Increased number of receptors [up regulation] e.g. H2-receptor antagonists.
• Depletion ofneurotransmitters e.g. dopamine with amantadine
• t release ofthe neurotransmitter e.g. | Ach release with ipratropium
• Counter regulatory mechanism e.g. salt &water retention with vasodilators.
Special types of tolerance:
a. Tachyphylaxis: acute tolerance but the same effect can not beobtained by
tdose e.g. tolerance due to depletion ofNEfrom few doses of ephedrine.
b. Cross tolerance: tolerance to related drugs e.g. cross tolerance between
different members of opioids.
[5] Psychological factors:
• Some patients may respond to a placebo the same way they respond to the
active dmg. The placebo may beused for psychological therapy & in control
studies to differentiate true drugeffect from that 2iy to psychological factors
[6] Drug interactions:
• The response to the drug may be affected byadministration of another drug:
Antagonism: decreasedresponse by a second drug.
Enhancement: summation, synergism and potentiation: increased response
in the presence of a second drug(seedmg interactions).
33
ADVERSE DRUG REACTIONS

The term "adverse reactions" is used for harmful effects of a drug, which
require reduction of dose, dmg withdrawal or immediate treatment.
Types of Adverse Reactions
Type A: Augmented (side effects and overdose toxicity).

Type B: Bizarre (hypersensitivity, idiosyncrasy).
Type C: Continuous (reactions due to long-term use).
Type D: Delayed (teratogenesis and carcinogenesis).
Type E: Ending of use (adverse effects following drug withdrawal).
Type A (Augmented)
a. Intolerance (at doses < therapeutic): tinnitus after a single, small aspirin dose
due to lower threshold to a normal pharmacologic action of drug.
b. Side effect (occurs at therapeutic dose) e.g.
i. I1* pharmacological action e.g. dry mouth from antihistamines.
ii. 217 pharmacological action e.g. thrush18 while taking antibiotics.
c. Overdose (at doses slightly> therapeutic): seizure with lidocaine.
d. Toxic effect(at very high doses) e.g. hepatotoxicity with acetaminophen.
TypeB (Bizarre)
1. Hypersensitivity (Allergic reactions)
• Immune-based adverse reactions. They are not dose-related but are
induced by prior contact with drugs that act as antigens.
2. Idiosyncrasy
• Genetically-mediated adverse effects e.g. porphyria, favism (see
pharmacogenetics).
TypeC (Continuous)
• Adverse effects occurring on chronic use of drugs e.g. analgesic nephropathy
or corticosteroids-induced osteoporosis, diabetes and hypertension.
18 Due to overgrowthof candidal infection.

34
TvneD (Delayed):
• This adverse effectmay occur even after stopping drug. There are 3 types
a. Mutagenicity: drag-induced gene abnormalities; with metronidazole.
b. Carcinogenicity: drug-induced neoplasm; with alkylating agents -
radioactive drugs.
c.Teratogenesis (teratos = monster; genesis = production): induction of fetal
abnormalities. It can be caused by some drugs when given early in
pregnancy. The most vulnerable period is weeks 3-10 ofintrauterine life.
Teratogenic drugs
• Thalidomide: phocomelia. • Cytotoxic drags: fetal anomalies
• Tetracyclines: dental hypoplasia. • 1131: fetal goiter
• Sex hormones (oral contraceptives). • Antiepileptics: cleft palate
• Adrenal steroids • Alcohol - smoking
TvneE (adverse effects following withdrawal of some drags)

1. Abstinence (withdrawal syndrome) in drag-dependent persons (addicts)
following withdrawal of narcotics, alcohol, hypnotics...
2. Addisonian crisis on sudden withdrawal of chronic corticosteroid therapy.
3. Angina or infarction may follow sudden withdrawal of p-adrenoceptor
blockers (due to upregulation of P-adrenoceptors -* t heart activity).
4. Hypertension and sympathetic over-activity onclonidine withdrawal.
5. Thromboembolism following withdrawal of oral anticoagulants.
Other Adverse Effects
1. Drug Abuse: the use of a drag for non-therapeutic purpose. It is more

common with drags acting on CNS causing drag dependence.
2. Iatrogenic Disease (Drug-Induced Disease): Drug prescribed for a disease
causes another disease, e.g. aspirin-induced asthma or peptic ulcer -
antipsychotic-induced Parkinsonism.
35
PHARMACOGENETIC DISORDERS
These are genetic abnormalities that are revealed onlyby the effect of drugs.
Acetylation Polymorphism
• The population is divided into slow and rapid acetylators. Drugs metabolized
by acetylation accumulate in the slow acetylators and produce toxic effects
more than in the rapid acetylators. Examples, in slow acetylators:
a. Isoniazid —> neuropathy and hepatitis.
b. Procainamide —• systemic lupus erythematosis (SLE).
Hemolytic Anemia due to G6PD Deficiency
• Congenital deficiency of glucose-6-phosphate dehydrogenase (G6PD)

enzyme renders RBCs readily hemolyzed in presence of some oxidant drugs
as antimalarials, sulfonamides and fava beans (favism).
Porphyrias
• Genetic disorders of porphyrin metabolism —*• | levels of porphyrins and their

precursors —• severe neurological disturbances & may cause death.
• Barbimrates and sulfonamides precipitate porphyria by increasing ALA-
synthetase activity with accumulation of porphyrin precursors.
Succinvlcholine Apnea
• Succinyl choline may cause respiratory muscle paralysis with apnea in

genetically predisposed patients due to failure of its breakdown due to genetic
defect in pseudocholine esterase responsible for its breakdown.
Malignant Hyperthermia
• Genetic disorder in which skeletal muscles fail to sequester Ca ++ in

sarcoplasmic reticulum following administration of succinylcholine and
halothane. This results in marked muscle rigidity & rise of body temperature.
36
Steroid-Induced Raised Intraocular Pressure

• Occurs in genetically predisposed individuals receiving corticosteroids.
Genetic resistance to anticoagulants
• Hereditary t in vitamin K reactivation —• Resistance to anticoagulants (e.g.,

warfarin) which inhibit synthesis of vitamin K -dependent clotting factors
through inhibition of vitamin K reactivation.
37
DRUG ALLERGY
• Allergic reactions are adverse effects mediated by immunogenic mechanisms.

• Most drugs are simple chemicals acting as incomplete antigens orhaptens.
• Drug allergy is dose-independent and occurs in minority of patients.
• Cross-allergy may occur within a group of chemically related drugs.
• Chieftargetorgans are skin, respiratory tract, GIT, blood & blood vessels.
Type I Reaction (immediate type; anaphylactic):

• IgE-mediated: antigen antibody reaction on surface of blood basophils or
tissue mast cells, e.g., asthma, anaphylaxis, angioedema (with penicillins).
Type II Reaction
• IgG or IgM antibodies are fixed to a circulating blood cell -> complement-
dependent lysis, e.g., hemolytic anemia (with methyldopa), systemic lupus
(with procainamide) & agranulocytosis (with chloramphenicol).
Type III Reaction
• Antigen antibody (IgG) complex is deposited in capillary beds —• serum

sickness syndrome &glomerulonephritis (with sulfonamides and penicillin).
Type IV Reactions (Delayed type; cell-mediated)
• Antigen stimulates T-cells to release lymphokines.
• Itis involved in allergic contact dermatitis from topically applied drugs.
Diagnosis of Drug Allergy
1. History and type of reaction. 2. Intradermal and conjunctival tests.

Measures against Allergy
Treatment: epinephrine - hydrocortisone - antihistamines.
Prophylaxis:
1. Cromolyn (inhibits histamine release)

2. Anti-IgE monoclonal antibodies.
3. Desensitization or hyposensitization.
38
DRUG INTERACTIONS
Drag interactions occur when one drug modifies the action ofanother drug in the
body. Clinically important drug interactions occur with:
1. Drugs that possess: Important Examples

a. A steep dose-response curve. • Oral anticoagulants.
b. Low therapeutic index (TI). • Oral hypoglycemics
c. Enzyme inducing or inhibiting properties. • Cardiac glycosides.
d. Zero-order & saturable kinetics.
• Antiepileptics.
2. Patients:
a. Receiving multipledrags.
b. Severely ill - impaired liver or kidney function.
c. At extremes of age
Types of Drug Interactions

• Pharmaceutical incompatibilities occur outside the body e.g., precipitation
when drags are mixed in solution for IV administration
• Pharmacokinetic; involving absorption, distribution, metabolism &excretion.
• Pharmacodynamic: interactions at the sites ofaction ornearby.
I. Pharmacokinetic Interactions
A. Interactions at site of absorption
• Tetracyclines chelate metals - 1 absorption of Ca2+, Mg2+, &

Al3+containing antacids.
• Drags that alter GI motility influence the rate and extent of absorption of other
drags (e.g., anticholinergics &prokinetic drags).
• Drugs that change the pH of the gut contents can also affect the rate of
absorption of other drags by affecting drug ionization.
39
B. Competition for plasma protein binding sites
• A drug with higher affinity will displace another drug with less affinity
increasing its free concentration and hence its effect.
• Clinically important protein binding interactions necessitate that the drug
should have a relatively small Vd so that most of drug is in the circulation
& more than 90% of the drug is plasma-protein-bound so that small
displacement of bound form —*• large increase in percentage of free form.
Examples of displacement interactions

• Aspirin displaces warfarin —*• bleeding.
• Sulfonamides & vitamin K displace bilirubin
hyperbilirubinemia —• kernicterus in the newborn.
C. Interactions involving metabolism

1. Enzyme Induction by enzyme inducers—>
• t Metabolism of drugs given simultaneously -*• J, level—• |effect
- Rifampicin —>f metabolism of oral contraceptives —> pregnancy.
- Phenvtoin -*t metabolism of vitamin D —» osteomalacia.
2. Enzyme inhibition by enzyme inhibitors—•

• | Metabolism of drugs given simultaneously—• f level —• potentiation
- Erythromycin inhibits metabolism of theophylline.
- Ciprofloxacin inhibits metabolism of theophylline, warfarin.
D. Interactions at Site of Excretion
• Alkalization of urine-»-tionization of acidic drugs ( aspirin) -»|tubular

reabsorption ->f excretion (useful in treatment oftoxicity)
• Acidification of urine -îonization of basic drugs (amphetamines)
-•itubular reabsorption ->f excretion (useful in treatment oftoxicity.
• Probenecid competes with penicillin for renal tubular excretion -• inhibits
its excretion —•prolongs its action.
40
II. Pharmacodynamic Interactions
A. Enhancement Interactions
• Summation (1+1= 2) i.e. additive effect. Example: Additive analgesic

effect of paracetamol + codeine.
• Synergism19 (1+1= 5): when two drags work together. Example:
sulfonamides plus trimethoprim act synergistically to block two sequential
steps inbacterial folic acid metabolism.
• Potentiation (a +b= B): occurs when two drags are taken together and
one of them (having no effect on its own) intensifies the action of the
other. Example: beta lactamase inhibitor (has no antibacterial effect)
intensifies the antibacterial effect of beta lactamase sensitive penicillins.
B. Antagonistic Interactions (1+1=0)
• p Blockers or a blockers with their agonists.
Beneficial Drug Interactions

• By combining drugs having different mechanisms of action or drags that
correct undesirable reactions of each other.
• Examples: multiple drug therapy for treatment ofhypertension, heart failure.
Categorization of drug interactions
• There are various systems for categorization of drag interactions. The

following is an example.
Category A:
• No known interaction
Category B:
• Drags may interact but no evidence of clinical concern.
• No action needed.
19 Theword synergism comes from twoGreek words: erg meaning "to work", and syn meaning
"together"; hence, synergism is a "workingtogether".
41
. General Pharmacology
Category C:
• Drugs may interact with each other in a clinically significant manner.

• The benefits of concomitant use usually outweigh the risks.
• Monitor Therapy. Dosage adjustments may beneeded.
Category D:
• Drugs may interact with each other ina clinically significant manner.
• A patient-specific assessment must be conducted to determine whether the
benefits of concomitant therapy outweigh the risks.
• Consider Therapy Modification: aggressive monitoring, empiric dosage
changes, choosing alternative agents.
Category X:
• Drugs may interact with each other ina clinically significant manner.
• The risks associated with concomitant use of these agents usually outweigh
the benefits.
• These agents are generallyconsidered contraindicated. Avoid Combination.
42
Prescription Writing
&
Dispensing Medication
I. Self-medication (OTC agents):

• OTC (Over-the-counter) agents are drags dispensed without aprescription as
they have a high safety margin e.g. simple analgesics, antacids, laxatives,
antihistaminics, antitussives & expectorants &nasal &oral decongestants.
Risks associated with the use of OTC drugs:
1. May aggravate preexisting disease e.g. nasal decongestant in hypertensives.
2. May cause drag interactions e.g. aspirin ->bleeding in patients on warfarin.
3. May lead to complications e.g. peptic ulcer with NSAIDs and electrolyte
disturbanceswith laxatives in the elderly.
H. Behind the counter drugs (BTC)

• Drags that can be prescribed by pharmacist without consulting the physician.
HI. Prescription-onlv medicines (PoM)
• Drugs that can not be dispensed without a prescription. In Egypt, there are 3
types of prescriptions:
1. Ordinary prescription: used for drugs requiring prescription by
specialists e.g. digoxin
2. Special prescription: used for some drags with low addiction liability
e.g. sedative hypnotics. These drags are called "table II drags".
3. Narcotic prescription: for highly addictive drags e.g. morphine.
Prescription forms aresupplied by local health authorities. The physician
writes 2 forms of prescription (one is keptby pharmacist to be dispensed
onlyoncewithin 5 days from its date). Dose is written both numerically
& alphabetically & thepatient's & doctor's identities are included.
4. e-prescription: electronic prescription; on the internet, permiting
conferencing betweenthe physician, the pharmacist and the patient
43
. . General Pharmacology
Patient Noncompliance
• Patients do not accurately follow physician's instructions in taking medication

resulting in under- or over-utilization ofthe prescribed drug.
Causes of noncompliance
• Disease cause: e.g. psychiatric & chronic diseases especially with minor
symptoms (hypertension...), extremes ofage and lonely patients.
• Drug causes: e.g. unpleasant taste or odor, undesirable route (injection,
rectal...) or complex regimen (multiple drugs, complicated instructions).
• Doctor causes: inadequate physician-patient relationship & lack of
supervision.
Categories of Teratogenic Risk
Category A: Controlled smdies failed to prove risk (e.g. vaginal nystatin)

Category B: No adverse effects in animals, but no controlled smdies on
pregnant women to ensure risk (e.g. amoxicillin, azithromycin)
Category C: Smdies in animals are suggestive but no controlled smdies on
pregnant women (e.g. co-trimoxazole, ciprofloxacin)
Category D: Evidence of fetal adverse effects, but the benefits outweigh the
risks (e.g. tetracyclines, sulfonamides when near term 'due to
increased toxicity to the new-bom')
Category X: Proven fetal risks outweigh any possible benefit.
44
• ' •' i '\'"'(
Autonomic Pharmacology
By the end ofthis chapter, the student will be able to:
• Discuss key biochemical and cellular events that take place in cholinergic and
adrenergic nerve terminals and at target organ junctions upon stimulation.
• Summarize the points of potential pharmacological intervention in the synthetic,
storage, release, receptor binding and termination steps of the neurotransmitters
acetylcholine and norepinephrine and ofthe neurohormone epinephrine.
• Discuss the subtypes of the adrenergic and cholinergic receptors including their major
peripheral locations and the major target organ responses to receptor stimulation.
• Identify prototype drugs that act to mimic, stimulate or block the: synthesis, storage,
release, receptor binding, or removal of acetylcholine, norepinephrine at nerve
terminals.
• Attribute the clinical use of different agonists or antagonists to their effects on

different autonomic receptors.
• Identify the physiological and pathogenic role of various autacoids (histamine ,
serotonin, eicosanoids, angiotensin and kinins). Summarize the points of potential
pharmacological intervention in the synthetic, storage, release and receptor binding of
such autacoids.
• Discuss the development ofvarious synthetic analogus for endogenous autacoids.

Adrenergic Pharmacology
ADRENERGIC PHARMACOLOGY
• The sympathetic system is an important regulator of activities of the heart &
peripheral vasculature especially in response to stress.
• Adrenergic neurotransmitters are responsible for transmission at all
postganglionic sympathetic neurons, except those ofsweat glands.
AdrenergicNeurotransmitters (endogenous catecholamines)

1. Norepinephrine (NE): The transmitter ofpostganglionic sympathetic fibers
& of certain tracts in the CNS.
2. Epinephrine (Epi): major hormone ofadrenal medulla. The adrenal medulla
receives preganglionic cholinergic neurons &releases epinephrine.
3. Dopamine (DA): Central transmitter in the extrapyramidal, mesolimbic &
mbero-infundibular pathways &in the CTZ. It is also aperipheral transmitter.
Synthesis, storage & release of adrenergic transmitters
• NE is synthesized in nerve cell (see fig) &stored in synaptic vesicles of adrenergic
neurons. Epi is synthesized in adrenal medulla by methylation ofNE.
• Membrane depolarizion -> Ca2+ influx into nerve terminal -»-fusion ofvesicle
with presynaptic membrane (partial exocytosis) -> discharge of NE & other
vesicle contents into synaptic cleft->NE activates a & p receptors.
• NE effect is terminated by reuptake into nerve endings or by metabolic degradation.
HO !—CH—NHa
TYROSINE
H COOH
HO. H I tyrosine hydroxylase
HO,^^-4-CH-l NHa DOPA

H COOH
COOI- aromatic L-omlno acid
decarboxylase
HCS— M *
>—C3—4—CHa—' DOPAMINE
dopamine p-hydroxytase
MO\ H \
HO ^^ <f CHa—NHa NOREPINEPHRINE
OH phonylothanolamlno-
"Ov H
HO—<Q>—$—CHa rf
M I N-melnyttransferase
EPINEPHRINE
OH CHa
45
Adrenergic Neuron
Synthesis, Release & Fate of NE
46
Drugs Affecting NE Release1

NE release is controlled centrally by nucleus tractus solitarus (NTS)2 &
peripherally by homotropic (transmitter affects its own release) &heterotropic (
transmitter affects release of another transmitter)3 regulation by presynaptic
neurons. •
J *
t Release I Release
• Activation of central/ • Activation of central/ presynaptic

presynaptic p receptors. CX2 receptors—*• negative feedback
by excess NE (homotropic).
• Tyramine
• Amphetamine • ACh (heterotropic; M2).
• Ephedrine. • Clonidine. <X2 agonists
• Nicotine (heterotropic;Nn) • Methyldopa y
Fate of catecholamines
I. Uptake
A. Uptake 1 (amine pump): actively transports NE from synaptic cleft into
neuronal cytoplasm to be stored in granules or metabolized by MAO
enzyme (the main fate of released NE).
•Blocked by: tricyclic antidepressants (TCA) - cocaine.
B. Vesicular: from neuronal cytoplasm to storage vesicles for re-use.
•Blocked by: reserpine (depletes stores).
C. Uptake II: to target organs for metabolism
• Blocked by: glucocorticoids.
1Tyramine, amphetamine & ephedrine release NEfrom adrenergic neuron. Reserpine depletes NE
stores & guanethidine inhibits NErelease (adrenergic neuronal blockers).
2Clonidine & methyldopa act on central 012 receptors in NTS—>| sympathetic discharge.
3Release of NE & Epi from adrenergic nerves & adrenal medullaby nicotine acting on Nn
presynaptic receptors —•! BP in smokers.
47
II. Enzymatic Degradation of catecholamines
• The monoamines, epinephrine, NE & DA are catecholamines (contain
catechol nucleus4). They are degraded mainly by oxidative deamination
by monoamine oxidase (MAO) & to a lesser extent by methylation by
catechol-o-methyl transferase ( COMT).
• The end product; vanilylmandelic acid (VMA) is excreted in urine -+ f
in pheochromocytoma (used in diagnosis).
• MAO inhibitors are used in depression & parkinsonism.
• COMT inhibitors are used in parkinsonism.
Classification of Adrenergic Receptors

I. Alpha adrenergic receptors
A. Alphai (stimulatory except on GIT &urinary walls)

1. Vasoconstriction
2. Relaxation of walls of GIT & urinary tracts. Coupled to Gq ->

3. Contraction of GIT & urinary sphincters. © PLC -» |IP3
4. Contraction of prostate & vas deferens. (|Ca2+) & DAG
5. Stimulate dilator pupillae -> active mydriasis. (© PKC)
6. Liver glycogenosis & K+ release.
B. Postsynaptic alphai (inhibitory except inplatelets &blood vessels)

1.1 Central sympathetic outflow -> J, BP.
Coupled to Gi ->
2. Inhibit lipolysis.
G adenylyl
3. Inhibit insulin secretion(predominant).
cyclase ->J.
4. Inhibit renin release.
cAMP -» GPKA
5. Stimulate platelet aggregation & vasoconstriction.
C. Presynaptic alphai
1. Inhibit NE release from sympathetic nerves.

2.1 Ach release in the heart & intestine.
4Catechol nucleus is a benzene ringwith 2 OH groups.

48
II. Beta-adrenergic receptors
A. Betai (excitatory) Coupled to Gs

1. Cardiac stimulation. protein-^©
2. Lipolysis -> t plasma FFA (pi and P3). adenylyl cyclase
3. f Renin secretion. -»tc-AMP-»
©PKA
B. Beta2 (inhibitory to smooth muscles)
1. Bronchodilation & mast cell stabilization.
2. Vasodilation of skeletal & coronary blood vessels.
3. Uterine and intestinal relaxation.
4. Stimulate insulin release (weak effect).

5. Liver& muscle glycogenosis & k+uptake.
6. Skeletal muscle tremors
III. Dopaminergic receptors
Di: vasodilation of renal, coronary, cerebral & mesenteric blood vessels.

Dr. Postsynaptic: central in the extrapyramidal, mberoinfundibular, &
mesolimbic pathways & in the CTZ.
Presynaptic: | DA & NE release from nerve endings.
Sympathomimetic Drugs
Classification According to Chemical Structure
Catecholamines: NE- epinephrine- isoprenaline -DA- dobutamine

• Contain catechol nucleus which is a benzene ring with 2 OH groups.
• Destroyed by MAO & COMT enzymes: cannot be given orally -shorter acting.
• Polar compounds:do not readily enter CNS (but exhibit some CNS effects).
Non Catecholamines: ephedrine, amphetamine,

• Not destroyed by MAO &COMT: can be given orally -longer acting.
• Readily enter CNS: strong CNS effects.
49
Sympathomimetic Drugs
Classification According to Mechanism of Action
B. Indirectly Acting B. Dual Acting

A. Direct
• Amphetamine Ephedrine
Acting
• Methylphenidate Pseudoephedrine
• Phentermine -Diethylpropion
Adrenergic Receptor Agonists
1 "1
Endogenous a Agonists p Agonists
Neurotransmitters
CTl OL2
0i P2
•NE: Oxymetazoline •Isoprenaline
ai CX2
Pi Selective ai
Selective pi
•Phenylephrine
•Dobutamine
•Epinephrine: •Methoxamine
ai ct2 •Midodrine
Pi P2 Selective p2
Selective ai
•Salbutamol
• Brimonidine
'Dopamine: • Salmeterol
• Apraclonidine
D Pi ai • Ritodrine
• Clonidine
• Methyldopa
N.B.:
• DA agonists: DA- dopexamine (Di D2 B2) - fenoldopam (Di) - bromocriptine (D2).
• Selective a 2- agonists are sympatholytics as they J, NE release.
50
DIRECTLY ACTING SYMPATHOMIMETICS!
Epinephrine
Pharmacological actions
I. Cardiovascular System
A. Heart (pi)
• tForce of contraction (positive inotropic).
• | Heart rate (positive chronotropic).
• | Conduction velocity (positive dromotropic).
• Enhances automaticity and causes arrhythmias.
B. Blood vessels
• VC of arterioles of skin, mucosa, splanchnic & renal vessels (ai).

• VC of veins (ai).
• Vasodilatation of skeletal & coronary vessels (p2 effect).
C. Effects on Blood Pressure
• t Systolic : vc (ai) & chronotropic & inotropic effects (Pi mainly).

• tDiastolic: cti.VC (may | with very low doses due to p2 VD of skeletal bv)
• t Mean BP (no reflex bradycardia as it is antagonized by chronotropic
& inotropic p effects).
• t Pulse pressure.
Epinephrine Reversal in Animals
• Hypotensive effect of epinephrine (P2-mediated VD of skeletal

vessels) is masked by its ai hypertensive effect. After a-
blockade, P2-mediated hypotensive effect is unmasked.
51
II. Respiratory System:
• Bronchodilatation (p2 action).
• Decongestion ofBVs ofmucous membrane ofupper respiratory tract (ai).
III. Eye
• Contraction ofdilator pupillae (ai) -* active mydriasis without cycloplegia.

• | IOP by decreasing aqueous humor formation.
IV. Effect on other smooth muscles
• Relaxation of GIT wall (P, a); a 2agonists -»• | presynaptic Ach release.
• Contraction of sphincters of GIT & urinary tracts (on).
• Inhibition ofuterine tone &contractions in last months ofpregnancy (p2).
V. Metabolic actions
• Hepatic glycogenosis -> p2 (mainly) & ai.

• Insulin release -> inhibited by a2 (dominant) &stimulated by p2.
• Lipolysis (pi & p 3) & inhibited by 0.2.
• Renin release (Pi) -> J, serum K+ (also decreased byf hepatic uptake; P2)
VI. Skeletal muscle: tremors -• p2 & central.
Therapeutic Uses
1. Anaphylactic shock (reverses bronchospasm & hypotension —• life saving).

2. Asthma if associated with locked lung.
3. Cardiac Arrest.
4. Arrests bleeding (topical hemostatic —>VC, e.g. in epistaxis).

5. Added to local Anesthetics to prolong their action.
6. Open Angle glaucoma (| IOP): dipivefnne (pro-epinephrine) is used instead
of epinephrine (since epinephrine is destroyed in alkaline medium).
Preparations and Dosage
• SC or IM 1:1.000 in mild anaphylactic shock.

• IV 1:10.000: severe anaphylactic shock - cardiac arrest (or intra-cardiac).
• Inhalation 1:100 in asthma.
• Topical: 1:100 in bleeding states - 1% solution for ophthalmic use.

52
Norepinephrine (noradrenaline)
• Natural catecholamine
• Acts on a &pi receptors as epinephrine (minimal effect on p2 receptors).
• a effect -> marked vasoconstriction ->t BP or gangrene.
• pi effect -> positive inotropic & chronotropic effect.
• Marked TT BP -> reflex vagal bradycardia which overcomes its direct
positive chronotropic effect.
• If atropine is given before norepinephrine, it will block the reflex vagal
bradycardia, then the direct positive chronotropic effect ofnorepinephrine
(tachycardia) will be apparent.
• Used in shock:
- Septic shock
- Cardiogenic shock (if BP < 70mmHg).
- Shock after resection of pheochromocytoma.
- Shock with pulmonary embolism.
Isoproterenol (isoprenaline)
• Synthetic catecholamine.
• Very potent p-receptor agonist (with little effect on a receptors).
• Pi effect —> +ve chronotropic & inotropic • Marked | | in HR
-> marked T in cardiac output. —• anginal
• P2 effect —> vasodilation —>l diastolic attack & sudden
& mean BP-> reflex t in HR. death.
• Used in:
- Bradycardia 2iy to heart block (rarely).
Dopamine & Dobutamine: see below.
53
Comparison between Dopamine and Dobutamine

Dopamine (D, pu ai) Dobutamine (pi)
Natural catecholamine. Synthetic catecholamine.
• Di-agonist fat low dose): No Di agonist effect.
- VD of several vascular beds, e.g., renal blood
vessels resulting in increased renal blood flow.
- Headache, nausea, vomiting.
Pi-agonist (atmoderate dose): • Bl-agonist:
-Cardiac stimulation - Cardiac stimulation:
(+ve inotrope & chronotrope) inotropic > chronotropic.
- Anginal painand arrhythmia. - Less arrhythmogenic.
ai-agonist (at high dose): No ai-agonist effect.
VC (including renal): hypertension, gangrene
Uses Uses
1.Acute HF & cardiogenic shock: • Similar to DA but preferred in

• DA is preferred in cases with hypotension (a normotensives (no a effect)
-•t BP) or renal impairment (Di -* renal VD). with preserved renal function
2. Chronic refractory HF (short term treatment). (no Di renal VD effect).
Administration (IV infusion titrated gradually) Administration: Similar to DA
• Dose range: 2 ug/kg/min->20 ug/kg/min • Dose range: 2.5ug/kg/min->20

ug/kg/min
Adverse effects
(Avoided by gradual titration of infusion )

1. Palpitation- anginal pain-arrhythmia (less with dobutamine).
2. Hypertension & gangrene (with dopamine).
3. Headache, nausea, vomiting (with dopamine).
54
Adrenergic Pharmacology . .
Dopexamine
• Adopamine analogue that activates p2 besides Di &D2 receptors.
• Very weak positive inotropic but powerful splanchnic vasodilator -» 1
afterload &improves blood flow to vital organs, including the kidney.
• Useful in shock following myocardial infarction, trauma, open heart
surgery in those with low cardiac output &peripheral vasoconstriction.
Fenoldopam
• Di receptor agonist -> peripheral VD in some vascular beds.

• It is used mainly IV for the treatment ofsevere hypertension.
Selective B i agonists
Advantages over nonselective B agonists

1. No cardiac complications inregular doses.
2. Longer acting (not metabolized by MAO or COMT).
3. May be given by many routes (oral, inhalation, parentral).
Therapeutic uses
1. Bronchial asthma: salbutamol/albuterol; shortacting
salmeterol; long acting
2. Prevent premature labor &threatened abortion (terbutaline &ritodrine).
Adverse effects (less with inhalation therapy):

1. Anxiety, restlessness and headache.
2. Tremors of skeletal muscle.
3. Tachycardia (at high concentration they stimulate pi receptors).
4. Tolerance on long term systemic use (preceptor downregulation).
5. Hypokalemia and muscle cramps.
6. Hypoxemia: (p2 effect-* VD > bronchodilation -> | blood oxygenation).
55
Selective on agonists
1. Phenylephrine
• An a i agonist.
• Longer acting than CA (not aCA-» not inactivated by COMT).
Uses:
a. Mydriatic for fundus examination (no cycloplegia; preferred to

atropine substitutes especially in patients with glaucoma).
b. Eye &nasal decongestant.
c. Hypotensive states to t BP.
d. Paroxysmal supraventricular tachycardia associated with marked
hypotension (t BP-» reflex vagal stimulation).
e. Local treatment for hemorrhoids.
2. Methoxamine
• a i agonist that acts like phenylephrine.

• It may induce prolonged t in BP due to vasoconstriction.
• Uses: hypotensive states (parenteral).
3. Midodrine
• Aprodrug that is hydrolyzed to desglymidodrine (a iagonist).

• Uses: postural hypotension (mainly).
Adverse effects of q- agonists
1. Hypertension & bradycardia.

2. Rebound nasal congestion &atrophic rhinitis (with local application).
56
Kndirectly acting sympathomimetics!

General features:
1. Act mainly by NE release; once NE stores are depleted^tolerance &tachyphylaxis.

2. They are non-catecholamines; so
• Not destroyed byMAO in the GIT-> Can be given orally
• Not metabolized by neuronal MAO -^ Longer duration of action
• Can penetrate the BBB -» Act on the CNS
3. They can lead to drug interactions with
a. MAOIs: serious hypertensive crisis (cheese reaction) may occur since
nerve endings ofpatients on MAOIs are studded with NE.
b. Reserpine: lose their effect as reserpinized nerves do not contain NE.
Nerve ending under Nerve ending under

Normal nerve ending
MAOIs treatment reserpine treatment
Members:
I. Amphetamine
II. CNS Stimulants e.g.5

• Methylphenidate - dextroamphetamine - methamphetamine.
III. Anorexigens for treatment of obesity e.g.*

• Phentermine -diethylpropion
5OtherCNS stimulants: Atomoxetine(NE reuptake inhibitor used in Attention Deficit

Hyperkinetic Disorders; ADHD); does not induce addiction.
6Other anorexigens: Benzphetamine & phendimetrazine.
57
Mechanism of action
• They act mainly by stimulating the release of NE &to a lesser extent by

inhibiting its uptake byadrenergic neurones.
CNS actions:
1. Strong CNS stimulation (penetrate BBB more than ephedrine)

2. Strong anorexigenic
Uses:
1. Narcolepsy7.
2. Attention Deficit Hyperkinetic Disorders ofChildhood (ADHD).
3. Obesity: short term treatment with phentermine &diethylpropion (low abuse
potential). Amphetamine is not used for fear ofdependence.
Adverse Effects:
1. Marked CNS stimulation ^hallucination, psychosis, convulsions &

dependence on prolonged use8.
2. Marked CVS stimulation -» palpitation, arrhythmia, hypertension.
3. Marked Anorexia.
4. New anorexigens -» 1*pulmonary hypertension & valvular heart diseases.
Tyramine fdecarboxvlated tyrosine)

• Indirectly acting sympathomimetic —> releases CA.
• High cone, in fermented foods (cheese, beer, fava beans, chicken liver).
• Metabolized byMAO inGIT, inactive orally due to a high Ist -pass effect.
Cheese reaction:
• Patients on MAOIs should avoid tyramine-rich food (e.g. old cheese) since
tyramine will escape metabolism & reach systemic circulation —* NE release
from neurons, studded with NE (due to MAOIs) -> hypertensive crisis.
7Modafinil: non-amphetamine for narcolepsy (|DA signaling or activity of wake-promoting

histamine neurons in tubero-mammillary nucleus.
8Amphetamine does notlead to dependence in narcolepsy or ADHD (unexplained reasons).
58
Mixed- or Dual-acting Sympathomimetic Drugsl
Members:
• Ephedrine
• Related compounds: pseudoephedrine
Mechanism of action
•They are dual acting sympathomimetic i.e. they act both by release ofNE
(similar to amphetamine but are much less potent) with some direct action on
the receptors (i.e. similar to epinephrine but are also much less potent).
CNS actions
• Mild CNS stimulation & anorexia as compared to amphetamine.
Uses
1. Epistaxis: topical ephedrine.

2. Oral nasal decongestants9: pseudoephedrine.
3. Spinal shock: ephedrine IMI (releases NE from anaesthetized sympathetic nerves).
4. Nocturnal enuresis (in children).
5. Urine incontinence (in adults).
Adverse Effects
1. Minimal CNS stimulation -> insomnia, anxiety.

2. Minimal CVS stimulation -> palpitation, hypertension.
3. Urinary retention.
3. Paradoxically, may induce sleepiness in children!!
9 Indirect-acting sympathomimetics are preferred to the direct-acting phenylephrine

(unpredictable absorption). Many oral OTC medications contain pseudoephedrine, least CNS
effects.
59
Choice of Sympathomimetic Drugs
1. Cardiostimulants (Pi mainly)

• Chronic refractory HF - acute HF &cardiogenic shock after AMI or open
heart surgery: DA (Pi &Di; renal VD) &dobutamine.
• Anaphylactic shock: epinephrine (ahVC; p,, f COP; p2, bronchodilation).
• Heart block (isoprenaline) or cardiac arrest (intracardiac epinephrine).
2. Vaspressors (a)
• Hypotensive states requiring peripheral VC as septic shock, spinal
shock &after sympathectomy (NE, ephedrine, phenylephrine).
• Chronic orthostatic hypotension (midodrine).
• PSVT with marked | in BP (phenylepherine -> |BP -• vagal stimulation).
3. Local vasoconstrictors (a)
• To prolong the duration oflocal anesthetics (epinephrine).
• Hemostatics e.g., in epistaxis (ephedrine, epinephrine).
• Nasal decongestants (oxymetazoline, phenylepherine).
4. Systemic nasal decongestants10 (a)
• Allergic rhinitis &sinusitis (pseudoephedrine, phenylepherine)
5. Ophthalmic applications (a)
• Mydriatic for fundus examination (phenylephrine)
• Conjunctival decongestant in allergy (phenylephrine, oxymetazoline)
• Simple glaucoma ( apraclonidine, brimonidine, dipivefrine)
6. Bronchodilators (P2): asthma (p2 agonists e.g. salbutamol - salmeterol).

7. Tocolytics (P2): premamre labor - threatened abortion (terbutaline & ritodrine).
8. CNS stimulants: narcolepsy- ADHD of children (amphetamine, methylphenidate).

9. Appetite suppressants: obesity (phentermine -diethylpropion).
10 a-agonists e.g. oxymetazoline arepreferred as local nasal decongestant (more VC); indirect agents
e.g. pseudoephedrineare preferred as systemic nasal decongestant(longer acting).
60
Beta Adrenoceptor Blockers (pBs)

• pBs are competitive antagonists of catecholamines at p-adrenoceptors.
Pharmacological actions of BBs
A. Cardiovascular Actions
1. Anti-anginal effect: improve imbalance between O2 supply &demand
A. [ O2 demand:
-1 HR &myocardial contractility.
-|BP.
- Inhibit lipolysis—>i fatty acid utilization.
B. t O2 supply:
-1 coronary filling during diastole (by | HR -• t diastolic period).
- Redistribution ofcoronary flow to sub-endocardial area.
1. A nti-iirrhythmic effect
• Block intrinsic sympathetic activity in slow fibres:

-1 Vmaxand delay conduction-*! SAN rate &AVN conduction.
4 Phase 4slope -> slow automaticity of sympathetic - induced ectopic focus.
3. Anti-hypertensive effect
• pVblockade (mainly)
- Suppress renin release.
- Negative inotropic &chronotropic effects.
• p2-blockade
- Central sympatholytic effect (block presynaptic P2 receptors in NTS).
- Peripheral sympatholytic effect (block presynaptic P2 receptors).
• Resettingofbaroreceptors.
• Some p-blockers are vasodilators.
4. Vasoconstriction (unopposed a actions)
• In ciliary vessels—»| aqueous humor production -* J, IOP.
• In mesenteric vessels —>j hepatic bloodflow (| dmg metabolism).
• In skeletal muscles —> | blood flow during exercise—• J,work capacity.
61
B. Noncardiovascnlflr Actions
1. Respiratory:
• Bronchoconstriction. ,
• Inhibit CA induced mast cellstabilization.

2. Metabolic
• Inhibit CA-induced glycogenosis-* delay recovery from hypoglycemia.

• i Insulin release-* glucose intolerance (not important ifpatient is on antidabetics).
• t Plasma TG11: | VLDL - [ HDL -1HDL/LDL ratio12.
• t Plasma K+during exercise (inhibit uptake by liver).
• Inhibit conversion ofT4 -* T3.
3. CNS
• CNS depression (lipophilic pBs).

• Anxiolytics.
Therapeutic Uses
• Mainly in hypertension, ischemic heart disease and cardiac arrhythmias.

1.2^ to Bi blockade
1. Hypertension.
2. Ischemic heart disease:
i. Angina pectoris, except vasospastic angina (may increase vasospasm).

ii. M. infarction (prophylactic &acute phase-* J, infarct size &mortality13).
3. Cardiac arrhythmias.
4. Heart failure (systolic): low dose carvedilol, bisoprolol, metoprolol.
5. Hypertrophic obstructive cardiomyopathy: relax septum -+J outflow resistance.
6. Hyperthyroidism & thyrotoxic crisis (propranolol):
Cardio-protective (Pi) -1 anxiety& tremors -inhibit conversion of T4 to T3.
11 Effect onTG isdue to unopposed alpha action which inhibits lipoprotein lipase. That iswhy itis
lacking in combined alpha & PBs& withp Bs with ISA and less withcardio-selective p Bs
because the presereved P2 action opposes the alpha action on lipoprotein lipase.
12 Effect on HDL/LDL ratio maybe due to changes in insulin sensitivity.
13 i Infarct sizeby itsanti-anginal & ^mortality by itsanti-arrhythmic effects.
62
Adrenergic Pharmacology .
II. 2*7 to Bi blockade

a. Open-angle glaucoma (timolol &betaxolol)
b. Prophylactic in oesophageal varices: non-selective BBs reduce portal
blood flow by: splanchnic vasoconstriction (p2 block) - |COP (pi block).
c. Prophylaxis ofmigraine (propranolol &timolol)
i.[ NE release which triggers attack.
ii. Vasoconstriction of extra-cranial blood vessels.
d. Essential tremors.
III. 21? to a blockade
a. Acute dissecting aortic aneurysm: (labetalol; ofchoice)

• Powerful antihypertensive (combined a &P)-»|dissection until surgery.
b. Pheochromocytoma (labetalol; ofchoice)
• If propranolol is used it should be preceded by an a- blocker to avoid
marked | BP due to unopposed a-action after p-blockade.
IV. 2*7 to CNS effects:
• Localized social anxiety disorder (mask symptoms during public performance).
Adverse effects, contraindications & precautions

A. Due to Bl blockade
• Bradycardia -heartblock.
• Heart failure (may be precipitated withhigh dose).
• Hypotension (more severe with vasodilator pBs).
B. Due to B2 blockade
• Cold extremities, fatigue & claudications (CI in peripheral vascular disease

& vasospastic angina).
• Bronchospasm (CI in asthma).
•Prolongation of insulin-induced hypoglycemia.
•Glucose intolerance.
•Hyperkalemia in susceptiblepatients (e.g. renal impairment & diabetes).
63
C. Other adverse effects
i. Hypertriglyceridemia (& glucose intolerance-* frisk ofischemic heart disease)

ii. CNS: nightmares &depression.
iii. Sudden withdrawal -* rebound angina &arrhythmias in ischemic heart

disease (due to up regulation of13 receptors; less severe with BBs with ISA)
-* gradual withdrawal is required to avoid rebound.
iv. Sexual dysfunction
Pharmacokinetics of p-hlnrk<»rs
• PBs are classified phannacokinetically into 3groups: lipophilic, hydrophilic &
balanced (properties in between those of lipophilic &hydrophilic).
• Esmolol is hydrophilic, yet it has avery short duration of action (ti/2 8min)
due to hydrolysis byplasma esterases.
Lipophilic Hydrophilic
Propranolol- metoprolol Atenolol- Nadolol
Carvedilol
Absorption • Well absorbed. • Irregularly absorbed.
First pass effect • Extensive • Less
Bioavailability • Less • More
Distribution • More CNS penetration -* • Less CNS penetration —• less

more CNS side effects. CNS side effects.
Elimination • Mainly hepatic -* suitable • Mainly renal —* suitable in

in renal impairment. hepatic impairment.
tVx • Short t!4 —* frequent • Longf/2 (except esmolol) -*

administration. once/ day administration.
64
Members of Different Generations of (3Bs
Propranolol
• Prototype beta blocker with the following characteristics:

1. Linophilic: short duration, CNS side effects & avoided in liver
dysfunction, thus newer agents with low lipid solubility were developed.
2. Non-selective: induces wide spread side effects thus newer generations
were developed: e.g., cardio-selective pBs, vasodilator pBs, & pBs with
intrinsic sympathomimetic activity (ISA).
3. Membrane stabilizing effect (MSA): induces local anesthesia of cornea
on topical application in glaucoma, thus replaced by PBs with no MSA
e.g., timolol (nonselective) &betaxolol (selective).
Generations of BBs
• Different pBs are distinguished by relative selectivity for pi & p2 receptors,

differences in lipid solubility, intrinsic sympathomimetic activity (ISA),
membrane-stabilizing activity (MSA) &vasodilator effects.
Lipophilic Balanced Hydrophilic Advantages

Non • Propranolol • Pindolol • Nadolol B B with ISA induce less:
selective (MSA) (ISA) (long acting) • Bradycardia.
PBs • Bronchospasm
• Vasospasm.
Selective • Metoprolol • Bisoprolol • Atenolol • Less bronchospasm.

PiBs • Esmolol • Less delayed
recovery from
hypoglycemia.
• Less risk of Raynaud's
phenomenon.
Vasodilator • Carvedilol • Celiprolol • Carvedilol
PBs (nonselective (piblocker decreases mortality
PB plus in heart failure.
plus P2
a-blockade) agonist)
65
Esmolol
• It is an ultra-short-acting pi-selective adrenoceptor antagonist.

• Hydrophilic but has a short Xm (8 min.) due to hydrolysis by plasma esterases.
• Used in: supraventricular arrhythmias & arrhythmias of thyrotoxicosis,
perioperative hypertension, myocardial ischemia in acutely ill patients.
Vasodilator ftBs
Labetalol
• Selective ai &non-selective pB (ct/p ratio 1:3).

• Used inmost hypertensive emergencies.
• Used in hypertension during pregnancy &labor (pre-eclampsia).
Carvedilol
• Nonselective pB &ai-selective blocker -* vasodilator pB.

• Beneficial in chronic heart failure (see CVS) -»
i. | Oxygen free radical-* antioxidant.
ii. Inhibits vascular smooth muscle mitogenesis14
Nebivolol
• Selective piB.
• Releases nitric oxide from vascular endothelial cells -> VD-> used
effectively in treatment of hypertension.
• Does not induce bradycardia—* not used in ischemic heart disease.
• Does not induce sexual dysfunction.
14 Independent of adrenoceptor blockade.
66
Alpha Adrenoceptor Antagonists

Classification
Non-selective Selective
Irreversible Reversible Alphai Alpha2
Long acting Short acting Selective Selective
• Prazosin • Yohimbine15
Phenoxybenzamine Phentolamine
• Doxazosin • Mianserin16
ai>tX2 a i = ct2
• Tamsulosin
Plus
direct VD
Other a Blockers: labetalol- carvedilol- ergot alkaloids.
Pharmacological actions of selective at blockers
I. Cardiovascular actions
1. Mixed vasodilators:
a. Arteriodilators-*! peripheral resistance—* |blood pressure.

b. Venodilators—*J, venous return—* postural hypotension.
2. Tachycardia (less than nonselective agents): nonselective agents block
presynaptic a 2receptors—*! NE release —* stimulates cardiac pi receptors.
3. Chronic use —* compensatory | in blood volume (fluid retention).
4. Prevent the pressor effects of usual doses of alpha agonists & convert
pressor response of epinephrine to a depressor effect(epinephrine reversal).
15 Yohimbine: (^-selective antagonist used asanaphrodisiac -+|NErelease —• stimulates ejaculation.

16 Mianserin isan antidepressant that increase NE release centrally.
67
II. Other actions
• Block a receptor -*decrease tone ofbladder neck muscles & prostate -*j
resistance to urine flow-* used in urine retention due to benign prostatic
hyperplasia (BPH).
• Relaxation ofvas deferens-* inhibition of ejaculation.
• Miosis - nasal stuffiness.
Therapeutic uses of a blockers17

1. BPH: prazosin, doxazosin,, tamsulosin.
2. BPH with essential hypertension: prazosin (tolerance develops due to
tachycardia & fluid retention).
3. Hypertension in pregnancy and labor (labetalol).
4. Most hypertensive emergencies (labetalol).
5. Pheochromocytoma:
- Medical treatment: before surgery or if inoperable: phenoxybenzamine is
preferred; irreversible blocker18.
- Intra-operativelv: if excess catecholamines results inhypertensive
emergency: (phentolamine + p B/ or labetalol alone).
Adverse Effects of a blockers
1. 1st dose postural hypotension19: J, bygiving small dose (1 mg) at bed time.
2. Tachycardia (marked with non-selective agents).
3. Impaired ejaculation and sexual dysfunction.
4. Nasal congesion, flushing, headache.
5. Drowsiness and nausea.
17 Other unlabeled uses of a blockers: Raynauds disease (prazosin, but CCBs preferred),
extravasation of a agonists (phentolamine prevents vasoconstriction & dermal necrosis).
18 Major use of phcnoxybenzamine & phcntolamine is pheochromocytoma (tumor of adrenal medulla;
releases Epi & NE->intermittent or sustained hypertension, headaches, palpitations tsweating.
19 With syncope, seen V2-I hour after 1st dose of prazosin due to postural hypotension.
68
Specific a blockers
Prazosin, terazosin and doxazosin

• Reversible highly selective ai blockers -> relative absence of tachycardia
as compared to phentolamine and phenoxybenzamine.
• Doxazosin preferred:
•Longer acting20
• Less lsl dose hypotension than prazosin & terazosin.
Tamsulosin & Alfuzosin
• Affinity for cua receptors on prostate & bladder neck muscle is higher than
for vascular am receptors -* tefficacy in BPH with minimal change in BP
-* less postural hypotensive effect than other a blockers.
20 ti/2 22 hours.
69
Centrally-Acting Sympatholytics
1. Methyl dopa
Mechanism of action:
• Prodrug -* metabolized in the brain to a-methyl NE which stimulates

central a 2receptors in brain stem (NTS) -> j central sympathetic outflow.
Uses
• Antihypertensive especially in pregnancy.
Adverse effects: (limit its use)

1. Sympatholytic:
• Sedation -drymouth
• Bradycardia.
• Sexual dysfunction.
• Diarrhea.
• Peptic ulcer aggravation.

2. Hepatitis, hemolytic anemia, systemic lupus (immune based, less common).
3. Salt and water retention -> tolerance & weight gain.
4. Depression (| DA, J, 5HTsynthesis21).
5. Parkinsonism & hyperprolactinemia (j DA).
21 Methyl dopa inhibits synthesis of DA, & 5HT by binding &inhibiting L-aromatic amino
acid decarboxylase which is responsible for their synthesis.
70
2. Clonidine
Mechanism of action
1. Activates postsynaptic 0:2 receptors in nucleus tracms solitarius and
imidazoline receptors in rostral ventro-lateral medulla -* ^central
sympathetic outflow —* j BP.
2. Acts on peripheral presynaptic 0:2 receptors on adrenergic neurons -* | NE release.
3. Stimulates postsynaptic a2 receptors -> I renin & aldosterone.
Uses
1. Diarrhea in diabetics with autonomic neuropathy.

2. Pre-anesthetic medication (sedative & analgesic).
3. Morphine withdrawal "*\
4. Menopausal hot flushes. I ^Sympathetic discharge
5. Migraine prophylaxis
6. Hypertensive urgencies.
7. Glucoma (apraclonidine & brimonidine)
•'•• -'.'-••'"•.'-,
Adverse effects
1. Sympatholytic
• Sedation -drymouth
• Bradycardia. .
''''''•.'..
• Sexual dysfiinction.
2. Rebound hypertension: treatedby a & P blockers e.g. labetalol.
3. Salt and water retention "^ tolerance & weightgain.
71
Cholinergic Pharmacology
CHOLINERGIC PHARMACOLOGY
Synthesis of Acetylcholine (ACh)

• Choline is transported by a membrane carrier from the extracellular lluicl into
the cholinergic neuron where it is aeetylated in the cytoplasm by acetyl CoA
forming ACh. The reaction is catalyzed by choline acetyl transferase.
Storage & Release of ACh

• ACh is stored in small membrane-bound vesicles, which are concentrated in
the terminals of cholinergic neurons. Arrival of an action potential triggers
Ca2+influx, which stimulates release of ACh by partial exocytosis.
• Action of ACh is terminated by rapid hydrolysis by acetylcholine esterase.
Control of ACh release by presynaptic receptors

• M: inhibitory (dominant).
• N„ facilitatory (ensures continuous supply of Ach in motor nerves).
• a: inhibitory (explains relaxation of gut smooth muscles by 0.2 agonists).
Muscarinic
Receptor
Choline
Acetyltransforaso
Acetylcholinesterase
Acetyl CoA I A
Acetylcholine
Choline \ / \|
Nicotinic
Choline Acetate
Receptor
Choline'
Presynaptic neuron
Postsynaptic target
Synthesis, Storage, Release & Fate of ACh
72
Cationic head
Ester group
4r> N+ of choline
/Acetyl gp^v
I. Binding
Esteratic site Anionic site
II. Cleavage
I
Acetylated Enz + Choline
III. Hydrolysis
Acetate Free Enzyme
Degradation of Acetylcholine
• ACh is degraded by choline esterase enzyme through 3 steps:
1. Binding: The acetyl (ester) group of ACh binds to the esteratic site of the
enzyme by a covalent bond & the N" (cationic) head binds to the anionic
site by a weaker ionic bond.
2. Cleavage: choline is cleaved leaving the acetylated enzyme.
3. Hvdrolvsis: hydration of acetylated enzyme releases acetate & the free
enzyme.
Types of Choline Esterases
• True (AChE): Present at terminals of cholinergic fibers & RBCs. Specific

for ACh , essential for life with slow regeneration in 120 days.
• Pseudo ChE: Present in plasma. Nonspecific -> hydrolyzes other esters as
succinylcholine. Not essential for life, rapidly regenerated by the liver.
73
CHOLINERGIC RECEPTORS & ACH ACTIONS
ACh mediates its effects by activating muscarinic & nicotinic cholinergic

receptors present centrally & peripherally:
I. Muscarinic receptors1 (blocked by atropine)

1. Mi receptors (excitatory): coupled to Gq -> © PLC —> | DAG & IP3 —•
• CNS—»excitatory
a. Arousal, learning & short-term memory (| Ach -> Alzheimer).
b. In basal ganglia, balance between ACh & DA controls movement.
c. In vestibular pathway —• vomiting
• Gastric enterochromaffin likecells -» histamine release-> |HCL
2. M2 receptors (inhibitory): coupled to Gi -• © Acyclase &| K outflux

• CNS-> inhibitory
• Presynaptic neurons —> inhibit ACh release.
• Heart:
a. SAN & AVN -> slowing ofheart -J. conduction &t refractory period (RP).
b. Atria -*l contractility -J. action potential duration -1 RP.
3. M3 receptors (excitatory): coupled to Gq -»© PLC -*• | DAG &IP3. -»•
• Smooth muscles—• stimulate wall (bronchi, GIT, urinary) & relaxes sphincters.
•
Eye —• miosis (©constrictor pupillae) - accommodation (©ciliary muscle).
•
Exocrine glands-* f All secretions (except milk2).
• Vascular endothelium —• NO release —• VD -> I BP.
II. Nicotinic receptors (excitatory): ligand-gated Na+/K ion channels ->

• Neuronal (Nn): in autonomic ganglia, presynaptic on motor nerves & in
adrenal medulla —• catecholamines release (blocked byetamon).
Muscle (Nm) -^skeletal muscle depolarization -* contraction (blocked bycurare).
CNS: Renshaw cell (blocked by dihydro-beta-erythroidine) - ADH release.
1There are 5 subgroups ofmuscarinic receptors: Mi - M5

2 Under control ofprolactin &oxytocin.
74
• ACh lacks specificity, irregularly absorbed (4* drug) & rapidly hydrolyzed if
given systemically—• only used after cataract surgery; instilled into eye —•
rapid & complete miosis (no choline esterase in aqueous humor).
CLASSIFICATION OF CHOLINOMIMETICS*
1
I. Directly acting (on cholinergic receptors) II. Indirect
— i Choline
A. Choline Esters* Esterase
- 4^ drugs —> low lipid solubility& poor CNS access. Inhibitors

- Not hydrolyzed by ChE —• more stable than Ach: (ChEIs)
1. Methacholine —• marked muscarinic effects.
2. Carbachol —»• muscarinic & nicotinic effects.
3. Bethanechol —*• marked muscarinic effects on GIT &

bladder—* prokinetic used in megacolon & urinary retention.
B. Natural Alkaloids
• Pilocarpine: 3^ dmg; selective M3 agonist on:

a. Eye: miotic used for:
i. Counteracting mydriatics after fundus examination,
ii. Alternating with mydriatics in iridocyclitis to prevent synechia,
ii. Glaucoma (preferred -M3 selective & long acting preparations,
ocuserts are available)
b. Exocrine glands: t secretion —• used in dryness of eye & mouth.
c. Scalp blood vessels: VD—> used as hair tonic.
C. Cevemiline
• SelectiveM3 agonist —> used in dryness of eye & mouth.
* Methacholine & belhanechol have weak nicotinic actions due to extra methyl group.
Carbachol is used inglaucoma & post operative paralytic ileus & urine retention (rarely).
75
CholinergicPharmacology
CHOLINE ESTERASE INHIBITORS
ChEIs
Mechanism of Action
• ChEIs act indirectly by inhibiting choline esterase -> accumulation of ACh.

• Neostigmine has also directeffect on Nm receptors at NMJ.
Individual ChEIs
1. Edrophonium (weak, short-acting, 2-10 min - reversible)

• Binds electrostatically to the anionic site of enzyme with rapid hydrolysis.
2. Carbamate Esters (medium-duration, 3-4 hours- reversible)
• The carbamoyl group binds covalently to esteratic site of enzyme (active
site) —*• carbomoylated enzyme (covalent bond is more resistant to
hydrolysis).
3. Organophosphates (very long duration - irreversible)
• The phosphate group binds irreversibly to the esteratic site of the enzyme.
• The covalent phosphorous enzyme bond is extremely stable and hydrolyzes
in water at a very slow rate (hundreds of hours).
• Ageing occurs in the phosphorylated enzyme bond within 2 minutes - 12
hours, after which recovery of enzyme cannot occur (strengthening of
covalent bond). Thus, choline esterase regenerators in organophosphate
poisoning should be givenearly before ageing occurs.
Ester g roup Cation ie hi
ACh
lAChEl
si-fee Anionic
\ \
Organophosphates Carbamates Edrophonium
(P group) (carbamyl group)
76
CLASSIFICATION & USES OF ChEIs*
I
Reversible
Irreversible
Simple Alcohols
Edrophonium (4^ compound) i

Organo
Short-acting —> used in diagnosisof myasthenia gravis.
phosphates
Carbamates • Malathion
1. Neostigmine (synthetic: stable) (Insecticides).

• 4^ —> poorly absorbed - cannot cross BBB or conjunctiva. -Sarin
• Muscarinic effects: on bladder & GIT—>\ peristalsis in post (Nerve gas)

operative paralytic ileus & urine retention. • Echothiophate:
• Nicotinic effects: t skeletal muscle power, used in: i. Antagonizes
i. Myasthenia (preceded by atropine to 0 muscarinic side atropine*
effects), after
ii. Antidote to neuromuscular blockers (preceded by atropine). fundus exam,
2. Physostigmine (natural; unstable) ii. Glaucoma
• 31* amine—• well absorbed, crosses BBB & conjunctiva.

Pyrantel
• Muscarinic effects: pamoate
a. Miotic: i. counteractsmydriatics e.g. after fundus exam.
• Paralysis of
ii. i IOP in glaucoma.
round worms
b. Atropine toxicity (central & peripheral atropine antagonist).
• Donepezil, rivastigmine: used in Alzheimer dementia.

• Pyridostigmine: neostigmine analogue preferred in myasthenia ' (tduration,
fewer visceral side effects; f selectivity on skeletal muscles compared to
neostigmine).
*Ecothiophate is the only CHEI that can antagonize atropine after fundus examination.
'Autoimmune disease of skeletal muscles -♦ antibodies that J number of nicotinic receptors on
motor endi>late -»weakness ofextraocular, bulbar, neck, followed by other muscles.
77
Uses Actions of Adverse Effects

Cholinomimetics Contraindication
(CI)
1. Alzheimer *v
1.Irritability
• Rivastigmine y 1. CNS (Mi) Ach is excitatory —*• <—
Convulsions
• Arousal & short term memory. (with agents that
2. Atropine toxicity
cross BBB)
• Physostigmine
2.Eye(M3)
3. Miotics:
• Miosis (© constrictor pupillae). * 2.Miosis
a. Glaucoma
b. To counteract • Accommodation (© ciliary muscle)
mydriatics • Above effects —* f outflow of aquous
humor ->|IOP. 3. Lacrimation -salivation,
• Pilocarpine.
• Physostigmine A f HC1 -• CI peptic ulcer
• Ecothiophate 3. Exocrine Glands (MO
t Salivary, sweat, bronchial, lacrimal & 4.Bradycardia

/" HC1 secretion. Cardiac arrest (—•
-A never given IV)
4. Dry eye &mouth CI Infarction
4. Heart (MO
• Pilocarpine
• Cevemiline
—• Precipitate atrial
• Bradycardia - AV block
fibrillation in
• \ Atrial contractility thyrotoxic pt(avoid)
5. Hair tonic • I Atrial refractory period (tconduction)
5. Bronchospasm
• Pilocarpine
5. Vascular endothelium (M3) /CI Asthma
6. Megacolon • Release of EDRF- t Urination-diarrhea
Bethanechol colic- N & V
\ ,6. Smooth muscles (M3) CI: urinary or intestinal
obstruction (—•
7. Post operative y Bronchospasm. rupture)
Paralytic ileus # * • © bladder wall & GIT motility & 0
Urine retention 7. Lid twitches,
sphincters —» micturition, defecation.
• Neostigmine. browache, frontal
• Bethanechol /. headache (with
7. Skeletal muscle (Nicotinic) eye drops)
8. Myasthenia &, • Depolarization —» contraction
Antidote for 8. Fasciculations
• High concentration -* persistent 9. paralysis
NM blockers
depolarization block-* paralysis.
• Neostigmine
78
Toxicity of Oreanophosphorus Compounds
• Organophosphorus compounds are highly lipid-soluble & are well absorbed

from all sites & cross BBB (echothiophate has 41* N+ -> jsystemic toxicity).
• Poisoning occurs due to suicide or exposure to drugs during spraying
insecticides (Parathion, Malathion) or nerve gases (sarin) during war.
Acute toxicity
• Excessive muscarinic effects (see table)5

• Nicotinic effects: fasciculation & flaccid paralysis.
• CNS effects: stimulation (convulsions) —• depression (coma & respiratory
depression).
Death is due to respiratory failure:
- Respiratory center depression.

- Paralysis ofrespiratory muscles due topersistent depolarization block.
- Excessive bronchial secretions with acute pulmonary oedema.
Chronic Toxicity: Chlorpyrifos & Malathion6-* delayed neuropathy.
Treatment of Oreanophosphorus Poisoning
1. Maintain vital signs:

Aspirate bronchial secretions, endotracheal intubation &artificial respiration.
2. Decontamination (to prevent further absorption):
Remove contaminated clothes - wash skin (Na hypochlorite) - gastric lavage.
3. Atropine (large doses) for CNS & muscarinic effects:
2 -5 mg/ 5 min —• full atropinization (until bronchial secretions &wheezes stop).
4. Choline esterase reactivators (oximes): PAM (pralidoxime)
Regenerates choline esterase (IV infusion as soon as possible before its ageing).
5. Diazepam: for convulsions.
5 Heart rate may bej or f (due to sympathetic©). The 1st symptom on exposure to nerve vapor
may be rhinorrhea & to nerve liquid is sweating.
6In houshold insectisidessprays (e.g. raid).
79
lANTIMUSCARINIC AGENTSl
Atropme & Atropine Substitutes
Atropine
• It is a tertiary ammonium ester of tropic acid —• well absorbed from the gut if
given orally or from conjunctiva after occular instillation & can cross BBB.
Mechanism of Action
• Atropine causes reversible competitive blockade of the actions of ACh at

muscarinic receptors (nonselective for muscarinic receptors).
Pharmacological Actions
l.CNS
• Stimulates cardioinhibitory center (vagal nucleus)—înitial bradycardia

• Respiratory center stimulation (blocks M2 receptors) .
Antiemetic (blocks Mi receptors in vestibular pathway).
Antiparkinsonian (blocks Mi receptors in basal ganglia).
2. Eye (effects persist for >72 hrs) j Aquous out flow ->f
• Mydriasis 7( paralysis ofconstrictor pupillae). [ IOP —> acute glaucoma
• Cycloplegia (ciliarymuscle paralysis in narrow anterior
& loss of accommodation for near vision). chamber
3. Secretions
• J. Salivation (—• dry mouth), J, lacrimation (—> drysandy eyes).

• 4 Sweating (-*f body temperature) & J. bronchialsecretions.
• Gastric secretion is least affected while milk secretion is unaffected.
4. Smooth Muscle
• GIT: relaxes wall & contracts sphincters —* constipating & antispasmodic.

• Bladderneck: contraction of urinary bladder sphincter—* urine retention.
• Bronchodilation.
7Passive, due to unopposed sympathetic activity ondilator pupillae

80
5. CVS
• Tachycardia (mainly) & |AVN conduction (blocks M2 receptors).

• Initial bradycardia: initial agonist activity —* central vagal stimulation
presynaptic M2 block -* f ACh release.
• Vasodilation (due to histamine release).
Clinical Uses of Atropine & atropine Substitutes
Atropine
Therapeutic Uses
1. Preanesthetic medication —înhibits secretions - dilates bronchi - anti-emetic -

inhibits reflex bradycardia - stimulates respiration.
2. Hyperactive carotid sinus - heart block - bradycardia (in infarction or digitalis
toxicity).
3. Organophosphate poisoning - mushroom poisoning (Amanita muscaria).
4. Cycloplegic in children (atropine is preferred to atropine substitutes in
children as their ciliary muscle is strong & atropine substitutes are weaker
cycloplegics than atropine). •*
5. Travelers diarrhea (plus diphenoxylate, anopioid antidiarheal) to enhance its
constipating effect & to decrease its abuse.
Atropine Substitutes
I. Scopolamine (Hyoscine) • Natural atropine substitute.
Uses • More CNS depressant than
• Mydriatic (briefer than atropine). atropine —*• drowsiness &
• Vomiting of motion sickness & amnesia.
Minieres disease (preferred as it is • May induce CNS excitement

more effective than atropine). & hallucination when used
• Preanesthesia in thyrotoxic & as preanesthetic in females
cardiac patients (pure antagonist; —• vivid dreams.
no initial bradycardia).
81
II. Synthetic atropine substitutes (more selective —• fewer side effects)

1. Mydriatic cycloplegics ( cyclopentolate -tropicamide - homatropine) for:
•Iridocyclitis; alternating with miotics toprevent synechia (homatropine).
• Measuring refractive errors & for fundus examination8.
N.B.: they are shorteractingthan atropine —»• action is easier to reverse —*
preferred to atropine (exceptin children).
2. Antisecretory antispasmodics:
4*y drugs (-> less absorption -* less CVS & CNS side effects)
• Glycopyrrolate: anti-secretory in preanesthetic medication & before
neostigmine to J.side effects during reversal of action ofNMBs.
• Hyoscine butylbromide: antispasmodic inrenal, biliary & intestinal
colic & in irritable bowel syndrome.
317 drugs: Dicyclomine; selective Mi blocker —> antispasmodic
3. Urinary atropine substitutes:
• Oxybutynin: used in nocturnal enuresis & in urge incontinence.
4. Antiparkinsonian (benztropine - benzhexol): Used in
•Dmg induced Parkinsonism: preferred to dopaminergic drugs.
•Adjuvants in Parkinsonism presenting with tremors & to control sialorrhea.
5. Bronchial atropine substitutes

Ipratropium (non selective M2 / M3 blocker)
•Inhaledbronchodilator (M3 blocker) —> no systemic atropine side effects.
•Used in asthma & COPD: delayed onset compared to beta 2 agonists.
•Tolerance develops due to block of vagal presynaptic M2 receptor —>t ACh.
Tiotropium (selective M3 blocker)
• Longer acting than ipratropium —* used once/d; for maintenace in COPD.
• Does not block M2 receptors —• no tolerance.
8
Mydriatic effect is required for fundus examination; miotics are given later to antagonize their
effect. Cycloplegia is required for measurement of refractive errors.
82
Adverse effects of atropine —* poisoning (Contraindications; CI)

1.Confusion, restlessness —• hallucinations, delirium & mania—* Mad as a hen.
2. Dry mouth and skin —>Dry as a bone.
3. Hyperthermia(complete skin dryness) —*Hot as a hare.
4. Vasodilation & flushing —>Red as a beet.
5. Tachycardia.
6. Blurred vision - photophobia-* Blind as a bat.
7. Acute glaucoma in patients with narrow anterior chamber(CI: glaucoma).
8. Urine retention in old patients with enlarged prostate (CI: enlarged prostate).
9. Constipation.
Treatment of atropine poisoning
• Gastric lavage.
• Physostigmine (antagonizes central & peripheral effects).
• Diazepam: to control CNS excitement.
• Cooling blankets: to treat hyperthermia in children (not aspirin).
Drugs with Atropine-Like Action
• Antiarrhythmics: quinidine - procainamide - disopyramide.

• Antihistamines (1st generation).
• Tricyclic antidepressants - antipsychotics- pethidine.
• Atropine substitutes.
83
SKELETAL MUSCLE RELAXANTS
• Drugs affecting skeletal muscle tone could be classified into 2 major divisions:
1. Neuromuscular blockers (mainly used as adjuncts to anesthetics).
2. Spasmolytic drugs (mainly used inspastic disorders of skeletal muscles).
NEUROMUSCULAR BLOCKERS (NMBs)

They are classified into 2 groups:
1. Nondepolarizing NMBs —* prototype: ^-mbocurarine.

2. Depolarizing NMBs —* prototype: succinylcholine.
Therapeutic Uses of NMBs
1. Adjuncts to general anesthesia: induce muscle relaxation —* facilitating

incision, decreasing cough & laryngospasm & allowing reduction of the
dose of the general anesthetic (nondepolarizing NMBs).
2. To assist mechanical ventilation (nondepolarizing NMBs—* paralyze
respiratory muscles so as not to interfere with mechanical ventilation).
3. Facilitation of endotracheal intubation
Succinylcholine is 1st choice-* rapid action9 —*J, risk of vomiting & aspiration
of gastric contents (rocuronium is an alternative)
4. Electroconvulsive therapy:
Control convulsions —* J. pain & injury (succinylcholine is 1st choice10).
• Succinylcholine has a rapid onset of action (1 min) & is short acting (5-10
min) due to rapid hydrolysis by pseudo ChE in plasma & liver, thus it is
reserved for short procedures; given by IV injection or infusion.
9Rapid action of the drug allows rapid intubation & removal of oxygen mask (oxygen mask -»f risk
of passage of oxygen to GIT with increased risk of vomiting & aspiration pneumonia).
10 Short acting competitive neuromuscular blockers are also used.
84
Nondepolarizing (Competitive) Neuromuscular Blockers

Mechanism of Action
• Small dose: competitive blockade of Nm receptors at motor end plate.

• Large dose: Blockpresynaptic Nn receptors —>J, ACh release.
Block ion channels ofNm receptors.
D-Tubocurarine (prototype)
• Produces flaccid paralysis lasting more than 35 min (long-acting).
• Small muscles of face, eye and neck are affected first and diaphragm last.
• Recovery occurs in the reverse order (diaphragm first).
• Effects are antagonized bv:
• Neostigmine: given at the end of operation to reverse the action of the

NMB (preceded by atropine to prevent bradycardia & cardiac arrest).
• Effects are potentiated bv:
• Anesthetics, e.g. halothane, ether (stabilize motor end-plate).

• Antibiotics, e.g. aminoglycosides (inhibit ACh release).
Adverse Effects and Precautions
1. Histamine release:
• Bronchoconstriction (CI: bronchial asthma).

• Allergy (CI: allergic patients).
• Hypotension
2. Ganglion blockade —* hypotension.
3. CI in renal disease (clearance depends on renal excretion).
Toxicity of Competitive Neuromuscular Blockers
• Respiratory muscle paralysis and hypoxia; treated by:

1. Artificial respiration.
2. Neostigmine, preceded by atropine to prevent bradycardia & cardiac arrest.
85
Newer NMBs:
• More potent than curare (except rocuronium) with no ganglion blockade &
less (atracurium) or no histamine (HI) release.
1. Pancuronium (long acting)

• Avoid in renal & CV diseases (excreted renally; vagolytic effect—*|HR).
2. Atracurium (intermediate duration; used for short procedures)
• May be given in renal or liver disease as it undergoes spontaneous
breakdown (Hoffman's reaction) in addition to its hepatic metabolism.
• Cisatracurium: less histamine release than atracurium —*fewer side
effects.
3. Vecuronium (intermediate duration; used for short procedures)

• May be given in renal but not in liver diseases (clearance is mainly hepatic).
• Offers cardiovascularstability preferred in CV diseases.
4. Rocuronium (intermediate duration; 20-35 min)
• Similar to vecuronium.
• Rapid onset of action —* alternative to succinylcholine for endotracheal

intubation.
5. Mivacurium (short acting; 10- 20 min)

• Hydrolyzed by pseudo ChE Qenzyme in renal disease—* prolongs effect).
• Slower onset than succinylcholine; if dose is increased to speed onset —* t
histamine release.
6. Gantacurium (rapid onset, very short duration of action)

• Profile similar to succinylcholine—* used for endotracheal intubation &
mechanical ventilation.
• Action is terminated by cysteine amino acid adduction followed by slow

non enzymatic hydrolysis. Thus, its action can be reversed with cysteine.
• Releases histamine at doses 3 times the ED-50.
86
Reversal of effects of neuromuscular blockers post onerativelv

1. Neostigmine: preceded by atropine or glycopyrolate.
2. Sugammadex:
• Encapsulates rocuronium & vecuronium in its lipophyllic core, allowing a
cone, gradient between plasma & NMJ, so NMBs diffuse away from
NMJ. The complex is then excreted in urine.
• Advantages over neostigmine: faster reversal with fewer side effects (not
preceded by anti-muscarinics, avoiding their troublesome side effects.
3. Cysteine: reverses the action of gantacurium
Depolarizing Neuromuscular Blockers

Succinylcholine
Mechanism of Action
Initial fasciculations (transient twitches):

• Succinylcholine binds to nicotinic receptors at NMJ—* initial
depolarization (fasciculation).
Phase I: Depolarization block

• Succinylcholine induces persistent depolarization of motor end plate since it
is slowly hydrolyzed by pseudo ChE (compared to ACh).
Phase II: Desensitization block (antagonized by neostigmine)

• On prolonged use, the membrane repolarizes but receptors are desensitized
to ACh (due to unknown cause).
N.B.: muscles are paralyzed in the same order as with competitive NMBs.
87
Adverse Effects and Contraindications (Cn
1. Succinylcholine apnea
• Genetic abnormality of pseudo ChE (or j pseudo ChE due to liver disease
or malnutrition) —* failure of succinylcholine breakdown —* prolonged
respiratory muscle paralysis —* apnea.
Management: Support ventilation

Phase I block -* blood transfusion (to supply enzyme).
Phase II block —* neostigmine preceded by atropine.
2. Fasciculations —*
a. Postoperative muscle pain (muscle damage due to unsynchronized

contractions—• CI: extensive muscle trauma.
b. t IOP —* CI: narrow-angle glaucoma andpenetrating eye injuries.

c. | Intra-gastric pressure —* vomiting with aspiration of gastric contents.
d. Hyperkalemia -* cardiac arrest -* CI: burns & trauma (| K+ outflux).
3. Bradycardia.
4. Malignant hyperthermia (genetic defect)

• Skeletal muscles fail to sequester Ca2+ in sarcoplasmic reticulum
following administration of succinylcholine & halothane —*
• f Muscle contractions (treated by spasmolytics as dantrolene).
• Hyperthermia (treated by cooling blankets).
• | Lactic acid (correct acidosis, water & electrolyte disturbance).
CI: in patients with a family history of malignant hyperthermia &

succinylcholine apnea
88
SPASMOLYTICS
• Spasmolytics are drugs that reduce muscle tone with minimal effect on active
contractions11.
Causes of spasticity (uses of spasmolytics)
1. Central causes12
• Cerebral palsy - stroke (hemiplegia).
ls nerve fibe\..
• Multiple sclerosis - spinal cord injury
2. Local causes: Muscle trauma - inflammation
3. Low back pain.

4. Drug induced: malignant hyperthermia.
Classification of spasmolytic drugs
A- Centrally Acting
i. Diazepam: GABA - A agonist used in most causes of spasticity.

Side effects: sedation & tolerance. ,.
i. Baclofen: GABA- B agonist at spinal synapses,

Uses: multiple sclerosis & spinalcord injuries.
Side effects: sedation less than diazepam.
iii. Tizanidine : ct2 agonist—* \ presynaptic inhibition of motor neurones in the
cord —*• used in multiple sclerosis or after stroke.
iv. Orphenadrine: acts in the brainstem—* used for acute muscle spasm due to
trauma or strain (—• anticholinergic side effects).
B- Peripherally acting
i. Dantrolene
• Inhibits Ca2+ release from the sarcoplasmic reticulum in skeletal muscle.

• Marked muscle weakness —*limits its use to malignant hyperthermia.
ii. Botulinum toxin:
• Inhibits AChrelease—* used locally in cosmetic therapy for wrinkles.
1' NMBs —* loss of both muscle tone and active contraction.

12 Upper motor neuron lesion, with damage to descending pathways in the spinal cord
-♦hyperexcitability of the alpha motoneurons in the cord.
89
- . Autacoids
AUTACOIDS
•
Autacoids are groups of chemically diverse substances produced by various
tissues in the body and act as local hormones. The most important autacoids
are:
• Biologically active amines e.g. Histamine andSerotonin.

• Vasoactive polypeptides e.g. Angiotensin and Kinins.
• Eicosanoids e.g. Prostaglandins and Leukotrienes.
|HISTAMINE|
(HI)
Synthesis:
• Histamine is synthesized by decraboxylation of theamino acid L-histidine
with L-aromatic amino acid decarboxylase enzyme.
Decarboxylase
L- Histidine ^ Histamine
Storage:
• Histamine is stored in storage granules inside mast cells (in most tissues e.g.
lung, skin & GIT).
Release:
• Histamine liberation: HI liberators are basic drugs (e.g. morphine, atropine,

curare, and hydralazine) that replace HI in storage granules without
degranulation.
• Immunogenic release: interaction of antigenic dmgs (e.g. penicillin) with IgE

on surface of sensitized mast cells results in increase in intracellular calcium &
release of the whole histamine- containing granules (exocytosis).
90
Autacoids
Pathogenic role of histamine
1. Allergy:
Histamine stimulates Hi-receptors —*immediate hypersensitivity reactions:
a. Local allergic response: localized Hi receptors stimulation on blood
vessels & nerve endings —*•
i. Arteriodilatation —*• redness.
ii. Venodilatation-*f capillary permeability & edema.

iii. Sensory nerve stimulation -* pain & itching.
b. Anaphylactic shock: generalized Hi receptors stimulation -* marked
arterial dilatation & hypotension.
c. Bronchial asthma: Hi receptors stimulation on bronchial smooth muscles
—• bronchospasm.
2. Vomiting of vestibular origin (e.g. motion sickness) is Hi-receptor mediated.
3. Peptic ulcer: H2 receptors mediate more than 70% of HC1 secretion.
Drugs that antagonize the action of histamine
1. Hi receptor blockers (anti-histamines): for allergic reactions; see below.
2. H2 receptor blockers (e.g. famotidine): for acid-relateddisorders; see GIT.
3. Mast cell stabilizers & 02 agonists: inhibit immunogenic HI release; see

respiratory pharmacology.
4. Epinephrine: physiological antagonism.
91
Autacoids
Hi-receptors Blockers (Antihistamines)

First Generation Antihistamines
CWorphenirarnine - promethazine - drnierihydrinate - doxylamine
Mechanism Actions Therapeutic uses Adverse effects
1. Hi-receptor a. Anti-allergic Allergic reactions1:

Inverse Block Hi • Rhinitis.
Agonist mediated allergy. • Urticaria.
• Anaphylactic shock
b. CNS Depression
1. Sedation • As OTC hypnotic. • Drowsiness;
2. Antitussive • Dry cough. • Agitation (in

children).
2. Muscarinic a. Antiemetic • Atropine-like

• Motion sickness.
Receptor side effects:

(Dimenhydrinate)
Blockade Dry mouth
• Pregnancy
Confusion
Vomiting
Urine retention
(Doxylamine)
Constipation,
Imbalance.
b. Antiparkinsonian Parkinsonism
3. a- Blockade • Postural
hypotension
1Antihistamines are ineffective in asthma —*can not antagonizeleukotrienes or excessiveHI released.

92
Autacoids ____^——
New generations Antihistamines
Azelastine2, fexofenadine, cetirizine, loratadine, desloratadine
• Used in allergic conditions.
• Less lipophilic -+ less crossing ofblood brain barrier -* less sedation.

• Delayed elimination ^prolonged action that permits single daily dosing.
• Still have varying degrees of autonomic effects.
• High doses cancross BBB —> sedation.
Itmay be preferred by some patients with allergic rhinitis as itis available as anasal spray.
93
„ Autacoids
ISEROTONINl
Synthesis:
Tryptophan hydroxylase Decarboxylase

Tryptophan • 5- OH - tryptophan • serotonin (5HT)
Storage:
• InGIT enterochromaffin cells, CNS neurons, and inplatelets.
Release:
• Released from blood platelets following platelet activation e.g. bythrombin.

• Released from CNS neurons on nerve stimulation.
Metabolism:
• By oxidation with MAO into 5-hydroxyindole acetic acid; "5HIAA".

• Urinary 5-HIAA is used indiagnosis3 of carcinoid syndrome (excess 5HT).
Reuptake:
• Serotonin is re-uptaken by nerve endings in the CNS by the monoamine pump.
Serotonin receptors & pathogenic role of serotonin

1. Anxiety: presynaptic 5HTia receptors stimulation in the limibic system —*
reduces 5HT release—* reduces anxiety.
2. Migraine: 5-HTib/id receptors stimulation on cranial blood vessels and
trigeminal nerve endings terminates acute migraine attack.
3. GIT motility disorders: prokinetics stimulate 5-HT4 receptors.
4. Carcinoid syndrome: 5HT © smoothmuscles—>• bronchospasm & diarrhea.
5. Psychosis: atypical antipsychotics block 5-HT2 receptors.
6. Depression: antidepressants ->t central 5-HT e.g. TCA, SSRI, NSRI, MAOIs.
7. Vomiting: 5-HT3 receptors mediate cytotoxic drug-induced emesis.
3Also used in diagnosis ofheparin-induce thrombocytopenia: normal platelets radiolabeled with

14C-serotonin arechallenged with patient's serum & heparin. Release of 14C-serotonin
signifies a positive test.
94
Autacoids
Drugs acting through serotonergic mechanisms
1. Drugs inhibiting 5-HT reuptake -*| central 5-HT; used mainly in depression
• Selective serotonin reuptake inhibitors (SSRI) or non selective inhibitors e.g.
norepinephrine-serotonin reuptake inhibitors (NSRI) & tricyclic anti
depressants (TCA).
2. Serotonin receptor agonists

a. 5-HTia agonists: Buspirone -> selective anxiolytics.
b. 5-HTib/id agonists: Triptans & Ergots -> anti-migraine dmgs.
c. 5-HT4 agonists: Tegaserode -* prokinetic in irritable bowel syndrome.
3. Serotonin receptors blockers

a. Selective 5HT/2 receptor blockers4
• Cyproheptadine & pizotifen: block 5HT2 & Hi receptors. Used in:
i. Carcinoid syndrome & serotonin syndrome (excess 5HT).
ii. OTC appetizers.
iii. Migraine prophylaxis.
• Atypical antipsychotics (e.g. resperidone) (also block D2 receptors).
b. Selective 5HT3 receptor blockers

• Ondanosetron (antiemetic).
Toxicity of serotonin
1. Serotonin syndrome (acute serotonin toxicity)
• Tremors, convulsions & hyperthermia (life threatening): due to | 5-HT
activity at postsynaptic 5-HTja & 5-HT2A receptors in the CNS on
administration of two serotonergic agents simultaneously, or a toxic dose of
a single drug (SSRI).
4Ketanserin is a selective 5HT2A blocker rarely used in hypertension (as it is an a-blocker) &
pre-eclampsia. Some antidepressants (e.g.mirtazapine, trazodone) block 5HT2 receptors.
95
Autacoids
2. Valvular heart disease (chronic serotonintoxicity)

• 5-HT stimulates fibrogenesis —* thickening of cardiac valves.
• Occurs on long term treatment with serotonergic drugs (e.g. ergots).
[MIGRAINE AND ANTIMIGRAINE DRUGSI

• An attack of migraine starts by a prodroma (irritability, fatigue, muscle aches),
followed byan aura (visual disturbances; scotoma) and in 30 minutes by
throbbing headache; starting unilaterally with nausea, vomiting & photophobia.
• Migraine is triggered by stress, hormonal changes (menstruation), disturbed
sleep pattern, weather changes & alcohol.
Pathophysiology of migraine (not fullyunderstood)

• Migraine may be due to release of pro-inflammatory vasodilatory
neuropeptides (e.g., CGRP) from nerve endings of trigeminal nerve into the
perivascular space —* dilation of dural vessels —* stretch of pain nerve endings.
Drugs used to terminate acute migraine attack
I. Mild analgesics: NSAIDs & acetaminophen (for mild infrequent attacks).

II. Triptans: "specific" antimigraine therapy: therapy for outpatients with
moderate to severe migraine is begun with a triptan.
Mechanism of action (selective 5HTib/id agonists)
1. Activate 5HTib/idreceptors on presynaptic trigeminal nerve endings to

inhibit release of vasodilatory neuropeptides.
2. Vasoconstriction of dural vessels —• prevent stretching of pain nerve endings.
96
Autacoids
Preparations of triptans
Sumatriptan: prototype5 (oral, SC, nasal spray)

Adverse effects:
1. Injection site reaction (with SC) or unpleasant taste (with intranasal).

2. Chest pressure (resolves spontaneously in 30 minutes).
3. Paresthesias, warmth, drowsiness, dizziness, weakness, malaise.
Contraindications & Precautions
1.Uncontrolled hypertension, ischemic stroke & IHD -* 1st dose given

cautiously in diabetics, hypertensives, men over 40 & in postmenopausals.
2. Pregnancy.
3. With serotoninergic dmgs: SSRIs or within 24 hrs of ergots -» 5HT syndrome).

HI. Ergots: 5HT ib/id agonists similar to triptans
1. Ergotamine tartrate (sublingual, oral, rectal); of choice in prolonged or
frequent headaches.
2. Dihydroergotamine (IV, IM, SC & intranasal).
Adverse effects & contraindications of ergots:
• GIT: Nausea, vomiting, diarrhea.

• Chest pressure.
• Vasospasm—* gangrene (CI peripheral vascular disease).
• CI. Pregnancy.
• Should not be used for long term (—* valvular heart disease).
IV. Antiemetics
• Parenteral metoclopramide (monotherapy in emergency; if ineffective

add IV dihydroergotamine).
• Oral metoclopramide —> added to other antimigraine dmgs (ergotamine)
to increase their absorption by its prokinetic effect.
V. Benzodiazepines & opioids
• Used in resistant cases (may lead to habituation & rebound headache).
5Zolmitriptan (nasal &oral), naratriptan, rizatriptan, almotriptan, eletriptan, frovatriptan (oral).
97
Autacoids
Drugs for migraine prophylaxis6
• Anti-migraine therapy should not exceed 10 days /month to avoid medication

overuse headache "MOH". Prophylactic drugs should then be administered:
1. Beta blockers: propranolol and timolol: are of choice
2. Antidepressants: amitriptyline
3. Anticonvulsants: valproate & topiramate. (J, Excess firing of trigeminal nerve).
4. Calcium channel blockers: nifedipine, verapamil (—* tolerance).
'Other agents which may be used (but not FDA-approved) include 5HT antagonists e.g.
pizotifen, mirtazapine, ACEinhibitors, angiotensin receptor blockers & botulinum toxin.
98
Autacoids
Prostaglandins (PGS) and Thromboxanes (TXS)
Phospholipid
Glucocorticoid
© I
Arachidonate Phosphorylcholine
i
1Cyd<M>xygtPttJC| 1S-llpoxygenaic |
Cyclic
eadoperoxides
1
PGI2 TXAj Leukotrienes
LTs
i 1 PAF
PGF, PGD, PGEj
Biosynthesis of Eicosanoids (PGs, TXs & LTs) & Platelet Activating Factor
• PGs & TXs are endogenous 20-C (eicosanoid) fattyacid derivatives with
profound physiological effects. They are involved in:
• Inflammation - thermoregulation.
• Regulation of: platelet function - vascular tone - bronchial tone.
• Gastro-protection - GIT motility.
• Regulation of renal and reproductive functions.
• PGs andTXA2 act on specific receptors:
1. IP receptors for PGh (prostacyclin).
2. TP receptors for TXA2.
3. DP receptors for PGD2.
4. FP receptors for PGF2o.
5. EPi, EP2 and EP3 receptors for PGE series.
99
Autacoids
Physiological Role of PGs Uses of PG Analogs Effects of PG Inhibition
1. Role in Inflammation • NSAIDs mediate their

• COX activation is analgesic & anti
responsible for formation inflammatory effects
of inflammatory by| PG synthesis
mediators (e.g. PGE2, (0 cyclooxygyenase)
PGI2,) which
• Corticosteroids induce
accompanies tissue
anti-inflammatory
injury.
effects by
• PGE, I2 & D2 in acute © phospholipase A2—*• |
inflammation potentiate PGs, LTs & PAF.
histamine & BK-* VD,

t capillary permeability,
t pain induced by BK.
2. Thermoregulation • Antipyretic effect of
• PGE generated by NSAIDs is due to G of
endogenous interleukin-1 PGE generation in
sets hypothalamic hypothalamus —* reset
thermostat at a higher thermostat.
level —* | temperature in
fever.
3. Gastro-protection • Misoprostol (PGE): • The ulcerogenic effects of

• PGE-* Given with NSAIDs or corticosteroids and
-1 Gastric HC1. steroids to j ulcer risk. NSAIDs are due to
- | Mucus secretion (but • Lubriprostone (PGEi inhibition of PGE
t gastric motility). derivative) —*| GIT syndesis iflpn\

secretions —* treatment
of constipation.
100
Autacoids
4. Kidney (PGE) • NSAIDs: I renal PGs

a. VD —*t renal blood —* Analgesic
flow. nephropathy Na+ &
b. Inhibits Na+ water retention,
reabsorption. Hyperkalemia.
c. t renin secretion.
5. Platelet Function: • Antithrombotic effect
Balance between of low dose aspirin is
PGI2-> inhibits due to selective © of
aggregation platelet TXA2
TXA2: t aggregation synthesis.
6. Vascular Tone • Epoprostenol (PGI2) • Indomethacin
• TXA2->VC. Late stage of pulmonary Inhibits PG synthesis

• PGE & PGI2 -• VD. hypertension (i.v. —• closes patent ductus
infusion) arteriosus in
• Patency of ductus
• Treprostinil (PGI2): Early respiratory distress
arteriosus depends on
stages of pulmonary
PGE2 and PGI2. syndrome (resulting
hypertension (i.v./ s.c./ oral/
from failure of closure
inhalation).
of ductus arteriosus in
• Alprostadil(PGEi):
infants).
Maintains patency of
ductus arteriosus in
congenital pulmonary
stenosis until surgery.
7. Ophthalmic: • Latanoprost (PGF2a): of
PGF2a —> | aqueous humor choice in simple glaucoma
outflow -* I IOP in (locally)
glaucoma
101
Autacoids
8. Reproduction • Alprostadil (PGEi): • NSAIDs © PGE &

Males: In erectile dysfunction PGF2a synthesis: used
•PGE -* -VD -* erection —* VD of cavernosal to prevent premature
& sperm motility arteries.
labor & dysmenorrhea.
Females: • Misoprostol7 (PGE):
•PGE-* Induction of abortion
- Cervical ripening • Dinoprostone (PGE2):
- Uterine contractions Induces labor/ abortion.
•PGF2a: uterine • Carboprost (PGF2a):

contractions Induction of abortion
9. Bronchial Tone • PGF2a->
• PGI2 - PGE -* dilation. bronchospasm thus

• PGF2a-PGD2-TXA2 dinoprost is given
—* bronchospasm. intra-vaginally &PGE2
is preferred.
Adverse effects of PG analogs
1. Latanoprost —* gradual change in iris color - keratopathy - comeal erosion

(rare)
2. Dinoprostone & misoprostol -* diarrhea.
3. Carboprost —*bronchospasm
4. Alprostadil —> penile pain, urethral burning, vaginal itching in partner

(locally), dizziness & tachycardia (if absorbed systemically).
7Misoprostol: Used for induction of abortion in the 1st trimester (+ mifepristone) and
is used alone in the 2nd trimester.
102
Autacoids
LEUKOTRIENES (LTS)|
PhosphoUpld
[ Pt»oq»hollp«s« A, |
I^Zileuton J
Glucocorticoid Arachldonate (Sy
H S-Upoatyttnaie \*^^
Leukotriene A4
LTB4
Chemotactlc
LTC4 LTD4 LTE4
Zafirlukast
Activation of receptors
Montelukast T=T^
Inflammatory reaction (VD, "("Capillary
permeability, Chemotaxis).
Bronchospasm, T Bronchial secretion
Synthesis: LTs are synthesizedfrom arachidonic acid by lipooxygenase enzyme.

LTs include:
1. LTB4: powerful chemotactic agent -* local accumulation of WBCs.

2. Cysteinyl LTs (LTC4, D4 & E4):
• Mediators of asthma —• potent spasmogens -♦bronchospasm: \ mucus -
inflammatory reactions.
• Present in sputum of patients with asthma, chronic bronchitis & allergic
rhinitis.
Inhibitors of LTs include:
1.Lipooxygenase inhibitors: zileuton.

2. LT receptor antagonists: zafirlukast and montelukast.
103
Autacoids
ANGIOTENSIN Ilj
(Powerful vasopressor)
• Low perfusion pressure

Juxtaglomerular e • Low plasma Na+
apparatus • Catecholamines
(3i receptors)
I. Drugs © renin
secretion: Angiotensinogen
l.p blockers
2. Clonidine, e
3. Methyldopa Renin
4. NSAIDs
Angiotensin I Bradykinin
II. Angiotensin converting m ACE sr\

©
enzyme inhibitors (ACEIs)
Captopril
Inactive
III. Angiotensin Receptor blockers Angiotensin II bradykinin
(ARBs) Valsartan t
ATi Receptors
I. II. III. IV.
Direct VC NE Release Aldosterone CeU
• tPeripheral • tPR Release Proliferation
resistance (PR) (Reinforces • Salt & water •Hypertrophy of

retention vascular &
• Renal VC sympathetic
•K+ excretion cardiac cells.
(efferent arteriole) effects)
N.B.: t Angiotensin II —* feedback inhibition of renin release.

Other Angiotensin II recentors: AT2: vasodilation & antiproliferative - AT4:
prothrombotic (tfibrinogen &t plasminogen activator inhibitori).
104
Autacoids
KININSl
• Potent vasodilator peptides formed by action of kininogenases on kininogens.

• They are inactivated by kininase I & II (ACE) which is inhibited by ACEIs.
Mechanism of Action
• Directly: on specific receptors: Bi receptors; stimulated mainly by Lys-
bradykinin & B2 receptors; stimulated mainly by bradykinin (BK).
• Indirectly: via phospholipase A2 & liberation of PGs.
Actions of Kinins
• Potentarteriolar dilators, increasing capillary permeability & lowering BP.
• Spasmogenic on uterus andbronchi —• bronchospasm andcough.
• Spasmogenic on intestine & | fluid secretion —* diarrhea.
• They produce pain and have a role in inflammation and allergy.
• Stimulate nasopharyngeal secretion in allergic rhinitis.
Therapeutic implications
1. Accumulated bradykinin caused by angiotensin converting enzyme inhibitors
(ACEIs) —* vasodilator and hypotensive actions & cough.
2. NSAIDs mediate part of their analgesic & anti-inflammatory effects by
inhibition of PG production induced by BK.
PLATELET-ACTIVATING FACTOR (PAF)
• Active lipid released from most inflammatory cells (neutrophils, macrophages,

eosinophils, mast cells, basophils) & platelets.
• Synthesized from phospholipids by phospholipase A2 -* inhibited by
Corticosteroids
Pathophysiological role of PAF

1. Inflammatory & allergic mediator; chemotaxin to eosinophils in bronchial mucosa.
2. Spasmogenic on bronchial & ileal smooth muscles.
3. Induces platelet aggregation.
105
<•:>,.: I)
•M
/ >
•-1
Lecture Notes
PHARMACOLOGY
Renal & CVS

Blood
Respiration
GIT
Faculty of Medicine
2019/2020
Lecture Notes
PHARMACOLOGY
Volume 2
Renal & CVS
Blood
Respiration
GIT
Faculty of Medicine
2019/2020
Preface

provides the most recent advances in drug therapy within aconcise framework.
Pharmacology Department; Ain Shams University. "Each ofus is unique in their
own way. We have something to leam from everyone". Colleagues and students
2019-2020
-3-
Head of Department
Authors
Prof. Dr. Olfat Hassan

Prof. Dr. Osama El Serafy Prof. Dr. May Hamza

Prof. Dr. Adel el Bakry Prof. Dr AtefEL-Esawy.
Computer graphics & designs: Dr. Essam Ghazaly - Dr. Mohamed Bahr
-4-
CONTENTS
Volume II
1. Renal Pharmacology 9-29
2. Cardiovascular Pharmacology 33-87
3. Blood Pharmacology. 91 -126
4. Respiratory Pharmacology 129-154
5. Gastrointestinal Pharmacology 157-185
-5-
I. RENAL PHARMACOLOGY

By the end of this chapter, the student should be able to:
• List 5 major groups of diuretics & relate them to their sites of action.
• List the major uses &toxicities ofthiazides, loop diuretics & potassium sparing
diuretics.
• Explain why loop diuretics are used in emergency cases and in edema refractory
to other diuretics.
• Explain the differences between the effects ofloop diuretics and thiazides on
blood electrolytes and how this relates to their therapeutic uses and side effects.
• Explain why spironolactone is ofchoice in edema ofhyperaldosteronism such as
liver cirrhosis while thiazides are not favoured.
• Explain why mannitol iscontraindicated in renal failure &heart failure.
• Discuss the different causes of refractory edema & their management.
• List the most common causesof disturbances of potassium homeostasis and their
management.
Renal Pharmacology
RENAL PHARMACOLOGY
Basic Physiology of the Kidney
The kidney performs two major functions:
• Excretion of waste products such as urea, creatinine and uric acid.

• Control of blood volume, electrolytes and acid-base balance.
Structure of the Nephron
• The nephron is the functional unit of the kidney. It is formed of a glomerulus,

proximal tubule, loop of Henle, distal tubule & collecting duct.
Blood Supply to the Nephron
• The afferent arteriole to the nephron branches to form the glomerular capillary
network from which arises the efferent arteriole.
• The efferent arteriole branches to form the peritubular capillary network

around the tubules and the loop of Henle
Afferent arteriole Efferent arteriole

PG—VD Angiotensin II —• VC
1. Filtration
Glomerular
2. Reabsorption
3. Secretion
capillaries
4. Excretion
Bowman's
capsule
Peritubular
capillaries
Maintenance of Glomerular Filtration in Hypoperfusion States
In renal hypoperfusion, glomerular pressure is | to maintain GFR through: f Ag

II —> VC of efferent arteriole & | PG -> VD of afferent arteriole-*! blood How .
-9-
Renal Pharmacology
Maintenance of glomerular filtration in hypoperfusion states
• The juxtaglomerular complex (baroreceptors in the afferent arteriole &

chemoreceptors in the macula densa in distal tubules) maintains glomerular
filtration during hypoperfusion by the following mechanisms:
a. In renal hypoperfusion states, low glomerular pressure activates
baroreceptors in the afferent arteriole & low NaCl concentration activates
chemoreceptors in the macula densa —• secretion of renin enzyme
-»tAngiotensin II —» VC of efferent arteriole —>f pressure in glomerular
capillaries thus maintaining GFR.
b. Activation of chemoreceptors in the macula densa also stimulates secretion
of PGs-* vasodilation of afferent arteriole —*f blood flow & glomerular
pressure thus maintaining GFR.
In renal hypoperfusion states (hypovolemia, diuretic therapy, heart failure,

liver cirrhosis, nephrotic syndrome), administration of ACEIs (—>• inhibit
efferent VC) or administration of the PG synthesis inhibitors NSAIDs (—•
inhibit afferent VD) causes marked reduction in glomerular filtration —> acute
renal failure.
-10
Renal Pharmacology .
Transport of Water & Electrolytes in the Nephron

• The main function of the kidney is to excrete waste products such as urea &
creatinine which are filtered in the glomeruli & not reabsorbed.
• Following glomerular filtration, most of the important blood constituents are
reabsorbed in the different segments of the nephron as follows:
1. Proximal Tubules
• 60% of filtered Na+ is reabsorbed as NaCl (Na+ is actively reabsorbed by Na+-
pump, CI" follows Na+ passively).
• 5% offiltered Na+ is reabsorbed as NaHC03 in exchange with H+ under effect
ofcarbonic anhydrase enzyme to preserve blood NaHC03.
• Ca2+, Mg2t and K+ reabsorption follows that ofNa+ to the same degree.
• Water is reabsorbed passively (proximal tubules, highly water permeable).
• Glucose &amino acids are reabsorbed by Na+ cotransport mechanism.
• Mannitol &sucrose are not reabsorbed -»• excreted as such in urine retaining
water (—• used as osmotic diuretics).
1. Thick Ascending Loop of Henle

• 25% - 30% offiltered Na+ is reabsorbed via active 2C17Na+/K+ pump.
• This segment is impermeable to water rendering the tubular fluid hypotonic
(diluting segment).
• Medullary hvpertonicitv: is created by active reabsorption of Na+ coupled
with passive transport of urea at this segment. It provides osmotic driving
forces for water reabsorption from collecting tubules under the effect ofADH
to conserve body water & concentrate urine. Renal PGs interfere with
medullary hypertonicity by inhibiting Na+ reabsorption -> diuresis.
3. Distal Tubules (including collecting duct)
• Early Part of Distal Tubule (diluting Segment): Continuation of the thick
ascending loop of Henle. Impermeable to water. There is active NaCl
reabsorption (10%).
-11
Renal Pharmacology
More Distal
• Na+ (5%) is reabsorbed in exchange with K+ or H+ via Na+/K+/H+ pump. .
• Na+ reabsorption is partly dependent on aldosterone &partly independent.
Collecting Duct
• ADH increases the permeability of the collecting duct to water which is

reabsorbed by the driving osmotic force of the hypertonic medulla.
DIURETICS
• Diuretics are drugs that cause a net loss of sodium and water from the body
through the kidney resulting in contraction of the extracellular fluid.
They include:
A. K+-losing diuretics
• Loop diuretics.
• Thiazides.
• Osmotic diuretics.
• Carbonic anhydrase inhibitors.

B. K+-sparing diuretics
• Spironolactone - amiloride - triamterene.
General Principles in Diuretic Therapy

1. Diuretics act by different mechanisms and at different sites along the nephron
(see table). Thus, they have a synergistic effect if they are combined together.
2. All diuretics (except spironolactone) have to reach their site of action in the
lumen of the nephron, by organic acid or organic base secretory systems (see
table). Therefore, any defect in delivery of diuretics to their sites of action (e.g.
in renal impairment) will result in diminished diuretic response.
3. Carbonic anhydrase inhibitors, thiazides and loop diuretics are organic acids
secreted by organic acid secretory systems and, therefore, compete with
secretion of otherorganic acids such as uricacidresulting in hyperuricemia.
-12-
Renal Pharmacology
4. Diuretics interfering with reabsorption of Na+ at earlier (more proximal) sites

lead to enhanced Na+ reabsorption in exchange with K+ & H+ at distal tubule
(aldosterone-dependent Na7K7H+ exchange site) —*• hypokalemia and alkalosis.
5. Diuretics inhibiting Na+ reabsorption at a certain site interfere with other renal
functions related to Na+ reabsorption at that site, for example:
a. Loop diuretics inhibit Ca2+ reabsorption at thick ascending loop.
b. K+-retaining diuretics inhibit excretion of K+ ahdMg2* ions in distal tubule.
Routes of Access to Sites of Action .

&
Efficacy of Diuretics
Diuretic Route of access to site Site of action Relative
of action efficacy
•Carbonic Organic acid secretion Proximal tubule 2
anhydrase
Inhibitors
•Osmotic Glomerular filtration Proximal tubule & 6
diuretics loop of Henle
•Loop diuretics Organic acid secretion Loop of Henle 10-15
•Thiazides Organic acid secretion Early Distal tubule 4
•Amiloride Organic base secretion Distal tubule and 1
•Triamterene Organic base secretion collecting duct
•Spironolactone Peritubular circulation
13-
\.
Renal Pharmacology
e
e Na+/K+/H+
Na+Cr exchange
reabsorption
Peritubular
K-SPARING
Efferent
arteriole capillaries
Glomerulus
Afferent
arteriole
Carbonic
Anhydrase
Inhibitors
9 NaHCo3
reabsorption
VHr-To renal
vein
To bladder and
external environment
Sites of Action of Diuretics
-14-
Renal Pharmacology
LOOP DIURETICS
(High ceiling1 - most effective diuretics)
Frusemide- Bumetanide- Torsemide
Mechanism of action
1. Block 2 C17Na7K+ reabsorption in thick ascending loop of Henle resulting in:

• Excretion of 20% of filtered Na+.
• Interference with medullary hypertonicity —* failure of water reabsorption
by medulla under effect of ADH —• excretion of water in excess of Na+.
2. Release vasodilator PGs which intensify the action of loop diuretics through:
• VD of Afferent arteriole —• | glomerular filtration.
• Inhibiting Na+ reabsorption at the ascending loop of Henle.
N.B: NSAIDs inhibit PG synthesis—• interfere with action of loop diuretics.
Other actions
i. Venodilator action —*• adds to their benefits in acute pulmonary oedema.

ii. Increase renal blood flow—»useful in acute renal failure.
Pharmacokinetics (in healthy subjects)

• Frusemide absorption is variable 10-100% (average 50%)-* try different doses
before considering drug ineffective.
• Bumetanide & torsemide are nearly completely absorbed —• do not require dose
adjustment on switching from oral to IV.
• Loop diuretics are highly bound to plasma protein (90%).
Loop diuretics are high ceilmg diuretics as they block nearly all reabsorption sites —♦ excretion of
20% of filtered Na+ (maximum capacity ofthe ascending loop).
-15-
Renal Pharmacology
Indications of loop diuretics
I. Emergency cases (as it is rapid with potent dehydrating effect; can be given IV)
1. Hypertensive encephalopathy.
2. Acute pulmonary edema (Venodilation).
II. Cases refractory to other Diuretics
1. Refractoryedema of severe CHF & renal insufficiency.

2. Refractory edema of liver cirrhosis (added to full dose of spironolactone).
3. Acute renal failure (jrenal blood flow).
III. Electrolvte& Acid-base Disturbances
1. Hypercalcemia: added to IV saline .

2. Hyperkalemia:
• Inhibit K+ reabsorption in loop of Henle & increase K+ excretion in
exchange with Na+ in distal tubules.
3. Dilutional hyponatremia:
• f water excretion more than Na+.
4. Distal renal tubular acidosis:
• t H+ excretion inexchange with Na+ at distal tubule.
Doses and Preparations
Frusemide: oral dose 80 mg (40 -120); IV dose 40 mg (20 - 60 mg).

Bumetanide (40 times more potent): oral and IV dose 1 - 5 mg.
Torsemide (10-100 mg)
2
In hypercalcemia IV saline may be sufficient alone for Ca2+ excretion as it corrects the
hypoperfusion responsible for | GFR & f tubular Ca2+ reabsorption.
Loop diuretics arc added if necessary —• inhibit Ca2+ reabsorption in loop of henle.
-16-
Renal Pharmacology
Adverse Effects
I. Metabolic & electrolyte disturbances
1. Hypovolemia - hypotension - collapse - hemoconcentration & thrombosis

(due to intensive diuresis in a short time).
2. Hypokalemia & alkalosis: f Na+delivered to distal tubules —• excretion of K+ &
H* in exchange with Na+ by aldosterone (avoided by adding spironolactone).
^ ™ '\ Inhibit reabsorption in loop ofHenle

4. Hypocalcemia J
5. Hyperuricemia (compete with uric acid for organic acid secretory system).
II. Other Adverse Effects
1. Ototoxicity (especially with aminoglycosides).
2. Interstitial nephritis (especially with cephalosporins).

3. Myalgia (bumetanide).
4. Sulfonamides-hypersensitivity3.
5. Refractoriness (see below).
Causes of refractoriness to loop diuretics & its management
A. Pharmacokinetic Causes
I. Defective intestinal absorption in decompensated HF:

Treatment: Give the diuretic IV.
II. Defective pp binding in hypoalbuminemic states (liver cirrhosis & nephrotic

syndrome) —> extravascular diffusion of diuretic —>J. renal excretion:
Treatment: Mix the diuretic with albumin prior to infusion.
III. Defective excretion of diuretics by acid secretory system in renal

impairment due to accumulation of acids:
Treatment: | Dose of frusemide to 5 folds.
3 Inpatients with sulfonamide allergy the loop diuretic ethacrynic acidmay be used.
-17-
Renal Pharmacology
B. Pharmacodynamic Causes
I. Hypertrophy of distal tubular cells (onchronic use —*-f Na+ reabsorption —•

blunts the action of the diuretic):
Treatment: Add thiazides to inhibit Na+ reabsorption in distal tubules &
amplify the effect of loop diuretics.
II. Na+ lost by loop diuretic is reabsorbed in exchange with K+ in distal
tubules (under the effect of aldosterone):
Treatment: Add the aldosterone antagonist spironolactone.
18-
Renal Pharmacology
THIAZIDE DIURETICS
(Moderately powerful [low-ceiling] diuretics)
Mechanism of Action
• Inhibit active electroneutral NaCl reabsorption in the early part of distal tubule
(diluting segment) causing excretion of 5-10 % of filtered Na+.
Vasodilator action
• This is the basis for their antihypertensive effect.
Therapeutic Uses
1
r i
I. CVS II. Renal
1. Hypertension 1. Nephrogenic diabetes insipidus

• Initially: diuresis —• | blood • Chronic therapy paradoxically decreases
volume. urine output in nephrogenic diabetes
• Persistent effect: due to insipidus (may be due to J, PG—> J, GFR
vasodilation. —> I urine volume).
2.CHF
2. Idiopathic hypercalciuria & Ca2* stones
• To overcome
• Chronic therapy —• J, GFR & f tubular
refactoriness to loop Ca2+ reabsorption —> J, Ca2+ excretion.
diuretics.
N.B.:
• Patients on thiazides have a reduced risk of osteoporosis & hip fractures as

they | Ca2+ excretion —»• thiazides are preferred in elderly hypertensives.
• Effectiveness of thiazides is reduced in renal impairment—>metolazone
(thiazide like preparation) is effective in impaired renal function.
-19
Renal Pharmacology
Adverse Effects
1. Hypokalemia4 &metabolic alkalosis, with | risk ofhepatic encephalopathy in

liver impairment5.
2. Hyponatremia & hypomagnesemia.
3. Glucose intolerance6.
4. Hyperlipidemia: t LDL & J, HDL —• coronary sclerosis.

5. Hyperuricemia.
6. Hypersensitivity.
7. Impotence.
Doses and Preparations
• Hydrochlorthiazide (short acting < 24 h): 25 mg 2 - 4 times/d.
Drugs related to Thiazides (long acting >24 h)

• Chlorthalidone: 100 mg.
• Indapamide: 2.5 mg once/d in hypertension, less metabolic side effects.
• Metolazone: effective in impaired renal function
4More common with thiazides than with loop diuretics because part of delivered Na+ by loop
diuretics is reabsorbed by thiazide area before reaching thearea ofNa+-K+ exchange.
5Hepatic encephalopathy in patients with liver impairment is due to alkalosis induced by
thiazides, which -»| lipid-soluble NH3 rather than water-soluble easily excreted NH,+.
Accumulation of NH3, due to failure of liver to convert it to urea—* its difiusion into brain
depleting excitatory glutamic acid —>coma.
Thiazide-induccd hypokalemia -»t K+outflux from pancreatic islet cells -* membrane
hyperpolarization -> 0 Ca2+ influx -• © insulin release.
-20-
Renal Pharmacology
POTASSIUM-RETAINING DIURETICS
(Weak diuretics; excrete only 5% of Na+ filtrate)
Mechanism
Inhibit Na+/K+/H+ exchange at thedistal tubule by two different mechanisms:

I. Indirect: Spironolactone & eplerenone (delayed onsetof action)
• Antagonize aldosterone receptor-binding resulting in decreased synthesis of
a specific protein that stimulates theNa+ pump (requires 3-4 days).
II. Direct: Triamterene & amiloride (rapid onset of action)
• Act independent of aldosterone —> block Na+ channels directly.
Indications
1. In CHF
• Spironolactone added to loop diuretics & ACEIs—•! mortality by 30%,

2. Edema of hyperaldosteronism
• Spironolactone is ofchoice: more effective7.
3. Hypokalemia and Hypomagnesemia
• Triamterene and amiloride, are preferable to spironolactone as they are more
rapid & shorter acting—> daily dosage adjustment possible.
• They are combined with KMosing diuretics (loop & thiazide diuretics) to
potentiate their diuretic effect & to antagonize their hypokalemic effect (more
effective than exogenous K+ & Mg** supplements).
Adverse Effects
1. Hyperkalemia & metabolic acidosis.

2. Gynecomastia: due to antiandrogenic effect of spironolactone.
Edema of hyperaldosteronism (liver cirrhosis, nephrotic syndrome & CHF) is resistant to other
diuretics since Na1 lost byother diuretics isreabsorbed again by excess aldosterone at NaVKTH*
exchange site in distal tubule (also directly acting K+-retaining diuretics are less effective than
spironolactone in hyperaldosteronism.
-21-
Renal Pharmacology
OSMOTIC DIURETICS
(MANNITOL)
(Powerful diuretic action)
Mechanism of Action
Mannitol is freely filtrated at the glomerulus with limited reabsorption by renal

tubules resulting in:
• Increase in osmotic pressure of tubular filtrate with retention of water and
increased urine volume (main effect —• useful as dehydrating agents).
• The high osmotic pressure of tubular filtrate opposing plasma osmotic
pressure inhibits Na+ reabsorption throughout the nephron but to a much
lesser extent than water (so, they are ineffective in edematous states with
Na+ overload).
Indications
1. Dehydrating agents for:

a. Rapid reduction of intracranial tension in cerebral edema caused by head
injury or brain surgery.
b. Rapid reduction of intraocular tension in acute congestive glaucoma.
2. Prophylaxis against acute renal failure:
• Mannitol prevents acute renal failure following surgery, trauma or

hemolytic transfusion reactions by maintaining high rate of urine flow,
preventing concentration of toxic agents which cause renal damage.
Adverse Effects & Contraindications

•
In impaired renal function (e.g. acuterenal failure), mannitol is not
filtered & persists in plasma-»• f intravascular volume —> heart failure
& dilutional hyponatremia-* CI in acute renal failure & congestive
heart failure.
22-
Renal Pharmacology
CARBONIC ANHYDRASE INHIBITORS (CAIs)

Acetazolamide - brinzolamide - dorzolamide
Mechanism of Action
• Inhibit carbonic anhydrase enzyme responsible for H* production —•

inhibition of Na*/!!* exchange at the proximal tubules—• inhibition of
NaHC03 reabsorption —• loss ofNaHC03 in urine leading to:
a. Diuresis with alkaline urine.
b. Decreased blood bicarbonate with metabolic acidosis.
N.B.: CAIs are weak diuretics as most of the fluid & Na+ lost are reabsorbed at
more distal nephron sites.
Indications
1. Emphysema and high altitude sickness (correct alkalosis by inducing

metabolic acidosis).
2. Epilepsy: suppress the irritable focus directly or by inducing acidosis.
3. Eye: treatment of glaucoma by decreasing formation of aqueous humor

[Methazolamide is preferred (less renal & systemic effects)].
4. Excretion of of acidic toxins as salicylates & barbiturates (alkalmize
urine).
Adverse Reactions
• Metabolic acidosis —> drowsiness & refractoriness to the diuretic effect.
• Calcium and phosphate stones due to alkaline urine.

• Hypersensitivity reactions as they are sulfonamide derivatives.
1The body preseves NaHC03 tobuffer acidosis.

-23-
Renal Pharmacology
DRUGS AND POTASSIUM HOMEOSTASIS
• K+ is the major intracellular cation with low concentration in the extracellular

fluids (3.5 - 5 mEq/1). The body maintains this low plasma K+ level through:
i. Promoting entry ofK+ into the cell by the Na+-K+ ATPase pump. Insulin &
p2 adrenergic receptor stimulation activate this pump,
ii. K+ excretion through kidney (mainly) & colon (limited amount). Both are
stimulated by aldosterone through the renin-angiotensin system.
Potassium Distribution
Insulin- agonists
Cell
Alkalosis
Na enters in exchange with H followed byits exit in exchange with K

Potassium Excretion
Hypovolemia
Pj Agonists (laxatives and diuretics) Prostaglandins
| Renin |
Angiotensinogen AngiotensinI
Angiotensin converting enzyme- W< " I ACEIs
Ax (")
Angiotensin
M Spironolactone
Aldosterone
T
I K+ excretion |
24-
Renal Pharmacology
DISTURBANCES IN K" SERUM LEVEL
Causes of Hypokalemia & Hyperkalemia
(See figure)
Hypokalemia Hyperkalemia
A. Increased K* entry into cells: A. Increased K+ exit out of cells:

1. Insulin (large dose in ketoacidosis). 1. Digitalis (0 Na+-K+ ATPase)
2. | CA in stress ([$2 agonist) 2. P blockers (pV blockade)
3. Alkalosis ( due to K+-losing diuretics 3. Acidosis (due to K+-retaining

orvomiting)9. diuretics &salicylates)10
4. Succinylcholine (partial
depolarization—• K+outflux).
B. Increased K+ loss: B. Defective renal K* excretion:

1. Renal loss: 1. Impaired renal function.
• Hyperaldosteronism 2. Hypoaldosteronism:
• K+-losing diuretics as loop • K+-retaining diuretics:
diuretics & thiazides. antagonize aldosterone
• Liquorice. action.
2. Extra-renal loss: • PiBs - NSAIDs: 0 renin release.

• Laxatives - severe diarrhea. • ACEIs: J. Ag II & aldosterone.
• ARBs: block Agll receptor
9it diffuses out ofcell to buffer the alkalosis -» K+diffusion into cells to maintain
electronegativity inside the cell.
10 H* diffuses into cell to buffer the acidosis—* K+ diffusion out of cell to maintain cell
electronegativity.
-25-
Renal Pharmacology
Hypokalemia
Causes: see table
To minimize or correct hypokalemia
1. Use K+-rich diet as banana.

2. Combine K+-sparing diuretics with K+-losing diuretics.
3. Drug holiday for patients taking K+-losing diuretics.
4. Administer KC1.
N.B.:
• Oral K+ has gastric & esophageal irritant effect and should be given with
plenty of fluids while sitting upright.
• IV potassium may cause phlebitis and should be given in large veins.
Hyperkalemia
(Life threatening condition due to fatal arrhythmias)
Causes: see table
Treatment: according to K+ level & ECG changes

l.IVCa2+:
It is the most rapid treatment used in severe cases. It stabilizes myocardial
membrane by opposing theeffect of hyperkalemia on membrane potential.
2. Increasing K* movement into the cells:
a. Insulin: small dose (6-8 units ) + glucose (20 g IV) to avoid
hypoglycemia. IV glucose which stimulates insulin release is preferred.
b. B2 agonistnebulizer (salbutamol).
c. IV sodium bicarbonate: induces alkalosis which increases influx of K+u
3. Removal of K* from bodv:

a. Loop diuretics.
b. Cation-exchange resins inhibit intestinal absorption of K+.
c. Dialysis in severe resistant cases.
" Excess alkalinization may inhibit ionization ofCa2+ aggravating the effect ofhyperkalemia on
membrane potential.
26
Renal Pharmacology
Magnesium
• Magnesium is the second most abundant intracellular cation.
Mechanism of action :
• Natural physiologic competitive Ca antagonist at L - calcium channels.

• Antagonist of NMDA glutamate receptors: analgesic, anticonvulsant, and
sedative properties.
• Interferes with acetylcholine release: muscle relaxation.
• Decreases release of catecholamines after sympathetic stimulus.
Indications:
1. Torsades de pointes13 &digitalis induced arrhythmias (Mg sulfate IV; inhibits

Ca entry)
2. Hypomagnesemia associated with myocardial infarction14.
3. Refractory hypokalemia secondary to hypomagnesemia.
4. Constipation: osmotic laxative (Mg sulfate, MgO, milkof magnesia).
5. Antacids.
6. Seizures in preeclampsia (anticonvulsant) - premature labor.

7. Adjuvant in anesthesia:
• Analgesic15, sedative.
• !Blood pressure response to tracheal intubation16.
• Inhibits Ach release at NMJ, potentiates competitive neuromuscular blockers.
8. Severe asthma attacks17.
9. Diabetic coma and diabetic patients.
10. Muscularpain relief 'Epsom bath salts', gel or in solution topically.
12 As acofactor, it isinvolved inmore than 300 known reactions, flow of transmembrane ions,
muscle contraction, neuronal activity, vasomotor tone, cardiac excitability, etc,....
13 Mg replaces Ca ion influx into the cell-* i QT interval and relieves torsade de pointes.
14 During acute myocardial infarction, 80% of patients develop hypomagnesemia in the first 48
hrs, due to f catecholamines6. Hypomagnesemia —♦depolarization —» tachycardia6
15 Analgesic effect is due to blockade ofNMDA receptors &|catecholamines release.
16 Due to a reduction in the release of catecholamines after sympathetic stimulation.
17 Inhibits histamine & Ach release, potentiates beta-agonists. Less benefit in moderate asthma.
r27-
Renal Pharmacology
Adverse effects:
• Diarrhea.
• Drowsiness.
• Hypotension.
• Asystole (with rapid IV administration).
• Teratogenic: category D (fetalskeletal abnormalities).
Hypomagnesemia18
• Hypomagnesemia is associated with:
• Refractory hypokalemia.
• Cardiac arrhythmia.
• Heart attacks due to coronary spasm.
• Seizures, and psychosis.
Predisposing factors for hypomagnesemia
• Diarrhea.
• Diabetes.
• Drug- induced (t renal excretion)
• Diuretics19 - Digitalis.
• Aminoglycosides - Amphotericin B.
Routes of administration
• Orally: e.g., laxatives, antacids.

• Intravenously: e.g., anticonvulsant in preeclampsia, anti-arrrhythmic.
Preparations
• Mg sulfate - Mg gluconate.
• Mg citrate- Mgoxide- Mg hydroxide (milk of magnesia).
• Mg trisilicate.
18 Hypomagnesemia is seen in 60% ofpatients in ICU, 7% ofadmissions for ketoacidosis, &70%

after coronary revascularization.
"Diuretics, specially chronic furosemide therapy, are the leading cause ofhypomagnesemia.
-28-
Renal Pharmacology
TREATMENT OF IDIOPATHIC HYPERCALCIURIA
(Common cause of calcium stones)
1. Low dietary Na+. *| ^blood volume _> j GFR &j wbular c&2+
1T.. ., ,, . .
2. Thiazides (chronic use). '
} reabsorption
3. Avoid restriction of dietary Ca2+:

Oral Ca2+ binds with oxalate in the intestine decreasing oxalate absorption —* j
urine oxalate. The low oxalate in urine prevents the formation of Ca oxalate
stones.
4. Avoid high protein diet:

Proteins produce acidosis which increases Ca2+ stones by the following:
1. Acids mobilize calcium from bone to blood and then to urine.
2. Intracellular acidosis consumes citrate decreasing its concentration in blood

& urine (urinary citrate normally prevents crystallization of Ca stone).
5. Avoid hypokalemia:
Avoid hypokalemia by giving K+ citrate: hypokalemia is associated with
increased intracellular acidosis which decreases citrate excretion in urine.
-29
•;:vii ./.''/
.;•;:):;; 0:
•:{! .';:: •jH'"-
!'•' i ; j'
i.
II. CARDIOVASCULAR PHARMACOLOGY
Antianginal drugs: By the end of this chapter, the student should be able to:
• Recognize the importance ofthe routine use ofaspirin and statins in reducing the
risk of ischemic heart disease.
• List the 3 major groups ofantianginal drugs &their antianginal mechanisms.
• Discuss the importance of p Bs as lsl choice maintenance therapy of classic
angina &why calcium channel blockers (CCBs) are preferred in vasospastic type.
• Differentiate between preparations of nitrates used for relieve of acute anginal
attack and those used for maintenance therapy.
• Differentiate between the effects of the 2 main groups of CCBs on the
cardiovascular system and how this relates to their uses and side effects.
• Point out the therapeutic uses of CCBs that are shared with beta blockers and
those in which beta blockers are contraindicated.
Drugs used in heart failure: By the end of this chapter, the student should be able to:
©Outline the pathophysiology of HF & the role of sympathetic & renin
angiotensin system activation as initial compensatory mechanisms &their role in
the increase in cardiac loads & further deterioration of myocardial contractility in
later stages.
• List drugs that are used to reduce preload, afterload &myocardial contractility in
CHF versus those used in acute heart failure.
• Discuss the beneficial effects of p Bs & spironolactone in reducing mortality in HF.
• Explain the beneficial effects ofdigoxin in HF with atrial fibrillation &why it is
no longer considered a first line drug in CHF.
• Explain how the increase in intracellular sodium & calcium are responsible for
both the beneficial effects of digoxin on myocardial contractility as well as for its
electrophysiological & arrhythmogenic effects.
Antihypertensive drugs: Bythe end of this chapter, the student should beable to:
• List the major groups of drugs used as monotherapy in hypertension.
• Discuss the choices of different antihypertensive drugs in different disease states.
• Explain why vasodilators such as ACEIs &ARBs are preferred to hydralazine.
Explain why nitroprusside is only used in severe cases ofhypertension .
Explain why low dose thiazides is preferred to high dose therapy.
•Discuss why the indications oflabetalol and esmolol differ from those of
bisoprolol in management of hypertension.
Explain the main differences between ACEIs and ARBs and why they are
preferred in diabetics and in patients with nephropathy.
Compare between the effects ofdifferent antihypertensives on heart rate.
Discuss the beneficial effectsof combinations of antihypertensives.
Antiarrhythmic Drugs: By the end ofthis chapter, the student should be able to:
• Classify antiarrhythmic drugs according to their electrophysiological effects.
• Discuss the choices of different antiarrhythmic drugs in various types of arrhythmias.
Cardiovascular Pharmacology
CARDIOVASCULAR PHARMACOLOGY
DRUG THERAPY OF ISCHEMIC HEART DISEASES
Cardiac ischemia results from an imbalance between myocardial O: supply

& oxygen demand.
If ischemia is transient -> If ischemia is persistent ->

Angina pectoris Myocardial infarction
Classic Angina
• Results when the work done by the heart is increased while the narrow
atherosclerotic corollaries fail to dilate & increase blood flow to meet the
increase in myocardial O: demand.

• Presents as anginal pain1 associated with transient ST segment depression.
• It usually occurs on exertion —* so also called exertion or effort angina. It is
relieved by rest or nitroglycerin.
Prinzmetal's Variant Angina2
• Results from a reversible coronary vasospasm with normal O2 needs—* so
also called vasospastic angina.

• Presents as anginal pain associated with transient ST segment elevation or
paradoxical T wave normalization.
1 Anginal pain is a sudden pressing chest pain radiating to the neck, jaw, shoulder. & arm,
caused by accumulation of metabolites in cardiac muscle.
2 Named variant as it occurs after variable levels of exertion even at rest & Prinzmetal after the
I" person who described it.
-33-
Unstable angina:
Results when an atheromatous plaque ruptures & a nonocclusive thrombus is

formed which partially occludes the coronary artery producing symptoms of
ischemia which are prolonged & may occur at rest (no fin serum markers).
Acute coronary syndromes3
These syndromes include a group of conditions ranging from unstable angina to
myocardial infarction (NSTEMI4, STEMI5). They occur in patients with
coronary atherosclerosis & represent varying degrees of coronary occlusion.
Drugs for Ischemic Heart Diseases
I. Drugs decreasing risk of ischemic attacks
A. Antiplatelets: e.g. aspirin, clopidogrel.

B. Hypolipidemic agents: e.g. statins.
C. Angiotensin converting enzyme inhibitors.
II. Antianginal Drugs
A. Organic Nitrates.
B. Beta adrenoceptor Blockers.
C. Calcium Channel Blockers.
D. Others:
i. Trimetazidine.
ii. Ivabradine.
iii. Ranolazine.
3In some classifications acute coronary syndromes also include classic & Prinzmetal's angina.
"Non ST elevation myocardial infarction: Occurs whenan intermittently occlusive thrombus causes
myocardial necrosis (t in scrum markers) but collaterals maintain partial viabilityofmyocardium
(non ST elevation, non Q wave), t In serum markers (troponin I & T orCK-MB) maynotbe
detectable for hours after presentation, thus it is initially indistinguishable from unstable angina.
5ST elevation myocardial infarction: Occurs ifthe thrombus occludes the coronary vessel &the
prolonged ischemia results in myocardial damage with | in serum markers plus ECG changes
(ST elevation, Q wave.). Presents withmore severe & persistent pain after nitroglycerin.
-34
A. Organic Nitrates
Molecular Mechanism of Action
• Nitrates bind to special receptors on vessel wall Nitrates release NO which is

converted by an SH-dependentenzyme into S-nitrosothiol.
• S-nitrosothiol activates guanyl cyclase -* fc-GMP —>i intracellular Ca** —*•
smooth muscle relaxation (e.g. vasodilation;selective venodilators).
Pharmacological actions
f T
I. Relaxation of Vascular II. Brief relaxation of other
Smooth muscles Smooth muscles
• Venulodilators —*• j venous return; Relaxation of GIT smooth muscles;
I preload. especially:
• Sphincter of Oddi.
• Arteriodilators (in higher dose) —>
i peripheral resistance; jafterload. • Cardiac opening ofoesophagus.
Mechanism of antianginal effect
A. J. O2 demand (relieve pain): | work done by heart through:

- Venular dilators —• J, venous return; [ preload.
- Arteriolar dilators (in higher dose) —• J, peripheral resistance; |afterload.
B. | 02 supply: | coronary blood flow:
- VD ofstenosed large epicardial coronary arteries6.
- VD of collaterals.
- Redistribution of blood to subendocardial ischemic areas7.

N.B.: Antiplatelet activity contributes to their antianginal effect.
6With moderate doses if atherosclerosis is not severe.

7Venodilatation —> pooling ofblood in splanchnic area &extremeties—> i venous return —>i
ventricular filling —»4 coronary artery compression in subendocardium —> redistribution of blood
flow to subendocardial ischemic areas.
-35-
Indications
1. All types ofangina pectoris.
2. Congestive heart failure & acute pulmonaryedema.
3. Acute myocardial infarction (early; j infarct size).
4. Hypertensive emergencies.
Adverse Reactions
1. Throbbing headache8-flushing.
2. Postural hypotension, dizziness & syncope(potentiated by sildenafil).
3. Reflex tachycardia (due to J,BP) —*• worsening of angina (joy adding a pB).
4. Rapid tolerance with chronic use9 (due toJ,SH groups required for nitrosothiol
. formation & VC due to activation of adrenergic & renin-angiotensin systems).
5. Withdrawal angina with sudden cessation.
6. Methemoglobinemia10 (rare)
Contraindications: severe hypotension occurs if nitrates are given—•

1. With sildenafil.
2. In hypertrophic obstructive cardiomyopathy.

3. In right ventricular infarction (J. preload-> .[.contractility -> marked J, BP).
4. In volume depletion & severe aortic stenosis(used cautiously).
Precautions
1. Drug is placed in tightly closed containers —• replenish supply / 3 months.

2. Instruct patientto sit while taking drug & to lie down if syncope occurs.
3. Remove tablet on relief so that only the minimal effective dose is used.
4. To avoid tolerance; allow a nitrate free period for 8 hrs/day.
5. Nitrates should not be abruptly stopped to avoidprecipitation of angina.
8Due to vasodilation ofmeningeal arteries.Treated byaspirin.

9Chronic use may result in endothelial dysfunction.
10 With chronic high doses (more with nitrites) -» oxidize Hb into metHb treated by methylene blue.
-36-
Preparations & kinetics11 .

1.Nitroglycerin & isosorbide dinitrate (ISDN)12 —> extensive 1st pass
a. Sublingual tablets & spray: rapid onset/ short-action: 2 min /30
min for nitroglycerin & 5 min /l hr for ISDN—• 1st choice for acute
attack13 &for immediate prophylaxis (ifexertion is expected).
b. Transdermal patch: (delayed onset /longest duration —> for long
term prophylaxis & CHF (applied for 14 hrs/d).
c. IV infusion —»for AHF or unstable angina.
d. Oral slow-release preparation: (alternative to transdermal). .
2. Isosorbide mononitrate
• No 1st pass hepatic metabolism —•higher bioavailability.

• Slower onset; longer action: given twice / day or oral extended
release preparation once or twice/ day.
B. p- Blockers
(Bisoprolol- Metoprolol)
Mechanism of antianginal effect

Long term prophylaxis
A. 1 O? demand:
• ^Frequency &severity of attacks.
-1 HR & contractility.
• Control HR at rest (50- 60 /min).
-|BP.
• Blunt the Tin HR & BP during exercise.
- Inhibit lipolysis —•J.FA utilization.
B. t Or supply:
- f coronary filling indiastole (4 HR -*• | diastolic period).

- Redistribution of coronary flow to subendocardial ischemic areas.
N.B.: Antiplatelet activity contributes to their antianginal effect.
All pBs are equally effective except those with ISA —• may t HR.
1' Also available as nitroglycerin ointment & chewable (ISDN) -»longer action -»300 min.
12 Converted in liver into 2 molecules of mononitrate.
13 Maximum of 3 tablets in 15 mins (5 mins apart). If painnotrelieved, patient is referred to hospital.
-37-
C. Calcium Channel Blockers (CCBs)

• CCBs act on ax subunit of L-type Ca** channel in conductive tissues (SAN &
AVN), cardiac myocytes & vascular smooth muscle includingcoronaries.
Classification of CCBs
I. Dihvdropyridine (PHP) P. Non-Dihvdropvridine (Non-PHP)
A. Short-acting: nifedipine • Verapamil

B. Intermediate acting • Diltiazem
• Nicardipine - nimodipine (have short halflives but extended

C. Long-acting release preparations for single daily
• Amlodipine - fenoldipine dose are available).
• Extendedrelease nifedipine
Pharmacological Actions of CCBs
I. Cardiovascular Actions
Vaso-selective Non selective
Vessels > Myocardium > SAN, AVN SAN, AVN > Myocardium =Vessels
A. Vascular Effects
• Peripheral arteriolar vasodilatation -> I PR -> i ABP.

• More marked with dihydropyridines14
B. Minimal direct cardiac depression : B. Direct cardiac depression:
• No effect on SAN & AVN conduction. • I SAN & AVN conduction

• Reflex Tachycardia: (nifedipine> amlodipine). • Bradycardia.
• Mild inhibition ofcontractility. • Suppress contractility.
NjB.: Verapamil is more cardio-depressant than diltiazem.
14 Nimodipine is selective oncerebral vessels.

•38
CardiovascularPharmacology
II. Other Actions of CCBs
• Relaxation of GIT, bronchial, urinary, uterine smooth muscles... etc.

• Inhibit platelet agreggation.
Adverse Effects of CCBs
I.DHP II. Non-DHP
1. Reflex tachycardia —> worsen angina. 1. Bradycardia & heart block15.

2. Hypotension - headache, flushing. 2. Hypotension - heart failure.
3. Ankle edema16 - dizziness - tinnitus. 3. Constipation (verapamil).
Therapeutic Uses
1. Angina (alltypes; of choice in vasospastic): diltiazem & long acting DHPs preferred:
A. 4 02 demand: due to
• Negative chronotropic & inotropic effects (more with verapamil & diltiazem).
• I Peripheral resistance (especially with DHPs)
B. T coronary blood flow: due to dilatation ofepicardial coronary arteries.
2. Hypertension: DHPs - verapamil - diltiazem (longacting DHPs inducesmooth
hypotension with less reflex tachycardia —• preferred to short acting DHPs).
3. Supra ventricular arrhythmia: (verapamil); see arrhythmia
- PSVT: (block AVN reentry).
- Control heart rate in atrial fibrillation & flutter.
4. Hypertrophic obstructive cardiomyopathy (HOCM)17

• Verapamil (of choice):
Relieves outflow tract obstruction through its
relaxant action —>l ventricular septal thickening.
5. Other uses:
• Peripheral vascular diseases - migraine prophylaxis - prevent premature labour.
15 Paradoxical cardiac acceleration in patients with AF +WPW.

16 Ankle edema is due to dilation of arterioles more than venules.
17 Thickening of interventricular septum which results inobstruction of flow through left ventricular
outflow tract. Aggravated by agents that tmyocardialcontractility & relievedby -ve inotropes.
-39-
Other antianginal agents
Trimetazidine:
• Metabolic drug that switches myocardial metabolism from FFAoxidation

(needs more O2) to glucose metabolism (needs less O2) —>l 02 demand.
• Given in combination with other antianginal drugs.
Precautions
1. Reduce dose by 50% in renal impairment.

2. Contraindicated in parkinsonism.
Ivabradine:
• Selectively inhibits the pacemaker If current —*|cardiac pacemaker

activity, slowing the heart rate and allowing more time for blood to flow to
the myocardium.
Indications
1. Ischemic heart disease.
2. Systolic heart failure.

Precautions
1. Contraindicated with CCBs(inhibits metabolism of CCBs).

2. Used cautiously with (3Bs.
Ranolazine:
• Inhibits late phase of Na current (late INa) ->i Na+ & Ca** overload,
improving diastolic function & improving oxygen supply & demand
balance.
• Used in chronic angina(alone or in combination), if other drugs fail.

Side effects:
1. Prolongs QT interval.
2. Drug interactions (extensively metabolized in liverby CYP3A4 ).
-40
Nitrates Dilatation of
Large
Epicardial Coronaries
-Vasodilatation pB
of col laterals | Coronary filling
-Redistribulion &
Redistribution of blood
of blood (low to
flow to subendocardial
subendocardia
ischemic areas
ischemic areas
vessels
I va bra dine PBs

Inhibits
CCB
pacemaker If
current —»HIR
iHR &Contractility
Nitrates
Venodilation BBs
•I Venous CCB
Return
Nitrates
i
, l
± Afterload
^Preload
Summary of Effects of Anti-anginal Drugs on O2 Supply & Demand
-41 -
Management of Ischemic Heart Disease
I. Life style modification for control of risk factors
• Stop smoking & alcohol intake.

• Reduce obesity- Diet: i saturated fat and cholesterol.
•••• Control hypertension, diabetes,...
II. Drugs decreasing atherosclerosis & risk of myocardial infarction:
• Antiplatelets (e.g. aspirin, clopidogrel).

• Hypolipidemic agents (e.g. statins).
• Angiotensin converting enzyme inhibitors.
III. Anti-anginal drugs (therapy aims to ^myocardial 02 demand)

• Acute anginal attack:
Nitroglycerin - isosorbide dinitrate (sublingual). If monotherapy
• Maintenance therapy for chronic angina

with P Bs is
unsatisfactory
- p Blockers (1st choice).
- Long-acting nitrates if needed (isosorbide mononitrate) -» switch to
- CCBs: alternatives if pBs are CI (e.g. in.asthmatics). another group

- Others: Trimetazidine- Ivabradine ', or combine 2-3
anti-anginal
N.B.:' CCBs are 1st choice in vasospastic angina
drugs.
as they relieve coronary spasm while pBs are
contraindicated as they may induce coronary spasm
IV, Management of acute coronary syndrome (aims to ^myocardial blood flow;)

• Antiplatelets: aspirin, clopidogrelTH^, incidence of thrombosis. i
• Anticoagulants: IV heparin orSC low-molecular weight heparin. |
• Antianginal drugs: nitroglycerin- p*Bs (J. risk of myocardial infarction).
• Angiotensin converting enzyme inhibitors.
• Statins (aggressive dose).
• Fibrinolytics; within first 6 hours of myocardial infarction.
V. Revascularization & angioplasty (except invasospastic angina).
-42-
|DRUG THERAPY OF HEART FAILURE

Definition of systolic heart failure
• Systolic heart failure (HF) is a condition in which the heart is unable to pump
an adequate supply of blood for the metabolic needs of the body at normal
ventricular filling pressures provided that there is an adequate venous return.
Types of Heart failure:
• Depending on the time course of HF: Acute (AHF) & chronic (CHF) heart failure.
• Depending on the level of COP: Low andhigh18 COP failure.
Clinical features of low COP failure
• If preload is markedly f "^ patient complains mainly from congestive

manifestations e.g. leg edema, congested tender liver (for Rt side HF) or
cough, hemoptysis, dyspnea up to pulmonary edema (for Lt side HF).
• If afterload is markedly f "^ patient complains mainly from low cardiac

output manifestations e.g. dyspnea 217 to pulmonary oligemia (in Rt side HF)
or dizziness, fatigue, cold hands, oliguria, cyanosis, syncope (in Lt side HF).
Pathophysiology of Heart Failure
• The heart receives blood returning from body organs (preload) in diastole to
eject it against peripheral resistance (afterload) in systole. HF results from
severely impaired contractility or marked t in one orboth cardiac loads19.
• Systolic ventricular dysfunction is characterized by:
i. ^Stroke volume (SV) & a concomitant increase in end diastolic volume
(EDV) -> j ejection fraction (SV/ EDV).
ii. |End diastolic pressure (EDP) in left ventricle—• fpulmonary venous &
capillary pressure —*• pulmonary congestion, dyspnea & pulmonary edema.
• Before this stage of HF, the body develops compensatory mechanisms to
maintain cardiac output. However these mechanisms eventually fail.
18 In anemia, thyrotoxicosis, or A-V fistula withno cardiac abnormality; treat underlying causes.
19 Dueto a l,y insult to themyocardium e.g., infarction, t hemodynamic loador inflammation.
43-
Neurohumoral compensatory mechanisms in HF
• Inability of the heart to maintain a normal BP & organ perfusion —* reflex

stimulation of baroreceptors—• activation of the adrenergic & renin-angiotensin
systems —• peripheral VC, taldosterone with salt & water retention, | heart rate
& left ventricular hypertrophy —^compensated HF.
• Persistent activation of the adrenergic & renin-angiotensin systems —• marked
T in preload & afterload on the already impaired cardiac muscle —• ventricular
dilation & f 02 consumption with fixed 02 supply —> damage of cardiac
myocytes—> more f EDV & EDP with more J,COP —• decompensated HF
Management of Heart Failure
I. II. III. IV.
i Preload 1 Afterload TContractilitv Protect Heart
Improve Improve Improve low &/or restore its
congestion low COP COP& function
congestion
Lines • Physical/ mental
• Salt & Fluid • Positive • p-blockers
of restriction. rest. inotropics. • Aldosterone
• Diuretics. • Arteriodilators antagonists
Treatment
• Venodilators
For • Loop diuretics • Digoxin
• ACEIs • P-blockers
Drugs CHF • ACEIs. • ARBs. Carvedilol
Used • ARBs. • Hydralazine Bisoprolol

• Nitrates Metoprolol
• Spironolactone
• Eplerenone
For • Loop diuretics • Nitroprusside • Dopamine.
AHF • Nitrates. • Dobutamine.
• Nitroprusside • Inamrinone.
N.B.: - ACEIs, ARBs & nitroprusside are mixed arteriovenodilators.

- Mortality rate in HF (30% per year) is j by ACEIs, ARBs, PBs &spironolactone.
-44-
Other Agents used in heart failure
1. Sacubitril-valsartan
• Combination of the ARB "valsartan" & "sacubitril" an inhibitor of
neprilysin enzyme that degrades atrial natriuretic peptide "ANP —•f ANP
—> Na excretion, diuresis, vasodilation. ANP also inhibits RAS.
• Used instead of ACEI or ARB in patients with class II - rv heart failure
with LVEF <40 %, with persistent symptoms despite optimal combination
therapy. Some clinicians use it from the start toJ. Mortality & morbidity.
2. Tolvaptam
• ADH antagonist (vasopressin, V2 receptor antagonist). Used in systolic
heart failure -* excretion of electrolyte-free water —• corrects dilutional
hyponatremia, secondary to increase ADH in heart failure1.
NJB.: N-3 polyunsaturated fatty acids can reduce mortality in CHF.
Order of therapy in CHF
1. Loop diuretics are introduced 1st for patients with congestive manifestations.
2. ACEIs —•during or after stabilization on diuretics. If not tolerated give ARBs.
3. Beta blockers (start with low dose) —• in patient stable on ACEIs or ARBs.
4. Mineralocorticoid receptor antagonists (MRAs):2 Ifstill symptomatic.
5. Sacubitril-valsartan: instead of ACEIs or ARB, if still symptomatic.
6. Ivabradine: added If HR > 70
7. Reduce dose of diuretic: If symptoms improved.

8. Digoxin or hydralazine + isosorbide dinitrate (fixed dose tablet): If not improved.
N.B.:
- ACEIs, beta blockers &MRAs should be increased to maximum tolerated dose.

- Heart lung transplantation if no improvement.
1Dilutional hyponatremia inheart failure results in resistance to loop diuretics

2Mineralocorticoid receptor antagonists for symptomatic patients with LVEF <35 % (with
adequate renal function & normal K level). Also recommended for patients who are post-ST
elevation myocardial infarction with an LVEF <40 %, who are already receiving ACE
inhibitor, andhave either symptomatic HF or diabetes. Therapy is limitedto patients with
baseline serum potassium <5.0 mEq/L &glomerular filtration rate >50 mL/min per 1.73 m2
-45-
Baroreceptor Reflex: J.COP &

BP—^Sympathetic Activation
Venular Arteriolar
VD VD
VC
| Preload | Afterload
."7 "F
Renin
Diuretics
,T
6Bs
Na+ retention » Protect
t Blood heart &
volume restore its
function
ACEIs
Aldosterone ^_
Ag-II Ag-I
V
Spironolactone ARBs
Eplerenone
Sacubitril-valsartan
Pathophysiology & Drug Therapy of Heart Failure
-46-
Individual Drugs Used in Heart Failure
I. VASODILATORS
VENODILATORS ARTERIODILATORS MIXED DILATORS
Nitrates 1. Sodium nitroprusside
• i Venous return • | Peripheral resistance & • In Acute HF.
&[ preload —> i afterload -*fCOP -> 2. AfTTJa

^systemic or improves symptoms of
• Best in CHF.
pulmonary low COP.
congestion —> 3. ARBs
improves • IfACEIs are not

congestive tolerated.
symptoms.
-47-
A. Angiotensin-Converting Enzyme Inhibitors

(ACEIs)
Mechanism of Action
• They inhibit the angiotensin converting enzyme, responsible for Angiotensin II

formation & bradykinin breakdown, resulting in:
• [ Angiotensin II.
• t Bradykinin —•fvasodilator PG & NO.
These effects lead to:
1. Vasodilatation of both arteries (T COP) & veins (I venous congestion).

2. Inhibition of aldosterone secretion —> Na+ & water loss with K+ retention.
3. Prevention of myocardial hypertrophy & remodeling following myocardial
infarction (with ACEIs that inhibit tissue ACE; e.g. fosinopril).
4. Block central & peripheral NE release induced by angiotensin II —> [ BP
without reflex tachycardia (blunt sympathetic reflexes).
Angiotensin I
ACEIs
(-)
Bradykinin Angiotensin II
(-) formation by
breakdown
by ACE
ACE
Angiotensin II
Kininasell
t Aldosterone Vasoconstriction Tne
\ © Cardiac & vascular
Salt& water retention Fibrosis- Myocytes Proliferation

K+ loss Remodeling
Formation & effects of Ag II & Sites of action of ACEIs & ARBs
-48
Advantages of ACEIs
• Improve exercise tolerance & congestive symptoms (Jpreload &

afterload) &| cardiovascular mortality in HF24.
• Renoprotective especially in diabetics.
• Do not induce reflex tachycardia, salt & water retention ... .etc
Indications:
1. Hypertension: see indications of ACEIs in hypertension.

2. Heart failure: all cases of LV dysfunction (early cases —>end stage HF).
3. Acute myocardial infarction
Used early in MI (in the first 24 hrs plus aspirin, fibrinolytics & PBs)25:
a. Inhibit aldosterone-induced remodeling & prevent heart failure
b. I sudden death (prevent arrhythmia 2iy to hypokalemia & sympathetic
overactivity).
4. Nephropathy: diabetic or nondiabetic.
Members of ACEIs;
•Cantopril: 1st ACEI, short acting (ty2 < 2 h) -> taken3 times/day (not a prodrug).
•Enalapril - Perindopril - Ramipril - Lisinopril - Fosinopril
• All (except lisinopril) are prodrugs requiring activation in liver.
• Long duration (given once/day) .
• Lisinopril may be given in jiver disease (no hepatic metabolism).
• Fosinopril is highly lipid soluble with dual elimination; hepatic & renal—>
no need for dose adjustment in renal disease. It may have a greater effect
on tissue ACE in the heart.
• Enalaprilat: active metabolite of enalapril. The only ACEI given IV—•

used in emergency.
24 Captopril was the first single drug observed to| cardiovascular mortality.
254 Mortality whengiven in pre-infarction period.
26 Long duration of action is due to long acting metabolites.
-49-
Side Effects of ACEIs
1
MOST COMMON MOST SERIOUS
Chronic dry cough Angioedema
• Late. • Early (but may occur later).
• (30% of patients). • Rare but fatal.
• Due to bradykinin • Due to bradykinin

accumulation. accumulation?
LESS COMMON SERIOUS
• 1st dose hypotension —• • Renal impairment (reversible):

start with low dose at
More common in high renin states:
evening.
a. Patients on diuretics—• [ diuretic dose
• Hyperkalemia:
or stop it 24 h before ACEIs.
- Especially if given
b. Bilateral renal artery stenosis -»CI
with K+- sparing
(since GFR is maintained by VC of
diuretics, PBs or in
efferentarterioleby Agll).
renal impairment.
• Bone marrow depression.
• Hypersensitivity:
- Rash & pruritis. • Fetotoxic: if given in last trimester.
• GIT: • Teratogenic if given in 1st trimester.

- Anorexia- vomiting.
- Taste disturbance.
- Diarrhea.
-50-
B. Angiotensin 11 Receptor Blockers

(ARBs)
Members:
• Old: Valsartan - Losartan.27

• New: Candesartan - Irbesartan - Eprosartan -Telmisartan.
• Block AJi receptor which mediates most of the pathological cardiovascular

effects of Ag II.
• Spare AT? receptor —> vasodilation & anti-proliferative effects.
Side effects (well tolerated):

1. Hyperkalemia.
2. Taste disturbance.
3. Angioedema.
4. Unsafe on fetus.
5. Acute renal failure (in renovascular hypertension or in hypovolemia).
Disadvantages compared to ACEIs
• Lack of vasodilator effects of BK.
Advantages over ACEIs
• No BK production—> no cough (angioedema still occurs).

• Antagonize Ag II formed by ACE &non-ACE pathways28.
• Avoid hormonal "escape" (t renin) seen with prolonged ACEIs therapy.
• t Activity of Agll at AT2 receptor->tVD & antiproliferative effects.
ARBs are alternatives to ACEIs if the latter are not tolerated.
27 Losartan is preferred in hypertension with stroke.

28 In heart, kidney & blood vessels, Ag IImaybe formed by enzymes other than ACE, e.g., chymasc.
-51-
C. Hydralazine
Mechanism of Action
• Arteriolar vasodilator: K+ channel opener —> hyperpolarization —* inhibition

of Ca2+ influx into vessel wall.
Disadvantage: chronic use —»• rapid tolerance due to reflex activation of
sympathetic & renin-angiotensin systems —• salt retention & f HR.
Indications
• Heart failure: given with nitrates, but ACEIs largely replaced it (as it
induces lupus syndrome in slow acetylators).
• Hypertension: IV in eclampsia.
D. Sodium Nitroprusside
Mechanism of Action
• Nitric oxide donor —>f c- GMP which induces vasodilation by inhibiting Ca2+
influx into the wall of blood vessels.
Indications: verypotent& rapidly acting, thus used in—*

1. Most hypertensive emergencies e.g. hypertensive encephalopathy.
2. Severe acute heart failure, especially with severe rise of BP.
Toxicity
1. Severe hypotension and myocardial ischemia (due to reflex tachycardia).

2. Cyanide29 &thiocyanate toxicity: CNS side effects &delayed hypothyroidism
Precautions
•Given byslow IV infusion (immediate onset with t m2 min).

• Solution is freshly prepared insaline.covered with opaque foil (sensitive to light).
•Frequent monitoring of BP (avoid drop of BP below 95 / 70 mmHg).
•Avoid prolonged administration to J, cyanide &thiocyanate toxicity.
29 Nitroprusside metabolism releases free cyanide ion —• converted to thiocynate &excreted in urine.
Cyanide toxicity istreated bysodium nitrite, sodium thiosulphate, hydroxycobalamin &methylene blue.
-52-
II. Diuretics
Mechanism of Action
• Diuretics are given for fluid control in cases with symptomatic HF & fluid
retention —• iplasma volume —> Jvenous return & preload —• J,pulmonary
congestion (J,orthopnea & nocturnal dyspnea) - J. peripheral (ankle) edema.
Preparations
• Loop Diuretics: 1st choice especially in refractory or pulmonary edema (IVI).

• Thiazides: may be added in refractoriness to loop diuretics.
• Spironolactone: added30 to loop diuretics & ACEIs—•I mortality by 30%,
by antagonizing systemic & local effects of excess aldosterone resulting in:
a. i Na+ retention and worsening of edema.
b. Minimize diuretic- induced hypokalemia -+| arrhythmia & sudden death.
c. I Myocardial hypertrophy & fibrosis induced by local aldosterone.
III. Beta Blockers
• Carvedilol, bisoprolol & metoprolol decrease mortality by 30% when added to

ACEIs &diuretics in hemodynamically stable patients31.
• Block the Sympathetic and Renin angiotensin system activation in HF.
Beneficial effects in HF
1.1 HR —> 1 coronary flow.

2. | Afterload and J. 02 demand.
3. Cardioprotection: block catecholamine & Ag II - induced arrhythmia,
myocardial damage & apoptosis.
4. Improve LV remodeling.
5. Resensitize the dowmegulated pi receptors (in long standing HF) -> improve
cardiac contractility.
30 Cautiously, to avoid hyperkalemia especially if ACEIs arc used or inpatients with renal impairment.
Jl Transient worsening in cardiac function mayoccur —> start with lowdose & gradually titrate to
more tolerable doses.
-53-
IV. Positive Inotropic Drugs

1. Cardiac Glycosides
Digitalis (Digoxin)
Mechanism of Myocardial Contraction
• Myocardial contraction occurs after influx ofCa2+ through specific channels:

1. Voltage-gated Ca2+ channel which is activated by membrane
depolarization.
2. Ligand-gated Ca2+channel which is activated by prreceptor stimulation.
• Ca2+ influx -> | intracellular Ca2+ -> Ca2+ release from SR -* f cytosolic Ca2+
—• t myocardial contraction by binding with relaxant protein troponin C.
• Cardiac relaxation occurs after cytosolic Ca2+ is reduced by reuptake ofCa2+
into the sarcoplasmic reticulum &Ca2+ exit in exchange with Na+ via the Na+ -
Ca exchange (Ca pump).
• Na+ is then pumped out in exchange with K+ by Na+/K+ ATPase.
Ca
2+
Pi Agonist
Ligand- (Dobutamine-
channels
Voltage-gated gated Dopamine)
$ /**=
Depolarization Ca
2+
Naâ** exchange / q&

l«n v pump
arcoplasmic reticulum
Na+
Na -K exchange
2+
Ca
Ca2* binds with relaxant protein (troponin C)

Digitalis J)
—• muscle contraction.
-54-
Molecular mechanism of action of digitalis (Na+ pump inhibition)

• Digitalis inhibits membrane-bound Na+/K+ activated ATPase responsible for
Na+ outflux in exchange with K+ influx -»• t intracellular Na+.
• t Intracellular Na+ ->inhibits outflux ofcytosolic Ca2+ in exchange with Na+
influx —• t cytosolic Ca .
• f intracellular Na+ & cytosolic Ca2+-» T activity of excitable tissues in
cardiac & smooth muscle & neurons (CNS) leadingto the following effects:
1. Positive Inotropic Effect
• f Cytosolic Ca2+ in myocardium -• inhibits troponin C (relaxant protein) -»

t myocardial contractility —• t COP in HF —*• maintains organ perfusion &
BP & | baroreflex stimulation of adrenergic & renin- angiotensin systems.
Consequences of positive inotropic effect
a. X Venous Pressure:
• Due to t COP with better cardiac emptying & subsequent filling; |
overstretching of the heart.
b. i Baroreflex sympathetic over-activitv:
• | Peripheral resistance & cardiac loads.
• I Cardiac over-stimulation (J, HR).
• I Renin (| Na+ retention & edema).
c. Diuresis:
• Due to T COP ->Trenal blood flow & GFR (plus a direct anti-
aldosterone action -> inhibition of Na+/K+ exchange in distal tubules).
2. Electrical effects:
• flntracellular Na+ & Ca^ -> shifts membrane potential towards firing
threshold at the end of action potential (AP) -*• delayed after-depolarization
(DAD) —»ventricular premature beats, tachycardia or fibrillation.
• Activates K+ channels -»• rapidly ends AP -*• 4 atrial APD &ERP -»• converts
atrial flutter to atrial fibrillation (AF) & paroxysmal AF to permanentAF.
-55
3. Autonomic effects
A. Vagal stimulation (attherapeutic dose)32

• Inhibits SAN ->J, HR (indicator for optimal digitalization).
• AVN block & T ERP->
- Bradycardia, heart block (treated by atropine).
- Protects ventricle from rapid atrial rate in atrial flutter and AF.
- Terminates attack of PSVT by interrupting AVN re-entry.
B. Sympathetic stimulation (at toxic dose) -*arrythmogenic potential.
4. CNS stimulation
• Vagal center stimulation (therapeutic doses).

• Vomiting; CTZ stimulation33 (supratherapeutic doses)
Visual & cortical stimulation—^visual disturbances, hallucinations (toxic dose).
5. Direct Vasoconstriction: f Ca2+ in vessel wall (offset by J, sympathetic

activity).
Pharmacokinetics
Variable between patients & in same patient with different preparations. Roughly:
• %of oral dose is rapidly absorbed; rest is inactivated by intestinal flora.
• %of drug is unbound to plasma proteins (wide tissue distribution —• CNS).
• %is excreted unchanged renally &rest by stool & hepatically •> tVl 36 hrs.
• Narrow safety margin: therapeutic level (0.5-1.5) close to toxic (>2 ng/ml).
Dosing of digoxin (Digitalization):

• To achieve therapeutic blood levels & to avoid toxicity: low dose 0.125-
0.25 mg/d (Css is reached in one week).
32
Due to central vagal stimulation, baroreceptors sensitization, t muscarinic transmission.
It also induces local GIT irritation.
-56-
Drug Interactions with Digoxin
I. Pharmacokinetic Interactions34
1. Erythromycin —•! inactivation of digitalis by killing GITflora-*fabsorption.
2. Antiarrhythmics (quinidine, amiodarone & verapamil) -*i renal excretion
of digoxin & displace it from tissue binding sites & from plasma proteins.
II. Pharmacodynamic Interactions
3S ^ t Digitalis - induced
1. Diuretics (—• hypokalemia & hypomagnesemia").
I Tachyarrhythmias
2. Hypercalcemia.
3. Sympathomimetics.
4. P Blockers & CCBs: inhibit SAN & AV node -> complete heart block.
Indications for Digitalis
l.CHF:
a. Symptomatic HF despitetherapy with diuretics & ACEIs.

b. HF plus AF (most solid indication): positive inotropic ->t COP in HF &
blocks AVN—» controls ventricular rate in AF.
2. Chronic AF without HF:
a. Plus verapamil or p B to control ventricular rate.

b. Before procainamide & quinidine to counteract their atropine-like action.
3. Paroxysmal supraventricular tachycardia: vagal effect onAVN ends attack.
Contraindications
1. AcuteMI & rheumatic carditis (irritable myocardium -* arrhythmia).

2. HOCM: inotropic ->t outflow tract obstruction.
3. Sick sinus syndrome -» converted to cardiac arrest (vagal effect).
4. AF+WPW: paradoxicalt HR (blocks AVN ->t conduction in accessory tract).
5. Partial/ incomplete heart block ->converted to complete heart block (vagal effect).
6. Ventricular tachycardia —» precipitates ventricular fibrillation.
34 Metoclopramide -• t GIT motility -âbsorption.. Anticholinergics ->i GIT motility -âbsorption.

35 Digitalis competes with K+ for its site on Na+/K+ ATPase. Mg2* opposes Ca +.
-57-
Digitalis Toxicity (GCCG)

1. GIT Upsets: anorexia, nausea, vomiting and diarrhea (early symptoms).
2. Cardiac Arrhythmia:
a. Supraventricular & ventricular; premature beats, tachycardia or fibrillation.
b. Sinus bradycardia and heart block (t vagal tone).
3. CNS manifestations: confusion, hallucination, yellow & green colored vision.
4. Gynecomastia (steroid nucleus).
Treatment of Toxicity
1. Stop digitalis & the K losing diuretic.

2. KC1: if serum potassium is < 3.5 mmol/1; C.I. in heart block36.
3. Lidocaine orphenytoin inV. arrhythmia (—• do not impair AV conduction)37.
4. Atropine in bradycardia and heart block (pacing is used if no response).
5. Digibind (fab): antibodies thatbinddigoxin —»eliminated in urine (infatal toxicity).
2. Dopamine
• t Renal blood flow (low dose-> D! renal vasodilation).

• TCOP (intermediate dose -• Pj cardiac stimulant).
• t BP with VC (high dose-> a( vasoconstriction).
Indications
• Acute HF & cardiogenic shock e.g. after MI or surgery especially if there is

renal involvement (-• renal VD) or hypotension (->t BP).
• Chronic refractory heart failure.
3. Dobutamine
• Positive inotrope (pi), minimal effect on HR & BP.

• Uses are similar to DA but used in normotensives (no a-effect) with
preserved renal function (no renal vasodilation).
36
Other contraindication: hyperkalemia or renal impairment.
37 Cardioversion (DC): may worsen digitalis arrhythmia thus reserved for ventricular fibrillation.
-58-
4. Phosphodiesterase III Inhibitors
Milrinone - Inamrinone
Mechanism:
• Inodilators, inhibit phosphodiesterase HI->| cAMP breakdown:

1.1 cardiac contractility —> |COP.
2. Vasodilation -»• arterial (J, afterload & PR), venous dilators (Jpreload &
pulmonary congestion) -* I left & right cardiac filling pressures.
Indications:
• Short term treatment of HF especially, acute or chronic refractory.
Adverse Effects:
• GIT upset.
• Thrombocytopenia - arrhythmia.
Acute De-compensated Heart Failure (ADHF)
A. Initial theranv includes the following:

• Supplemental 02: for ADHF with decreased 02 saturation.
• TV loop diuretic38: for ADHF + pulmonary edema (except in severe
hypotension or cardiogenic shock).
• Vasodilators: e.g. IV nitroglycerin (in non hypotensives). Nitroprusside
on
may be used if significant afterload reduction is needed .

• Morphine: in patients with MI (avoid in ADHF without acute MI40)
B. Positive inotrones41 : dobutamine or milrinone.
C. Venous thromboembolism prophylaxis: in hospitalized patients.
38IV bolus dosing, if inadequate, give continuous infusion of loop diuretic & add a thiazide.
39 Hypertensive emergency, acule aortic ormitral regurgitation.
40 Limited evidence of benefit & increased need for ventilatory support.
41 In systolic HF (e.g. documented low ejection fraction) severe ADHF, hypotension orshock. Severe
cases require mechanical cardiac assistance & ultrafiltration if refractory to diuretics.
-59-
IDRUG THERAPY OF SHOCK]

Shock occurs when the circulation of arterial blood is inadequate to meet the
tissue metabolic needs (diminished tissue perfusion).
Types
1. Hypovolemic shock: intravascular volume is depleted due to

• Hemorrhagic shock (loss of blood).
• Bums (loss of plasma).
• Vomiting, diarrhea or excessive sweating (loss of fluids & electrolytes).
2. Cardiogenic shock: mostly due to acute myocardial infarction.
3. Distributive shock: J. systemic vascular resistance as in:
• Septic shock.
• Anaphylactic.
• Neurogenic: during spinal anesthesia & psychic trauma.
Hemodynamic profiles of the types of shock
Physiologic Pump Tissue

Preload Afterload
variable function perfusion
Pulmonary Systemic Mixed
Clinical Cardiac
capillary wedge vascular venous 02
measurement output
pressure resistance saturation
Hypovolemic 1 i T i
Cardiogenic t i T i
Distributive J,or<-» t i t
N.B.: Obstructive shock: a subtype where there is obstruction of a main channel

ofblood flow, e.g. massive pulmonary embolism, dissecting aortic aneurysm.
-60-
Management of different types of shock
A. Hypovolemic shock:
1. Rapid volume repletion: delayed therapy can lead to ischemic injury &
to irreversible shock and multi-organ system failure:
• Atleast 1-2 liters of isotonic saline42 to restore tissue perfusion are
initially given rapidly & continued at rapid rate if BP remains low.
• Patients with non-hemorrhaeic shock: isotonic crystalloid solution
rather thana hyperoncotic starch or albumin-containing solution.
• Patients with hemorrhagic shock: Red blood cell transfusions.
N.B.: efficacyof IV bicarbonate in patients with marked
hypoperfusion who develop lactic acidosis is uncertain.
B. Septic shock43
1. Secure airway and correct hypoxemia.
2. Restoration of tissue perfusion
• Intravascular volume repletion: boluses of IV fluids: crystalloid
solution ratherthan a hyperoncotic starch solution or albumin.
• Vasopressors: if patient remains hypotensive: norepinephrine is preferred.
• Inotropic therapy or blood transfusions: For patients whose
Scv02 remains <70 % after intravenous fluid and vasopressortherapy.
3. Identification and treatment of the site of infection
• Antibiotics after appropriate cultures.

• Empiric broad spectrum antibiotics if source of infection is unidentified.
• Abscesses should be drained & extensive soft tissue infections excised.
4. Glucocorticoids.
5. Nutritional support and glucose control.
42 For large volume lactated-Ringers solution or0.45% saline solution with 75 mmol/L ofsodium
bicarbonate may beused instead of isotonic saline toavoid hyperchloremic metabolic acidosis.
43 Syndrome ofsystemic inflammation &widespread tissue injury due to infection. Ranges from mild
sepsis to septic shock. Termed systemic inflammatory response syndrome in absence ofinfection.
-61-
C. Cardiogenic shock: (mostly 2^ to MI, 50% mortality)

1. Ventilation support to correct hypoxemia and, in part, acidosis
2. Early Aspirin + heparin
3. Sympathomimetic inotropes (e.g. DA, dobutamine (in normotensives).
4. Norepinephrine (for refractory hypotension).
5. Reperfusion should be attempted in all patients:
• Revascularization is the best for all patients (PCI or CABAG).
• Fibrinolytics for ST elevated MI if revascularization is not feasible.
6. Antiplatelets: in addition to earlyaspirin, a thienopyridine e.g. clopidogrel
& a GP Ilb/nia e.g. eptafibatide may be added for highrisk patients.
7. Withhold beta blockers & calcium channel blockers.
D. Anaphylactic shock44:
1. Epinephrine: (1st &most important) IM4S or IV ifnot responding.
2. Airway: intubation if signs of impending obstruction from angioedema.
3. Place patient in recumbent position, and elevate lower extremities.
4. Oxygen: via facemask, or up to 100percentoxygenas needed.
5. Normal saline: for hypotension, rapid IV infusion of 1 to 2 litres46.
Additional Drugs
• Salbutamol: For bronchospasm resistant to IM epinephrine.

• Hi antihistamine: IV diphenhydramine for reliefof urticaria & itching.
• H2 antihistamine: IV ranitidine.
• Glucocorticoid: Consider giving methylprednisolone 125 mg IV.
Treatment of refractory symptoms:
• Epinephrine TV!47: ifinadequate response to IM epinephrine &IV saline.

• Vasopressors48: in addition to epinephrine.
• Glucagon TV: Patients on beta-blockers may not respond to epinephrine.
Anaphylaxis: serious allergic reaction, rapid onset & fatal cardiorespiratory arrest.
45 Epinephrine (1 mg/mL preparation): Give 0.3 to 0.5 mg IM, can repeat every 5to 15 min.
Repeat as needed; massive fluid shifts with severe loss of intravascular volume can occur.
47 Epinephrine 2to 10 ug/ minute by infusion pump titrated according to BP, HR &02.
48 Vaspressors are given byinfusion pump titrated according to BP, HR &02.
-62-
IhypertensionI
Definition:
• Hypertension is an abnormal sustained rise in arterial blood pressure "ABP"

(optimal level: < 120/80 mmHg).
• Stages (according to systolic BP/ diastolic BP)49:
• Stage 1 (mild): 140/90 -> 160/100
• Stage 2 (moderate): 160/100-• 180/110
• Stage 3 (severe): >180/110
Hypertensive encephalopathy: acute severe rise of ABP that may result in serious
complications e.g. cerebralhaemorrhage —• emergency, requiring aggressive therapy.
Aetiology:
• Essential hypertension: is due to unknown cause50 —> drug therapy is not

curative but is life long.
• Secondary hypertension: is due to known causes e.g. renal, endocrinal,

drugs... etc —> treatment ofthe cause can be curative.
Drug-induced hypertension
1. Oestrogen/ Contraceptives. 4. Glucocorticoids.

2. NSAIDs. 5. Liquorice & its derivatives.
3. Sympathomimetics (e.g., in OTC cold medicine).
Why treat hypertension?
• Hypertension is a silent killer as it induces vascular damage -> affects heart,

brain & kidneys (—>target organ damage, heart failure, ischemic heart disease,
stroke & renal failure) & retinal artery -> blindness.
• Treatment is not symptomatic but hypertension shouldbe always treatedeven if it
is silent to prevent or reversetarget organ damage.
49 Isolated systolic hypertension: If SBP is> 140 mmHg while the DBP is <90.
50 However, there isexaggerated vascular muscle tone that can in part explain the Tin the ABP.
-63
Treatment Strategy
I. Evaluation: The patient should beevaluated for presence of:

• Correctable aetiology (e.g. ifhypertension is drug- induced —»• stop drug).
• Major risk factors that can t TOD e.g. smoking, hyperlipidaemia, diabetes.
•TOD: e.g. hypertensive kidney diseases or clinical cardiovascular disease
(CCD) e.g., ischemic heart diseases.
II. Life style modification •Life style modification alone is

• Stop smoking. enough in mild cases with no
• Regular exercise. TOD, diabetes or CCD but if
• Weight reduction. hypertension is beyondmild
• Restrict salt-TK+. stage or if there is diabetes,
• I Saturated fat & cholesterol. CCD or TOD-> initiate drug
therapy.
HI. Drug Therapy;
Choice of drugs51 is based on:

1. Age, sex and race (black patients respond better to thiazides or CCBs &
relatively poorlyto ACEIs or PBs (low renin level).
2. Concomitant diseases e.g. diabetes, bronchial asthma, etc.
3. Concomitantly administered drugs (to avoid drug interactions).
4. Effect of drugs on quality of life.
5. Drug cost & duration of action (long acting preparations -* t compliance).
6. Bedtime versus morning dosing:
Average nocturnal BP is 15% < daytime values (dip).
"Non-dipping," is a stronger predictor of adverse cardiovascular outcomes
than daytime BP.
• Shifting at least one antihypertensive medication from morning to evening
canrestore the normal nocturnal blood pressure dip.
Choice is not based on efficacy or degree ofCV protection except in the high risk patients in which
ACEIs or ARBs offer better CV protection since their cardioprotection is independent ofBP lowering.
-64-
Initial Monotherapy52:
Classes of drugs for initial monotherapy
• Thiazide diuretics (in low dose). • Long acting CCBs.

• ACEIs «ARBs.
Sequential monotherapy
• Sequential monotherapy allows 60 to 80% of patients with mild hypertension

to be initially controlled with a single agent.
• It is recommended in patients who can be initially treated with monotherapy
(i.e., BP < 20/10 mmHg above goal BP) and who do not respond well to a
moderate dose of antihypertensives. Strategy:
• Switch to drug 2 (rather than increasing dose of drug 1oradding a 2 drug).
• If this is ineffective, switch to drug 3.
Addition of a second drug:
•If sequential monotherapy is ineffective or unacceptable, use 2 ormore drugs.

• Eventually, more than one drug is needed inpatients initially controlled:
First-line Standard Combination Therapy in Hypertension
Long acting (DHP) CCBs + long acting ACE inhibitor or ARB.
Combination Therapy, recommended if BP is > 20/10 mmHg above goalS3:

• If patient is using long-acting (DHP) CCB or a long-acting ACE inhibitor or
ARB -> add the second one.
• In patients on a thiazide diuretic-^ discontinue the thiazide & start the

standard combination therapy above.
• Preferred 2nd drugs in patients on pBs: thiazides or a (DHP) CCB.
52
Other drugs (used in special situations): PBs without intrinsic sympathomimetic activity (e.g. in
ischemic heart diseases), a!-blockers (in prostatic obstruction), direct vasodilators e.g.
hydralazine (eclampsia), nitroprusside (hypertensive emergencies), a-methyldopa (pregnancy).
In non-obese already being treated with and doing well on combination of a thiazidediuretic
& long-acting ACEI, replace thiazidewith a long-acting DHP CCB. In obese, the
combination of a thiazide diuretic and a long-acting angiotensin inhibitor can be continued.
-65-
Management of Resistant Hypertension
Combined therapy
Single Fixed dose combination (ACEIs Or/ ARBs +CCD (DHP) +Thiazide
O
If uncontrolled
Normal kidney function

Abnormal kidney function
Normal serum K
Add mineralocorticoid antagonist Add alpha blocker plus beta blocker

carvedilol or metoprolol
Beneficial effects of drug combinations in hypertension
1. Additive combination theranv:

• ACEI + CCB (DHP or NON DHP).
• ARB+ CCB (DHP only) or PB + CCB(DHP).
NJJ.: in addition to the additive antihypertensive effect ofPBs &CCBs, pBs
also counteract the reflex tachycardia induced by CCBs.
2. Synergistic combination theranv
• Thiazides nlus pBs or thiazides plus ACEIs

• Thiazides synergize with most antihypertensives by decreasing volume expansion.
Other synergistic mechanisms include:
• Activation of renin-Ag system by thiazides potentiates pBs & ACEIs in obese,

black & elderly; with low renin (PBs & ACEIs work mainly in high renin states).
• Reduction in antihypertensive effect of diuretics, 2ry to their activation of
renin-Ag system, is counteracted by inhibitory effects of PBs, ACEIs or
ARBs on the renin-Ag system.
• ACEIs & ARBs neutralize metabolic effects of thiazides (PBs worsen them).
-66-
Central
Sympatholytics
Block P2 in
NTS
• f»
0:2
Methyl dopa
NTS
Reset
Inhibitory
Baroreceptors
impulses from
baroreceptors to
Suppress Renin -ve inotropic VMC
-ve chronotropic
Blood
Vessel
ACEIs & ARBs

|Blood
Inhibit
Volume
Renin -
angiotensin
system cii-Blockers
Diuretics Vasodilators
BP is controlled at 4 sites: heart, blood vessels, kidney (renin - angiotensin system)

& baroreceptors*. f BP above 120/80mmllg—+ f inhibitory impulses from
baroreceptors to VMC —* j sympathetic activity—* J.BP. In hypertension,
baroreceptors are set at a level of BP > 120/80mmHg. pBs reset the baroreceptors
Sites of Actions of Different Classes of Antihypertensive Drugs
• Baroreceptors arc continuously sending inhibitory impulses lo VMC. IfBP jbclow 120/80, fewer inhibitory
impulses arc scnl lo the VMC-> Tsympathctic activity —>f BP. IfBP f, the inhibitory impulses arc | to I BP.
-67-
I. Thiazides Diuretics
Mechanism of Action
• Initial hvnotensive response (within 1st week): mediated by diuretic action

-> J. plasma volume & cardiac output.
• Delayed hypotensive response (continues for at least 12 weeks): mediated

by vasodilatation 2** to J,Na level in blood vessel wall.
The initial hypovolemic response is essential for the delayed response*
Indications
• Thiazides are the best initial therapy for uncomplicated mild to moderate
essential hypertension (cheap & have proven efficacy). Other indications:
A. Compelling indications54: Hypertension with

• Diabetes.
• High risk for coronary heart disease.

B. Favorable indications:
• Elderly, obese & black (low renin).

• Hypertension with osteoporosis or recurrent renal stones 55 .
• Isolated systolic hypertension56.
Adverse effects in antihypertensive doses
1. Sulfonamide hypersensitivity (absolute contraindication).

2. Impotence (relative contraindication).
3. Sleep disturbances.
N.B.: metabolic side effects may occur if used in high dose.
* Volume depiction -^ 1 level of acentral digitalis-like hormone -> T Na+-K+ ATPase activity -^
Na' is pumped out of smooth muscles (despite partial return ofblood volumeto baseline level).
54 [ Mortality, CV complications & stroke.
55 Thiazides given for >2 years: i Risk of fracture hip as they I Ca^ excretion.
56 Do notI SBP by>20mmHg for fear of lowering theDBP -• t CV mortality.
-68-
Preparations
a. Low dose chlorthalidone 12.5-25 mg (& possibly indapamide):
• Longer acting thiazide analogue which isconsidered of choice .

b. Low dose hydrochlorothiazide; 6.25 - 25 mg/day
• Not associated with activation of the renin-angiotensin system -* more

effective than higher doses & even more effective than loop diuretics.
• Not associated with metabolic adverse effects.
c. Metolazone:
• More potent analogue useful in resistant hypertension 2,y to volume

expansion (e.g. renal impairment, high salt diet, long term use of
vasodilators).
Thiazides or loop diuretics?
• Thiazides are preferred in mild to moderate non complicated essential

hypertension but loop diuretics are needed in:
• Fluid overload due to heart failure or renal disease.
• Resistant hypertension (due to volume expansion)59.
57 It significantly reduced the risk of cardiovascular events and heart failure. It is superior in
controlling systolic blood pressure esp. nocturnal blood pressure.
58 Salt-sensitive hypertensives (with low renin level) as in elderly, black patients respond better
to diuretics than to ACEIs & p-blockers (which act on renin-angiotensin system).
59 Blood pressure above 140/90 mmHg in patients below age 60 and above 160/90 mmHg in
those over age 60, despite intake ofthree or more antihypertensive medications.
-69-
II. p-Adrenergic Blockers

Mechanism of Action
• By-blockade (mainly)
• Suppression of renin release (65%).

• Negative inotropic & chronotropic effects (15%).
• B 7-blockade
• Central sympatholytic effect (block &receptors in NTS ->JNE).

• Peripheral sympatholytic effect (block presynaptic p2 receptors ->J,NE).
• Resetting ofbaroreceptors.
• Some p-blockers are vasodilators.
Advantages & Disadvantages

• Protect against coronary heart disease & | CV mortality60.
• Do not protect against cerebrovascular events.
• Impair glucose tolerance & | risk of new onset diabetes
Preparations
• Any pB can beused except those with intrinsic sympathomimetic activity61.
• Vasodilator beta blockers are preferred e.g. carvedilol & nebivolol.
Indications (used less often for initial therapy in absence ofa specific indication)
A. Compelling indications: in hypertension with
•Coronary heart disease (angina pectoris or post MI).
• Systolic heart failure.
•Atrial flutter/ fibrillation (if rate control is desired).
B. Favorable indications:
•Hypertension with: hyperthyroidism (high COP), essential tremors, migraine.

•Peri-operative hypertension.
60 The observation that BBs after acute MI improved long-term survival raised the question of
whether similarcardioprotection exists in hypertensives without clinical coronary disease. Three
trials showed no benefit, one (metoprolol) showed benefit & one (atenolol) showed worsening.
61 Selectivity of BBs has noplace inchoice since it is lost atantihypertensive doses.
-70-
III. Angiotensin-Converting Enzyme Inhibitors
Mechanism:
• Peripheral vasodilatation 2* to I Ag-II and t BK.

• I Aldosterone secretion.
Indications:
A. Compelling indications: in hypertension with

ARBs are
• Systolic heart failure.
alternatives if
• IHD: high coronary disease risk & Post-MI.
ACEIs are not
• Diabetes mellitus.
tolerated.
• Proteinuric chronic renal failure.
B. Possible indications:
• Hypertension 2^ to unilateral renal artery stenosis.

• Hypertensive urgency.
N.B.: Aliskiren is a selective renin inhibitor, as effective as ACEIs or ARBs .
IV. Calcium Channel Blockers (CCBs)

Mechanism:
• Peripheral arterial vasodilatation and itotal peripheral resistance.

• Diuretic action (t renal blood flow).
• J, Aldosterone secretion (prevent fluid retention).
Indications: no absolute indications in hypertensive patients

CCBs are alternatives to other drugs in:
1. Isolated systolic hypertension —» alternative to thiazides.

2. Hypertension with migraine -* alternative to pBs.
3. Hypertension with IHD, orAF (rate control) -»• alternative to pBs.
4. Hypertension with asthma or peripheral vascular diseases (worsened by PBs).
62 Aliskiren should not be combined with ACEIs or ARBs. May induce, diarrhea, cough, angioedema
(less oftenthan ACEIs). Metabolized by CYP 3A4 —> manydrug interactions, CI in pregnancy.
-71-
Preparations
• Amlodipine (long acting).

• SR- preparations of short acting agents63.
Standard Combination Therapy in Hypertension
• Longacting (DHP) CCBs+ longactingACE inhibitor or ARB.
Other antihypertensives
I. Central Sympatholytics (see adrenergic system)

A. Methyldopa:
• c<2 agonist; antihypertensive especially in pregnancy.

B. Clonidine:
• 0C2 & imidazoline receptor agonist used in hypertensive urgencies.
II. Qti- selective blockers (prazosin - doxazosin)64(see adrenergic system)

• They are not 1st choice in any type ofhypertension as they induce postural
hypotension, tachycardia & fluid retention —> tolerance.
• Mainly used in essential hypertension with benign prostatic hypertrophy.
in. Direct vadodilators (see CHFl
• Hydralazine: used in eclampsia.

• Nitroprusside: used inhypertensive emergencies.
63 Long acting agents ofCCBs are used, since short acting agents —»t HR due to reflex sympathetic
stimulation -> myocardial ischemia& Tmortality.
Phentolamine &phenoxybenzamine arenonselective a blockers used in pheochromocytoma (not in
hypertension as they induce excessive reflex tachycardia-*t BP(tolerance toantihypertensive effect).
-72-
CHOICE OF ANTIHYPERTENSIVES
Recommended Drugs Drugs better to be avoided
Pregnancy • ct-methyldopa (of choice). • ACEIs -ARBs: teratogenic,

fetotoxic.
•Early • Labetalol.
• Diuretics -> I bloodvolume.
• Nifedipine (long acting)
•Labor (eclampsia) • Labetalol- Hydralazine.
Diabetes • Low dose thiazide. • PBs-> mask symptoms of
hypoglycaemia & delay
• ACEIs or ARBs: reno-
recovery.
protective, improve glucose
tolerance. • Full dose thiazides -> tglucose.
Asthma • CCBs: (relax bronchi). • BBs (especially, non-selective) ->

bronchospasm.
COPD • ACEIs (-+ cough) or ARBs.
• Thiazide diuretics.
Angina65 • pBs( of choice). • PBs in vasospastic angina.

• CCBs (favourable effect).
• ACEIs or ARBs.
Systolic • ACEIs (orARBs) - diuretics. • PBs in de-compensated HF.

HF • Spironolactone /eplerenone if • Verapamil or diltiazem
renal function is preserved).
• P blockers: for stablecases.
Chronic kidney • ACEIs or ARBs (if renal • ACEIs, ARBs &K+ sparing
disease function is preserved). diuretics in severe renal
impairment.
• Loop diuretics.
• CCBs.
PVD • CCBs. • PBs.
Isolated systolic • Thiazide diuretics.

hypertension
• CCBs.
Lactating women • Enalapril- captopril-benzapril. • Other ACEIs- ARBs.

• Metoprolol-atenolol- labetalol.
• Amlodipine.
• Methyldopa-nifedipine.
• Thiazides in large dose.
• Spironolactone- thiazides
65 ForpostMI: PBs - ACEIs (forsystolic dysfunction) - spironolactone (aldosterone antagonists).

-73-
HYPERTENSIVE CRISIS
Hypertensive Urgencies
• Severe | in BP (systolic > 220 mmHg and/or diastolic BP > 120 mmHg)
without TOD in relatively asymptomatic patient.
• It can be managed with oral drugs with relatively rapid onset of action66.
• Drugs used: frusemide, captopril, atenolol.
Hypertensive emergencies
• Severe | in BP (systolic > 220 mmHg and/or diastolic BP > 120 mmHg)
with acute progressive TOD & life threatening complications e.g.
hypertensive encephalopathy67. It requires IV drugs.
A. In most H. Emergencies
• Nitroprusside.
• Nicardipine (except acute heart failure).
• Labetalol (except acute heart failure).
• Fenoldopam (except in glaucoma).
B. In specific H. Emergencies
Nitroglycerine: in acute coronary syndrome.

Esmolol: in aortic dissection and perioperative hypertension.
Phentolamine: in excess CA (pheochromocytoma, clonidine
withdrawal...).
• Enalaprilat: in acute left ventricular failure.
66 In previously treated patients control BP byreinstitution ofdrug if patient is not adherent to

treatment or t dose if adherent to treatment. Restricting salt intake ±diuretic may be enough in
patientswith t Na+ intake.
Neurological signs: confusion, headache, visual disturbances, vomiting and convulsions.
-74-
DRUG THERAPY OF-ARRHYTHMIA
Types of cardiac tissue based on electrophysiological properties

I. Non-automatic tissue: Atria & Ventricles
• Non-automatic tissue cannot initiate an impulse but is excitable i.e. can
respond to an adequate impulse by generating an action potential.
II. Automatic tissue: SAN, AVN, Purkinje fibres
• Automatic tissuecan initiatean impulse which excitesthe rest of the heart.
Phases of cardiac action potential
I. Non-automatic Tissue
• During diastole, contractile tissue has a resting membrane potential^ - 90 mV

i.e. it is in a polarized state with inside of thecells -verelative to outside.
• Arrival of an impulse from automatic tissue depolarizes the membrane to -
70 mV which briefly opens Na+ channels. Entry of Na+ into cells elevates
the potential to +30 mV (phase 0).
• Phase 1 is due to K+ outflux. This is followed by a plateau (phase 2) due to
opening ofCa** channels when the potential exceeds -55 mV; influx ofCa++
is prolonged but is of small magnitude so that it is balanced by the already
existing K+ outflux. Finally, membrane is repolarized (phases 3) when Ca**
channels close due to unopposed outflux of K+.
Phase 1
+ 10mV Phase2, Ca**artm the cell,
lPBUltoi ofcontractton
Phase 0,Na+
enters the cell Phase3, R*
Depolanxation exits the ccD
Hepolanzttttos
90mV RestingPotential
Depolarization
-75
II. Automatic Tissue (SAN - AVN - Purkinje)

• During phase 4 (diastole), the membrane of automatic tissue undergoes
spontaneous diastolic depolarization due to an inward pacemaker current
(slow Ca** current in SAN/AVN or fast Na* current in Purkinje fibers)
which overcomes an outward decaying K* current.
• Phase 0 is triggered in Purkinje fibers when membrane potential reaches
threshold (-70 mV) as in non automatic fibers. However, phase 0 in SAN &
AVN is triggered at -55mV & is slower to rise (depends on slow Ca** influx).
• SAN has the greatest slope of diastolic depolarization —>fastest to reach
threshold, thus, it is the pacemaker from which the impulse is triggered &
propagates through the AVN to His bundle & Purkinje system to stimulate
all of the ventricular tissue, simultaneously.
Important Terms
APD: action potential duration - ERP: effective refractory period.

• During the APD, the heart is refractory since the depolarizing potential
during theAPD inactivates sodium68 & Ca**channels.
• The ERP is slightly longer than APD. It can be T by:
• TAPD e.g. K*-channel blockers.
• Blocking Na* & Ca** channels e.g. Na* channel blockers in Purkinje
fibers & CCBs & p-blockers in AVN.
68 Voltage-gated Na+ channel has an inner h-gate &outer m-gate. It exists in 3 states:
1. Activated: both h & m - gates areopen during phase 0 to initiate AP.
2. Inactivated: m-gateopen, h-gate closed during the rest ofthe AP; it cannotrespondto a stimulus
as h-gate is voltage independent.
3. Resting: inner h-gateopen & outer m-gate closed. It can respond to depolarization (-70
mv) as its m-gate is voltage-dependent.
-76
Phases of Cardiac Action Potential
Important Parameters & Their Significance

Slow Automatic Fast Automatic Non-automatic
SAN & AVN Purkinje Atrial & ventricular
Phase
Parameter & its

Resting potential
significance Slow diastolic depolarization
Mechanism
Phase 0 • Slow Ca** influx • Fast Na* influx • Fast Na* influx
Vmax-* Conductivity
Phase 2: Plateau • Absent • Balanceof inwardCa**& outward K*

APD -» ERP current
Phase 3 • Outward K+efflux
APD — ERP
Phase 4 • Slow diastolic • Slow diastolic • Restingpotential
• Slopeof phase 4 depolarization due depolarization due due to balance
to a pacemaker to a pacemaker between inward

t slope—•
Ca** current Na* current Na*& outward K*
enhanced
overcoming an overcoming an currents.
automaticity
outward K* outward K*
current current
N.B.: Phase 1 is dueto K* outflux or CI" influx (it is absent in SAN & AVN).
Vmax = maximum slope of phase 0: determines conduction velocity: drugs
decreasing Vmax delay conduction, e.g. Na*-channel blockers in Purkinje;
adenosine, CCBs & PBs in AVN.
-77
Mechanisms of Arrhythmia
I. Disturbance in impulse generation

1. Disturbed automaticity of automatic tissue:
• TSympathetic activity (anxiety, thyrotoxicosis) -» f Ca" influx
—> | slope of*diastolic depolarization—* sinus tachycardia
• t Vagal tone (digoxin toxicity) -> | K' outflux -> I slope of diastolic
depolarization —> sinus bradycardia.
2. Automaticity in non-automatic tissue [ectopic pacemaker; slow responses)

• Ischemia initiates abnormal ionic currents in non-automatic tissue.
II. Disturbance in impulse conduction: heart block - re-entry arrhythmia

Re-entry Arrhythmia:
• In a normal heart, impulses move in one direction & cannot return to

close a circuit. Impulses passing in opposite directions along 2 pathways
(I, II) are conducted at equal velocities —» meet, extinguish one another &
die out, never returning to the point of origin.
• Re-entry (circus movement) occurs if continuous circulation of an impulse
occurs (due to difference in conduction velocity or refractoriness between the
2 pathways, e.g. due to ischemia) allowing one impulse to re-enter point of
origin & re- excite heart -* paroxysmal arrhythmias whose rate depends on
the number of times the impulse passes through circuit before it dies out.
-78-
Examples of re-entry arrhythmias:
• Ventricular tachycardia, atrial flutter (AF), atrial fibrillation (AF).

• Paroxysmal supraventricular tachycardia (PSVT). PSVT is either:
a. AV nodal reentrant tachycardia (AVNRT): Re-entrant circuit is in AVN
• AVN is divided into a fast & a slow pathway. A premature beat finds fast pathway
refractory, passes in slow pathway (SP) to ventricles & passes retrogradely to atria
in fast pathway (FP) which by now has recovered from refractoriness.
b. Atrio-ventricular re-entrant tachycardia (AVRT): e.g., WPW syndrome

Re-entrant circuit is at atrio- ventricular junction with a slow pathway in AVN & a
fast accessory pathway (AP) connecting atria with ventricles. There are 2 types:
i. Orthodromic: atrial impulse passes in AVN & quickly re-enters atrium via AP.
ii. Antidromic; impulse created in the atrium. & travels down AP and pre-excites the
ventricles retrogradely & back to atria via AVN.
Accessory
Pathway
Antidromic AVRT
VYVVVVWW
-79-
Antiarrhythmic Drugs
Vaughan Williams classification
Class I: Na+-channel blockers69. All can be given
• Class la: procainamide, quinidine,, disopyramide orally except
• Class lb: lidocaine, phenytoin, mexiletine, tocainide, lidocaine- esmolol -
• Class Ic: propafenone, flecainide, encainide adenosine- ibutilide.
Class II: p-blockers.

Class III: K'-channel blockers70: amiodarone, sotalol, ibutilide.
Class IV: Ca^ channel blockers71: verapamil and diltiazem.
Non-classified: adenosine - digoxin - magnesium sulfate.
Class I Agents
Pharmacodynamic & Electrophysiological effects
Class la Class lb Class Ic
Procainamide Lidocaine Propafenone

1. Na* channel Blockade • Moderate • Rapid Dissociation • Slow dissociation
(on fast fibers): dissociation rate—* from normal -» marked
i. ^Vmax &delay conduction, moderate conduction tissue—* minimal

conduction block
ii. i phase 4slope block &1 effects on normal
&i automaticity.
-»|automaticity automaticity. conduction.
hit ERP/-APD This effectis modified by the effecton K-channels as follows
2. K+ channel effect • No effect on K+

• Block K+channel-> • TK+efflux-»
(on fast & slow fibers) -»~APD/TERP74
T apd/TTerp72 U APD>| ERP73
69 Na +channel blockade (in fast fibers) -»1) iV^,, & delayed conduction; if marked -♦ wide QRS duration. 2) i
Excitability &membrane stabilization 2ry to prolonged ERP (without t APD). 3)Suppress automaticity.
70 K+-channel blockade (in fast & slow fibers) -» prolong ERP & APD; if marked -» prolonged QT interval.
71Ca++ channel blockade (in slow fibers)-* 1) IV^ & delayed AVN conduction; if marked -» prolonged PR
interval. 2)Prolong ERP (without T APD). 3)Suppressed automaticity of SAN (i HR)
72 This is the sum of 2 effects: Na' channel blockade -> T ERP without affecting APD & K+ channel
blockade -»T ERP 2,y to t APD (very useful inatrial re-entry).
73 This is the sum of 2 effects: Weak Na+ channel blockade -» t ERP without affecting APD and T K+
conductance -» i ERP f to i APD (This mayworsen atrial re-entry).
74 Propafenone has additional Ca Channel blocking activity 2ry tobeta adrenoceptors blockade
80-
Class la Agents
Procainamide & Quinidine
• Pharmacodynamics (Class la; see before)

• Autonomic Effects
1. Antimuscarinic: paradoxical ventricular tachycardia in atrial flutter &

fibrillation->t AVN conduction (more with quinidine) -»• blocked by
adding digitalis, (3 Bs or verapamil.
2. Ganglion blockade with procainamide.
3. oc-blockade with quinidine
Therapeutic Uses
• Broad-Spectrum -»• ventricular & SV arrhythmias including WPWS.

N.B.: Procainamide has largely replaced quinidine due to the increased risk of
"Torsade de Pointes" & excessive antimuscarinic effects of quinidine.
Adverse Effects
1. Cardiotoxicity
• Hypotension (ganglion blockade with procainamide & oc-blockade with quinidine).
• Slowing of conduction & myocardial depression.
• "Torsade de Pointes" arrhythmia (f QT) —• syncope (more with quinidine).
2. Thromboembolism75 - thrombocytopenia.
3. Systemic lupus (with procainamide limits its long term use).
4. Cinchonism: tinnitus, loss of hearing, blurred vision (with quinidine).
5. GIT: diarrhea, nausea and vomiting.
Disopvramide (Class la)
• Broad spectrum, similar to procainamide & quindine with marked negative
inotropic (—»HF) & antimuscarinic effects —• glaucoma, urine retention.
75
Stagnation of bloodin atria in long standing AF (without heparin) —• thrombus formation &
showers of emboli onreturn to sinus rhythm & improvement of contractility.
-81-
Class lb Agents
I. Lidocaine (local anesthetic & anti-arrhythmic)

Pharmacodynamics: Class lb (see before)
• Lidocaine has minimal effects on normal tissue butselectively blocks
inactivated sodium channels in ischemic, depolarized tissue —> marked
conduction block &|automaticity.
Uses: Ventricular arrhythmias
• Selective on ischemic & depolarized tissues76 thus it is used in:
1. V. tachycardia in cardiac surgery or M. infarction (least cardiotoxic).
2. Digitalis-induced arrhythmia (does not f digoxin level —• safe).
N.B.: it is ineffective in atrial flutter & fibrillation (as it i ERP) & in

PSVT 77 as it has no effect on AVN conduction
Dosage (it is ineffective orally due to extensive lst-pass metabolism)

• IV bolus followed by maintenance infusion as it has very short tYi
Adverse Effects
1. Cardiac: it is the least cardiotoxic anti-arrhythmic drug, but still it may

precipitate cardiac arrest or worsen impaired conduction in diseased hearts.
2. CNS: perioral parasthesias, dizziness, tremors, convulsions.
II. Mexiletine & Tocainide (Class lb)
• They are lidocaine congeners with minimal 1st pass metabolism (so-called
oral lidocaine). Their toxicities limit their usefulness
III. Phenvtoin (Class lb)
• An antieplipetic drug that can be used in digitalis - induced arrhythmia.
76 Na* channels are deactivated -> outergateopen-» f lidocaine binding -» jeffect.

77 Dangerous ->1 ERP of atria & accessory pathway-»T rate of re-entrant tachycardia e.g.
PSVT, AF.
-82-
Class Ic Agents
Propafenone
Pharmacodynamics:
• Class Ic (see before).

• Beta blocking effect
Therapeutic uses
1. SV arrhythmias (AF; Af and PSVT)

2. Ventricular arrhythmias (resistant cases).
Adverse effects:
1. Arrhythmias - A-V block- heart failure.

2. Taste disturbances, constipation.
3. Bronchospasm.
4. Dizziness - blurred vision
Class II Agents
p-Adrenoceptor Blockers
Propranolol - Esmolol - Atenolol
Pharmacodynamics
Block p-adrenoceptors —> block intrinsic sympathetic activity in slow fibres:

• 4 SAN & AVN activity.
• I Phase 4 slope inpacemakers (slow automaticity).
Therapeutic uses: broad spectrum
1. Arrhythmias due to sympathetic overactivity: exercise, emotion, anesthesia,
thyrotoxicosis, pheochromocytoma.
2. Arrhythmias following myocardial infarction-*! mortality.
3. IV esmolol can be used for termination of PSVT.
•83
Class III Agents

A. Amiodarone
Pharmacodynamics: blocker ofK+, Na+ &Ca++ channels and p- blocker:

K+ channel blockade (main): delays repolarization ->fAPD &ERP in all
cardiac tissue &accessory tracts—• blocks reentry arrhythmia (PSVT, AF, Af).
Na+ channel blockade: suppresses ectopic pacemaker (J, phase 4slope) &
slows conduction (J, Vmax in fast fibres).
CCB -+ coronary & peripheral vasodilation, J. sinus rate & AVN conduction.
Therapeutic Uses:
Broad-Spectrum -»• ventricular & SV arrhythmias, including VVPWS.

Kinetics & Dosage (long t,/2; 35-103 days)
• Full effect isreached after a lag period of 1-3 weeks —• given as a loading
dose followed by maintenance dose (oral or IV)
• Displaces digoxin from plasma proteins —> jtoxicity.
Adverse Effects: Cumulative in most tissues
1. Cardiac: bradycardia, heart block, hypotension (less risk of Torsade de Pointes).

2. Corneal micro deposits (asymptomatic).
3. Hypo- or hyperthyroidism (heavily iodinated) Precautions
4. | Liver enzymes. • Chest x ray/ 3 months.

5. Pulmonary infiltrates & fibrosis. • Liver functions/ 6 months.
6. Peripheral neuropathy & myopathy.
• Thyroid functions/ 6 months.
7. Photosensitivity.
Dronedarone:
• Related to amiodarone but devoid of iodine —> minimal toxicity.

• Therapeutic uses: similar to amiodarone.
B. Sotalol
Action: nonselective p- blocker with class III antiarrhythmic effect.

Uses: ventricular arrhythmias - maintenance of rhythm in AF& Af.
Adverse Effects:! risk of "Torsade de Pointes"(limits use to serious airhythmias).
-84
Class IV Agents
Verapamil & Diltiazem
Pharmacodynamics:
Block Ca2t current in slow fibres

• i SAN & AVN activity.
• I Phase 4 slope in pacemakers (slow automaticity).
Uses: Supra ventricular arrhythmias
1. AF &Af: prevents transmission ofhigh atrial rate to ventricle (blocks AVN).
2. Termination of PSVT.
Side Effects
1. Paradoxical acceleration in AF associated with WPW syndrome -> blocks

conduction in AVN butnot in fast accessory pathway (AP) -»• transmits high
atrial rate to ventricles.
2. Adverse effects of CCBs (see before)
Adenosine
Pharmacodynamics
• Binds A! receptors —• opens K+ channel -> hyperpolarization -»• j Ca2+ influx -»

a. SAN ->| rate.
b. AVN -*[ conduction velocity -1 ERP -> Terminates PSVT.
• Dilates coronary & peripheral blood vessels.
Uses: Terminates PSVT
Dosage: rapid IV bolus; may be repeated once after 1-2 minutes (ultra short; tVl: 15 s).
Side Effects (transient)

1. Chest pain & dyspnea (Ax receptors; bronchospasm CI in asthma).
2. Headache flushing (A2 receptors; vasodilation).
3. Sinus bradycardia, arrest or AV block (CI in AV block).
85-
Magnesium sulfate
Pharmacodynamics
• Natural physiologic competitive Ca antagonist at L - calcium channels:

• Slows SAN rate.
• Prolongs conduction time in myocardial tissue.
Uses: Given IV in
• Digitalis induced arrhythmia associated with hypomagnesemia.

• Torsades de pointes.
Choice of Antiarrhythmic Drugs

Broad therapeutic classification of anti-arrhvthmic drugs:
• Lidocaine; phenytoin or mexilitine: used in V. arrhythmias.
• Verapamil, adenosine, digoxin: used in SV arrhythmias.
• Class la & lc, PBs, amiodarone, sotalol: Broad-spectrum.
Atrial flutter (Aft & fibrillation (AF): DC in unstable hemodynamics

1. Pharmacologic cardioversion (classIc, III, la):
• Propafenone (best for atrial fibrillation).
• Ibutilide (best for atrial flutter) 78.
• Procainamide, quinidine, (+ digoxin, pBsor verapamil to blockAVN ).
2. Maintenance of rhythm after conversion79
• Propafenone (+ verapamil), flecainide.
• Amiodarone - sotalol.
• pBs.
3. Ventricular rate control (block AVN)):

• PBs - verapamil/ diltiazem - digoxin (if there is HF).
4. Anticogulants: to avoid thromboembolism.
78 Dofetilide is also best for atrial flutter.

79 Quinidine may beused.
-86
PSVT80
• Adenosine or verapamil (1st choice).
• pBs &procainamide IV (2nd choice).
Ventricular Tachycardia: DC in unstable patients; if stable, give IV-»
1. Amiodarone.
2. Lidocaine. j- 1st &2nd choices

3. Procainamide - sotalol (provided left ventricle function is normal)
Bradycardia:
• Atropine (best).
• Cardiac pacing(if atropme fails).

• Isoprenaline.
Cardiovascular agents for lactating women
Methyldopa
Nifedipine (avoid amlodipine)

Spironolactone
Hydrochlorthiazide small dose (avoid thiazides inlarge dose)
Enalapril- captopril-benzapril (avoid other ACEIs and ARBs)
Metoprolol -atenolol- labetalol
Quinidine - procainamide
Lidocaine
Verapamil
Digoxin
80 Procainamide -» 1st choice in antidromic AVRT. Drugs blocking slow AVN are used in orthodromic
but avoided in antidromic if diagnosis is uncertain, since ECG changes may not distinguish this
anhythmia from V. tachycardia. If case is V. tachycardia it will degenerate into fibrillation due to
shortening of ventricular ERP by these drugs especially adenosine & digoxin. Moreover, if AF is
concomitantly present; AVN block -»t conduction across fast AP -»V. fibrillation.
-87-
III. BLOOD PHARMACOLOGY

Bythe end of this chapter, the student should be able to:
• Identify the 3 major drug groups (antiplatelets, anticoagulants and fibrinolytics)
involved in management ofthrombotic diseases and compare their utiltyin
venous & arterial thrombosis.
• Differentiate between the 3 main groups of anticoagulants, their mechanisms,
adverse effects, control of therapy and available antidotes.
• Explain why warfarin has adelayed onset ofaction and how this relates to the
anticoagulation protocol.
• Explain the problems encountered with warfarin therapy and how the availability
of other groups of anticoagulants reduced such problems.
• Discuss the choices of different anticoagulants in patients with liver or renal
diseases
• Diagram steps of platelet aggregation &show the site ofaction ofdifferent

antiplatelet drugs.
• Explain how specific fibrinolytics offer advantages over non specific agents.
• List3 drugs used in management of excessive bleeding.
• Listthe main groups of hypolipidemic agents & discuss the value of
combination therapy and mention rational combinations & undesirable ones.
• Namethe 2 mostcommon types of nutritional anemias and their causes.
• List the preparations of iron & vitamin B12 used in therapy.
' Identify drug groups inducing hematological disorders as wellas those used in
management of such disorders.
••-,, • !.• • •• ft'
.'••{"M-.:!',;i-;
•; i.Llf,: r"'
•"-t(; :;f!:
BloodPhannacology
BLOOD PHARMACOLOGY
DRUG THERAPY OF THROMBOSIS
Thrombosis
• Thrombosis is a pathological condition resulting from inappropriate activation
of the hemostatic mechanisms i.e. platelet aggregation & coagulation (fibrin
formation).
Types ofthrombi
• Arterial(white) thrombus: formed mainly of platelets (in a fibrin mesh). It is
associated with atherosclerosis and can interrupt blood flow resulting in
ischemia ordeath of tissue (infarction). -» managed mainly bv antiplatelets
& fibrinolytics.
• Venous (redl thrombus: formed mainly ofa fibrin tail with a white head (
few platelets). It is associated with stasis of blood. It may detach and travel
resulting in emboli (e.g., deep venous thrombosis inlower limb -» pulmonary
embolism) "> managed mainly bv anticoagulants.
Drugs used in Management of Thrombotic Disease
r Antiplatelets
Fibrinolytics
Anticoagulants • Interfere with
• Induce lysis of fibrin
• Interfere with aggregation of
synthesis or inactivate (thrombus).
platelets.
coagulation factors.
-91
. . BoodPhaimxology
Ianticoagulants
Coagulation
• Clotting factors are synthesized in liver and are present in an inactive form in the
circulation. They are inactivated by antithrombin (natural anticoagulant).
• Stimulation ofthe coagulation cascade (bytissue factors from injured tissue &
mediators on surface ofplatelets)-* sequential activation ofclotting factors
finally forming factor Xa .
• Factor Xa activates prothrombin (factor II) -> thrombin (factor Ha).
• Thrombin catalyses hydrolysis offibrinogen -• fibrin (incorporated in clot).
• Cross linking offibrin strands stabilizes clot -^hemostatic platelet- fibrin plug.
• The fibrinolytic system is activated simultaneously (plasminogen-* plasmin-*
fibrinolysis) inorder to dissolve the clot (thrombus).
Classification of Anticaeulants
A. Parentral anticoagulants:
I. Indirect thrombin inhibitors: Heparin - LMWHs.

II. Indirect selective inhibitor of factor Xa: fondaparinux.
III. Direct thrombin inhibitors: argatroban - bivalirudin - desirudin.
B. Oral anticoagulants:
I. Warfarin: inhibitor of synthesis of clotting factors (n, VII, DC, X).

II. New oral anticoagulants fNOAO
1. Direct thrombin inhibitor: Dabigatran.

2. Direct inhibitors of factor Xa: Rivaroxaban- apixaban.
-92-
BloodPharmacology
A. Parentral Anticoagulants
Direct Thrombin Inhibitors l Heparin-Antithrombin

complex
I
Thrombin
Ha IXfl
Slight e e
LMWHs -
Antithrombin Fondaparinux-Antithrombin
complex complex
Site of action of Parentral Anticoagulants
I. Indirect thrombin inhibitors (Heparin - LMWHs)

Heparin
Chemistry
• Sulfated mucopolysaccharide with high MW.

• Highly acidic with electronegative charge.
1. Anticoagulant action: (effective both in vitro and in vivo)

Mechanism: combines with antithrombin (natural anticoagulant factor)
forming heparin-antithrombin complex which accelerates the inhibitory effect
of antithrombin on activated clotting factors specially:
- Factor Ila (Thrombin) - factor IXa - factor Xa.
2. Slight vasodilator effect -> canalization of thrombus.
3. Plasma-clearing effect by stimulating lipoprotein lipase enzyme.
-93-
BtoodPhamacotogy
Pharmacokinetics
• Immediate onset ofaction after IV injection and short duration (4-6 h).
• 80 %hepatic metabolism, 20 %excreted renally, unchanged.
• Does not cross placenta &is not secreted in milk (high MW) -» can be used
during lactation orpregnancy.
Routes of Administration & Doses
• IV bolus (5,000 IU), followed by TV infusion (1,000 IU/h); guided by aPTT).

• SC: 5,000 IU (low dose of heparin) for prophylaxis, 2hours preoperative and
every 12 hours postoperative for 5-7 days.
Heparin should not be given by IMI as hematoma can occur.
Control of Theranv
• aPTT (activated partial thromboplastin time) should be kept as close as

possible to twice normal value (normal value 30-35 seconds).
Adverse Effects1
1. Hemorrhage ttt: protamine sulfate (antidote)
2. Hair loss (alopecia).
3. Hematoma if given by IMI.
5. Hyperkalemia (monitor K level if heparin isgiven for more than 7 days f.
6. Osteoporosis (on long term use, specially in pregnancy).
7. Thrombocytopenia (regular plateletcount is required)
a) Early: mild due to direct effect on platelets.
b) Late: severe due to immunoglobulin-induced plateletaggregation.
ttt: replace heparin by direct thrombininhibitorsor fondaparinux
1Heparin may induce thrombosis due to depletion ofantithrombin

2Hyperkalemia ( 2^toaldosterone deficiency) may result due to inhibition of an
enzyme necessary for aldosterone synthesis by heparin.
-94-
BloodPharmacology
Low-Molecular-Weight Heparins (LMWHs)

(Dalteparin - Enoxaparin -Tinzaparin)
• They are fractions ofthe standard heparin (unfractionated heparin) thus they
have a low molecular weight.
• They are mostly given subcutaneously.
Mechanism of Action
• They bind to antithrombin increasing its inhibitory effect on factor Xa and to
a lesser extent on thrombin (Factor IIa).
Advantages of LMWHs
1. Equal efficacy to unfractionated heparin.
2. Greater bioavailability from sc sites.
3. Long ti/2 -* given subcutaneously once ortwice/day.
4. Less thrombocytopenia & osteoporosis.
5. Less risk of bleeding.
II. Indirect selective inhibitor of factor Xa: Fondaparinux

• Synthetic pentasacharide molecule, derivative ofheparin.
• Binds to antithrombin with high specificity -êfficient inactivation of factor Xa.
• Long ti/2 -* given once daily sc.
• Low risk of heparin - induced thrombocytopenia.
• Used in venous thromboembolism. & heparin - induced thrombocytopenia.
• Bleeding is its major side effect: not antagonized byprotamine sulfate.
• Requires less monitoring than heparin (due topredictable pharmacokinetics).
Protamine sulfate
• Highly basic with low MW carrying electropositive charge.

• Neutralizes heparin (each 1 mg neutralizes ~ 100 IU heparin).
• Partiallyantagonizes LMWHs but does not antagonize fondaparinux.
• Has a slight anticoagulant effect -* avoid overdose.
-95
. BloodPharmacology
III. Parentral Direct Thrombin Inhibitors
• Directly bind to thrombin independent of antithrombin -» more inhibition of
fibrin-bound thrombin.
• Given intravenously.
• Bleeding is its majorside effect.
Argatroban
• Preferred in heparin-induced thrombocytopenia in patients with renal

insufficiency (cleared hepatically not renally).
• Used in coronary angioplasty in patients with heparin-induced
thrombocytopenia.
Bivalirudin3
• Used in coronary angioplasty

• Also inhibits platelet activation.
3Bivalirudin: hirudin analogue.
-96-
BloodPharmacology
B. Oral Anticoagulants
I. Warfarin
Mechanism of Anticoagulant Action (effective only in vivo)

• Inhibition of vitamin K epoxide reductase enzyme -» prevention of
reactivation of vitamin K -* interference with hepatic synthesis of vitamin K-
dependent clotting factors (II, VII, IX, X).
Precursor Functioning
clotting protein Reduced clotting protein
vitamin K
II, VII, IX, X
Epoxide
reductase
Warfarin
Vitamin K
Vitamin K
epoxide
Epoxide reductase
Pharmacokinetics
• Well absorbed after oral administration 100% bioavailability).

• More than 99 % bound to plasma proteins.
• Metabolized by liver & excreted by kidney.
• Delayed onset with long duration of action (up to 6 days).
• Crosses placenta.
• Secreted in milk (negligible amounts -> safe during lactation).
Dosage of Warfarin
Loading dose: 5- 10 mg/day (followed by maintenance dose).

Maintenance dose: 5-7 mg/day (according to INR).
-97-
. BtoodPhawauulogy
Control of Theranv
• PT (Prothrombin Time):
Should be kept as close as possible to twice normal value (12 s).
• INR (International Normalized Ratio )4:
Should be kept at 2-3.
Antidotes
• Fresh frozen plasma.

• Vitamin Kj.
Adverse Effects
1. Hemorrhage.
2. Skin necrosis5 (especially in patients with protein Cdeficiency).
3. Teratogenic (avoid all through pregnancy).
Disadvantages
• Delayed onset (2-3 days are required for depletion of already formed
coagulation factors) -* requires overlapping therapy with heparin (see
anticoagulation protocol).
• Narrow therapeutic index
• Requires routine monitoring of coagulation.
• Drug interactions.
4 INR is the ratio of the prothrombin time in the patient to mat in a normal non
anticoagulated person. Designed to avoid variations between laboratories.
5 It is due to inhibitory effects of warfarin on synthesis of protein C.The latter is a

natural anticoagulant whose level drops at a rate faster than mat of the clotting factors
-»transient hypercoagulation -* venularthrombosis -» skin necrosis.
-98-
BoodPharmacology
Drug Interactions with Warfarin

Requiring Dose Adjustment
Effect is increased by I II Effect is decreased by ||

[
Paraffin Oil
Interferes with vitamin GIT
K absorption
Vitamin K
Cholestyramine
Broad-Spectrum Interferes with
Antibiotics _ absorption
Anticoagulants
Interfere with synthesis of warfarin
of vitamin K (although it may
also interfere with
Blood Vit K absorption)
Aspirin - Sulfonamides Plasma
Displace proteins (PP)
warfarin from PP
Aspirin Platelets
Antiplatelet effect Vitamin K
Anabolic Steriods Coagulation t Coagulation factors

Quinidine factors Oral
4 Coagulation factors contraceptives
f Coagulation factors
Liver
Enzyme Inhibitors Q. Warfarin © Enzyme Inducers

• Amiodarone Metabolism • Rifampin
• Erythromycin • Carbamazepine
• Chloramphenicol
Vit K epoxide
• Fl.quinolones Reductase
• Some Hereditary
Cephalosporins ,Hereditary Resistance
t Vitamin K
e.g., to warfarin
reactivation
Cefoperazone
-99
BoodPharmacology
II. Newer Oral Anticoagulants (NOAO

Rivaroxiban - Apixaban - Dabigatran -
Advantages over warfarin
1. More rapid onset and offset.

2. No monitoring is required with less risk of bleeding.
3. Less drug interactions with CYP450 interacting drugs.
Comparison of Oral Anticoagulants
Warfarin Rivaroxaban Dabigatran

Mechanism • I Hepatic synthesis • Direct competitive . Direct competitive
of clotting factors reversible inhibitor of reversible inhibitor of
(II - VII-IX-X). factor Xa Thrombin
Onset • 36-72 hours • Within 30 min . Within 30 min
Duration • Up to 6 days • 24 hours • 24-36 hours
Monitoring • INR • No .No
Antidote * Vitamin K • NONE • Idarucizumab
Interactions * Significant • < warfarin • < warfarin
Renal • No dose • Dose adjustment . Dose adjustment

impairment adjustment. • Avoid if creatinine • Avoid if creatinine
clearance <15ml/min clearance <15ml/min
Pregnancy Teratogenic • Unknown . Unknown
N.B.:
• Apixaban is similar to rivaroxaban with less risk of bleeding.

• Dabigatran is a prodrug with very low bioavailability6. Absorption depends
on acid environment —> decreased by proton pump inhibitors.
• Food increases bioavailability of rivaroxaban.
6 Bioavailability: dabigatran: 6.5%, rivaroxaban: 80%, warfarin: 100%.

Dose: rivaroxaban 10-20mg once /day, dabigatran 150mg twice/day, if creatinine clearance > 30ml /min.
-100-
BloodPharmacology
Reversal of new oral anticoagulants action in toxicity
1. Activated charcoal -âbsorption (ifgiven within few hours ofingestion).
2. Prothrombin complex concentrate (PCC): reverses rivaroxaban effect.
3. Dialysis for dabigatran; idarucizumab (antidote, recently approved by FDA).
Indications}(limits propagation &prevents formation ofnew thrombi)
1. Prophylaxis of deep venous thrombosis/pulmonary embolism after knee or
hip surgery (Heparin, LMVVH, fondaparinaux, warfarin, apixaban and
rivaroxaban. Dabigatran used following hip surgery only).
2. Treatment of deep venous thrombosis/pulmonary embolism (heparin
followed by warfarin, apixaban, rivaroxaban can be used as a single-drug
approach, whereas dabigatran and edoxaban are proceeded with LMWH).
3. Stroke prevention in AF cases (warfarin, NOACs used in non-valvular AF).
4. Rheumatic valve disease or mechanical heart valves (Warfarin)
5. Chronic coronary or peripheral artery diseases (Rivaroxaban plus aspirin)
6. Arterial thrombosis: coronary, cerebral; Acute coronary syndrome (Heparin)
7. Cardiac & vascular surgery (heparin) - Hemodialysis (heparin).
Contraindications of Anticoagulants
I. Increased risk of bleeding

Hemophilia- purpura- head injuries- intracranial hemorrhage.
Severe hypertension- threatenend abortion - active peptic ulcer - active TB.
II. Allergy
Protocol for anticoagulation
Heparin (initially), followed by concomitant administration oforal anticoagulants

for 2-3 days before stopping heparin (guided by INR).
Rivaroxaban is approved as initial oral treatment of deep vein thrombosis (DVT).
1The recommended dosage ofrivaroxaban is 15mg twice daily for the first 21 days followed by
20mgonce daily for continued treatment and prevention of recurrence.
-101-
Blood Pharmacology
ANTIPLATELET DRUGS
Platelet Aggregation
• Damage of vessel wall -» exposure of collagen in subendothelium -> platelet

adhesion (enhanced by factor VIII and von Willebrand factor) followed by
activation-* release reaction (ADP, fibrinogen TXA2, etc....).
• ADP binds to its receptor on platelets -» exposure ofglycoprotein GP Hb/IIIa
receptor on platelet membrane.
• Fibrinogen binds to the GP Ilb/IIIa receptor linking adjacent platelets

-* aggregation.
Gpllb-llla
complex
von Willebrand
factor
Subendothelium
Steps of Platelet Aggregation.
-102-
BoodPharmacology
Classification of antiplatelets according to mechanism of Action
I. Drugs Acting on Platelet COX Enzyme
Acetvlsalicvlic acid (Aspirin)

• Prototype antithrombotic
• Low-dose aspirin (75 - 325 mg/day oral): inhibits platelet thromboxane A2
synthesis by inhibiting (irreversible acetylation) of COX -1 enzyme .
• Aspirin is the main antiplatelet drug used. Clopidogrel or dypiridamole
may be combined to it or given to patients intolerant to it.
II. Drugs Increasing cAMP
1. PGI2 analogue (epoprostenol)

• Stimulates adenyl cyclase—> fcAMP.
• Potent antiplatelet & vasodilator.
• Very short duration (minutes)—> given by IVL
2. Dipyridamole & Cilostazol (oral)
• Inhibit phospho-diesterase ->i cAMP breakdown.

• Vasodilator & antiplatelet.
• Dipyridamole is a weak antiplatelet —>combined with warfarin or aspirin.
• Dipyridamole: prefered to aspirin for combination withwarfarin (less bleeding).
III. Drugs acting on platelet ADP & fibrinogen Receptors
1. Drugs inhibiting ADP receptors -înhibit expression of fibrinogen receptors

• Ticlopidine- clopidogrel - prasugrel - ticagrelor (oral)
2. Drugs blocking GP Ilb/IIIa Fibrinogen Receptor

• Tirofiban . eptifibatide . abciximab (mono-clonal antibody)
(All are given IVI; short term therapy).
8Low dose aspirin is selective on platelets because platelets are exposed toaspirin inthe portal
circulation before its acetylation by first pass metabolism. Since platelets arenonnucleated,they
cannot resynthcsizc new COX. Thus antiplatelet effect of aspirin remains for 7-10 days (life span
of platelet) after which new platelets arc formed with new COX. Vascular endothelial cells are
nucleated thus can regenerate COX. Thus prostacyclin synthesis recovers rapidly.
-103-
BoodPharmacology
Therapeutic uses of antiplatelet drugs (mainly in arterial thrombosis)

1. High risk of myocardial infarction (AMI): e.g., previous attack or angina (aspirin).
2. Acute coronary syndrome (aspirin +clopidogrel9 or abciximab).
3. Coronary bypasses grafting, angioplasty & stent insertion (aspirin plus
clopidogrel or abciximab).
4. Prosthetic heart valves: Jthrombo-embolism (dipyridamole plus warfarin).
5. Transient ischemic attacks- thrombotic stroke (dipyridamole plus aspirin).
6. Hemodialysis- cardiopulmonary bypass- pulmonary hypertension (epoprostenol).
7. Intermittent claudication (cilostazol).
N.B.: Antiplatelets may be given in atrial fibrillation if anticoagulants are CI.
Side effects of antiplatelet drugs :
1. Aspirin: oral once /day

1. GIT: gastric irritation, bleeding ulcers. 3. Hypersensitivity
2.\ Risk of bleeding. 4. Hyperuricemia.
2. Ticlopidine: (oral) GIT irritation -neutropenia
3. Clopidogrel; oral once /day(preferred to ticlopidine; less risk of neutropenia)
• Bleeding-rash - Gastric irrigation,,diarrhea. (
• Clopidogrel is a prodrug-* avoid with omeprazole as it inhibits its activation in liver.
4. Prasugrel: (oral)
• Increased risk of bleeding (CI: in patients with history of TLA or stroke)
5. Ticagrelor: bleeding - shortness of breath
6. Dipyridamole (oral): Steal phenomena -dizziness- headache- GIT disturbance.
7. Epoprostenol (IVD: Flushing, headache, hypotension.

8. Abciximab (IVD: bleeding, thrombocytopenia, arrhythmia.
9. Cilostazol (oral):
• Headache, dizziness - GIT upset: nausea, dyspepsia, diarrhea
• Tachycardia, palpitations, peripheral edema.
Ticlopidine, prasugrel & ticagrelorare also used in acute coronary syndrome.
-104 -
BoodPharmacology
Arachidonic Acid Aspirin

e
Cycloxygenase
(COX) i Selective on Platelet
COX
Endoperoxides
I TXA2 Synthesis
Prostacyclin Thromboxane A2
Prostacyclin Endothelium Platelets
Analogue \ 1/ e
(Epoprostenol)
Stimulates
Dipyridamole - Cilostazol
Adenyl-cyclase
Inhibit
Phospho-diesterase
Antiplatelet Drugs Acting on Platelet COX enzyme & cAMP
Fibrinogen binds to its receptor
Platelet Exposure of
e ADP
Adhesion & GP Hb/IIIa
-> receptor
ADP release (fibrinogen )receptor 4
Prasugrel - Clopidogrel Tirofiban - Eptifibatide
Site of Action of Antiplatelets on Platelet ADP & Fibrinogen Receptors
-105-
BoodPhannacaiogy
FIBRINOLYTICS (THROMBOLYTICS)
• Drugs that cause lysis of thrombus. They are given intravenously.
Mechanism of Action
• Fibrinolytics are plasminogen activators. They activate plasminogen to plasmin

which causes degradation of fibrin:
_, . Plasminogen
Plasminogen • plasmin—• dissolves fibrin (clot)
. . activators
(natural plasma
glycoprotein)
N.B.:
• Plasmin digests not only fibrin but also fibrinogen and factors V & VIII. So
bleeding may occur if excess plasmin circulates in plasma.
The ideal fibrinolytic is that which activates plasminogen bound to fibrin

(fibrin-specific) without activating free plasminogen in plasma.
So its effect is localized to clot -» 4 risk of bleeding.
Indications of Fibrinolytics
1. Acute myocardial infarction (most effective if given early within 6 hours).

2. Pulmonary embolism.
3. Deep venous thrombosis.
4. Thrombotic stroke (tPA within 3 hours).
5. Obstructed arterio-venous shunt & occlusion of intravascular catheter.
Fibrinolytic therapy should be started as soon as possible

aftet the onset ofthrombosis or embolism (since they become
resistant to lysis as they age).
-106-
BoodPlianttacology
Classification of Fibrinolytics 10
'' i r
Fibrin-Nonspecific Fibrin-specific
(1- generation) (2— generation)
Tissue Plasminogen
A. Streptokinase (SK) Activators (tPA)
B. Urokinase (UK)
Alteplase - Tenecteplase
Reteplase
• Non clot-selective: activate both • Clot-selective: greater affinity

circulating & clot (fibrin)-bound for activating clot (fibrin)-bound
plasminogen: plasminogen than circulating
A. SK: acts indirectly forming a plasminogen.
complex with plasminogen which
then activates free plasminogen
Advantage: (cheapest & most
widely used).
B. UK: directly activates plasminogen

Advantage: (non antigenic).
Advantages
Disadvantages
• 4 Bleeding risk (clot-selective).
• t bleedingrisk (non clot-selective)
• Nonantigenic.
• Antigenic (SK).
• Tenecteplase is given as a single
• Given as intravenous
IV bolus dose (longer 11/2).
infusion—^loading dose followed by
• Reteplase: longer t m
maintenance dose.
10 Source: streptokinase: cultures of p-hemolytic streptococci, urokinase: cultures of human renal

cells & urine, altcplasc (human tPA): recombinant DNA tech. & tenecteplase: mutant of tPA.
-107-
BoodPltanttacology
Adverse Effects
1. Bleeding (more with fibrin-nonspecific agents -* treated by stopping infusion,

fresh blood & antifibrinolytics).
2. Antigenicity (fever, allergy & hypotension) with streptokinase11 -> start
therapy with a large loading dose to neutralize antibodies).
3. Recurrence of thrombosis.
Contraindications
1. Recent surgery.
2. Gastrointestinal bleeding.
3. Hypertension.
4. Cancer.
5. Pregnancy.
6. Children & old age.
Fibrinolytics should be followed by

anticoagulants & antiplatelets because as
the clot dissolves local thrombin increases,
-> t platelet aggregation & thrombosis.
11 Due toantibody formation following previous streptococcal infection.
-108-
BoodPharmacology
DRUGS USED IN BLEEDING DISORDERS
I. VITAMIN K
Fat-soluble vitamin essential for hepatic synthesis of factors II, VII, DC and X.
Deficiency of vitamin K leads to spontaneous hemorrhage.
Types of Vitamin K
1. Natural 2. Synthetic
• Bile salts essential for absorption. • Water-soluble -* no need for bile.
- Ki in plants (IM - oral). -K3

- K2 synthesized by GIT bacteria. -K4
Indications of Vitamin K
1. Overdose of anticoagulants & salicylates.
2. Hemorrhagic diseases in newborn.
3. Vitamin K deficiency (in obstructive jaundice or malabsorption syndrome).
Adverse Effects
• Rapid IV injection results in:

1. Dyspnea.
2. Chest pain.
3. Flushing.
109-
BloodPharmacology
II. FIBRINOLYTIC INHIBITORS (ANTIPLASMIN)

1. Aminocanroic Acid
• Competitive inhibitor of plasminogen activators.
Uses
1. Bleeding due to fibrinolytics.

2. Adjunct therapy in hemophilia.
3. Bleeding states resulting from damage oftissues rich in plasminogen
activators (e.g. after prostatic surgery, tonsillectomy).
Adverse Effects
• Hypotension.
• Abdominal discomfort.
• Intravascular thrombosis.
2. Tranexamic Acid
• Analog of aminocaproic acid that is more potent with fewer side effects.
III. Plasma Fractions
• Given when there is deficiency ofone ofthe coagulation factors, e.g.:

• Factor VIII given in hemophilia.
• Factor IX.
• Fibrinogen.
Cryoprecipitate
Plasma protein rich in factor VIII, von Willebrand factor &firbinogen.
-110-
BoodPharmacology
DRUG THERAPY OF ANEMIAS
• Normal erythropoiesis requires certain exogenous substances (iron, folic acid &
vitamin Bi2) & some endogenous factors (intrinsic factor, erythropoietin &
colony stimulating factors).
DRUG THERAPY OF IRON-DEFICIENCY ANEMIA
(Microcytic Hypochromic Anemia)
IRON
Iron Absorption
• Takes place in upperpart of small intestine (acid medium t solubility).

• Ferrous iron is more readily absorbed than ferric.
Factors Enhancing Iron Absorption

1. Infancy, adolescence and in iron-deficiency anemia (t demand)
2. Ascrobic acid, HC1 & succinic acid -* t absorption ( ferric -» ferrous).
Factors Reducing Iron Absorption12

1. Gastric resection and malabsorption syndrome.
2. Desferoxamine (chelates iron).
3. Antacids.
4. Tannic acid (precipitates iron).

5. Tetracyclines & iron bind together ** 4« absorption of both.
6. Calcium in dairy foods -* 4 iron absorption.
7. Phosphates, oxalates and phytates (form insoluble iron complexes).
12 Foods that decrease non-heme iron absorption have littleeffecton absorption of heme iron.
Heme iron is found in meat, non-heme iron is found in plants and in iron supplements.
-Ill-
good'Pharmacology
Indications of Iron Theranv:
1- Prophylactic, to prevent development of iron-deficiency anemia (IDA):

30-60 mg/day elemental iron13.
2- Treatment of IDA:
200-400 mg/d elemental iron14.

Iron-Deficiency Anemia due to:
1. f Demand: premature infants, children during rapidgrowth, pregnant and

lactating women.
2.1 Absorbtion: after gastrectomy & in malabsorption syndrome.
3. Chronic blood loss, e.g., occult GITbleeding, heavy menstrual bleeding,
during hemodialysis, ankylostomiasis.
4. | in blood formation: during treatment of severepernicious anemia with
vitamin B12 (depletion of iron stores), during treatment with erythropoietin
(formation of RBCs at a high rate).
Iron Theranv (Oral - IV - IM)
I. Oral Iron Theranv Ferrous salts
•Effective & cheap (treatment of choice). are usually

used as
•Oral preparations include ferrous sulfate,
gluconate and fumarate. ferrous iron is
•Different Fe salts provide different amounts of elemental Fe efficiently

absorbed.
(range from 12-33% )
•New agents: polysaccharide-iron complex 150 mg,
carbonyl iron 150mg contain 100% elemental iron.
• Heme iron polypeptide: More expensive than above agents.
•Given after meals to J, GIT disturbances (carry risk of âbsorbed portion).
•Continue iron till Hb is normal & for an extra 2-3 months to replenish stores.
Elemental iron is the total amount of iron inthe supplement available for absorption.
In Fe deficient individuals, about 50-100 mgof Fe can beincorporated into hemoglobin daily,
and about25% of oral Fe given can be absorbed.
-112-
BoodPharmacology
Adverse Effects of Oral Iron Therapy

1. GIT disturbances: nausea, epigastric pain, constipation (given after meals -
start with small dose then gradually increase).
2. Black stools (maskdiagnosis of GI bleeding).
3. Black staining of teeth(iron sulfide in mouth).
II. Parenteral Iron Therapy
Indications (= Causes of failure of oral iron therapy)

1. Noncompliance tooral therapy (severe GIT disturbance orulceration).
2. Malabsorption syndrome causes failure of iron absorption.
3. Severe anemia, e.g. in malignancy.
Calculation of Parentral Iron
(There are many formulae to determine parenteral iron required to

correct anemia & replenish stores).
e.g.
Total iron deficit (mg) = Body weight [kg] x (Target Hb - Actual

Hb) [g/1] x 2.4 + 500 [mg] (for iron stores)
-113-
Bood'Pharmacology
Parenteral Iron Preparations

A. Iron dextran
B. Iron sucrose complex & Iron sodium gluconate complex.

C. Newer preparations: Ferric carboxymaltose, Ferumoxytol
• Given by deep IMI or by IV infusion15 (as a total dose infusion, TDI).
Advantages of TDI
1) Avoids non-compliance of the patient.

2) Avoids unpleasant effects of IMI.
3) Allows delivery of the entire dose of iron necessary to correct iron
deficiency at one time.
Adverse Reactions of parenteral iron therapy
• IM: local pain - tissue staining.
• IV: headache, fever, urticaria, lymphadenopathy & anaphylactic shock
(with Fe dextran, start with a small test dose).
Iron Toxicity
Acute Iron Toxicity (more in children)

• Abdominal pain, vomiting, bloody diarrhea, dyspnea followed by metabolic
acidosis, cardiovascular collapse, convulsions, coma & death.
Treatment (urgent and immediate)
1. Raw egg or milk -* bind & precipitate iron as albuminate or caseinate
until a chelating agent is available.
2. Desferrioxamine:
• 1-2 g IMor IV -» chelates iron promoting its excretion in urine.

• 5 g in 100 ml water swallowed or by stomach tube (after gastric
lavage with bicarbonate solution16.
3. IV infusion of saline, dextrose or bicarbonate -* correct water &
electrolyte disturbance.
15 Start with a small test dose.

16 Bicarbonate forms insoluble iron salts.
-114
BoodPharmacology
Chronic Iron Toxicity
It occurs in:
1. Patients receiving many red cell transfusions.

2. Patients with hemochromatosis; ah inherited disorder characterized by t
Fe absorption -* hemosiderosis (Fe3+ preciptation in vital organs).
Management
1. Venesection 17 (ifno anemia) -» repeated weekly.

2. Desferoxamine IM or SC.
3. Large intake of tea -* tannins binds iron.
Anemia of chronic disease:
• It is a functional iron deficiency anemia.

• Occurs when there is infection and inflammation with release of cytokines that
stimulate the release of hepcidin from the liver.
• High levels of hepcidin prevent absorption & release of iron from its storage
sites (sequestrated anemia).
• To be differentiated from iron deficiency anemia, there is normal or high
serum ferritin.
• Not treated with iron but its treatment is to treat infection & inflammation.
,7A single venesection of 500 ml blood removes 200mg iron.
-115
_ BoodPharmacology
DRUG THERAPY OF MEGALOBLASTIC ANEMIA
(Vitamin B12 and Folic Acid Deficiency)
I. Vitamin B12
• Cobalt-containing compound synthesized by bacterial flora in colon.
• Called extrinsic factor to differentiate it from an intrinsic factor (a glycoprotein
formed by parietal cells, necessary for vitamin Bi2 absorption).
Functions of Vitamin Br>: It is essential for:
1. Cell growth and replication (DNA synthesis).

2. Maintenance of normal myelin sheath, erythropoiesis and cell maturation.
3. Normal metabolic functions of folate.
If vitamin B12 absorption is stopped, it takes 5 years for

megaloblastic anemia to develop since its daily requirement is 2 ug
& body store is relatively high.
Pernicious Anemia
• It is a severe form of megaloblastic anemia due to deficiency of intrinsic factor

(congenital, aftergastrectomy). The disease is characterized by:
1. Megaloblastic anemia (largered cells highly susceptible to destruction).
2. Subacute combined degeneration of brain, spinal cord & peripheral nerves.
3. Atrophic gastritis.
Preparations of Vitamin Bi?
A. Cyanocobalamin
B. Hydroxycobalamin (preparation of choice):
1. More slowly absorbed.
2. More bound to plasma proteins.
3. Slowly excreted.
4. More sustained rise in serum cobalamin.
-116-
BoodPharmacology
Therapeutic uses of Vitamin Bn
A. Megaloblatic Anemia
1. Pernicious anemia: vitamin Bi2 is given for life by IMI.

• Initial therapy: 1,000 ug/day for 1-2 week to replenish stores. Then
1,000 p-g/week till normal blood count.
• Maintenance therapy: 1,000 ug/month for life.
2. Megaloblastic anemia due to diphylobothriasis.
• It is treated by vitamin Bi2and praziquantel.
3. Drug-induced megaloblastic anemia:
• Neomycin, colchicine andantiepileptics reduce absorption of B|2.
B. Neurological Conditions
• Peripheral neuritis in diabetes &retrobulbar neuritis in heavy smokers.
II. Folic Acid
(Pteroylglutamic Acid)
• Source: liver, yeast and green vegetables.

• Essential for DNA synthesis.
• Vitamin Bi2 is essential for activation of folic acid. So vitamin Bi2 deficiency is
often associated with folic-acid-deficiency anemia.
• No neurological abnormalities are associated with folate deficiency.
Folate deficiency develops more rapidly than vitamin B12 deficiency

since daily requirement is high and body store of folate is low.
-117-
. . BoodPharmacology
Causes of Folic Acid Deficiency
1. Inadequate dietary supply orincreased demand (e.g. pregnancy, lactation).

2. Diseases in small intestine.
3. Alcoholism.
4. Drug-induced folic acid deficiency;
a. Phenytoin, phenobarbitone & oral contraceptives (interfere with folate

absorption).
b. Methotrexate, trimethoprim & pyrimethamine (inhibit dihydrofolate
reductase enzyme) [Treated by folinic acid].
Therapeutic uses of folic Acid
1. Nutritional megaloblastic anemia.

2. Malabsorption syndrome.
3. In alcoholics and pregnant women.
4. Patients with liver disease & with hemolytic anemia.
5. With anticonvulsant drugs.
6. Patients on dialysis (as folic acid is removed each time).
-118-
BoodPftamiaccfogy
DRUG-INDUCED BLOOD DISORDERS
A. Hemolytic Anemia (destruction of RBCs)

1. In G6PD-deficient subjects
1. Antimalarial drugs.
2. Aspirin.
3. Sulfonamides.
4. Quinine and quinidine.

2. As a Hypersensitivity Reaction
1. Penicillin 2. Sulfonamides.
3. Autoimmune Hemolytic Anemia: methyldopa.
B. Thrombocytopenia
• Heparin - rifampin - indomethacin - quinine - quinidine.
• Treatment: stop the drug - platelettransfusion - corticosteroids.
C. Bone Marrow Depression (aplastic Anemia oragranulocytosis)

• Cytotoxic drugs - chloramphenicol - chlorpromazine - thiouracil.
Treatment of agranulocytosis or aplastic anemia
1. Blood transfusion to replace lacking components.
2. Treatment according to cause(if known).
3. Corticosteroids: reduce bleeding due to thrombocytopenia.
4. Broad-spectrum antibiotics, e.g. penicillins to treat infections.
5. Bone marrow transplantation (treatment of choice) followed by
immunosuppression with cyclosporin to prevent graft rejection.
6. Erythropoietin.
Erythropoietin tlV or SC)

1. Regulatorof erythropoiesis (acts on stem cells).
2. Used in anemia of chronic renal failure & severe anemia of cancer & AIDS.
3. It decreases the need for transfusion as it elevates red blood cell level.
-119-
BloodPhanrBcology
DRUG THERAPY OF HYPERLIPEMIA
• Myperlipidemia (hyperlipoproteinemia) is an increase in plasma lipoproteins &

is one of the risk factors for ischemic heart disease.
• Cholesterol and TGs are insoluble in blood & therefore carried as lipoproteins.
Types of Lipoproteins
1.Chylomicrons (TGs): formed in GIT from dietary TG.

2. VLDL: synthesized in liver; formed mainly of TGs (synthesized from FAs derived
from lipolysis ofTG by intracellular lipase in adipose tissue) & some cholesterol
(synthesized from HMG-CoA by HMG-CoA reductase)
3. IDL (TGs. cholesterol): derived from VLDL hydrolysis by lipoprotein lipase.
4. LDL (cholesterol): derived from hydrolysis of IDL. Plasma LDL cholesterol is
uptaken by liver through LDL receptors.
5. HDL (protective) -> removes cholesterol from tissues to be degraded in liver.
. HMG CoA —- HMG CoA

MOuetaM )
UVA
BI.ECUCT
•Cooled pf /""»''
y"\J &looc<Js
S \ andC ) • Di'o MMt
PORTAL VEN
"^ FM.C
xnOM.
\
FMy urifH
♦
Qfycwiul
/I
S
A
Cfytomcront
INTESTINE
tratc*
oJtmifuton *
•- XMtonH
ZIZDt
Clromceo jjxaM PERIPHERAL TISSUES
twnoYff o( C [FAT. MUSCLE)
- 120-
Bood Pharmacology
Etiology of Hypeiiipidcmias:
1— (genetic origin): hereditary.
2,vdueto:
• Diseases: DM, hypothyroidism, nephrotic syndrome, obesity.

• Drugs: P blockers, diuretics, progesterone, alcohol.
Statins
Inhibit HMG-CoA reductase
Ezetimibe
| Hepatic cholestrol synthesis LDL receptor
jCholestrol
absorption in
GIT Llwr
Bile acid
Sequestrants
Loss of
intestinal bile
acids->|
conversion of
MDlprccuriori
cholesterol to
"T^r Adipose
bile acids in
il.inlip
Tissue TG
liver
Fim forty acids
y. muidt. or adipox 1111u •
Intracellular
Lipase
Lipw
Fibrates
protein
tHydrolysis of
lipase Nicotinic
VLDL
Acid
&
chylomicrons
| Hydrolysis of TG in
by adipose tissue
Stimulating by Inhibiting
Free Fatty
lipoprotein intracellular lipase-*J.
Acids
lipase-* I FAs supply to liver -»
plasma TG
Hypolipidem jVLDL synthesis
Drugs
u
-121 -
floodPharmacology
Management of Hvperlipidemias
I. Diet
1. Avoid saturated FAs (animal fats). Use unsaturated FAs (plant fats), e.g. olive
or sunflower oil: Polyunsaturated FAs -» t conversion of free cholesterol
(active) to cholesterol ester (inactive) -»I hepatic free cholesterol
-* compensatory t LDL receptors -* t uptake of LDL -» i plasma LDL.
2. Regular fish oil in diet: contains omega 3 FAs -» reduction in TGs &
formation of inactive TXA3 instead of TXA2(aggregatory).
3. Vitamins E & C (antioxidants)- black tea & nuts: may I LDL & t HDL.
II. Exercise:t HDL - t insulin sensitivity delaying maturity-onset DM.

III. Drug Therapy: Used when dietary and risk factor management fails.
A. HMG-CoA Reductase Inhibitors (Statins)

(Simvastatin - Fluvastatin - Atorvastatin)
Main Mechanism of Action
• Structural analogs of HMG-CoA18 (precursor of cholesterol) -» inhibit

HMG-CoA reductase (the rate-limiting enzyme in cholesterol biosynthesis).
• I Cholesterol synthesis in liver -* compensatory t synthesis of LDL
receptors -* t uptake of LDL in liver -» i plasma LDL-cholesterol.
Additional Effects
• i TGs (to some extent) and t HDL.

• Cardiopreotective: vasodilators- 4- atherosclerosis (stabilize plaque).
Therapeutic Uses
• Hypercholesterolemia.
• Combined hyperlipidemia (t cholesterol andTGs).
18 Hydroxy-methylglutaryl-CoA.
-122-
BoodPlkMinacology
Adverse Effects
• Myopathy and muscle damage leading to renal failure in patients with renal
dysfunction especially when combined with fibrates or nicotinic acid.
• Increase in serum liver enzymes (CI in hepatic dysfunction).
• Cataract.
• GIT disturbances.
B. Bile Acid Sequestrants

(Cholestyramine - Colestipol)
Mechanism
• Anion-exchange resins; bind bile acids in intestine—> prevent absorption.

• Loss of bile acids -* t conversion of cholesterol into bile acids in the liver.
• I Cone, of intrahepatic cholesterol -» compensatory t LDL receptors -» t

hepatic uptake of circulating LDL -» l serum LDL-cholesterol.
Therapeutic Uses
• Hypercholesterolemia (in addition to statins when response to statins is

inadequate or in cases where statins are contraindicated).
• Addition of statins offsets the compensatory t in cholesterol synthesis
resulting from 4- hepatic cholesterol with long term cholestyramine therapy.
Adverse Effects
1. GIT disturbance.
2.1 Absorption of digitalis and warfarin (binding).

3.1 Absorption of fat-soluble vitamins (due to loss ofbile salts in stool).
-123-
' '' BoodPharmacology
C. Activators of Lipoprotein Lipase (Fibrates)

(Fenoflbrate - Gemfibrozil)
Main Mechanism of Action
• Agonists at PPAR-a receptor subtype -* expression of genes responsible for

t activity of plasma lipoprotein lipase enzyme -» hydrolysis of VLDL and
chylomicrons -* I serum TGs levels.
Additional Effects
• t Clearance (uptake) of LDL by liver& t HDL.
Therapeutic Uses
Hypertriglyceridemia - combinedhyperlipidemia if statins are contraindicated.
Adverse Effects
1. GIT disturbances.
2. Gallstones.
3. Muscle pain & myopathy (patients with renal impairment are at risk).
D. Inhibitors of Lipolysis
Nicotinic Acid
• It was the first and cheapest hypolipidemic drug.

• It I both TGs (VLDL) and cholesterol (LDL) levels.
Mechanism
• Potent inhibitor of lipolysis in adipose tissue -» I mobilization of FFAs to

liver -» 4* VLDL (after few hours).
• Since LDL is derived from VLDL, I VLDL -» I LDL (after few days).
• tHDL.
Therapeutic Uses
• Hyperlipidemia (t VLDL, t LDL).

• Severe hypercholesterolemia, combined with fibrate or cholestyramine.
-124-
BoodPharmacology
Adverse Effects (limit its use especially after introduction of statins)

• Cutaneous flush (PG-mediated; I by aspirin) & pruritus.
• GIT disturbance.
• Glucose intolerance.
• Gouty arthritis (hyperuricemia).

• Myopathy (rare).
E. Ezetimibe
• Inhibits intestinal cholesterol absorption.

• Used in hypercholesterolemia together with statins & diet regulation.
• Side effects: diarrhea - abdominal pain.
Combination Therapy
If no improvement within 6 weeks with a single drug, dose should be t. If no

improvement after 3 months, change the drug or consider combination therapy:
• Bile acid sequestrants can be safely combined with statins or nicotinic acid.
• Nicotinic acid + statins (cautiously -» myopathy).
• Fibrates (except fenofibrate) + statins (contraindicated -» myopathy).
• Ezetimibe + statins (synergistic effects).
125
BoodPliamBCoJogy
Newer agents for treatment of dvslipidemia19
1. Microsomal triglyceride transfer protein fMTP) inhibitors: Lomitapide

•Inhibit MTP (involved in formation of hepatic VLDL & intestinal
chylomicrons from TG) —> J,VLDL —>J,LDL accumulation in plasma.
•Use: restricted to patients with familial hypercholesterolemia through a
restricted program.
•Side Effects: accumulation of TG in liver, f transaminases , steatorrhea.
2. Anti-sense inhibidon of apo B 100 synthesis: Mipomersen

• i Level of LDL and Lp(a).
• SC injection available for familial hypercholesterolemia through a
restricted program
3. Cholestervl estertransfer protein (CETP) inhibitors20: anacetrapib, evacetrapib

• T HDL and 1 LDL.
•Currently in phase 3 clinical trials.
4. AMP kinase activation:
t fatty acid oxidation

f insulin sensitivity
Inhibits cholesterol and TG synthesis.
19
Proprotein convertase subtilisin/kexin type 9(PCSK 9) inhibition: parenterally twice weekly -»
J LDL, TG, apo B100 and Lp(a). Under investigation because of established role of PCSK 9
in normal neuronal apoptosis and cerebral development.
20
Torcetrapib was withdrawn from clinical trials as it t cardiovascular events & deaths.
-126-
IV. Respiratory Pharmacology
By the end of this chapter, the student should be able to:
Classify antiasthma drugs into short-term reliever bronchodilators & long-term
controller anti-inflammatory dmgs.
Recall the management strategy for asthma according to the guidelines of the
global initiative for asthma(GINA).
Explain why short acting f32-agonists are 1st choice bronchodilators.
Explain why antimuscarinics are alternatives in patients intolerant to |32-
agonists or theophylline especially the cardiac & elderly.
Explain whytheophylline is considered a 2ndor 3rd line drug in asthma.
Explain why inhaled corticosteroids are first choice controllers while oral
steroids are reserved for resistant cases.
Explain why inhalation long acting p2-agonists have to be combined with
corticosteroids and are not to be given alone as controllers.
Explain why leukotriene antagonists are preferred in children.
Explain why cromolyns are controllers used in mild cases of asthma combined
with corticosteroids & are not given during acute attacks.
Describe the lines of management of status asthmaticus.
Classify antitussives according to theircentral or peripherl mechanisms.
Recall the advantages ofdextromethorphan .
Recognize the dangers of over the countermedication.
Ill
.:. >
Respiratory Pharmacology
RESPIRATORY PHARMACOLOGY
DRUG THERAPY OF BRONCHIAL ASTHMa|
• Bronchial asthma is a chronic inflammatory disease of the airways

(most commonly allergic), characterized by reversible bronchial
obstruction with bronchial hyper-responsiveness. ,
• Hyper-responsive bronchi constrict easily to a wide range of specific or
nonspecific stimuli (triggers) that are too weak to affect non- asthmatics
-> recurrent episodes of expiratory airflow obstruction with shortness of
breath, wheezes, chest tightness & cough, worsening at night & early
morning.
Causes of Bronchial Hyper-responsiveness
1. Remodeling
• Remodeling of bronchial wall results from repeated exposure to triggers

which results in repeated inflammation & repair of bronchial wall -»
epithelial damage & exposure of nerves to chemical mediators, collagen
deposition & wall thickening with narrowing of bronchial lumen.
• Remodeling -» hyper-responsiveness of bronchi which constrict easily to
endogenous (Ach & histamine) & exogenous stimuli -» recurrent attacks.
2. Autonomic Disturbance
• Bronchial hyper-responsiveness may also be due to:

1. t Vagal tone.
2. 4> p-adrenergic response to stress (l circulating epinephrine).
-129-
Types of bronchial asthma according to triggers
1.1 Antigen-induced asthma (most common): common allergens include

pollens, furred animal (cats, dogs), house dust mites, and cockroaches.
II. Non-antigen induced asthma
• Cold air or exercise- induced asthma.
• Viral chest infection-induced asthma.
• Aspirin-induced asthma.
• Asthma associated with COPD .
Pathogenesis of Asthma
(Multifactorial)
• Patients with antigen induced asthma have f IgEantibodies (genetic).
• Inhalation of allergen by patients with hyper-responsive bronchi triggers
an attack which consists of 2 phases:
I. Immediate Phase (bronchospasm^:
• Starts 10 min after exposure to antigen, reaches a maximum at 30 min &

resolves within 1 to 3 hours, spontaneously or with treatment.
• Exposure to a specific antigen (pollens,....) -» antigen-antibody (IgE)
interaction at the surface of mast cells -* release of chemical mediators
(histamine, 5-HT& bradykinin - LTs C & D) -* bronchospasm.
N.B.: In other types, non-allergic factors (virus, cold, aspirin,...) serve as

triggers.
1COPD (chronic obstructive pulmonary disease): an inflammatory disease which is

mainly due to smoking & pollution. It is characterized by airflow limitation that is not
fully reversible. It includesemphysema, (destruction & distention ofalveoli); chronic
bronchitis (chronic cough & sputum; mucus hyper-secretion) and small airways
disease (small bronchioles are narrowed) -» chronic cough, dyspnea & wheezes with
chest hyperinflation & diaphragmatic fatigue.
-130-
II. Late Phase (sustained bronchospasm & inflammation)

• Due to continuous antigen exposure or refractory bronchoconstriction;
starts 3 hrs after exposure, is maximum in 8 hours & resolves in 24 hrs.
• Continued exposure to antigen or other triggers also releases cytokines
(interleukins - TNFa...) from lymphocytes & mast cells -* attraction &
activation of neutrophils & eosinophils in bronchial mucosa -» release of
inflammatory mediators (LTs - PGD4 - TXA2 - PAF- adenosine) -»
1. Sustained bronchoconstriction. "\ Clinical Picture
2. Thickened mucosa due to: I Bronchial obstruction
VD - edema - inflammatory cell influx. I results in wheezes,
3. Hyper-secretion of viscid mucus in lumen. dyspnea & cough.
Drugs Used in Bronchial Asthma1

+ *
Short-term Relievers Long-term Controllers
(Bronchodilators) (Anti-inflammatory Drugs)

As needed Daily (except omalizumab &Anti-IL)
Relieve acute bronchospasm 4> Hvper-responsiveness - I Recurrences
• Short-acting 02-agonists •Corticosteroids (most effective).

(SABA) •Long-acting & agonists (LABA) plus
•Antimuscarinics. steroids, notalone2.
Short-acting theophylline. •Leukotriene pathway Inhibitors.
•SR theophylline (long-acting)
•Cromolyn & nedocromyl.
•Omalizumab(every2-4 weeks).
• Anti-IL5/5R- Anti-IL4R (every 4-8 weeks)
1LABA are Is' choice "add -on therapy" to steroids, given separately or in acombination inhaler
device. Adding LABA, theophylline or LT antagonists | need for increasing corticosteroid dose.
-131
Avoid
Triggers Triggers
' \===S ^ Antigen ) f Virus 1 fsmokingl
11\ perresponsive Bronchi

due to
Wall Autonomic
Remodeling Disturbance
t Vagal tone
1 Epinephrine
Anti-inflammatory
Long-term
controllers
£ Bronchodilators
Short-term
• I Bronchial Earlj Phase
Relievers
hyper- Bronchospasm
responsiveness.
• 4 Recurrence.
Late Phase
Sustained bronchospasm
&
Inflammation
Pathophysiology of Bronchial Asthma & its Management
-132-
Classification of Astl
Asthma1 &its Management
f
Intermittent Persistent
Controlled Asthma" (mild, moderate, severe)

"Partlycontrolled & uncontrolled
S step strategy for management of asthma (according toseverity)
Step 1: (for controlled asthma). As-needed reliever in
• As needed Low dose ICS (budesonide)- formoterol. all steps:
• Alternatives:
low dose ICS/
- Low dose ICS whenever SABA is taken. formoterol as
formoterol has rapid

Step 2
onset with rapid relief.
• Initially:
Alternative:
- Low dose ICS.
Short acting P2 agonist
- OR Asneeded Low dose ICS (budesonide)- formoterol.
(SABA)
• Alternatives:
- LTantagonist.
- Low dose ICS whenever SABA is taken.
Step 3
• Initially: Low dose ICS + LABA.

• Alternatives:
- Medium dose ICS
- LowdoseICS+ LTantagonists.
Asthma isclassified into: intermittent & persistent (mild, moderate& severe) according to:
i. Broncho-constricrive episodes: < 2 days /week, > 2 days/week but not daily, daily,
continual, respectively,
ii. Night time symptoms: <2 days/ month, 34 times/ month, >1time/week but not daily,
sometimes every night, respectively.
iii.Peak expiratory flow: near normal inintermittent &mild persistent, 60-80% of normal
inmoderate persistent and <60% of normal insever persistent.
-133
Step 4
• Initially: Medium dose of ICS + LABA.

• Alternatives:
- High dose ICS.

• Add-on:
- Tiotropium (> 6 years).

- OR LT antagonist.
Step 5
• Initially: High dose of ICS + LABA.
• Add-on:
- Tiotropium.
- Anti-IgE (omalizumab) (> 6 years).
- Anti-IL5 /Anti-IL5R2
-Anti-IL4R (> 12 years)3.
- Other controller: add-on Oral CS but consider side effect.
NB.:
•
Cromolyn & nedocromil sodium are rarely used. May be used in
long-term control of mild persistent asthma (plus ICS); never alone.
Theophylline is not recommended by several guidelines especially in
children below 12 years.
2
Anti-IL5: mcpolizumab (SC) (> 12 years), reslizumab (IV) (> 18 years).
- Anti-IL5R: benralizumab (SC) (> 12 years).
Uses: add-on therapy" in severe uncontrolled allergic asthma uncontrolledon high dose
ICS/LABA. Adverse effects: headache, injection site reaction.
Duplimab (SC). Add-on therapy" in severe uncontrolled allergic asthma uncontrolled on high dose
ICS/LABA or requiring maintenance OCS. Side effects: injection site reaction, eosinophilia.
-134-
Individual Drugs
A. Bronchodilators
1. Adrenoceptive Agonists.
2. Antimuscarinics.
3. Methylxanthines (Theophylline).
2. Muscarinic
Antagonists
1. fc Agonists Muscarinic
receptors Vagus n.
Tone
© adenylyl
cyclase
P2
receDtors
tcAMP
Tone
Adenosine
receptors Adenosine
0PDE Tone
v-<. "
3. Theophylline Blocks adenosine
receptor
Control of Bronchial Tone & Site of Action of Bronchodilators
• Bronchial tone is relaxed by circulating epinephrine

acting on p2 receptors (no adrenergic innervation).
• NO is the main inhibitory neurotransmitter for bronchial
smooth muscle.
135-
1. Adrenoceptor Agonists
Selective 02 Agonists
Mechanisms of Action
• Stimulate p\j receptors increasing intracellular cAMP. They induce:

1. Bronchodilation.
2. Inhibition of release of mast cell mediators &cytokines.

3. Increased bronchial mucociliary clearance.
• Long acting B2 agonists (LABAs) potentiate anti-inflammatory effects of
corticosteroids (fnuclear localization of steroid receptor) -» t asthma
control.
Classification & Uses of Selective fc Agonists8

I
Short-Acting Long-Acting
Salbutamol (albuterol) -Terbutaline Salmeterol - Formoterol
(Inhalation-oral - IV) (Inhalation)
• Rapid onset & short acting (4 hrs) -» • Slower onset & long acting (12
used as short-termrelievers by hours) -* used as control
inhalation ("as needed") in: medication in:
1. Asthma. 1. Asthma (+ corticosteroids).
2. COPD. 2. COPD (maintenance).
» Prophylactic in exercise induced Prophylactic in exercise induced
asthma (inhaled 10 min before asthma (inhaled 1 hour before
exercise). exercise •* longer protection).
ft
Short acting oralf52 -agonists areusedin children who cannot use inhalers.
Long acting agents arelipid soluble —• dissolve in smooth muscle membrane.
Formoterol (rapid onset) —*• can be also used asrescue medication (+ ICS).
136-
Adverse Effects of Selective B, Agonists (less with inhalation therapy)

1. Tremors (mostcommon) - anxiety.
2. Tachycardia (high cone. -* stimulate Pi receptors).
3. Tolerance; down regulation of P receptor with regular use.
4. Hypokalemia and muscle cramps
5. Hypoxemia: iflung ventilation/perfusion ratio worsens (p2 stimulation •*

vasodilation more than bronchodilation -» insufficient blood oxygenation).
N.B.:
• Inhalation LABAs (salmeterol, formoterol) are commonly given in a

combination inhaler device with corticosteroids since they should notbe given
alone as controller medication as theiranti- inflammatory effect is insignificant
& their bronchodilator effect masks the progression in asthma severity -*t
risk of mortality.
• Oral LABAs (SR salbutamol, SR terbutaline &bambuterol. prodrug ofterbutaline)
may be used as controllers ifadditional bronchodilation isneeded.
Non-selective Adrenoceptor Agonists
Epinephrine (a Pi P2)
• Largely replaced by selective p2 agonists due to:
- Shorter action.
- Non-selectivity -*
1. Pi effect -» dangerous tachycardia & arrhythmia.
2. a Effect -»t BP
• Mainly used in acute attacks of bronchospasm especially in

anaphylaxis (—• rapid P2 bronchodilation, Pi cardiostimulant & cti VC;
decongestant effects).
Ephedrine
• Rarely used due to CNS side effects & availability of more effective agents.
-137-
2. Antimuscarinic Drugs
Members
Short-Acting Long-acting
Ipratropium Tiotropium
• Atropine substitutes; antagonists on bronchial muscarinic receptors.

• Given by inhalation alone or with p2 agonists, with minimal systemic
adverse effects ofatropine (quaternary compounds poorly absorbed).
Mechanism of Action
• Block M3 receptors in bronchial musculature -» blockade Of vagally-

mediated bronchospasm and mucus secretion.
Indications of Ipratropium
1. Bronchodilator of choice in:
• Asthma induced bypsychogenic stimuli or P-blockers.

• Asthmatic patients intolerant to the tachycardia oranxiety of p2-agonists or
theophylline especially cardiac, elderly &thyrotoxic patients.
2. Acute severe asthma (adjuvant to p2 agonists).
3. COPD (responds better than asthma9).
Disadvantages of ipratropium
1. Tolerance: blocks presynaptic M2 receptors on cholinergic nerve terminals -»

fACh release, reducing its effectiveness.
2. Delayed onset of action & less effective than P2 agonists in asthma.
Tiotropium
• Long-acting antimuscarinic used as maintenance therapy in COPD.

• Advantage: its use is not associated with tolerance.
9Since vagal- induced bronchospasm is the only reversible cause ofbronchial obstruction in COPD.
-138-
3. Methylxanthines
• Methykanthines include: caffeine, theophylline and theobromine that are
present naturally in coffee, tea, cola, cocoa and chocolate.
• Caffeine is more selective on CNS & cerebral vessels while theophylline
is more selective on smooth muscles.
Mechanisms of Action (not completely understood)

1. Inhibit phosphodiesterases -» t intracellular cAMP resulting in:
a. Direct bronchodilation.
b. Anti-inflammatory -»
- I Mast cell mediators release.
-1 Cytokines -* inhibit late asthmatic response.

2. Blockadenosine receptors -» bronchodilation.
Pharmacokinetics
• Xanthine bases and their salts are absorbed from GIT.

• 90 % metabolized in the liver by cytochrome p 450.
• Saturable kinetics-*T risk of toxicity
Factors Affecting Theophylline Clearance

Requiring Dose Adjustment
r \
t.» & Serum level t t in tin & Serum level i i in
• Neonates & elderly. • Children.
• Hepatic disease & heart failure. • Heavy smokers.

• Viral infections. • Heavy drinkers
• Enzyme inhibitors: • Enzyme inducers:
Erythromycin- oral contraceptives Rifampicin - phenobarbital,
Ciprofloxacin -zileuton-zafirlukast. phenytoin - carbamazepine.
*Dose ^ Dose
-139-
Actions- Adverse Effects & Precautions ofTheophylline
Pharmacological Actions Adverse Effects -
Precautions
1. Anti-asthma effect
• Bronchodilation -* relieve acute bronchospasm.

• Anti-inflammatory (modest effect) -> control
chronic asthma.
2.Skeletal muscle
• t Contractility &reverse fatigue ofdiaphragm

in COPD-» I dyspnea.
3. CNS stimulation • Headache.
• Alertness- insomnia - nervousness. • Insomnia- Anxiety.

• Tremors - convulsions (high dose). • Convulsions.
• Respiratory stimulant.
4. CVS
• +ve inotropic & chronotropic -» sinus »Tachycardia & arrhythmias.

tachycardia & arrythmia (high dose). »Cardiac arrest11—•give
• Vasodilation in high doses -» hypotension 10
slowly IV.
• VC of cerebral blood vessels. • Hypotension.
5. GIT • Anorexia- nausea ,vomiting
• t HC1. (give with meals; CI peptic
• Gastric irritation. ulcer.
• Proctitis (suppositories).
6. Kidney: weak diuretic action.
7. ^ Risk of toxicity: Monitor serum level -
• Narrow safety margin & saturation kinetics. adjust dose (see kinetics).
10 Low dose caffeine in soft drinks -»t CA-* VC -*t peripheral resistance -» slight t BP.
" Cardiac arrest is due to stimulation ofcardio-inhibitory center.
-140-
Disadvantages of theophylline
Theophylline is considered a2nd or 3rd line drug in asthma due to:
1. Saturation kinetics requiring drug monitoring (therapeutic level 10-20 mg/L).
2. Narrow safety margin.
3. t Risk of drug interactions.
Advantages of theophylline
1. Cheap.
2. Can be given by many routes.
Indications
1. Bronchial asthma (as a2nd or 3rd line drug)

i. Short-term reliefof acutebronchospasm (short-acting preparations),
ii. Long-term control, especially nocturnal asthma (SR Theophylline),
iii. Acute severe asthma.
2. COPD (bronchodilator & reverses diaphragmatic fatigue).
3. Respiratory stimulant in neonatal apnea (caffeine is also used)
Preparations
• Aminophylline is a combination of theophylline & ethylenediamine

to increase its solubility. Can be given by many routes: orally, rectally
or slowly IV (loading dose followed by IV infusion).
• SR Theophylline: slow-release preparations are long-acting (given
orally once or twice/ day) -» less fluctuation ofplasma level -
effective as control medication & in nocturnal dyspnea.
• Low dose theophylline: provides full anti-inflammatory effect -»
less frequent side effects —• no need to monitor level.
-141-
B. Anti-inflammatory Drugs
• The goal of asthma treatment is to achieve and maintain clinical control
(by suppressing inflammation using long term controller medication).
Long term controllers include
1. Glucocorticoids.
2. Long-acting p2 agonists plus steroids, not alone.

3. Leukotriene pathway inhibitors:
- 5-Lipo-oxygenase inhibitors -» Zileuton.
- LT Receptorantagonists -* Zafirlukast- Montelukast.
4. SR Theophylline.
5. Cromolyn & nedocromil.
6. Omalizumab.
Phospholipids
Phospholipase A2 e Glucocorticosteroids
Arachidonic Acid
5 - Lipoxygenase @ Zileuton
Leukotrienes
Zafirlukast
LT receptor © Montelukast
1
Inflammation
&
Bronchospasm
Anti- inflammatory Drugs Acting on Arachidonic Acid pathway
142
1. Glucocorticoids
Mechanism of Action
1. Immunosuppressive & anti-inflammatory

• 4, Cytokines & inhibit phospholipase A2-» I influx of inflammatory
cells & I mediators release -» I bronchial inflammation & hyper-
responsiveness -» 4 recurrence of attacks.
2. Potentiate p2 agonists
• I Tolerance to p2 agonists by 1 down regulation of p2 receptors.
Indications in Asthma (mainstay of asthma therapy)
1. Control Medication
• Given by inhalation.
• Severe cases may require oral administration (in early morning to
coincide with circadian rhythm of CS to I adrenal suppression).
2. Rescue medication in acute exacerbations not responding to p2 agonists
(oral 7-day course).
3. Acute severe asthma, (oral or IV).
Preparations and Routes of Administration
1. Inhalation:
Beclomethazone - budesonide - fluticasone - mometasone.
Ciclesonide:
• Prodrug, activated by bronchial esterases.

• High 1st pass metabolism & tight plasma protein binding -* less systemic
side effects
• Less frequent candidiasis.

2. Oral: prednisone - prednisolone.
3. Parenteral: methylprednisolone - hydrocortisone.
-143-
Adverse Effects
Minimized bv:
1. Oropharyngeal candidiasis. Gargling & spitting following
2. Hoarseness of voice.
3. Cataract - glaucoma.
} inhalation.
Use "spacer device".
4. Osteoporosis
5. Retardation of growth.
Systemic side
6. Hypertension.
>- effects with oral
7. Diabetes.
therapy, reduced by
8. Cushing syndrome.
inhalation.
9. Adrenal suppression.
-144-
2. Leukotriene Pathway Inhibitors
Mechanism of Action
1 r
Zileuton
• 5-Lipooxygenase inhibitor -» 4 LTs Synthesis.

• Not commonly used due to liver toxicity & frequent dosmg .
Zafirlukast-Montelukast
• LTs receptor antagonists -> bronchodilation &anti-inflammatory

effect.
Indications
1. Control medications in persistant asthma

• Alternatives to inhaled steroids in mild persistant asthma (for
patients intolerant to steroids orcannot use inhalers)
• Added to steroids in moderate or severe persistant asthma.
2. Drug ofchoice for control ofaspirin-induced asthma (responds well to LTs
antagonists since it is due to t LTs production from arachidonic acid
through lipooxygenase pathway following blockade of cyclooxygenase
pathway by aspirin).
3. Inhibit exercise-induced asthma if given before exercise.
Advantages
1. Oral therapy (easier than inhalation especially in children).

2. Long duration of action.
3. Well tolerated (minimal side effects).
Adverse Effects
1. Headache.
2. Dyspepsia.
3. Drug interactions due to enzyme inhibition (zafirlukast).
12 Acontrolled release preparation for twice daily administration isnow available.

-145-
3. Cromolyn & Nedocromil Sodium
Mechanism of Action (weak anti- inflammatory)
1. Inhibit mast cells degranulation -* inhibit release of mediators -» inhibit
early response to antigen (mast cell stabilizers).
2. Inhibit eosinophil activation -» inhibit late inflammatory response to antigen.
Actions & Uses (aerosol or microfine powder)
• Prophvlacticallv: Inhibit antigen & exercise-induced asthma if
inhaled shortly before exercise or before an unavoidable exposure to
an antigen (ineffective during an acute attack).
• Chronic use (4 times /d): long-term control of mild persistent asthma
(plus ICS) -» 4- bronchial hyper-responsiveness -» I recurrence of
acute attacks.
• Other uses: allergic rhinoconjunctivitis (nasal spray/eye drops).
Adverse Effects (limited to site ofadministration as itis poorly absorbed)

1. Throat irritation - cough - bronchospasm (with microfine powder; I by prior
inhalation of p2 agonists).
2. Stinging in the eye (with eye drops).
Ketotifen (relatedto cromolyn)

• Mast cell stabilizer & antihistamine; infrequently used in asthma.
4. Omalizumab
• Humanized anti IgE monoclonal antibody.

• Binds to circulating IgE -* inhibits binding of IgE to mast cells.
• Used subcutaneously13 as "add-on therapy" in severe uncontrolled allergic
asthma (ttlgE)-* I frequency & severity of exacerbations.
Adverse Effects: t risk of anaphylaxis.
13 Every 2 or4 weeks.

-146
Management of Acute Exacerbations
Acute exacerbations may be mild moderate or severe.

1. Mild acute Exacerbation
• Give inhaled short acting P2 agonists14

2. Moderate acute Exacerbation
• Add oral corticosteroid (for 5-7 days) if incomplete response to P2
agonists & continue the P2 agonist.
3. Severe acute Asthma (Status Asthmaticus)
• A severe acute attack precipitated by infection, emotions or allergy.
• It is refractory to the usual lines of treatment due to down regulation of P
receptors, mucus plug andacidosis.
• It is an emergency condition requiring hospitalization for:
1. Endotracheal intubation and suction of bronchial secretion.
2. Humidified oxygen inhalation.
3. IV fluids, correction of acid-base balance, electrolytes & dehydration.
4. Drug theranv includes15

a. Salbutamol inhalation16 ± ipratropium inhalation.
b. Systemic glucocorticosteroids:
-Oral prednisone (if patient can swallow) continue for 5-7 days.
-Methylprednisolone IV injection (switch to oral when possible).
c. Aminophylline IV infusion (may also be given in severe cases???).
d. Artificial respiration (ifno response)17.
e. Antibiotics for infection - avoid sedatives (depress respiration).
14 Up to 3 doses of 2-4 puffs at 20min intervals, then /3 hrs for 24-48 hrs.
15 Mg sulphate may be used intravenously in patients who failed to respond to other drugs
16 Salbutamol may also be given iv
17 Halothane may begiven to induce bronchodilation
-147
Respiratory Stimulants
A. Specific Stimulants (specific antagonists)

• Flumazenil: reverses benzodiazepine - induced respiratory depression.
• Naloxone: reverses morphine - induced respiratory depression.
B. Nonspecific stimulants (analeptics^
• Awaken patients from deep sleep &anesthesia, stimulate respiratory center
(directly orreflexly) & induce convulsions inhigh doses.
Members & Uses
• Doxapram (largely replaced by artificial respiration -»• safer) used in:

1. Acute respiratory failure inCOPD with hypercapnea &drowsiness.
2. Postoperative respiratory depression (accelerates post anesthetic recovery).
• Caffeine - aminophylline: in neonatal apnea.
QIrritant NH3 vapor: in psychotic fainting (stimulates olfactory nerves ->
reflex stimulation of respiratory center.
Drugs Contraindicated in Bronchial Asthma
.&
COPD
1. P-blockers: propranolol
2. Histamine liberators: morphine, hydralazine, tubucurarine...
3. NSAIDs: aspirin, indomethacin
4.Cholinomimetics: neostigmine
-148
DRUG THERAPY OF COUGH
• Cough is a physiological protective reflex through which excessive

bronchial secretion (mucus) or foreign bodies are expelled outside
respiratory tract.
• It occurs due to stimulation of irritant cough receptors in respiratory
passages or outside (esophagus, heart or ears).
• Cough reflex iscontrolled bycough center inthe medulla.
Management of cough:
I. Specific treatment: treatment of cause.

II. Nonspecific treatment: antitussives - mucolytics - expectorants.
• Nonspecific drug therapy is indicated if cough is not resolved, causing
insomnia, fatigue or bladder incontinence or in patients undergoing eye
surgery.
Causes of cough & their Specific Therapy

1. Acute cough18: upper respiratory viruses irritating respiratory tract receptors.
2. Chronic persistent cough:
• Smoking -» stop smoking to avoid bronchial irritation & mucus
hypersecretion.
• Rhinosinusitis -» decongestants & antihistamines -» 4> postnasal
discharge (drip) irritating cough receptors.
• Asthma - COPD -» bronchodilators.
• Reflux esophagitis -» anti-reflux drugs reduce reflux of HC1 thus

reducing itsstimulatory effects oncough receptors in esophagus.
• ACE inhibitors -» nifedipine; calcium channel blocker.
• Other causes of chronic cough: lung tumors...
18 Cough lasting < 3 weeks. It stops after infecton resolves.

-149-
Nonspecific Drug Therapy of Cough
' '
''
Dry nonproductive cough Productive cough
* *
Treated by antitussives Treated by mucolytics
(cough suppressants) & expectorants
Antitussives (Cough Suppressants)

A. Central Antitussives (in moderate to severe cough)
I. Opioid antitussives:
1. Codeine
• Opioid antitussive with moderate analgesic effect.

• Inhibits cough center in the medulla.
Side Effects
a. Drowsiness.
b. Paradoxical excitement (in children below 6 years).

c. Mild dependence.
d. Constipation (on chronic administration).
e. Respiratory depression (when used in large doses as analgesic).
2. Pholcodeine
• Semisynthetic opioid derivative with fewer adverse effects than codeine.

3. Dextromethorphan
• Selective opioid antitussive, inhibiting cough center in medulla.

• Preferred to codeine due to reduced liability for dependence , constipation
or respiratory depression (in antitussive doses).
-150-
II. Antihistamines (Diphenhydramine)

• Sedative antitussives (sedation reduces sensitivity of cough reflex).
• Anticholinergic effect contributes to antitussive effect therefore better
than newergenerations of antihistamines.
• Side effects: sedation - anticholinergic effects (dryness of secretion).
In bronchiectasis (suppurating bronchial inflammation) or

chronic bronchitis, antihistamines-* harmful sputum
thickening & retention. Thus mucolytics are used.
B. Peripheral Antitussives
• Used to treat mild & moderate dry cough, e.g. sore throat & laryngitis.
1. Volatile oils (menthol and camphor) and liquorice

• Protect respiratory tract irritant receptors by a mucin layer (demulcents).
• Given as lozenges or compressed tablets that dissolve in mouth.
• May be inhaled in a hot steam.
2. Benzonatate
• Has local anesthetic effect on pulmonary stretch receptors and irritant

receptors in respiratory mucosa.
N.B.: Cough syrup or glutinous sweets with no cough medication possess a

soothing effect on irritant receptors (demulcents).
-151-
Treatment of Productive Cough
1. Expectorants
• Expectorants liquefy bronchial secretion by increasing its volume (except

aromatic) & reducing its viscosity, thus facilitating sputum removal
through coughing.
• They stimulate bronchial secretion either directly by acting on bronchial
glands or reflexly through gastric irritation.
Members
1. Guaifenesin: gastric irritant; given with a full glass ofwater.

2. Aromatic: volatile oils in water vapor: menthol - tine, benzoin or tolu.
3. Nauseant: syrup ipecac- ammonium chloride or carbonate.
4. Alkaline: Na+, K+ acetate or citrate.
5. Na+ & K+ Iodides:
• Expectorants: stimulate bronchial glands directly &reflexly.
• Mucolytics: enhance proteolytic enzymes in mucus.
Adverse Effects of iodides
1. Respiratory irritation (CI: acute bronchitis &asthma).

2. Gastric irritation
4. Iodism: excessive secretions ofexocrine glands (lacrimal,
salivary...).
5. Spread of infection inTB (CI: TB bronchitis).
-152
2. Mucolytics
• Mucolytics decrease viscosity ofbronchial secretion; potentiating expectorants.
Mechanism of Reduction of Mucus Viscosity by Mucolytics
1
Acetylcysteine Bromhexine
Carbocvstiene
Break disulfide bonds Depolymerizes mucus

of thick mucus. mucopolysacharide
ground substance.
Indications of Mucolytics (oral - inhaled orinstilled in tracheostomy tube)

1. As mucolytics in:
- Asthmatic bronchitis - COPD - Bronchiectasis.
- Pulmonary cystic fibrosis19 - Care oftracheostomy.
2. Paracetamol toxicity: acetylcysteine (supplies liver with SH-group to
conjugate paracetamol metabolites).
Adverse Effects of Mucolytics

1. Gastric irritation.
2. Hypersensitivity
3. Bronchospasm (acetylcysteine).
Water vapor inhalation is an excellent expectorant and mucolytic.
,9Dornase alpha (recombinant Human DNase): a mucolytic that cleaves DNA ofinvading
neutrophils in mucus is used incystic fibrosis.
-153-
Cough Mixtures and Cold Remedies
• Cough mixtures and cold remedies are over the counter medications (OTC)
i '
used in cases of common coldand cough.
• Thev contain several of the following ingredients:
• Antitussives-» dextromethorphan.
• Expectorants -* guaifenesin.
• Mucolytic -> bromhexine.
• Bronchodilators -» salbutamol.
• Decongestants -» phenylephrine - pseudoephedrine - nasal

oxymetazoline- naphazoline.
• Antihistamines -* diphenhydramine.
• Analgesics -^paracetamol (caffeine may be added as adjuvant).
Disadvantages of Cough mixtures and Cold remedies

1. The use ofunnecessary medications in the mixtures (it is better to treat each
symptom of common coldseparately).
2. Hidden ingredients may be dangerous or may result in drug interactions:
• Decongestant sympathomimetics are dangerous in hypertensives or may
increase BP dangerously in patients on MAOIs.
20
Their presence inthe preparation may not be expected.
-154-
V. GASTROINTESTINAL PHARMACOLOGY

By the end ofthis chapter, the student should be able to:
• Identify different groups of drugs used in peptic ulcer disease and describe
their mechanisms of action & adverse effects.
• Discuss the advantages ofproton pump inhibitors over H2 antagonists.
• List different drugs used in various types of vomiting and identify the
receptors withwhich they interact.
• Recognize the importance of metoclopramide as a widely used antemetic, its
adverse effects & the advantages of domperidone overit.
• Identify at least 2 drugs commonly used as antidiarrheal agents.
• List 4 drugs with different mechanisms ofactions that are used as laxatives.
• Discuss the choices of drugs used in different causes of constipation.
• Discuss the choices of drugs used in irritable bowel syndrome according to its
different presentations.
• Discuss the different mechanisms bywhich dmgs used in bleeding esophageal
varices act.
Gastrointestinal Pharmacology
GASTROINTESTINAL PHARMACOLOGY
DRUG THERAPY OF ACID - RELATED GIT DISEASESi
• Acid-related GIT diseases occur in 25% of adult people. They are induced or
aggravated by gastric HC1. The most important of these diseases are:
A. Peptic Ulcer (PU)

1. Duodenal ulcer (DU): the most common type; caused by | HC1 &
chronic Helicobacter pylori (H. pylori) infection.
2. Gastric ulcer (GU): usually caused by chronic NSAIDs therapy.
3. Stress ulcer: caused by severe medical or surgical stress.
4. Zollinger-Ellison syndrome: f HC1 secretion by a gastrin- producing
tumor —*• multiple ulcers.
B. Acute gastritis and gastric erosions (in children).
C. Gastroesophageal Reflux Disease (GERD)
• More common than peptic ulcer.
• Reflux symptoms (e.g. heart burn) occur in 50% of people.
Regulation of HC1 Secretion
• The parietal cells in gastric mucosa contain receptors for the three main
stimulants for HC1 secretion: gastrin (G), histamine (H2) & ACh (M3)
• Activation of M3 & gastrin receptors on parietal cells —•Intracellular Ca2+
-> © proton pump (K7 H+ ATPase) ->T HC1 secretion.
• Activation of Mj & gastrin receptors on gastric enterochromaffin like (ECL
) cells —• © histamine release from ECL cells.
• Released histamine stimulates H2 receptors on parietal cells —> activation of

adenylcyclase —* fcyclic AMP —»• © protonpump.
• PGE2receptors activation in parietal cells —> J, histamine-stimulated c-AMP
production —• © proton pump —• J. HC1 secretion (PGE2 is protective).
-157-
Mi Gastrin receptor
Enterochromaffin-like Cell
\ Vagal Histamine
H2 antagonists
(+)
ACh H2 receptor
/ Gastrin receptor
M3
Parietal cell
Proton
pump
K+ rt
Misoprostol
Inhibitors
HCI secretion & Site of Action of Drugs inhibiting HCL Secretion
HCI secretion by proton pump (K / H ATPase) is stimulated by

gastrin, histamine (H2)& ACh (M3)& inhibited by PGE2.
Mi & gastrin receptors on enlerochromaffin -like cells release
histamine which acts on H2 receptors on parietal cells —»|cAMP
—> HCI secretion .
-158-
DRUG THERAPY OF PEPTIC ULCER
• Most cases of peptic ulcer are caused by:

i. H. pylori infection: a noninvasive, microaerophilic gram-negative organism
—• t gastrin-induced HCI secretion, gastritis and its toxin induces mucosal
damage,
ii. Chronic use of NSAIDs.
Integrity of Gastrodudenal Mucosa

Depends on the Balance between
Defensive Mechanisms Aggressive Mechanisms

• Mucus - bicarbonate. • HCI - pepsin - bile.
• PGE2 - blood supply. • H. pylori infection.
Risk Factors for PU
1. Stress.
2. Smoking: t HCI - | bicarbonate - induces VC (leading to ischemia)

antagonizes acid suppressive drugs.
3. Alcohol - caffeine - theophylline (mucosal irritants -| HCI)
4. Drugs decreasing PGs: NSAIDs - corticosteroids.
-159-
Pathogenesis of Peptic Ulcer & Lines of Treatment
Peptic Ulcer results from an imbalance between aggressive & defensive

mechanisms in gastric or dudenal mucosa:
1. f HCI secretion: treated by —> antisecretory drugs (proton pump inhibitors

-H2 antagonists - anticholinergics & misoprostol) - neutralization of
secreted acid (antacids).
2. Infection with H. pylori: treated by —> anti H. pylori therapy (antibiotics
plus antisecretory drugs with or without bismuth).
3. Inadequate mucosal defense against HCI: treated by —> mucosal or
cytoprotectives (sucralfate, misoprostol and colloidal bismuth).
Treatment of gastric ulcer

1. Treatment with anti-secretory drugs is the main line.
2. Mucosal protective drugs & antacids are rarely needed.
Treatment of duodenal ulcer

1. Treatment with anti-secretory drugs.
2. H. pylori eradication therapy.
3. Mucosal protectivedrugs & antacids are rarely needed.
-160-
GastrointestinalPharmacology
Anti - secretory Drugs

1. Proton Pump Inhibitors (PPIs)
Omeprazole - Lansoprazole- Pantoprazole - Rabeprazole - Esomeprazole
Mechanism of Action
•Act on the final step of HCI secretion. -> Most effective acidsuppressants.
•They are prodrugs which, upon absorption into circulation, reach parietal cells
& are convertedin the acid medium in secretorycanaliculi, into active form.
•Active form inhibits H+/K+ ATPase (proton pump) of parietal cells -> inhibits
H+ secretion into gastric lumen -»• \ gastric acid production .
• Inhibit basal & meal stimulated acid secretion (98% , 1-2 h after 1st dose).
•They possess anti- H. pylori effect1 (lansoprazole most potent).
Pharmacokinetics
1. Weak bases destroyed by gastric acidity & ionized in acid stomach (not readily
absorbed) —>given inenteric-coated form, readily absorbed in alkaline small intestine
2. Should be given about 30- 60 minutes before meals .
3. Food .[.bioavailability by 50% (so taken on empty stomach)3.
4. Repeated administration -*[ gastric acidity -»| bioavailability4.
5. Long duration (onset 1 hour & lasts for 24 hours (VA = lh but PPIs bind covalendy to
PP and synthesis of new pumprequires 24 hours.).
6. Metabolized in the liver.
12iy to inhibition of HCI secretion (which potentiates action of antibiotics) & direct inhibition
of a P-typeATPase enzyme in the bacteria.
2PPIs only inhibit active pumps. However, ina fasting state, only 10% ofpumps are actively
secreting acid and susceptible toinhibition. Administer PPIs ~ 1 hourbefore a meal, so that
peak serum concentrations coincide with maximal pump activity
3PPIs must be administered in the fasting state, when gastric motility is low. Bioavailability
is decreased approximately 50% byfood because larger amplitude movements crush the
protective coatings, exposing the prodrugs tothe stomach acid (which is inhigh concentration)
and causing them to be inactivated.
^Preparations ofPPIs are either single coated (enclosing the dosage form asa whole) ordouble
coated (coat enclosing drug particles andanother enclosing the dosage form). Double coating
ensures that the drug is not released in stomach. Preparations with single coating arc liable to
disintegrate instomach releasing the drug that isinactivated by gastric acidity. Repeated
administration of these preparations-* | gastric acidity -»t bioavailability
-161-
Adverse effects
1. GIT: abdominal pain, nausea, vomiting, diarrhea or constipation.

2. CNS: headache, dizziness, somnolence.
3. Hypochlorhydria -*
• t Risk of infection (e.g. hospital acquired pneumonia &H. pylori).
• Gastric tumor (in animals): bacterial colonization -* tcarcinogenic nitroso compounds.
4. Vitamin B12 deficiency (long term use)
5. Enzyme inhibition (clinically insignificant).
1. H2-Receptor Antagonists
Cimetidine - ranitidine - famotidine - nizatidine
Mechanism & Pharmacological Actions
• Reversible competitive antagonists of H2 receptors onparietal cells.

• Complete inhibition of histamine mediated but partial inhibition of ACh or
gastrin mediated HCI secretion.
• Potent inhibition of nocturnal or fasting but less inhibition of daytime
(meal-stimulated) acidsecretion5.
Individual H2 Antagonists
Cimetidine: 1st member developed, but its use is limited due to its enzyme
inhibiting, antiandrogenic & CNS side effects.
Newer members developed to minimize adverse effects of cimetidine6:
Ranitidine
• More potent than cimetidine, less enzyme-inhibiting & antiandrogenic effects.

• Anti-/f. pylori effect (most efficient).
• 50% bioavailability (hepatic first pass effect)
• 50% metabolized in liver(CI in hepatic dysfunction).
Nocturnal HCL secretion depends on HI, meal stimulated secretion depends on gastrin ,Ach & HI
'Nizatidine: 100% bioavailability (no P'-pass effect) -* used in liver dysfunction. Completely
excreted by kidney —> CI in renal dysfunction, no enzyme-inhibiting orantiandrogenic effects.
-162-
Famotidine
• The most potent.

• Cytoprotective effect.
• 50% decomposed by gastric acidity.
• 50% bioavailability.
• Excreted mainly by kidney (preferred in liver dysfunction).
• No enzyme-inhibiting or antiandrogenic effects.
Adverse Effects of H? Blockers
1. Headache, diarrhea or constipation.

2.Tolerance, rebound hyperacidity & recurrence (upregulation of H2 receptors).
3. CNS: sedation, confusion, hallucination7 (mostly with cimetidine).
4. Antiandrogenic, | prolactin, gynecomastia, galactorrhea, impotence (mostly
with cimetidine).
5. Enzyme inhibition —* drug interactions (mostly with cimetidine).
6. Hypotension & bradycardia ifgiven rapidly IV in intensive care8.
Advantages of PPIs over H? antagonists:

• Higher efficacy -> better symptomatic relief & higher response rates.
• More prolonged effect (= 24 hs—> given in single daily dose; versus twice
daily dosing with H2 antagonists).
• More effective in anti H. pylori regimen.
7Especially intheelderly orin renal orhepatic dysfunction.

8Block cardiac H2 receptors.
-163-
Indications of Antisecretory Drugs
1. Peptic ulcer
• PPIs are preferred especially in severe cases.
• H2 antagonists in mild or moderate cases (healing is delayed for 8 weeks
& recurrence is common).
2. Anti- H. Pylori regimens
• PPIs are preferred.
• Ranitidine bismuth citrate may be used.
3.GERD
• PPIs are preferred.

• H2 antagonists are used to cover the nocturnal HCI secretion.
4. Zollinger Ellison syndrome
• PPI are preferred.
• High dose of parenteral preparations are given early to cover vomiting period.
5. Stress ulcer: toJ, risk of bleeding.
6. Acute gastritis in children & gastric erosions. Parenteral
7. Bleeding oesophageal varices: to preventrecurrence. preparations
8. To avoid aspiration pneumonia during surgery.9
e.g. obstetric anaesthesia before caesarian section.

-164-
Mucosal Protectives
(Cytoprotectives)
1. Sucralfate
• It is an aluminium salt of sulfated sucrose.
Mechanism
1. In acid medium, the negatively charged sulfate groups bind to the

positively charged proteins in the ulcer base, forming a protective barrier
against acid, bile and pepsin (also inactivates the latter two).
2. Increases PG synthesis andmucus and bicarbonate secretion.
Uses
• Stress ulcer prophylaxis (mainly).
Adverse Effects
1. Nausea, vomiting and dry mouth.

2. Flatulence, constipation.
3. Al3+ toxicity: chelates phosphates -»• osteomalacia &encephalopathy in renal
diseases.10
Precautions
• Sucralfate is active only in gastric acid medium, so if antacids or H2

blockers are given they should be at least 1 hour apart (given on an empty
stomach, 4 doses/day; 3 in between meals & one before sleep).
• Binds some drugs (e.g. tetracycline) ->| absorption, so given at least 2
hours apart.
'"Since normally 5%of the drugis absorbed orally.
-165-
2. Misoprostol
Mechanism:
Synthetic PGE! analog; cytoprotective through:

• i HCI secretion (by acting on the PG receptors on parietal cells -> J,
histamine-stimulated c-AMP production).
• Increases mucosal blood flow -> stimulates mucosal renewal.
• Stimulates secretion of mucus & bicarbonate.
Uses
• Selective forNSAID-induced gastric ulcer (healing effect) ifPPIs fail.

• It is also given prophylactically with NSAIDs or corticosteroids.
Adverse effects
• Diarrhea & colic (most common).

• Vaginal bleeding &uterine contractions (CI in pregnancy-* abortion).
3. Colloidal Bismuth
Mechanism
1. Anti-//. pylori activity (main effect).

2. Mucosal protective:
Chelates proteins in ulcer base -• protective coat against acid &pepsin ( &
inactivates pepsin) -f mucosal bicarbonate , mucus & PG.
Use
• Anti- H. pylori therapy: as ranitidine bismuth citrate which dissociates in

stomach into bismuth (anti-//. pylori activity) &ranitidine (antisecretory).
Adverse Effects
1. Teeth &tongue discoloration - black stools (confused with bleeding).

2. Encephalopathy and neurotoxicity especially in renal disease.
Do not give for more than 2 months & do not restart within 1 year.
-166-
Gastrointestinal'Pharmacology
Anti-//. py/o/7'Drug Therapy

• Eradication of//, pylori infection results in rapid healing & J, recurrence.
• It is achieved by combination therapy with:
I. Antimicrobials:
1. Clarithromycin:
• Of choice due to better acid stability & efficacy (J, recurrence).
• In addition to its antimicrobial effect, it f plasma level of ranitidine
bismuth citrate (enzyme inhibitor).
2. Amoxicillin.
3. Metronidazole1 (in patients allergic to amoxicillin), tinidazole.

II. Acid suppressants (PPIs, or ranitidine bismuth citrate)
• Antibiotics alone are ineffective as organism hides inside mucus, under
epithelial folds to avoid HCI. If HCI secretion is suppressed; organism
comes out, multiplies -* tsusceptibility to antibiotics. Thus high dose acid
suppressants are included in anti-//. pylori regimens
III. Colloidal bismuth: bismuth subcitrate or subsalicylate.
High efficacy anti-//. pylori Triple therapy2
• 14 days: Lansoprazole + Clarithromycin + Amoxicillin (or metronidazole)3.

• Followed by 4-6 weeks: PPI therapy to allow ulcer heal.
Resistance is common due to | use in amocbiasis.

2Quadruple therapy (with added bismuth) may also be used.
Concomitant therapy: PPI + Amoxicillin+ Clarithromycin (bid)+ Metronidazole (tid)
-167
Antacids
• Antacids are weak bases that reduce gastric acidity by neutralizingHCL
1. Neutralize gastric acid (duration 1-2 hrs).

2. Decrease peptic activity (pepsin is inactive at pH > 4.5).
3. Reduce H. pylori colonization.
4. | mucosal PG production (promote defense mechanism).
5. Adsorbent (to pepsin, bile &toxins), astringent13 and demulcent14 effects
(with Al3+ &Mg2+ salts only).
Therapeutic Uses (taken 1 and 3 hours after meals & at bedtime)

1. Rapidly relieve pain & help healing of peptic ulcer.
2. Relieve dyspeptic symptoms.
3. GERD (rapid pain relief).
Drug Interactions
• Antacids can affect rates of dissolution, absorption, bioavailability and renal

elimination of many drugs through:
1. Changing gastric or urinary pH.
2. Delaying gastric emptying.
3. Chelation:
Al3+ salts can form insoluble complexes with fluoroquinolones,

tetracyclines, digoxin and iron salts —• J, absorption (do not give antacids
within 2 hrs from administration of these drugs).
13 Precipitate surface proteins.

14 Soothing effect onthe mucous membrane.
-168
Types of Antacids
£
Local Antacids Systemic Antacids
NaHCOg
AI* Hydroxide
Advantages
Disadvantage: constipation.
• Rapid onset.
Mg2* Salts • Potent (t pH > 7).
Disadvantage: diarrhea. Disadvantages
1. Systemic alkalosis on long-

Ca24" carbonate term use.
Disadvantages 2. Rebound hyperacidity.

1. Constipation. 3. Na+ content is dangerous in
2. Rebound hyperacidity (Ca2+ —• acid HF,hypertension or renal
secretion) —• Jpainrelief& healing. disease.
3. Milk-alkali syndrome (systemic 4. t C02 -»flatulence, eructation.

alkalosis - hypercalcemia). 5. Alkaline urine —• renal stones.
4. | C02 -• flatulance & emctation.
Choice of antacids15
• Al3+ hydroxide & Mg2+ salts do not result in C02 release or systemic
alkalosis thus they are the most commonly used antacids, alone or
combined (to neutralize the effects of each other on bowel habit).
• Antacids should be cautiously used in elderly & renal impairment since:
- Al3+ antacids —*• chelate phosphates thus may induce osteomalacia,
hypophosphatemia, encephalopathy & | risk ofAlzheimer dementia.
- Mg2+ antacids -* CNS depression.
15 Sodium bicarbonate is added for effervescent formulations (e.g. withranitidine) or in immediate release
PPI preparations (e.g. withomeprazole).
-169-
Precautions to Avoid NSAIDs-induced Ulcer

1. Use low doses and avoid combinations ofNSAIDs (| toxicity without added benefit).
2. Use topical preparations whenever possible.
3. Co-administer PPIs or misoprostol.
4. Avoid combination with corticosteroids except in selected cases.
5. Use cautiously in the elderly.
DRUG THERAPY
OF
GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Pathogenesis of GERD
• GERD involves involuntary regurgitation of gastric acid, pepsin & bile

from the stomach to the esophagus.
• The most important responsible mechanism is a defect in esophageal
motility -> Transient Lower Esophageal Sphincter Relaxations (TLESRs)
—• regurgitationof gastric contents.
• Adefect in gastric motility -> delayed emptying &subsequent reflux may
also be involved.
• Reflux may be asymptomatic if esophageal luminal clearance is normal but

if esophageal peristalsis is defective -* delayed clearance of acid -»
prolonged exposure ofmucosa to HCI, pepsin and bile -» mucosal damage.
• Symptoms: heart burn (mainly).
• Complications: dysphagia, esophagitis, ulcer, bleeding, stricture &cancer.
• Nonesophageal complications : cough ,asthma , laryngitis &chest pain.
Therapeutic Goals
• Symptomatic relief- healing ofesophagitis - prevention ofcomplications.

• Acid suppression is the most effective means ofsymptom relief and healing
ofesophagitis, but does not cure the disease. So there is high relapse rate.
170
Lines of Treatment of GERD
A. Life-Style Modification (delays or prevents recurrence)

1. Remaining upright or in a semisitting position for 2 hours after meals.
2. Elevation of head of patient during sleep.
3. Diet:
• J, Meal size (large meal —* distention of stomach —> j pressure gradient

between esophagus & stomach -* increasing reflux).
• Food to be avoided: citrus fruits (mucosal irritants) - fried or fatty food,
caffeinated drinks, chocolate, peppermint, spices (J. LES pressure).
4. Drugs to be avoided
• Anticholinergic drugs & tricyclic antidepressants (delay gastric emptying).

• Nitrates & calcium channel blockers (smooth muscle relaxants).
• Smoking, alcohol, caffeine.
B. Drug therapy of GERD (Combination Therapy)

1. Antacids containing alginic acid (regularly after meals):
• Alginate forms a floating gel which blocks the reflux & coats esophagus
-> rapid pain relief.
2. Acid-suppressive agents:
• PPIs (the main & most effective treatment).

• H2 antagonists are backup drugs. A night dose may be combined with
PPIs to cover nocturnal breakthrough in HCI release.
• Recurrence rate is very high thus usually combined with prokinetics.
3. Prokinetics (promotility agents), e.g. metoclopramide & domperidone:
• Increase gastric motility and emptying.
• Improve LES tone & esophageal motility —> I reflux & tluminal clearance.
4. Eukinetic drugs: inhibit transient lower esophageal sphincter relaxations
• Baclofen (GABA-B agonist).
171-
DRUG THERAPY OF VOMITING
• Vomiting may occur due to a variety of conditions, e.g. motion sickness,

pregnancy, drugs, radiation, GITdisorders, myocardial infarction, hepatitis.
Pathophysiology of vomiting (see figure on next page)

• The brainstem vomiting center is located in the medulla. It is rich in
muscarinic, histamine Hj and serotonin 5-HT3 receptors.
• Efferent impulses from this center coordinate movements of abdominal
skeletal muscles andsmooth muscles of the stomach —• vomiting.
• The vomiting center responds to afferent impulses from:
1. Chemoreceptor trigger zone (CTZ):
• Responds to chemicals in blood(drugs, toxins, and uremia) or

radiation therapy.
• It is rich in D2, 5-HT3, opioid and neurokinin-1 receptors.
2. Vestibular system:
• It is important in motion sickness.

• It is rich in muscarinic and histamine Hi receptors.
3. Viscera (GIT disorders, hepatitis and myocardial infarction):
• The vagal afferents in the GIT mucosa are rich in 5-HT3 receptors.
Irritation of gastrointestinal mucosa (e.g. by chemotherapy,
radiation therapy,...) causes release of mucosal serotonin and
activation of the 5-HT3 receptors which stimulate vagal afferent
impulses to the vomiting center and CTZ.
4. Higher centers
• Responsible for psychogenic & anticipatory vomiting due to

emotions, pain, sights & smells.
The CTZ is outside the BBB thus is accessible to drugs
172
Antiemetic Drugs
Antiemetic drugs act bv inhibiting inputs to vomiting center;

1. D2 antagonists: - metoclopramide - domperidone - promethazine
2. 5-HT3 receptor antagonists17: e.g. ondansetron,
3. Antihistamines: e.g. diphenhydramine, dimehydrinate, meclizine.
4. Anticholinergics: e.g. hyoscine.
5. Neurokinin-1 receptor antagonists: e.g. aprepitant
6- Sedatives: benzodiazepines e.g. lorazepam and diazepam.
NJB.: - Corticosteroids are potent antiemetics, with unknown mechanism.
- Dronabinol is a cannabinoid acting on opioid receptors in CTZ.
Receptors Involved in Vomiting Reflex & Site of Action of Antiemetics
SEDATIVES
II,
ANTAGONISTS Higher Centers
Motion
Anticipatory
sickness Vomiting
CTZ Drugs - Uremia

5-HT3 - D2 - Opioid Radiation
Vomiting center
- neurokinin-1 (M- H,-5-HT3)
Coordinates movements of stomach
Visceral & abdominal muscles
T Disorder
: ) GIT
: -y5-HT,
i
: D2-5-HT3-Neurokinin 1
: ANTAGONISTS
VOMITING
"' Other D2 antagonists: ilopridc

17 Othcrs:granisctron. dolasetron & palonosetron (has higher receptor binding affinity (better control of
acute cytotoxic-indnced cmesis (CIE) & longer t ,. (better control of delayed CIE). Repeated dosing
within 7days is not recommended.
-173-
Choice of Antiemetics (depends on the cause of vomiting)

I. Vomiting due to motion sickness (prophylactically better than curatively).
• HI antagonists: e.g. diphenhydramine, dimehydrinate, meclizine.
• Antimuscarinics: e.g. hyoscine (transdermal patch is better tolerated).
II. Vomiting due to drugs, toxins and uremia:
• D2 receptor antagonists e.g. metoclopramideand domperidone.
III. Vomiting due to cytotoxics (combinations of antiemetics are used)

• 5-HT3 antagonists: ondansetron (1st choice, prophylaxis & treatment).
• Corticosteroids potentiate ondansetron.
• DA antagonists: domperidone & metoclopramide.
• Neurokinin-1 antagonists: aprepitant.
• Sedatives (prior to cytotoxics to avoid anticipatory vomiting).
• Dronabinol (a cannabinoid).
IV. Postoperative & post radiation nausea & vomiting:
• Ondansetron - Metoclopramide.
V. Anticipatory and psychogenic vomiting: sedatives.

VI. Nausea & vomiting of pregnancy: [if clearly indicated to avoid teratogenicity]
• Meclizine + pyridoxine - doxylamine.
• Promethazine - metoclopramide - cortigen B6.
N.B.: cortigen B6 (a corticosteroid plus vit. B6) is used in manytypes ofvomiting.
Ondansetron (5-HT3 Antagonist)
• Selective 5-HT3 receptor antagonist in CTZ & vomiting center & in viscera.
Uses
1. Nausea and vomiting due to chemotherapy or radiotherapy.

2. Postoperative nausea and vomiting.
Adverse Effects
Headache - constipation - warm or flushing sensation in head or epigastrium.
174
Metoclopramide
• Most widely used antiemetic & prokinetic drug acting centrally & peripherally.
Mechanism of Action & Uses
1
Antiemetic Prokinetic
Central Peripheral
D2 antagonist in CTZ D2 antagonist & Cholinomimetic
Promotes gastricemptying bv:
• | Gastric motility& esophageal peristalsis.
• | Tone of LES- relaxes pyloric antrum.
Uses Uses
• Most causes of vomiting • GERD.
except motion sickness: • Gastric atony (delayed gastric emptying &

• Drug-induced. diabetic gastroparesis).
• Uremia or toxin-induced. • Endoscopy: facilitates GIT intubation.
• Radiation - induced. • GIT radiology (bariummeal).
• Postoperative vomiting. • Acute migraine attack: to accelerate gastric
• Vomiting in GIT disorders. emptying & facilitate absorption ofanalgesics.
Adverse effects
1. Central D2 antagonist effects

• Drowsiness & nervousness (common).
• Extrapyramidal adverse reactions (dystonia, parkinsonism...).
• {Prolactin, menstrual disturbances, galactorrhea, gynecomastia, impotence.
2. Peripheral prokinetic effect: diarrhea.
Domperidone (antiemetic & prokinetic)

• Similar to metoclopramide; less extrapyramidal effects (does not readily cross BBB).
-175
DRUG THERAPY OF DIARRHEA
• Diarrhea involves both an increase in the motility of GIT and a decrease in

the absorption of fluid resulting in loss of electrolytes and water.
• Diarrhea can be caused by infectious agents, toxins, food, anxietyor drugs.
• It ranges from mild cases to a major cause of death & malnutrition in
children.
Pathophysiology of diarrhoea:
• Osmotic diarrhea: due to saline purgatives or carbohydrate malabsorption

• Secretory diarrhea: due to exudation into GIT e.g. laxative abuse or
bacterial toxins as vibrio cholera & E. Coli.
• Motility diarrhea: due to disordered intestinal motility e.g. prokinetic drugs,

autonomic neuropathy or hyperthyroidism.
• Fatty diarrhea: due to malabsorption syndrome secondary to mineral oil or
bile salts/pancreatic secretion deficiency.
Lines of Management
1. Oral rehydration solution (ORS)18 in conscious patients, IV fluids in severe

cases (to correct fluid & electrolyte balance, more important than drugs).
2. Diet: avoid fat, milk, high fiber food.
3. Frequent fluid intake & tea (astringent, precipitates surface proteins).
4. Specific antimicrobial therapy against causative organisms:
• Floroquinolones for most bacteria except Clostridium difficile
• Metronidazole for Clostridium difficile, amoebiasis & giardiasis .
5. Symptomatic treatment: antidiarrheal agents.
18 In many small bowel diarrheal illnesses, intestinal glucose absorption via sodium-glucose co-
transport remains intact. Thus, the intestine remains able to absorb water if glucose and salt
are also present to assist in the transport of water from the intestinal lumen.
-176-
ANTIDIARRHEAL AGENTS
I. Antimotilitv Agents: diphenoxylate, loperamide (opioid- related)
Mechanism of Action
• Act on presynaptic opioid receptors in intestinal mucosa19 —• j ACh release

—> J, peristalsis allowing water andsaltto be absorbed back into thebody.
• Spasmogenic effect (t smooth muscle tone)with diphenoxylate.

Atropine is combined with diphenoxylate to:
1. Relieve its spasmogenic effect.

2. Discourage abuse (which mayoccur with prolonged use).
3. May contribute to the antidiarrheal action.
Advantages
• At therapeutic doses they do not crossBBB (act only peripherally).

• Loperamide is the least tocross BBB -* much lower abuse potential.
Uses
1. In mild to moderate acute diarrhea.
2. To control chronic diarrhea e.g. in irritable bowel syndrome (loperamide).
Overdose Toxicity (with diphenoxylate)

• CNS and respiratory depression.
• Paralytic ileus.
Contraindications
( 1. Severe colitis, bloody diarrhea, fever &systemic infection as they j GIT

motility and lead to retention of toxins —• toxic megacolon.
2. Acute gastroenteritis in infants and children (—> paralytic ileus &
respiratory depression).
19 Submucosal & myenteric plexus.

-177
II. Drugs increasing stool viscosity (less effective)

a. Adsorbents (pectin, kaolin,)
• Provide protective coat on intestinal mucosa.
• Adsorb toxic substances, bacteria & fluid -»J,stool liquidity.
• May interfere with absorption of otherdrugs.
b. Bulk forming
• Methylcellulose —•jstool liquidity
III. Colloidal bismuth compounds
• Widely used in acute non-specific diarrhea.

• Bismuth subsalicylate is also used inTraveler's diarrhea (due to E. coli):
a. Bismuth —*• direct antimicrobial effect and binds enterotoxins.
b. Salicylate content ->|PG synthesis ->| fluid secretion in bowel.
-178-
Idrug therapy of constipationI

Anti-constipation drugs are used to treat constipation by enhancing colonic transit.
Classification According to Mechanisms of Action
1. Bulk Laxatives 2. Osmotic Laxatives
Indigestible fibers that are Non absorbable salts or sugars that hold
unabsorbed in GIT —»• adsorb water by osmotic force —> f stool fluidity &
H20 forming a bulky emollient intestinal distension —> stimulate peristalsis.
gel —• distend colon • MgSC>4 - MgO (milk of magnesia).
& stimulate peristalsis. • Lactulose.
• Bran - Psyllium • Sorbitol.
• Methyl cellulose • Polyethylene glycol solution (PEG).
3. Stool Lubricants 4. Stool softeners
Paraffin oil Soften hard stools —» easy passage.

• I Water absorption from • Evacuant enema & glycerin
stools —* lubricates hard suppository: | water content of stools.
stool. • Docusate: | water entry into stools by
decreasing its surface tension.
5. Stimulants/ Irritants
They irritate the colon -> stimulate peristalsis chemically

• Castor oil -> hydrolyzed to ricinoleic acid-> stimulates small
intestinal peristalsis -> potent fast effect.
• Bisacodvl-^ stimulates colonic peristalsis -> mild delayed effect.
• Anthraquinones (cascara - senna - aloes) -> release emodin ->
absorbed from the small intestine -> enters the enterohepahc
circulation to be excreted in the colon (delayed onset: 6-8 h).
179
Types of anti-constipation drugs
Laxatives: mild effect -> well formed stool (e.g. bran)

Purgatives: moderate effect -> loose stool (e.g. lactulose)
Cathartics: strong effect -> watery stool (e.g. magnesium sulphate)
Uses
1. Constipation20 (unless contraindicated):

i. Intermittent constipation —• is best treated by high fiberdiet, plenty of
fluids & exercise.
i. Constipation with lowbulk stool —*• bulk- forming or osmotic agents,

iii. Constipation with lowfrequency of defecation —*• stimulant agents,
iv. Constipation with hard stool —> stool softeners,
v. Constipation with impactedstool—> lubricants (parrafin oil)
2. After anal surgery—> lubricants (parrafin oil).
3. Colonic preparation —• castor oil, bisacodyl & PEG solution are given before
surgery, colonoscopy & abdominal x-ray to clean the colon.
4. Hepatic encephalopathy —• lactulose.
5. Ingested poison & taenia solium treatment —> MgS04.
6. Irritable bowel syndrome.
Bulk - forming agents
7. Obesity. plus large amount of
8. Gall stones fluids
General Adverse Effects
1. Cathartic habit and atonic colon 21.

2. Abdominal cramps.
3. Diarrhea, dehydration and hypokalemia.
4. Abortion and excretion in milk during lactation.
20 Castor oil should not be taken at night due to its rapid effect while bisacodyl should be
taken at night since its action is delayed for 6 hours.
21 Cathartic colon isdue to degeneration of Aeurbach's plcxus.& loss of normal defecation
mechanism. The colon is distendedwith stool till it contracts by its myogenic property with
evacuation of large volume of stool.
-180-
Special Adverse Effects
Bulk - forming agents
• Hard stools & intestinal obstruction if not taken with plenty of fluids.
• Bloating & flatus (due to bacterial digestion of the plant fiber).
• I Absorption of iron (anemia), Ca (osteoporosis) and fat (steatorrhea).
Paraffin oil
• Decreases absorption of fats (steatorrhoea) and fat-soluble vitamins.

• Leakage causing eczema around anus- bowel lymph node granulomata.
• Lipid pneumonia22.
Senna
• Mutagenic.
Docusate
• Intestinal obstruction.
Bisacodyl
• Purple coloration ofurine23.
Lactulose
• Flatulence - abdominal colic - diarrhea.
• Aggravates diabetes.
Contraindications
1. Undiagnosed acute abdomen (e.g. appendicitis).

2. Intestinal obstruction (—• rupture).
3. Hemorrhoids.
4. Pregnancy (—*• abortion)
22 Lipid pneumonia occurs due to back leakage of paraffin into theoesophagus when thepatient lies down
during sleep -> enters the lung
23 This occurs in alkaline urine. Phenolphthalein; another ingredient usuallypresent in most OTC
laxatives turns urine pink. These canbe usedasbedside test to diagnose suspected laxative use(e.g. in
hypokalemic patients)
-181-
IRRITABLE BOWEL SYNDROME
• Irritable bowel syndrome (IBS) is a chronic relapsing disorder occurring in

80 % of adults. It is characterized by abdominal distension, pain, diarrhea,
constipation or both. It is associated with anxiety or depression.
Management
1. Diet
• Small frequent meals to avoid gas distension.

• Diet rich in soluble fibers.
• Reduce insoluble fibers (bran, raw fibrous vegetables, unpeeled fruits).

• Avoid flatulogenic foods: beans, cabbage, cauliflower, legumes, onion,
eggs, lentils, grapes, caffeine & carbonated drinks.
2. Improvement of bowel disturbance
• Patients with predominant diarrhea: loperamide - diphenoxylate.

• Patients with predominant constipation:
- f Fiber content of diet.
- Bulk laxatives e.g. psyllium (but may f gas production & bloating).
- Osmotic laxatives (MgO or lactulose).
3. Relief of abdominal discomfort and pain
• Anticholinergics & direct smooth muscle relaxants.

• Antiflatulent drugs (simethicone & charcoal): for gas distension.
• 5HT3 receptors antagonists (alosetron): for diarrhea- predominant IBS
- Modulates visceral afferent pain sensation & intestinal motility - J.Central
response to visceral stimulation (side effect: constipation - ischemic colitis).
• 5HT4 receptors agonists (tegaserod): for constipation-predominant IBS
- Stimulates peristalsis by its prokinetic effect (side effect: diarrhea)
• Kappa receptor agonists (trimebutine): for pain-predominant IBS.
4. Unabsorbable antibiotics: for enteric pathogenes e.g., rifaximine
5. Relief of depression and anxietv: antidepressants & anxiolytics.
-182-
Gastrointestinal Phannacology
HEPATIC ENCEPHALOPATHY
(Defectivebrain functions 2^ to liver cell failure)
Hepatic encephalopathy is characterized by disturbance in consciousness and

behavior resulting from an increase in brain ammonia and other toxins due to
failure of the liver to detoxify them. It is aggravated by:
• Excess NH3 (hypokalemia - excess dietary protein - GIT bleeding).
• Infection and hypoglycemia: may disturb brain function.
Treatment
1. Treatment of precipitating factors: infection, GIT bleeding, hypokalemia or

hypoglycemia.
2. H2 Antagonists: decrease acidity, gastric erosions and bleeding.
3. Drugs decreasing portal pressure: j bleeding of esophageal varices:
• Octreotide - vasopressin (plus nitrates) - P Blockers
4. Decrease ammonia by:
• Decrease dietary protein.
• Evacuant enema with lactulose .
• Lactulose ( mainstay of therapy, see below)

• Neomycin (kills bacterial flora which form ammonia from proteins).
• Probiotics e.g. Lactobacillus -> displacement of urease-containing
bacteria.
• Stimulation of ammonia metabolism:
i. Ornithine-aspartate: increase ammonia removal by hepatocytes via

stimulation of glutamine synthesis,
ii. Sodium benzoate
5. Flumazenil: benzodiazepine receptor antagonist24
24 The GABA-receptor complex isactivated inhepatic encephalopathy possibly through t

endogenousbenzodiazepine receptor ligands.
-183-
Lactulose
Mechanism
A nonabsorbable synthetic disaccharide digested by colonic bacterial flora

into shortchainorganic acids —• acidifies coloncontents leading to:
• Binding of ammonia.
• Inhibitionof ammoniaproducing bacterial flora.
• Osmotic laxative effect.
Uses
1. Hepatic encephalopathy.
2. Constipation.
Adverse Effects
1. Flatulence.
2. Abdominal colic.
3. Diarrhea.
4. Aggravates diabetes
-184-
DRUG THERAPY OF ESOPHAGEAL VARICES
(Dilated lower esophageal veins)
1. p-blockers
2. Nitrates
iCOP
•
Dilate Portal vein

Constrict splanchnic
blood vessels
1. Nitrates
1. Vasopressin
2. p-blockers
Control of Bleeding Varices
1. IV vasopressin or terlipressin"
Constrict mesenteric blood vessels —>| portal blood flow.
2. IV vasopressin combined with IV nitroglycerin (^systemic vasoconstriction
induced by vasopressin & accentuates its portal hypotensive actions.
3. Octreotide:
- Direct vasoconstrictor of splanchnic arterioles.

- Inhibits release of peptides contributing to hyperdynamic circulation in
portal hypertension.
4. IV ranitidine: immediately after control to prevent re-bleeding.
Prophylaxis of variceal bleeding in patients with cirrhosis26
• Non-selective p blockers (e.g. propranolol and nadolol) —>
i. Block adrenergic VD tone in mesenteric arterioles —> unopposed a VC —>[ portal
inflow,
ii. .[Cardiac output(COP).
Vasopressin analog released in a slow & sustained manner at vascular smooth muscle.
Prophylaxis with isosorbide mononitrate —• j mortality in patients > 50 years.
-185-
Lecture Notes
PHARMACOLOGY
Endocrine
Chemotherapy & Immunotherapy
NSAIDs & CNS
Faculty of Medicine
2019/2020
Lecture Notes
PHARMACOLOGY
Volume 3
Endocrine
Chemotherapy & Immunotherapy

NSAIDs & CNS
Faculty of Medicine
2019/2020
Preface

provides the most recent advances in drug therapy within aconcise framework.
Pharmacology Department; Ain Shams University. "Each ofus is unique in their
own way. We have something to leam from everyone". Colleagues and students
2019-2020
Head of Department
Authors

Prof Dr. Olfat Hassan

Prof. Dr. Osama El Serafy Prof. Dr. May Hamza

Prof. Dr. Adel el Bakry Prof. Dr Atef EL-Esawy.
Computer graphics &designs: Dr. Essam Ghazaly - Dr. Mohamed Bahr
4-
CONTENTS
Volume III
1. Endocrine Pharmacology 9-62
2. Chemotherapy 65 -132
3. Immunopharmacology. 135 -148
4. NSAIDs & Gout therapy 151-164
5. CNS Pharmacology 167-237
-5-
I. ENDOCRINE PHARMACOLOGY
Intended Learning Outcomes TILOsI
By the end ofthis chapter, the student should be able to recognize the following ILOs
Hypothalamic & pituitary hormones: the student should be able to
• Identify the uses of octreotide.
• Compare between different routes ofadministration ofGnRH and their clinical
implications.
• List the uses of bromocriptine.
• Identify drugs used in acromegaly.
•Compare between the use of cosyntropin and gluccorticoids.
Discuss the effects of vasopressin and its analogs on vascular smooth muscle
and the kidney.
• Recognize the adverse effects of vasopressin and its analogs.
Antidiabetic Drugs: the student should be able to

• Compare between different preparations of insulin.
• Describe the mechanisms of action of oral antidiabetics.
• Compare between the different anidiabetic drugs regarding their tendency to
induce hypoglycemic effects & weight gain.
• Explain why in severe renal or liver diseases, insulin & not oral antidiabetics
must be used.
• Explain why during stress & in pregnancy & lactation, insulin & not oral
antidiabetics must be used.
• Explain why metformin is contraindicated in renal & liver failure & in severe
hypoxia.
• Recognize that rosiglitazone may indue heartfailure.
• Describe the strategies for managing of type 1 & type 2 diabetes.
• Recognize that metformin is recommended for initial management of type 2
DM & recall its advantages.
• Discuss when & why 5% glucose, K+ & HC03 are administred in ketoacidosis.
Drugs & Bone Calcium Homeostasis: the student should be able to

• Review the regulation of calcium homeostasis and the physiological actions of
parathyroid hormone, calcitonin and vitamin D.
• Discuss the beneficial effects of drugs used in osteoporosis.
• List drugs that lowerblood calcium in hypercalcemia.
• List 2 Vitamin D preparations suitable forpatients with poorrenal function.
• Explain why alendronate is taken while sitting & with a full glass of water.
• Discuss the clinical significance of the anti-vitamin D effectof corticosteroids.
Antithyroid Drugs: the student should be able to
• Recognize the 3 possible options (thionamide therapy, radioactive iodine or
surgery) for management of thyrotoxicosis & discuss the basis for choice
between these options in different cases. Recognize that thionamides must
still be given in all cases.
• Outline the steps of synthesis & release of T3 &T4 & the site of action of
antithyroid drugs.
• Explain the rationale for the use ofpropranolol in treatment ofhyperthyroidism.
• List the indications of iodide salts in thyrotoxicosis & explain why they are
not used in long term therapy.
• Listthe most common adverse effect of thionamides &the most serious one.
• Explain why methimazole is preferred to propylthiouracil for treating
hyperthyroidism.
• Explain why propylthiouracil is preferred to methimazole during pregnancy.
• List 3 beneficial effects of hydrocortisone in thyrotoxic crisis.
Corticosteroids: the student should be able to
• Recognize the adverse effects of corticosteroids as an extension of then-
widespread pharmacological actions.
• Discuss the different precautions required during therapy with corticosteroids.
• Compare between different preparations of corticosteroids versus the natural
hormone.
• Recognize the widespread use of corticosteroids &the choices of different
preparations.
• List the inhalation corticosteroid preparations and their advantages.
• Explain why steroids are used in stress, cerebral edema & hypercalcemia.
Sex Hormones: the student should be able to

•
Discuss the types and mechanism of action of contraceptives.
Explain why progetins are added to estrogen in contraceptive pills.
•
Recall the adverse effects of oral cotraceptives. Recognize that most are due
to estrogen. List those induced by progestins.
Describe the differrent mechanisms of drugs used in female infertility.
•
Discuss how the difference in site of action of clomiphene and tamoxifen
results in differences in their therapeutic uses.
• Compare the effects of estrogen receptor modulators & estrogen on bone,
breat and uterus.
• List the of adverse effects of anabolic steroids.
• Compare the mechanisms of action of finasteride and flutamide and their uses.
Endocrine Pharmacology
ENDOCRINE PHARMACOLOGY
I CLINICALLY IMPORTANT HYPOTHALAMIC HORMONES
1. Hormones for diagnostic purposes:
- Growth hormone-releasing hormone: diagnosis of growth hormone deficiency.

- Corticotropin-releasing hormone: to test hypothalamic pituitary function in ACTH
deficiency or excess.
- Thyrotropin-releasing hormone: diagnosis of mild hyper or hypothyroidism.
2. Gonadotropin-Releasing Hormone (GnRH)
- Gonadorelin (Synthetic).
- Leuprolide & nafarelin (GnRH analogs).
Uses:
1. Given in SC pulses to t gonadotropins to stimulate ovulation in infertility.
2. Given continuously1 to inhibit gonadotropins release in: cancer prostate -

endometriosis (inhibit ectopic menstruation) - in-vitro fertilization.
N.B.: In "in-vitro fertilization" endogenous gonadotropin release is inhibited &
exogenous FSH is given to induce follicular maturation at a selected time.
Adverse effects:
• Headache - hot flushes-depression

• Vaginal dryness- decreased libido- ovarian cyst.
• Osteoporosis.
Contraindications: pregnancy -lactation
GnRH antagonists: ganirelix- deaarelix
Uses:
• Controlled ovarian hyper-stimulation (inhibit LH surge).

• Advanced prostatic cancer.
1Continuous administration -» tachyphylaxis due to down regulation ofpituitary receptors.

-9-
3. Growth Hormone-Inhibiting Hormone (Somatostatin)
• It Inhibits release of growth hormone, GIT hormones, insulin & glucagon.

• Its short ty, (1-3 min) & non-specificity (inhibits other secretions) limit its use.
Octreotide: long-acting somatostatin analog (t>/} 80 min -» preferred).

Uses (given sc)
1. GIT tumors secreting VIP - gastrinomas -glucagonomas.
2. Bleeding esophageal varices (of choice; see GIT)
3. Carcinoid syndrome.
4. Acromegaly.
Adverse effects
• Nausea -vomiting -abdominal cramps- gall stones.

• Pain at site of injection.
• Vitamin B12 deficiency.
4. Prolactin-Inhibiting Hormone (= Dopamine)

Bromocriptine
• Orally active DA agonist

• Inhibits prolactin secretion.
• tgrowth hormone secretion (in normal) butparadoxically inhibits it in acromegaly
Uses
1. Prolactin-secreting adenomas.
2. To stimulate ovulation in infertility due to hyperprolactinemia.
3. Amenorrhea & galactorrhea in hyperprolactinemia.
4. To prevent breast engorgement (suppresses physiologic lactation).
5. Parkinsonism (orally active DA agonist).
6. Acromegaly: 4 GH secretion. Drugs used in Acromegaly
Octreotide - Bromocriptine - L-dopa

Adverse effects:
• Nausea- orthostatic hypotension - confusion.

N.B.: other DA agonists; cabergoline (long half-life; given twice/week).
-10-
ICLINICALLY IMPORTANT PITUITARY HORMONESl
A. Anterior Pituitary Hormones
1. Growth Hormone (GH):
Somatropin : recombinant human growth hormone

Uses:
• Promotes growth in growth hormone deficiency.

Side effects:
• Hyperglycemia.
• Edema-myalgia.
• Enzyme inducer.
2. Thvroid-Stimulating Hormone (TSH)

Therapeutic Uses
1. Diagnostic: differentiates between Is and 2a Hypothyroidism.

2. Adjuvant to I131 therapy in metastatic thyroid carcinoma.
3. Andrenocorticotrophic Hormone (ACTH)

• Stimulates adrenal cortex to release glucocorticoids (mainly) & androgens.
Cosyntropin:
• Synthetic ACTH developed to avoid ACTH-induced allergy.
Therapeutic Uses
1. Diagnostic (mainly): in patients with abnormal corticosteroid production.

2. Anti-inflammatory & immunosuppressive in chronic conditions (glucocorticoids
are preferred since cosyntropin is given by injection & its mineralocorticoid activity
can not be separated from its glucocorticoid effects).
-11-
4. Gonadotropins FSH. LH
• Stimulate spermatogenesis & testosterone secretion in males.

• Stimulate ovulation & ovarian estrogen & progesterone production in females.
Clinically Used Gonadotropins
1. Human Menopausal Gonadotropins (hMG)2:

• Menotropins (FSH + LH).
• Urofollitropin (FSH)., recombinant FSH (r-FSH).
2. Human Chorionic Gonadotropins (hCG)3: Similar to LH.
Therapeutic Uses (parentral)
1. Infertility {<$ & $) - in vitro fertilization.
2. Undescended testis.
3. la or 2a amenorrhea due to lack of gonadotropins.

Adverse Effects
1. Hyperstimulation syndrome: enlarged ovary - ascites - hemoperitoneum.

2. Multiple births.
3. Spontaneous abortions.
4. Gynecomastia in males.
2Extracted from urine of post menopausal females.

3Produced by human placenta & excreted inurine.
12
B. Posterior Pituitary Hormones
1. Vasopressin "Antidiuretic Hormone (ADH)"
ADH acts on vascular (Vi)& renal & extrarenal (V2) receptors.
ADH analogues
I
1. V, Selective 2. V2 Selective
Terlipressin - Felypressin. Desmopressin.

I
1 I 1
V? Recentors V? Receptors
Vi Receptors
Vascular Renal Extrarenal
(Vasoconstriction) (Antidiuresis) (t clotting factors)
• Large doses of ADH, act •ADH acts on renal V2 •ADH -> t release
on vascular Vi receptors -» receptors -* t reabsorption of factor VIII & von
vasoconstriction -» t BP. of H20 in collecting ducts. Willebrand factor.
Uses
Uses E3
1. Bleeding in esophageal ADH-sensitive Diabetes 1. Haemophilia A.
varices & during surgery in Insipidus. 2. Von Willebrand
portal hypertension. Vasopressin disease.
(tt splanchnic VC) • Weak V2 selectivity. Desmopressin
Terlipressin a Short-acting.
(Preferred to ADH) • Given SC or IM.
- Longer acting Desmopressin
- Less side effects Preferred to ADH:
2. Prolong the action of local • V2 selective: -» more

anesthetics. potent antidiuretic,
Felypressin minimal VC.
a Safer than epinephrine a Long-acting.

in cardiac patients. • Given intra-nasally.
-13
Adverse Effects
1. Vasoconstriction: marked facial pallor - coronary spasm -1 BP.

2. Colic.
3. Allergic reactions.
4. Water intoxication: avoid drugs potentiating its effect:
a Carbamazepine: sensitizes renal tubules to ADH.
Vasopressin (ADH) antagonists
• Increased ADH secretion resulting in water retention &hyponatremia occurs in:

1. Syndrome of inappropriate secretion of ADH (SIADH) e.g., in lung cancers,
head injuries.
2. CHF
• ADH antagonists that mav be used in such conditions include:

1. Demeclocycline (used in SIADH, largely replaced lithium).
2. Vaptans (used in SIADH, CHF with hyponatremia):
i. Conivaptan: nonselective V]& V2 antagonist, given IV.
ii. Tolvaptan: selective V2 antagonist, given orally.
Adverse effects:
• Polyuria.
• Thirst.
• Hypernatremia.
• Infusion site reactions.
-14
2. Oxytocin
Actions
1. Breast: contraction of myoepithelial cells lining ducts of the breast -» squeezing

milk out of lactating breast (milk ejection).
2. Uterus: contraction of smooth muscles of the uterus.
3. Induction and maintenance of labor.
Therapeutic Uses of Svntocinon (Synthetic Oxytocin)

1. Induction of labor: uterine enertia, incomplete abortion; IV.
2. Postpartum hemorrhage; IM (but ergometrine ispreferred).
3. Impaired milk ejection; nasal spray.
Toxicity
1. Uterine rupture.
2. Fetal asphyxia.
3. Water retention and intoxication.
Oxytocin antagonist: Atosiban
Uses:
• Premature labor (iv infusion).
-15-
I INSULIN & ORAL ANTIDIABETIC DRUGS I

Hormones Secreted by Islets of Langerhans4
1— " "
Insulin Glucagon Somatostatin
Secreted by p cells Secreted by a cells Secreted by 8 cells

(During feeding) (During fasting)
• Anabolic hormone • Mobilizes stored • Inhibits
-» storage of glucose, NH2 acids & secretion of
glucose, amino- fatty acids into blood to insulin &
acids & fatty acids. maintain blood glucose. glucagon.
NjB.: Amylin is produced by p cells. It decreases appetite, slows gastric emptying,

reduces inappropriate glucagon secretion and reduces food intake.
INSULIN
Insulin is a protein consisting of two amino acid chains, alpha (21 aa) and beta (30
aa) connected by two disulfide bridges.
Insulin is synthesized as a precursor (pro-insulin) which is enzymatically cleaved in
P cells into C peptide and mature insulin which are stored in granules & secreted in
equimolar amounts. C peptide determination is an estimate of insulin secretion.
Insulin secretion is regulated mainly by blood glucose levels (and also by other
hormones and autonomic mediators).
4GIT hormones that may modulate glucagon and/or insulin secretions include glucagon-like peptide-1 and ghrelin.
-16-
Metabolic Effects of Insulin & Metabolic Disturbances in Diabetes

• Insulin affects carbohydrate, fat & protein metabolism by acting on specific insulin
receptors in 3 principle tissues: liver - skeletal muscle -adipose tissue.
I. Effect of Insulin on Carbohydrate Metabolism
• Insulin 4 blood glucose level by:

a. t Hepatic glucose storage -» 4 hepatic glucose production (© glycogenesis, 0
glycogenosis & gluconeogenesis).
b. t Uptake & storage of glucose in:
-Skeletal muscle^^. ©glycolysis -» energy production.
© glycogenesis -* glycogen storage.
- Fat cells > t glycerol -» TGs synthesis.
• Insulin deficiency in diabetes results in t blood glucose by t glucose production
from liver and 4 glucose uptake by skeletal muscle and fat cells.
• If glucose level exceeds renal threshold -» glucosuria-> osmotic diuresis
(polyuria) -» dehydration -» thirst -* polydypsia.
II. Effect of Insulin on Fat Metabolism
• Insulin promotes fat storage through:

- © Plasma lipoprotein lipase -» hydrolysis of TGs from circulating lipoproteins
-» t free fatty acids (FFAs) supply to adipose tissue.
-1 Glucose uptake in fat -» t glycerol which binds FFAs -* t TGs.
- 0 Lipolysis (© intracellular lipase) -* 4 FFAs mobilization to blood.
• Insulin deficiency in diabetes results in:
-1 Lipolysis -» T free fatty acids in blood.
- t Breakdown of fat for energy supply -» t Acetyl CoA which in absence of
aerobic CHO metabolism -» t ketone bodies.
III. Effect of Insulin on Protein Metabolism
• Insulin promotes protein storage through:

- 4 Protein breakdown in liver-1 Protein synthesis in skeletal muscle.
• Insulin deficiency-* t protein breakdown & 4 synthesis -» muscle wasting.
-17-
Mechanism of Action of Insulin
• Insulin acts on a specific receptor5 consisting oftwo a and two P subunits.

• a Subunits are extracellular & carry the insulin binding site. The P subunits span the
cell membrane, their intracellular end has tyrosine kinase activity.
• Insulin binds to a subunits —• tyrosine kinase autophosphorylation —» "[activity of
intracellular proteinkinases affecting metabolic enzymes as phosphorylase, lipase...
Insulin Counter-regulatory Hormones
Released during stress -» antagonize insulin effects on blood

glucose -* f insulin requirements:
a Glucagon - Catecholamines - Corticosteroids
• Growth Hormone - Thyroxine
Diabetes Mellitus
Diabetes is a disease characterized by chronic hyperglycemia due to an absolute or

relative lack of insulin (reduced sensitivity to its action [insulin resistance]).
It is diagnosed bv;
• Fasting blood sugar (FBS) > 126 (normal < 120 mg/dl).
• 2-hours blood sugar after oral 75 g glucose> 200 (normal < 140 mg/dl).
• Glycated hemoglobin (AlC)
• AlC > 6.5% (upper limit in nondiabetic = 6.1%).

• Target for therapy according to the American Diabetes Associations 7%
N.B.: the degree in reduction of AlC gives an idea about efficacy of therapy.
s Insulin receptor number isincreased byexercise, high fiber diet and 4body weight.
-18-
Types of Diabetes
• Type 1 DM
• Type 2 DM
• Other specific types: e.g. Genetic defects of beta-cell function, diseases
ofthe exocrine pancreas, endocrinopathies6 ordrug orchemical induced.
• Gestational diabetes mellitus
Type 1 DM Type 2 DM
Pathogenesis Pathogenesis
• Absolute insulin deficiency due to • Resistance to both endogenous and
massive P cell destruction. exogenous insulin commonly
• May be immune mediated or accompanied by insufficient insulin
idiopathic. release.
• Insulin must be given to control • It may be adequately treated without

hyperglycemia (insulin dependent). exogenous insulin.
• Ketoacidosis is liable to occur. • Ketoacidosis is rare.
Drugs Inducing Diabetes7
1. Glucocorticoids
TInsulin resistance by
2. Oral contraceptives }; affinity to receptors
3. Thiazide diuretics (4 Insulin release)
4. Beta blockers (glucose intolerance)
6Endocrinopathies include: acromegaly, hyperthyroidism, glucagonoma, somatostatinoma, Cushing's syndrome,

pheochromocytoma, aldosteronoma.
7Atypical or typical antipsychotic agents may be associated with worsening hyperglycemia. Some ofthese agents
areassociated with weight gain, obesity,hypertriglyceridemia, and development ofdiabetes mellitus, by an as-
yel-unidentificd mechanism. Monitoring for diabetes is advised in these patients.
-19-
Drug therapy of diabetesl

Insulin Therapy
Preparations of Human Insulin (biosynthetic " recombinant DNA")
Ultra- rapid Short-Acting Intermediate-Acting Long-Acting"

Ultra- short (NPH)
Regular or Glargine9
Lispro - Aspart - Crystalline Zinc
Glulisine (Isophane)
• Ultra-rapid onset, • Rapid onset, • Intermediate onset •Slow onset-

very short duration. short duration and duration long acting
-» given SC 15 -» given SC -» given SC 2-4 (broad cone,
minutes before 30-45 min times /d in type 1 plateau) -» SC
meals. before meals. -» may be given once or twice
once/d in type 2 /day
• Variable absorption
> 50%
Advantages10 Advantages Advantages Advantages

• Can be mixed with
• Rapid absorption & • Used IV/ IM in • Maximum
rapid onset -> better emergencies: regular insulin11. effect
Premixed fixed maintained
postprandial ketoacidosis....
concentrations are for 24 h -» t
glycemic control.
available. compliance.
•Useful in all forms
• Very short duration
of diabetes except
of action -» less risk
ketoacidosis.
of hypoglycemia.
Inhaled insulin; Afrezza (rapid acting human insulin inhalation powder)

• Covers prandial insulin requirements.
• Type 1diabetics on afrezza as prandial insulin must also use SC, long-acting insulin.
• Disadvantages;
• Fine dose adjustments are not possible.

• Not recommendedin smokers & contraindicated in cases of chronic lung disease.
8Insulin detcmir isanother long acting analogue with a duration ofaction > 12 h.
9Should not be mixed with other types ofinsulin in same syringe. Anew long acting insulin analogue: Degludcc
may be mixed with rapid-acting insulins without altering the kinetics ofDegludec or the rapid-acting insulin.
10 Available as premixed fixed concentrations with protaminated lispro (NPL) or protaminated aspart (NPA).
1' Canbe mixed with insulin Lispro or Aspart immediately before injection
-20-
Indications of Insulin Therapy [Compare with CI of sulfonylureas!

1. Type 1 DM.
2. Type 2 DM. : insulin is added if diet regulation & exercise plus metformin or other
oral antidiabetics fail to control hyperglycemia.
3. DM with pregnancy & lactation: To avoid risk of sulfonylurea-induced
hypoglycemia in fetus & newborn.
4. DM with stress & emergency: regular insulin is used in diabetic ketoacidosis,
surgery, infection, myocardial infarction or severe psychic stress (oral
hypoglycemics fail to control hyperglycemia as stress -*f insulin requirements).
5. DM with severe liver or renal disease: To avoid risk of hypoglycemia by sulfonylurea.
6. Treatment of hyperkalemia: Insulin enhances k+ influx into cells.
N.B.: Insulin use in pregnancy, lactation, stress, emergency or hyperkalemia is

temporary.
Adverse Reactions of Insulin
4
I. Hypoglycemia III. Immune Reactions IV. Lipodystrophy
Most frequent (Due to anti-insulin

• Lipohypertrophy: Due to
and antibodies)
repeated injection at same
most serious A. Insulin resistance:
site -* change site regularly.
• Insulin requirements
See below >120 units/d.
• Lipoatrophy13
B. Allergy: Extremely rare.
• Urticaria (rare).
H. t Body Weight
N.B.: Hypokalemia mav occur when high doses of insulin are used (e.g. in treatment of
ketoacidosis).
12 Insulin may be a Is1 -line therapy in type 2patients with AlC >10 %, fasting plasma glucose >250
mg/dL, random glucose consistently >300 mg/dl, or ketonuria.
13 Lipoatrophy was formerly seen with animal insulin as itforms immune complexes atinjection site.
-21
Insulin-induced Hypoglycemia
• Most frequent adverse effect.

• It can be very serious -» brain damage.
• Causes: insulin overdose, 4 food, physical effort.
Warning signs:
• Adrenergic©: t HR, sweating, tremors (masked by p-B).

• Neurological signs: Dizziness, convulsions or coma.
Treatment:
• Rapid administration of glucose (sugar or candy).

• IV glucose or glucagon 1 mg IM or SC.
To avoid hypoglycemia, patient should be aware

of warning signs & carry few pieces of sugar.
22-
Oral Antidiabetics14
I. Insulin Secretagogues
• Sulfonylureas : e.g. glimepiride
• Non-sulfonylureas :e.g. repaglinide
II. Insulin Sensitizers
• Biguanides: metformin
• Thiazolidinediones (Tzd): pioglitazone
IH. a-glucosidase Inhibitors e.g. acarbose
IV. Sodium-glucose co-transporter 2 (SGLT2) inhibitors: e.g. canagliflozin
V. Dipeptidyl peptidase-4 (DPP-4) Inhibitors: incretin enhancers e.g. sitagliptin
Other antidiabetics (SC)
• Incretin mimetics (e.g. exenatide.),

• Amylin analogues (e.g. pramlintide)
14 Expected ! in A(C with monotherapy: sulfonylureas or biguanides (1-2%), non sulfonylureas or Tzd
(0.5-1.5%), a-glucosidase inhibitors orDPP-4 inhibitors(0.5-0.8%), insulin (1.5-3.5%).
-23-
Thiazolidinediones
Sulfonylureas
Muscle Adipose Non-Sulfonylureas
tissue
DPP-4 Inhibitors
a-glucosidase
Inhibitors y
Insulin Pancreas
Blood Glucose
Gut
Kidney
Liver
hibitors
Site of Action of
Antidiabetic Drugs Biguanides
-24-
I. Insulin Secretagogues
A. Sulfonylureas
Mechanism of Action
• t Insulin secretion by binding with specific receptors on Bcell membrane linked to

ATP-sensitive K+ channels (K+ ATP) -» blocks channels -* depolarization -* Ca2+
influx -* insulin release from granules (Main action).
• i Glucagon on chronic use.
Indication:
• Type 2 DM: If initial therapy with metformin + diet control + exercise fail or if
metformin is contraindicated.
Sulfonylurea Preparations
1st Generation: tolbutamide—
• Less frequently used due to adverse effects & drug interactions.

2nd Generation
• 150 times more potent than 1- generation, (t receptor affinity).
• Fewer adverse effects & interactions.
Members:
• Glipizide (short acting) 16 .

Gliclazide17 (intermediate acting)
Glibenclamide (long acting - more hypoglycemic risk).
Glimepride18: long acting (24 h) given once/day.
Acts on a different receptor at K ATP channel.
is
Other ("generation agents: chlorpropamide, tolazamide, acctohcxamidc.
16 Glipizide: (6- 12 h),gliclazide: (15 h), glibenclamide (24 h).
17 Available asmodified release tablets (MR) for once daily use.
18 Peak effect is after 2-3h so should be given before themainmeal.
-25-
Contraindications of Sulfonylureas
1. Past history of allergy to sulfa compounds.

2. Type 1 DM as they require functioning P cells.
3. DM with pregnancy & lactation: they cross placenta & are excreted in milk —»
hypoglycemia in fetus & newborn.
4. DM with stress, e.g. infection, surgery, trauma or myocardial infarction (ineffective
and ketoacidosis is liable to occur as stress increases insulin requirements).
5. DM with liver or renal disease—* t risk of hypoglycemia as their action is prolonged
since they are metabolized in liver & are excreted in urine.
Adverse Reactions
1. Hypoglycemia: more with drugs with long tVl as glibenclamide particularly if

elimination is impaired e.g. in elderly, renal or liver disease.
2. Hypersensitivity: drug allergy as skin rash.
3. Heavy weight (weight gain).
26-
B. Nonsulfonylureas Secretagogues19
(Meglitinides, e.g. Repaglinide)
Mechanism of Action:
• Similar to that of sulfonylureas.
Advantages
• Very rapid onset with shorter duration than sulfonylureas-* brief stimulation of
insulin secretions —>
a. Less hyperglycemia postprandially (t insulin secretion immediately after meal).

b. Less hypoglycemia during late postprandial phase (less insulin secreted several
hrs after meal).
• May be used in patients with a past history of allergy to sulfa compounds.
Disadvantages & adverse effects
• Frequent dosing (3 times/day; prandial)

• Weight gain (less than sulfonylureas).
• Mild hypoglycemia (less than sulfonylureas).
Precautions:
• Repaglinide should be used cautiously in liver impairment.
19 Others: nateglinide
-27-
II. Insulin Sensitizers
A. Biguanides
(Metformin)
Mechanism of Action (not fully understood)

1. ^Hepatic glucose production by inhibiting gluconeogenesis (Main effect).
2. Direct stimulation of glycolysis in skeletal muscles & adipose tissue -» rapid
removal of glucose from blood with slight t in blood lactate.
3. i Intestinal glucose absorption with mild anorectic action.
Advantages of metformin
• No increase in bodyweight—* I Insulin resistance.

• No hypoglycemia (i.e. euglycemic acts in hyperglycemia only).
• No drug interactions (no plasma proteins binding or hepatic metabolism).
Indications of Metformin21
• Initial therapy of type 2 diabetes together with diet regulation & exercise.
Side Effects
1. GIT: Metallic taste, anorexia, dyspepsia & diarrhea (common, minimized by starting
with small dose and gradually increasing it).
2. Lactic acidosis (dangerous but infrequent): Metformin is CI in renal failure, liver
failure & severe hypoxia (as HF, MI, pneumonia and alcoholics) due to t risk of
lactic acidosis (anaerobic metabolism) in these patients.
20 The molecular mechanism of action is via activation the adenosine monophosphate (AMP)-activatcd protein
kinase (AMPK). AMPK-indcpcndcnt effects of the drug have recently been identified.
21 - The use of metformin +insulin intype 1DM isconsidered if an adult with type 1diabetes and a BMI of 25
kg/m2 or above wants to improve their blood glucose control while minimising their effective insulin dose.
- Metformin may be used in metabolic syndrome and polycystic ovary syndrome (off label use) to managethe
associated insulin resistance.
-28-
B. Thiazolidinediones (TZDs)
(Pioglitazone)
• Euglycemics, with delayed therapeutic effect (since their mechanism of action

involves gene regulation).
Mechanism of Action
Insulin sensitizers: agonists for PPAR-y receptor22, in muscle, fat & liver -*:
i. Enhanced adipocytes differentiation with synthesis of new fat cells sensitive to
insulin which -» I circulating fatty acids through:
a. t Uptake of circulating fatty acids into fat cells.
b. © intracellular lipolysis -» I FFA mobilization to blood.
ii. 4 Circulating FFA -* 4> insulin resistance -» t glucose uptake by skeletal muscles &
fat cells & I hepatic glucose production -* I blood glucose.
Indications
• Used as monotherapy or in combination in type 2 DM.
Adverse Reactions 24
• Weight gain.
• Fluid retention -» edema-* mav precipitate heart failure in some patients.
Precautions
• Avoid in heart failure & liver dysfunction.

• Monitor for signs/symptoms of liver injury during use.
• Consider risk of fracture prior to initiation and during therapy.
22 The nuclear receptor peroxisome-proliferator activated receptor-gamma regulates insulin-

responsive genes involved in carbohydrate & lipid metabolism & in adipocytes differentiation.
23 If metformin & sulfonylurea arecontraindicated.
24 Rosightazone, another TZD.T LDL cholesterol, risk ofstroke, heart failure & MI —suspended in
Egypt.
29-
III. Alpha Glucosidase Inhibitors

Acarbose- Miglitol
a-glucosidase ^
l/IlgUattlA,I12iriUca Monosaccharides
A >
Not absorbed Absorbed
|e
Ot-Glucosidase Inhibitors
Mechanism of Action
• Normal brush border of intestine contains a-glucosidase which converts

oligosaccharides into monosaccharides (glucose) which are absorbed.
• Acarbose inhibits alpha glucosidase enzyme -» I glucose absorption.
Advantages
• Limits the postprandial rise in blood sugar -» "insulin sparing effect".

• No hypoglycemia.
Indications
• Adjuvants to sulfonylureas in type 2 DM in patients intolerant to metformin.
Adverse Effects
• GIT upset: flatulence - abdominal pain - diarrhea.
N.B.: Symptoms are due to fermentation of undigested carbohydrates in colon -» gas

release.
30-
IV. Sodium-glucose co-transporter 2 inhibitors
SGLT2 inhibitors
Canagliflozin - Dapagliflozin - Empagliflozin
Mechanism of Action
• Inhibit the sodium glucose transporter 2 in the proximal tubules of the kidney -»•
prevents the reabsorption of filtered glucose in the kidney —*• removing excess
glucose in the urine.
• Reduce HbAlc, weight, and blood pressure.
25
Indications :
• Type 2 diabetes: monotherapy or combined with metformin or TZDs.
Advantage; Given orally once daily
Adverse effects:
• Infections in the genitourinary systems

• Mild hypoglycemia if used with insulin or otheroral antidiabetic therapy
• Increased risk of bone fractures.
Precautions:
Adequate renal function needed.
25 Its use in type 1DM isunder investigation

31-
V. Dipeptidyl peptidase (DPP)-4 Inhibitors

Sitagliptin - Saxagliptin - Linagliptin -Alogliptin
Mechanism of Action
DPP-4 rapidly degrades incretins (e.g. GLP-1) that are released from GIT following
meals to lower blood sugar. Inhibition of DPP-4 —•f plasma incretins —»• | glucose-
dependent insulin secretion &4-glucagon secretion—»4postprandial hyperglycemia.
Indications: orally once daily
• Type 2 diabetes: monotherapy or combined with metformin or TZDs.
Adverse effects (well tolerated)

• Nasopharyngitis & upper respiratory infections - joint pain.
Subcutaneous Antidiabetics
I. GLP-1 receptor agonists (incretin mimetics; more stable than natural GLP-1)
Exenatide twice/day - Liraglutide once/day - Dulaglutide once /week
Mechanism of Action:
l.Tglucose-dependent insulin secretion-tacute responsiveness of p-cell to secrete insulin

2. Suppress inappropriately elevated postprandial glucagon secretion.
3. Slow gastric emptying, & reduce food intake (liraglutide is used in obesity).
Adverse effects: Nausea (most common, especially with high doses).
II. Amvlin Analogues: Pramlintide
Mechanism of Action
Analogue of amylin (hormone co-secreted with insulin following food intake):
1. Decreases post prandial glucagon secretion.
2. Delays gastric emptying and improves satiety.
Indications:
• Type 1 & II diabetes, prior to meal, adjunct to insulin (but not in same syringe).
Adverse effects:
1. Hypoglycemia (reduce insulin dose by 50% on initiation of pramlintide therapy).
2. Nausea & vomiting- anorexia.
32
Management of Diabetes
The Four Cornerstones of Treatment of Diabetes are:
• Life style (diet regulation & exercise-* t insulin receptors) - education - medication.
NJ£.: Caloric restriction is not initially required in patients with type 1 DM
(underweight), but is necessary when insulin therapy results in fweight.
Drug Therapy
A. Drug Therapy of Type 1 DM:
Insulin therapy27
• Intensive therapy28: multiple doses or insulin pump.
• Conventional therapy: 2 injections (mixture of intermediate & regular insulin; 2/3
of dose in the morning & 1/3 in the evening).
• Insulin dose should be increased during stress (infection, surgery,...).
B. Drug Therapy of Type 2 DM: (If the HbAlC target is not achieved after 3 months,
consider the next step)
• Step 1 (monotherapy): lifestyle modification + metformin (unless contraindicated)
• Step 2 (dual therapy)29: lifestyle + metformin +basal insulin or another oral drug.
• Step 3 (triple therapy): lifestyle + metformin + 2 other drugs (basal insulin may be
one of them).
• Step 4 : lifestyle + metformin + basal insulin + mealtime insulin or GLP-1 agonist
N.B.:
• If initial therapy with metformin is CI or not tolerated —• start with another oral drug.
• Consider initiating therapy with a dual or triple combination if AI C is > 9%.
• Consider initiating combination insulin therapy if AlC is > 10 especially if symptoms
are present or any catabolic features are in evidence.
27 The amylin analogue pramlintide may be added to insulin in management of type 1 DM.
28 Intensive insulin for tight control is prescribed toall type 1DM. &for typc-2 patients requiring tight
control. Long or intermediate insulins arc used to cover basal insulin requirements. Short or ultrashort
insulinsarc taken before each meal according to carbohydrate in meal & pre-meal blood glucose.
29 The bile acid scqucstrant colcscvclam & the D2-dopaminc agonist bromocriptine are considered
among drug choices for dual & triple therapy by American Associationof Clinical Endocrinologists.
-33-
Comas in Diabetes
A. Hypoglycemic Coma (see adverse effects of insulin & sulfonylureas)

B. Diabetic Ketoacidosis (Polyurea, vomiting, dehydration, t respiration, coma)
Absolute insulin deficiency is due to stopping insulin or exposure to stress (surgery,
infection...).
Management30 (see fig)

1. Fluid replacement (3-5 L): 1M andmost important.
• Isotonic saline initially followed byhalftonic solution if serum Na+ rises.
• 5% glucose if blood glucose falls to 250 mg/dl to maintain plasma osmolality thus
avoiding brain edema & to avoid hypoglycemia.
2. Insulin therapy
• Regular insulin (low dose IV infusion; or IM) until blood acetone disappears.
• IV Dose: I by half if blood glucose falls to 250 mg/dl.
• Once patient is stable & eats & drinks normally, switch to 4 times/d SC.
3. Potassium Replacement
• Initial K+ level is often high due to acidosis & there is noneed for K+.
• Insulin reverses acidosis -» intracellular shift of K+ -» I serum K+ level requiring
KC1 administration according to K+ level:
- 20 mmol/1 (if normokalemic)
- 40 mmol/1 (if hypokalemic).
4. Bicarbonate
• Mild acidosis is spontaneously correctedby insulin.

• Bicarbonate is given in severe acidosis (pH < 7.1) and should be stopped when pH
reaches 7.2.
5. Treat underlying cause: e.g. infection (as perianal abscess) with broad spectrum
antimicrobials.
30 This treatment plan is an example ofdifferent treatment plans for diabetic ketoacidosis. Different hospitals
follow different plans.
-34-
Management of Metabolic Disturbances in Diabetic Ketoacidosis
Insulin Deficiency
I (In Parallel)
t IIcpatic glucose [ Peripheral glucose Rapid Lipolysis
Production
Uptake
t Circulating
FFA
Broken down
Hyperglycemia Insulin in Liver to
Ketone Bodies
t Plasma Ketoacidosis
Osmolality Osmotic Diuresis
1 I
Movement Water & Na Loss Vomiting
of water /
out of Brain f /
Cells
Dehydration
IV Fluid Excreted
Replacement In Urine
'Most Important" & Breath
Renal
Hypoperfusion
Hyperventilation
I (Air Hunger)
Impaired Excretion of
H'& ketones
HC03
1
(IfpH<7.1). More Acidosis; PH < 7
-35-
1AGENTS AFTOCTINGBOMCALaiM HOMEOSTASIS
Major sites at which drugs produce their effects on Ca2+ metabolism include:
a GIT: 10-20% ofdietary Ca2+ is absorbed under influence ofvitamin D.
• Kidney: 99% offiltered Ca2+ undergoes renal tubular reabsorption.
• Bone: the major storehouse for Ca2+ (1 kg/70-kg human adult).
Bone Formation and Resorption
• Bone is composed of:

1. Osteoid: organic matrix formed mainly of collagen & other proteins.
2. Hydroxyappatite crystals (calcium phosphate crystals): deposited in the osteoid
converting it into hard bone matrix.
• Bone is a dynamic tissue; it is continuously remodeled by a balance between:
• Resorption of old bone by osteoclasts.
• Synthesis of bone matrix & mineral deposition by osteoblasts.
Agents involved in
Bone Mineral Homeostasis
i
r
Endogenous
1
Exogenous
_i
r 1 r 1
Major Minor
Bisphosphonates Fluoride
1 Raloxifene Thiazides
l l Calcitonin
Denosumab
PTH Vitamin D Strontium
Estrogen
Cinacalcet
Glucocorticoids
PTH = parathyroid hormone.
-36-
A. Endogenous Agents Affecting Bone Calcium Homeostasis
1. Vitamin D
Mechanism of Action
• The active metabolite of vitamin D (calcitriol) enters the nuclei of targetcells -»

stimulate production of specific mRNA -» directs ribosomal synthesis of Ca2+-
P043" carrier proteins necessary for Ca2+ transport.
Actions
Increases serum Ca2+ & POi3' levels through:

1. GIT: stimulates Ca2+ &P043" absorption by small intestine.
2. Bone: t bone resorption by osteoclasts (excess vitamin D in normal)
Stimulates osteoblasts -» Ca2+ deposition (in rickets).
3. Kidney: t Ca2+ &P043' proximal tubular reabsorption.
Indications of vitamin D
1. Prevention and cure of rickets in children & osteomalacia in adults.
2. Osteoporosis.
3. Hypoparathyroidism.
reparations
• Vitamin D 2 is derived from plants & Vitamin D 3is produced in skin by

ultraviolet rays, both are present in diet.
• Vitamin D is activated by hydroxylation first in liver (25 -OH) then renally (1-a-
OH) under PTH control.
Important preparations include:
1. Dihydrotachysterol (AT 10): D2 analog (requires activation)

2. l-a-(OH) D3 (alfacalcidiol)
3.1,25-(OH)2 D3 (calcitriol)
Alfacalcidiol & calcitriol are used in renal rickets & renal
failure (do not require renal activation).
-37-
II. Parathyroid Hormone (PTH)
• Secreted by parathyroid gland.

• Secretion is increased by I Ca2+ &t P043' (reverse is true).
Actions: t serum Ca2+ & 4 P043" levels through:

1. Bone:
• t bone turnover (bone remodeling; resorption followed by formation):

-1 PTH (e.g., tumor) -» bone resorption -»t serum Ca2+.
- Low dose (intermittent) -* bone formation.
2. Kidney:
a. Enhances Ca2+ reabsorption.

b. Blocks phosphate reabsorption -* phosphaturia.
c. Stimulates production of active form of vitamin D (calcitriol) which promotes
intestinal absorption of Ca2+ and P043".
Uses:
• Osteoporosis: Teriparatide (recombinant PTH); stimulates bone formation.
Adverse effects of Teriparatide : Dizziness & tachycardia
III. Calcitonin
» Secreted by parafollicular cells of thyroid gland inresponse to t plasma Ca2+.

Actions: I serum Ca2+ & P043" levels through:
1. Bone:
• I Bone resorption - 4 Rate of bone turnover.
2. Kidney:
• I Reabsorption ofCa2+ & P043" at proximal convoluted tubules -> t excretion.
-38-
Indications
1. Paget's disease31.
2. Hypercalcemia.
Adverse effects:
1. Nausea, vomiting, bad taste.

2. Flushing of the face, swelling of hand.
3. Runny nose, nasal bleeding & nasal irritation (with nasal spray).
Preparations
• Porcine calcitonin
• Salmon calcitonin (t t./a & t potency).

• Human calcitonin.
Actions of PTH, Vitamin D and Calcitonin
PTH Vitamin D Calcitonin
GIT Absorption tCa2+&P043* tCa2+&P043- 4 Ca2+ & P043"

BONE t Resorption t Resorption (innormal) 4 Resorption
or formation (in rickets)
RENAL tCa2+ tCa2+ 4Ca2+
Reabsorption 4 P043" t P043" 4 P043"
Serum tCa2+ tCa2+ 4Ca2+
Ca2+&P043 4 P043" t P043" 4 po43"
31 Uncontrolled osteoclastic bone resorption & 2° t bone fonnation (expanded & poorly
mineralized).
-39
IV. Estrogens
• Inhibit bone resorption induced by parathyroid hormone.

Indications: Prevention & treatment of osteoporosis in post menopausal women
(hormone replacement therapy may increase risk of cancer).
V. Glucocorticoids
Actions: 4 Serum calcium level and bone collagen through:

1. Anti-vitamin D -* 4 activation of vitamin D in liver, thus 4 Ca2+ absorption
from intestine.
2. Catabolic -* 4 bone collagen synthesis.

Indications:
• Hypercalcemia due to: malignancy - Vitamin D intoxication.
Chronic systemic use of glucocorticoids causes osteoporosis.
-40
B. Exogenous Agents Affecting Bone Calcium Homeostasis 32
1. Bisphosphonates (Etidronate, pamidronate & alendronate)

1. Bind directly to bone -» retard dissolution & formation of hydroxyappatite crystals
(inhibit bone turnover, mechanisms is unclear).
2. Inhibits an enzyme necessary for osteoclasts survival (alendronate).
3. Inhibition of 1, 25(OH)2 Dproduction &intestinal Ca2+ transport.
Indications
1. Hypercalcemia associated with malignancy.

2. Osteoporosis33 by increasing bone mineral density.
3. Paget's disease of bone: 4 bone turnover.
Adverse effects. CI & precautions
• Gastric & esophageal irritation (take with a full glass of water while sitting upright
for 30 min) -» CI: peptic ulcer - esophageal motility disorders.
• Osteonecrosis of the jaw
• Given cautiously in renal impairment.
2. Raloxifene:
• Selective estrogen receptor modulator (partial agonist) with effects similar to

estrogen on bone (inhibits bone resorption) but not on breast or uterus -» no risk
of cancer.
Adverse effects & Contraindications
• Hot flashes, sweating, or leg cramps.

•Thrombophlebitis & thromboembolism (CI history of venous thrombo-embolism).
32 Mithramycin: (cytotoxic antibiotic—* thrombocytopenia) & gallium nitrate (nephrotoxic): 4 bone

resorption. Used in hypercalcaemia & Paget's disease (resistant cases).
33 Daily,weekly, monthly, every 3 months schedules of several bisphonates as well as annual infusions
of zoledronatc, arc available. Beneficial effects persist over several years, but discontinuation results in
a gradual loss of effects.
-41-
3. Denosumab
• Monoclonal antibody that inhibits RANKL34 -» inhibits osteoclast formation &

function -» inhibits bone resorption.
• Uses: postmenopausal osteoporosis in women at high risk of fracture & those

intolerant or unresponsive to other osteoporosis therapies.
• Subcutaneous injection every 6 months.
Adverse effects:
1. Increased risk of infections
2. Dermatological reactions.
3. Hypocalcemia, osteonecrosis of the jaw and atypical fractures.
4. Strontium
• t Bone formation (calcimimetic. stimulates Ca** sensing receptors causing pre-

osteoblasts to differentiate into osteoblasts).
• Inhibits bone resorption (inhibits osteoclasts).
• Uses: severe osteoporosis, prevents fractures in older women.
• Side effects: May induce myocardial infarction & allergic reactions.
5. Cinacalcet
• Calcimimetic: tSensitivity of parathyroid Ca** sensing receptors35 to blood

Ca** cone. —> 4 PTH secretion—• 4 Ca**—»• used in hyperparathyroidism.
6. Fluoride
• Accumulates in bone -» stabilizes hydroxyappetite crystals (unknown mechanism.)

• t Bone formation - t mineral content of bone.
• Given with Ca2+ supplements (may cause osteomalacia ifgiven alone).

• Uses: Prophylaxis in dental caries (in tooth paste) - osteoporosis (investigational).
7. Thiazides: decrease renal Ca2+ excretion—* 4 Kidney stone formation.
34 RANKL: receptor activator of nuclear factor kappa-B ligand.

35 Antagonists toCa** sensing receptors are being developed & may beused inhypothyroidism &to
stimulateintermittent PTH secretion in treatment of osteoporosis.
-42-
Disturbances in Calcium Homeostasis & their Management
I. Hypercalcemia (-» polyuria -» dehydration & coma) due to:

- la Hyperparathyroidism - cancers36 - hypervitaminosis D.
- Thiazides - immobilization - sarcoidosis.
Treatment
1. Saline diuresis
• Initial infusion of saline -» reverses dehydration & restores urine flow resulting
in diuresis &t Ca2* excretion (frusemide may be added to t urine flow &
inhibit Ca2* reabsorption -» 4 serum Ca2*).
2. Other measures (more prolonged medical treatment)37
Bisphosphonates - calcitonin - glucocorticoids.
II. Hypocalcemia (tetany, paresthesia, muscle cramps, convulsions) due to:

- Hypoparathyroidism - Ca2* or vitamin Ddeficiency - renal failure.
Treatment
• Acute: calcium gluconate 10% slowly IV.

• Chronic:
1. Calcium gluconate tablets. 2. Vitamin D and AT 10.

3. Al(OH)3: binds phosphate in gut -» hypophosphatemia -* © formation of
active Vit. D -» t Ca2* absorption.
III. Rickets & Osteomalacia [poor bone mineralization (4 Ca2* or P043-)]
A. Treatment of Nutritional Osteomalacia and Rickets
Calcium + vitamin D (IM in malabsorption).

B. Treatment of Renal rickets (failure of renal activation of vitamin D)
Calcium + calcitriol or alfacalcidiol (do not require renal activation).
36Tumors secreting PTH-like substance.

37 Mithramycin andgallium nitrate may also be given. Phosphate IV; if others fail but
dangerous-*suddenhypocalcemia & acute renal failure.
-43-
IV. Osteoporosis (4 bone mass -* t risk of fractures, with normal mineralization of

remaining bone)
Causes
1. Estrogen or androgen deficiency (most common in postmenopausal females and

may occur in older men).
2. Cushing's disease (t glucocorticoids) - Thyrotoxicosis.
3. Chronic use of: heparin - aluminum antacids- phenytoin- proton pump inhibitors.
4. Immobilization.
Treatment of osteonorosis
I. Drugs •I Bone Resorption

• Bisphosphonates (Alendronate).
• Raloxifene.
• Denosumab.
• Cyclic Estrogen (post menopausal; mainly).

II. Drugs t Bone Formation
• Teriparatide.
• Anabolic steroids (post-menopausal & in elderly males).
III. Others
• Ca & vitamin D (idiopathic osteoporosis in men & post-menopausal women).

• Strontium (reserved for severe osteoporosis).
44-
Actions & Uses of Agents Affecting Bone Ca Metabolism
Oestrogen - Raloxifene
PTH
• Postmenopausal
(Excess)
osteoporosis
Teriparatide
• Osteoporosis
Denosumab
Osteoporosis
Strontium
(© bone formation
&© resorption) Calcitonin
• Osteoporosis Paget's disease

Hypercalcemia
Fluorides
Prophylaxis for
dental caries
Vitamin I) ) Bone turnover
• Rickets Bisphosphonates
• Osteomalacia • Paget's disease
• Osteoporosis \ Vitamin D dependent

• Osteoporosis.
• Hypopara Ca2' absorption in GIT • Hypercalcemia

thyroidism
PTH -depedent renal

Thiazides Activation of Vit. D -»
l,25-(OH)2D
I Renal Ca2+ 9
stones
Ca2' reabsorption
Glucocorticoids
• i Hepatic activation of vitamin D —> j vit. D-dependent Ca2' absorption in GIT.

• Uses: in hypercalcemia of malignancy or vitamin D intoxication.
-45-
THYROID HORMONES AND ANTITHYROID DRUGS
The thyroid gland synthesizes and secretes two types of hormones:

A. Iodine-containing hormones: T% Ti.
B. Calcitonin.
Actions of Thyroid Hormones
1. Normal growth & development of nervous, skeletal & reproductive systems.

2. Control of metabolism of fats, carbohydrates, proteins and vitamins.
Preparations: T4& T338
Levothvroxine: Synthetic Tj (Eltroxine)

• Dmg of choice in myxedma and cretinism (T3 is added to avoid polymorphism in
D2enzyme (converts T.» to T3).
Iodides
actively
uptaken
by thyroid
gland
Thionamides
Iodides
Sympathetic
Activation
PB t a3
Proteolytii
f Release
e
Lithium
Converted to T3 ^m^^^^^m j4 &f3

Site of Action of Anti
l e
Uptake into Cell &NucIeus < L-Carnitine
thyroid Drugs
38 Thyronine Na+: synthetic T.?; faster-acting, shorter duration, higher cost than T4. It is used in:
Myxedema coma - Diagnostic test in borderline hyperthyroid states.
-46-
Synthesis & Secretion of T3 and T439 & Antithyroid Drugs

Synthesis & Secretion of T3 & T4 Antithyroid Drugs
I. Iodide trapping
• Oral I131 is trapped &
• Iodides are actively uptaken from blood by
concentrated in thyroid
thyroid gland.
gland to emit P rays.
• Uptake is stimulated by TSH
II. Oxidation • Inhibited by
• Iodide is oxidizesd to iodine by thyro- thionamides
peroxidase enzyme.
III. Organification • Inhibited by

• Iodination of tyrosine residues on thionamides & high
thyroglobulin —> formation of doses of iodides
monoiodotyrosine (MIT) & diiodotyrosine

(DIT).
IV. Coupling • Inhibited by

• MIT and DIT are coupled to form T4 and T3
thionamides.
stored in the follicles as thyroglobulin.
V. Release • Inhibited by iodides

• Proteolytic release of T4 &T3 from and lithium carbonate
thyroglobulin (bound to thyroxine binding

globulin in blood
VI. Conversion • Inhibited by propranolol

• T4 is converted to T3 by 5' deiodinase in propylthiouracil &
peripheral tissues. corticosteroids
VII. Tissue uptake: entrv into cell nucleus to • L-Carnitine
induce effects (activity of T3: 3-4 times> T4).
39Iodine, necessary for synthesis of thyroid hormones, is derived from ingested food or iodine
supplements given orally. Ingested iodine is converted into iodide.
-47-
ANTI-THYROID DRUGS
(ATD)40
I. Thionamides
Members:
• Propylthiouracil (PTU)
• Methimazole(preferred as it is given once daily) (MMI)
Mechanism of Action
1. Prevent thyroid hormone synthesis by inhibiting peroxidase enzyme -* inhibition of

iodide oxidation, organification & coupling of MIT & DIT.
2.PTU: inhibits peripheral conversion of T4 to T3 -* conversion of T4 to rT3 (inactive).
Therapeutic Uses
1. Hyperthyroidism: treatment is continued for 1-2 years (most useful in young patients
with small gland and mild disease)41.
2. Preparation for subtotal thyroidectomy (very large gland or multiple nodular
goiters): Treatment is continued until patient is euthyroid.
3. To reduce thyrotoxic symptoms while waiting for radioactive iodine to act.
4. Thyrotoxic crisis (PTU inhibits conversion of T4 to T3).
Adverse Effects42
1. Maculopapular rash (most common).
2. Immune reactions e.g. agranulocytosis (most serious; but rare)43.
3. Hepatic necrosis (with PTU); cholestatic jaundice.
4. Fetal goitre with MMI (PTU is preferred during pregnancy) ; crosses placenta as
MMI but is extensively bound to plasma proteins).
40 Ipodate: iodinated radio-contrast media. Inhibits hormone release & conversion of T4 to T3. Used
as an alternative to iodides or thionamides if they are contraindicated - adjuvant in thyroid storm.
It is preferred to combine ATD and thyroid hormone to avoid frequent adjustments of ATD doses.
42 Lithium has been used to block release of thyroid hormone inpatients intolerant to ATDs.
WBC counts prior to initiating ATD, since mild leukopenia is common
WBC is useful for comparison if subsequent WBC counts are obtained.
-48-
II. Iodide Salts and Iodine
Pharmacological Actions (high doses)

1. Inhibits organification.
2. Inhibit thyroid hormone release by inhibiting proteolysis.
3. Decrease size and vascularity of hyperplastic thyroid gland.
Escape Phenomenon
• Iodides lose their effectiveness after 2 weeks. This is due to compensatory t in TSH
which stimulates T3 & T4 release with loss of iodide effect.
Indications [rapid onset of action (1-2 days)]

1. Thyrotoxic crisis or storm.
2. Preparation for thyroidectomy.
Preparations; Lugol's iodine (iodine in potassium iodide).
III. Radioactive Iodine
Mechanism of Action
1. Oral I131 israpidly absorbed and concentrated by the thyroid gland.

2. It emits p rays (cytotoxic) with poor penetration causing severe damage of the
thyroid without damaging surrounding structures.
Indications
1. Hyperthyroidism in adults over 45 years.

2. Hyperthyroidism in patients not fit for surgery.
3. Recurrence after medical or surgical treatment.
Adverse Reactions
1. Hypothyroidism.
2. Recurrence.
3. Radiation thyroiditis: tt release of thyroid hormones—* cardiac complications;

avoided by pretreatment with ATDs prior to I131 to deplete hormone stored in gland.
Contraindicated; in young, pregnant & lactating (—>genetic damage &cancer)
-49-
IV. p-Adrenoceptive Blockers

44
(Propranalol or Nadolol)
1. Antagonize sympathetic overactivity in thyrotoxicosis (cardioprotective).

2. Inhibit conversion of T4 to T3 -» divert T4 to the inactive rT3.
Indications
1. Symptomatic: controls thyrotoxic symptoms until antithyroid drugs orI131 work.

2. Storm: Thyroid storm.
3. Surgery: Preoperative medication for thyroidectomy.
Thyroid Crisis or Storm

• Occurs in untreated patients; precipitated by surgery, severe infection or illness.
Treatment (drugs are given parenterally or by nasogastric tube)
1. Propranolol: to antagonize sympathetic overactivity (cardioprotection).
2. PTU: to 4- hormone synthesis & inhibit conversion of T4 to T3.
3. Iodides: 1-2 hours after propylthiouracil to 4 hormone release45.
4. Hydrocortisone: inhibits conversion of T4 to T3- adrenal support.
5. Lithium: to I hormone release if patient is allergic to iodides or intolerant to PTU46.
6. Correct fluid balance and hyperthermia - treat HF - arrhythmia.
7. Plasmapheresis and peritoneal dialysis in resistant cases.
Preparation of patients before thyroidectomy
• Antithyroid drugs until euthyroid (6 weeks).
• Beta blockers
• K iodide is given for 15 days prior to surgery (decrease size & vascularity of gland).
• Thyroid supplements after operation.
Patients who cannot tolerate PBs may be treated with calcium channel blockers (diltiazem).
45 Iodides will be utilized in synthesis of hormone if synthesis isnot previously inhibited by PTU.
46 L-carnitinc supplementation may prevent symptoms in hyperthyroidism& thyroid storm.
-50
CORTICOSTEROIDS
The adrenal cortex secretes a number of steroid hormones into circulation:
• Glucocorticoids: Cortisol (hydrocortisone).

• Mineralocorticoids: aldosterone.
• Sex hormones.
I. Cortisol
• The major glucocorticoid in humans.

• Secretion is controlled by ACTH secreted from the anterior pituitary.
• Rate of secretion changes in a circadian rhythm governed by ACTH secretion that
peaks in early morning & troughs at midnight.
• 95% of Cortisol (also all glucocorticoids and mineralocorticoids) circulates in
blood bound to a globulin; Corticosteroid binding globulin (CBG).
II. Aldosterone
• Most important mineralocorticoid (inhibits Na+ excretion & stimulates K+ & H+

excretion) with minimal glucocorticoid activity.
• Very important in regulating blood volume & pressure.
Control of Aldosterone Secretion
1. Renin-angiotensin system activation by hypovolemia & hyponatremia (most

important).
2. Hyperkalemia.
3. ACTH (weak).
N.B.: 2a hyperaldosteronism occurs in CHF, livercirrhosis, nephrosis.
Mechanism of Action of Corticosteroids
• They enter cells where they combine with steroid receptors in the cytoplasm
forming a macro molecular complex which enters the nucleus where it interacts
with chromosomal constituents and alters gene expression -* effects on organs and
tissues.
-51-
Pharmacological Actions, Adverse Effects & Precautions of Glucocorticoids

Pharmacological Actions Adverse Effects & Precautions
I. Metabolic Effects
• Carbohydrates: | blood glucose: - Hyperglycemia —> diabetes.
© Gluconeogenesis, | glucose utilization. CI: diabetes.
• Fat Metabolism: Permissive effect on CA- - Moon face.
induced lipolysis - redistributes fat from -1 abdominal fat.

extremities to face, abdomen & shoulders. - Buffalo hump - obesity.
• Proteins Metabolism - Muscle wasting: thin arms & legs.
Catabolic (except in liver). - Thinning of skin.
- Retardation ofgrowth (children).
- Osteoporosis (J, protein & Ca2+).
• Salt and Water Metabolism
a I Ca2t absorption from GIT. - Osteoporosis (CI).

a Weak mineralocorticoid action: - Edema - f weight.
- TNa+ reabsorption. - Hypertension - heart failure (CI).
- Hypokalemic alkalosis.
-1 K* excretion.
Precautions: diet rich in K+. Ca2+.
proteins and poor in Na+.
II. Anti-inflammatory & immunosupressive - Mask manifestations of
• I VD & edema of acute inflammation. inflammation.
• I Healing - J, fibrosis. -Delay healing of wounds.

Mechanism - Spread of infection.
• I Eosinophils, macrophages, monocytes & CI: severe infection, e.g. TB.
lymphocytes cone, migration & function.

• Inhibit cytokine release.
• Inhibit phospholipase A2 -> J PGs, LTs, PAF.
• I COX 2 expression.
III. Adrenal suppression Adrenal suppression: To avoid:
a Prolonged use of high doses —> J, ACTH - Use small doses (f in stress) &
a Sudden withdrawal —• acute adrenal insufficiency alternate-day schedules.
- Carry card" I am on steroids".
- Gradual withdrawal.
IV. GIT: t HCI & pepsin -J, mucus. Peptic ulcer (CI).
V. CNS: euphoria- behavioral changes. Psychosis - depression (CI).
VI. Other effects: f Hemoglobin, RBCs, platelets & Other side effects
polymorphonuclear leukocytes - Glucoma, cataract.
- Hirsutism, acne.
-52-
N.B.:
•Iatrogenic Cushing: adverse effects due to exogenous glucocorticoids.

•HPA axis suppression may occur if large doses are required for more than 2 weeks.
Recovery of full adrenal function takes 2-18 months after withdrawal.
Preparations of Corticosteroids
A. Preparations with Primarily Glucocorticoid Activity
. . I. Cortisol (hydrocortisone) _._ ,
Disadvantages of Cortisol ;
1. Mineralocorticoid activity. • .; ; i jj
2. Short duration: (ty, dramatically t in liverinsufficiency)!- -.::-.:. :.~r ;
3. Poorly absorbed through normal skin (but readily absorbed through inflamed
skin & mucus membrane). /• j'"" ] i
II. Synthetic Preparations ;: _] '
:; • i j
Prednisone - prednisolone - methylprednisolone - dexamethazone. '
Advantages over Cortisol ...... '
i
1. Mineralocorticoid activity is less with prednisolone & absent with

> i
dexamethazone.
2. Longer duration of action. "" *"" " "' \

~3.More-absorption-throughskuir- - •; •
N.B.: Prednisone is preferred in pregnancy: minimal effect on fetusr Prodrug"
___ _.
•
. _
! not activated in the fetus liverto the active form prednisolone. Any !j
prednisolone formed bymother will bemetabolized.into^prednisoneJ>y,„ :< '
r- -*
placental enzymes.
B. Preparations with Primarily Mineralocorticoid Activity
Fludrocortisone
• Synthetic preparation with potentmineralocorticoid & glucocorticoid activity
Fluodrocortisone is used for replacement therapy in

hypoadrenal states, e.g. after adrenalectomy.
-53-
C. Preparations for Bronchial Asthma
• Beclomethazone, budesonide, fluticasone, triamcinolone, ciclesonide inhalation

Advantages in Asthma
1. Readily penetrate airway.

2. Very short half lives after entering the blood (if swallowed while being inhaled)
due to extensive 1- pass metabolism so that systemic effects and toxicity are
greatly reduced.
Short Anti-inflammatory
Cortisol
1-12 hours Salt retaining effect
Cortisone IM
Prednisone
Prednisolone
Medium IS
I2-.V) hours
Methyl
Prednisolone
Triamcinolone
I"
Betamethazone
Long
Dexamethazone
36-55hours
Fluodrocortisone
Corticosteroid Preparations
Activities are relative to that of Cortisol (considered 1)
Adopted from Lippincot illustrated review (6 "' Edition)
-54-
Therapeutic Uses
I. Adrenal Disorders
A. Acute Adrenal Insufficiency (Addisonian Crisis)

1. Saline & 5% glucose -» maintain fluid & salt balance & blood sugar.
2. IV hydrocortisone hemisuccinate.
3. Fluodrocortisone is started when total Cortisol dose is 4 to 50 mg/d.
4. Treat precipitating factors, e.g. antibiotics for infection.
B. Chronic Adrenal Insufficiency (Addison's disease)

1. Oral hydrocortisone: dose is t during stress or surgery.
2. Fluodrocortisone (orally): maintains Na+ balance & BP.
II. Non-adrenal Disorders
A. Anti-allergic:
• Bronchial asthma
• Allergic conditions: skin, eye, GfT.

B. Immunosuppressants in:
• Autoimmune diseases: systemic lupus - rheumatoid arthritis.
• Organ transplantation, skin grafts.
III. Other Uses
1. Cerebral edema: I VD - 4- exudation of fluids.
2. Malignancies: I lymphocytes in leukemia - lymphomas- | appetite, hemoglobin,

RBCs & platelets in patients on cytotoxic drugs.
3. Anti-stress in: bleeding - trauma - septic & anaphylactic shock (t VC effect of
CA - t glucose level, providing energy to counteract stress).
4. Hypercalcemia: anti-vit. D(4» vit. Dactivation in liver -» I Ca2+ absorption).
5. Respiratory distress syndrome: accelerates lung maturation (IM 48 hrs before birth)
Inhibitors of the synthesis or function of adrenal steroids
•Ketoconazole: antifungal used in cushing disease (inhibitsadrenal steroid synthesis).

•Spironolactone: aldosterone antagonist used in hyper-aldosteronism, heart failure,
hypertension & in hirsutism in women (blocks androgen receptor in hair follicle).
-55-
SEX HORMONES
Female Hormones Male H<)rmones
1
1 1 '
Estrogen Progestins Androgens

Estradiol Progesterone Testosterone
(major ovarian estrogen)
Natural sex hormones are rapidly metabolized in the liver,

therefore have low bioavailability so not used clinically.
Synthetic Estrogens
(Ethinylestradiol - Diethylstilbosterol)
Uses
1. Oral contraceptive pills.

2. Replacement therapy:
a. Primary hypogonadism (in girls).
b. Postmenopausal hormonal replacement therapy (HRT).
• 4 Menopausal Symptoms: flushing, sweating, mood changes.
• 4 Osteoporosis.
• Cardioprotective 4 LDL, t HDL (prevents atherosclerosis).
Adverse Effects
1. Nausea - breast tenderness - weight gain.

2. Endometrial hyperplasia - t risk of endometrial & breast cancer.
3. Hypertension & thromboembolim (t blood coagulation).
4. In male: feminization - impotence - 4 libido - gynecomastia.
-56-
Synthetic Progestins
(Norethindrone - Norgestrel - medroxyprogesterone)
Uses
1. Hormonal contraception (major use).

2. Dysmenorrhea (inhibit ovulation).
3. Endometriosis (long-lasting ovarian suppression).
Adverse Effects
1. Irregularbleeding followed by amenorrhea.

2. Depression.
3. Edema - hypertension - weight gain.
4. 4 HDL.
5. Hirsutism, acne (androgenic).
Oral and Implantable Contraceptives
Mechanism of Action
1. Suppression of ovulation: inhibit FSH & LH.

2. Change cervical mucosa (thick & more acidic) -» inhibit sperm penetration.
3. 4 Endometrial glycogen deposition -* inhibit implantation.
Types
A. Oral Preparations
1.Combined Preparations
Combination of estrogen and progestin (most effective).
2. Progestin-Only Preparations (Minipills)
Less reliable but no risk of thromboembolism.
B. Parenteral Progestin Preparations
a. Implants (norgestrel) —•5 years.

b. Depot injections (medroxyprogesterone acetate) —>3 months.
Indications
1. Contraception. 2. Regulation of menstrual cycle.
-57-
Adverse Effects & Contraindications (CI) of combined contraceptive pills

I. Minor Risks
1. Nausea, vomiting, headache.

2. Breast tenderness.
3. Edema.
II. Intermediate Risks
1. Bleeding (low dose), amenorrhea (large dose).

2. Acne, hirsutism, skin pigmentation.
III. Major Risks: mostly from estrogen. Modern preparations contain low-dose
estrogen—>4 risks.
1. Cardiovascular: t in females over 35 & smokers:
a. Thromboembolism - pulmonary embolism.

b. Hypertension - stroke - myocardial infarction.
CI: myocardial infarction and cerebrovascular disorders.
2. Carcinogenic47
t Riskof cervical?? & breast cancer (estrogen): 4 by adding progestins.
CI: 1. Estrogen-dependent tumors of breast & uterus.

2. Undiagnosed vaginal bleeding.
3. Cholecystitis - gall stones -jaundice -* CI in liver disease.

4. Depression: caused by progesterone.
Drug interactions
• Enzyme inducers: e.g. rifampicin —êfficacy of oral contraceptives—*' pregnancy.
47 Combination oral contraceptives | risk ofovarian cancer and endometrial cancer. This may be
due to the progestin, which opposes estrogen-induced proliferation, throughout the entire 21 days.
-58-
Partial-Agonist Estrogens and Progestins
A. Selective estrogen receptor modifiers
1. Clomiphene
Mechanism of Action: Partial-agonist estrogen that acts centrally:

• Blocks central estrogen receptors in hypothalamus preventing normal feedback
inhibition of estrogen on FSHRH & LHRH in hypothalamus -* stimulation of
ovulation and corpus luteum formation.
Uses (oral)
Ovulation inducing agent in infertility:
1. Female infertility due to disorders of ovulation.

2. with gonadotropins in "in-vitro fertilization".
Adverse Effects
Hot flushes - multiple pregnancies - overstimulation of ovaries.
2. Tamoxifen
Mechanism of Action
Selective estrogen receptor modulator; partial agonist acting peripherally:

• Antagonist:
Prevents endogenous estrogen from activating receptors in estrogen-sensitive

breast cancer.
• Agonist:
i. On bone: preserves bone mineral density (prevents osteoporosis in patients

with breast cancer.
ii. On uterus: increase incidence of endometrial cancer (<1%)
Use: treatment of hormone-sensitive breast cancer.
Adverse Effects: Hot flushes - vaginal discharges - menstrual irregularity.
-59
3. Raloxifene
Mechanism:
• Selective estrogen receptor modulator (partial agonist), similar to estrogen on

bone but not on breast or uterus -* no risk of cancer.
Use:
• Treatment of osteoporosis
Side effects:
• Hot flashes - sweating.

• Leg cramps.
CI. History of venous thrombo-embolism.
-60
B. Antiprogestins
i 1
Mifepristone Danazole
1. Mifepristone
Mechanism: competitive inhibitor ofprogesterone &glucocorticoid receptors48.
Maior use: Therapeutic abortion (e.g. in intrauterine fetal death).
2. Danazole49
Mechanism
• Weak androgen with anti-progestin and anti-estrogenic effects.

• Inhibits FSH and LH output -» 4 ovarian and testicular functions.
Uses50
1. Endometriosis.
2. Fibrocystic disease of breast.

3. Hereditary angioedema
Side Effects
1. Androgenic: acne - hirsutism.

2. Hypoestrogenic: flushing - sweating.
3. Amenorrhea, irregular menstruation.
Ovulation-Inducing Agents (in treatment of infertility)
1. Clomiphene.
2. Human chorionic gonadotropins.
3. Human menopausal gonadotropins: menotropins- urofollitropin
4. Gonadorelin (synthetic gonadotrophin releasing hormone): in sc pulses.
5. Bromocriptine: DA agonist -* 4 prolactin level in hyperprolactinemia.
48 Mifepristone is also used incushing syndrome.

49 Danazole is a partial agonist atandrogen, progestin &glucocorticoid receptors.
50 Danazole is also used in inherited angioedema and haemophilia
-61-
Androgens
(Testosterone propionate - Methyltestosterone)
Actions
A. Androgenic: sex organs development, 2a sex characters, © spermatogenesis.

B. Anabolic: f proteinsynthesis -1 bone & muscle development.
Uses: male hypogonadism.
Anabolic Steroids
(Stanozolol)
• Synthetic androgens with high anabolic and low androgenic activities.

• They promote tissue building processes (—• may be abused by atheletes).
Indications
1. Chronic debilitating diseases, e.g. cancer.

2. Osteoporosis: postmenopausal & in elderly males.
3. Prolonged immobilization.
4. To stimulate growth in boys with delayed puberty.
Adverse Effects
1. Virilization - acne in $; azospermia - t libido in males.

2. Short stature in children (due to premature closure of epiphysis)
3. Cholestatic jaundice - cancer liver.
Antiandrogens
Finasteride
• Inhibitor of prostatic 5-a reductase that converts testosterone into active

dihydrotestosterone—> used in Prostatic Hyperplasia.
FlutamideS1
• Competitive inhibitors at androgen receptor.
• Used in: cancerprostate - excess androgenic effects in females (acne & hirsutism).
^yproterone isanother antiandrogen used as flutamide & inhypersexuality inmales.

Bicalutamide is replacing flutamide as it is less hepatotoxic & is given oncedaily.
-62-
II. CHEMOTHERAPY
By the end of this chapter, the student should be able to recognize the following ILOs
General chemotherapy: the student should be able to
• Classify antimicrobials according to their mechanisms of action.
• Understand time- dependent & cone- dependent killing actions of antimicrobials.
• Recall the differences between different groups of penicillins.
• Recognize that penicillins are the safest antimicrobials except for the risk of
hypersensitivity.
• Identify 2 major toxicities for each antimicrobial drug group.
• List some examples of nephrotoxic antimicrobials.
• List some examples of hepatotoxic antimicrobials.
• List some examples of drugs that should be avoided in children.
• Explain why clindamycin and broad spectrum antimicrobials may induce
pseudomembraneous colitis.
• Discuss choices of antimicrobials for staph, anerobes, gram negative and gram
positive infections.
• Recognize the fact that aminoglycosides are used parentrally in serious gram
negative infections but not against anerobes.
• Recognize the difference in the shift of spectrum of newer generations of
quinolones versus that of cephalosporins.
• Discuss clinically significant pharmacokinetic features of some antimicrobials,
(e.g. renal elimination of aminoglycosides)and of individual members within
the same group e.g. doxycycline versus other tetracyclines &ceftriaxone
&cefoperazone versus other cephalosporins.
• Explain why the use of chloramphenicol is limited.
• List 3 special problems associated with antituberculous therapy.
• Explain the rationale behind combining penicillin with aminoglycosides, and
sulfonamides with trimethoprim.
• List other beneficial antimicrobial combinations.
Special chemotherapy : the student should be able to
• Identify the mechanism of action, uses & adverse effects ofmetronidazole.

• Explain why chloroquine is given in amebic hepatitis.
• Explain why a luminal amebecide is given in all forms of amebiasis.
• Identify the target enzymes and choice of drugs in different viral infections.
• Classify antifungal drugs according to their indications in different fungal
infections.
• Describe the mechanism of action of antifungal drugs.
• Recall the toxicity of amphotericin.
• Explain why flucytosine is combined with amphotericin.
• List the differences between ketoconazole and other azoles.
• Explain why nystatin is given orally and vaginally in candidal infection.
Chemotherapy
CHEMOTHERAPY
Chemotherapy includes:
1. Antimicrobial Agents
• They include antibacterial, antifungal and antiviral drugs.
• When derived from living organisms, they are termed "Antibiotics".
• They are more selective on microorganisms with less toxic effects in human
as they act on structures or chemical reactions specific to microorganisms.
2. Antiparasitic Agents
• Anthelmintics and antiprotozoal drugs.
3. Anticancer Chemotherapy
ANTIBACTERIAL CHEMOTHERAPY
Classification of Antibacterial Drugs
A. Classification according to effect on bacteria:
• Bactericidal: kill the microorganisms & eradicate the infection with no need
for the body defense mechanisms e.g. penicillins & aminoglycosides.
• Bacteriostatic: stop growth of microorganisms with the need for' the body
defense mechanisms to eradicate the infection e.g. .(tetracyclines |&
chloramphenicol. j
N.B.: A bactericidal drug jshould not be combined with a bacteriostatic agent
for a "highly sensitive^ organism" (The bacteriostatic drug will inhibit the
growth oFthe'bacteria abolishing the action of the bactericidal one which
acts only on rapidly growing or dividing organisms).
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Chemotherapy
B. Classification according to antibacterial spectrum:
• Broad-spectrum (on gram +ve & -ve), e.g. broad-spectrum penicillins,

cephalosporins, tetracyclines, chloramphenicol, quinolones, co-trimoxazole.
• Against Gram +ve organisms, e.g. penicillin G, penicillinase-resistant
penicillins, erythromycin, clindamycin, vancomycin, bacitracin, daptomycin,
streptogramins & linezolid
• Against Gram -ve organisms, e.g. aminoglycosides & polymyxin.
C. Classification according to mechanism of Action:
1. Inhibitors of cell wall synthesis: e.g. pVlactams, vancomycin, bacitracin.

2. Inhibitors of protein synthesis: e.g. tetracyclines, aminoglycosides, macrolides,
clindamycin, chloramphenicol, streptogramins & linezolid
3. Inhibitors of nucleic acid synthesis: e.g. quinolones, rifampicin.
4. Inhibitors of metabolic pathways: folate antagonists, e.g. sulfonamides,
trimethoprim, co-trimoxazole (comb, of sulfonamides & trimethoprim).
5. Drugs disrupting cell membrane: e.g. polymyxin, polyenes, daptomycin.
Inhibitors of cell wall synthesis Inhibitors of Protein Synthesis.

pMactams - Vancomycin
Tetracyclines-Aminoglycosides- Macrolides
Bacitracin.
Clindamycin- Chloramphenicol,
Streptogramins - linezolid
Transcription i Translation
mRNA
Protein
Inhibitors of Nucleic
Folic &
Acid Synthesis
Quinolones Folinic Acid
Rifampicin. Synthesis
Drugs disrupting cell membrane Folate Antagonists

Polymyxin- Polyenes -Daptomycin Sulfonamides-Trimethoprim
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Chemotherapy
Aminoglycosides
i. Inhibit initiation
Aminoacyl t-RNA - Tetracyclines
Complex Inhibit binding of
Amino end
ii. Misreading of of polypeptide aminoacyl t-RNA
genetic code (charged t-RNA)
mRNA
0 Codon
Ribosome ready for recognition
next aminoacyl tRNA 5'/ site site
3tp:
2 GDP
Q Peptide
0 Translocation bond fonnation
Erythromycin Chloramphenicol
Clindamycin Inhibits
Inhibit Peptide chain
aminoacyl elongation
Translocation 50 S subunit
Streptogramins-Linezolid
Mechanism of Action of Antimicrobials Acting on Protein Synthesis
Steps of protein synthesis: To initiate translation, the m-RNA, transcribed from the
DNA template is attached to the 30 s subunit of ribosome to which The 50 s subunit binds
forming the 70 s subunit. This subunit moves along the m-RNA such that successive
codons on the m-RNA pass along the ribosome from the A site to the P site. Reading of the
genetic code on m-RNA is followed by:
Binding of t-RNA carrying the required amino acid to the A site on ribosome.
Transpeptidation: transfer of polypeptide on P site to bind with t-RNA on A site
Translocation: movement of ribosomes & translocation of polypeptide from A site to P
site, leaving the A site empty for receiving a new t-RNA.
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Chemotherapy
[inhibitors of cell wall synthesis

• Require proliferating organising-*' little or no effect on non-growing bacteria.
• No effect on organisms devoid of cell wall, e.g. Mycoplasma.
• Less toxic on human cells (mammalian cells have no cell wall).
• Thev include:
1. Beta-lactam antibiotics.
2. Vancomycin.
3. Bacitracin: Effective against Gram +ve organisms.
Nephrotoxic —*• only used topically.
BETA-LACTAM ANTIBIOTICS
Thev possess a B-lactam ring. Thev include:
1. Penicillins. 2. Cephalosporins & cephamycins.

3. Carbapenems. 4. Monobactams.
PENICILLINS
• They possess a common nucleus: aminopenicillanic acid with a p-lactam ring.
Mechanism of Action
• Bactericidal.
• Inhibit transpeptidation or cross-linkage (last step in bacterial cell wall synthesis),

through binding topenicillin binding proteins (pbps1).
• t Activity of autolysins produced by some bacteria leading to cell wall lysis.
^-Lactamase
• Enzyme secreted by some bacteria, e.g. Staphylococci, leading to
inactivation of P-lactam antibiotics -* resistance to these drugs.
1Both susceptible and resistant Gram -ve & Gram +ve organisms have pbps. Resistance of Gram
-ve bacteria to narrow spectrum penicillins arises from presence of an outer membrane with
pores too small to allow adequate penetration ofthe drug & access to the pbps.
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Chemotherapy
Preparations of Penicillins
Due to different R groups attached to P-lactam ring, members of penicillins differ in:
• Spectrum.
• Stability to gastric acidity.
• Susceptibility to bacterial P-lactamase.
1. Natural Penicillins [Penicillin G (benzylpenicillin) and Penicillin V).

• Narrow spectrum (Gram +ve cocci & bacilli) & Gram -ve cocci.
• Penicillin V is acid-stable (so can be given orally).
• Penicillin G is less stable to acid (so given parenterally).
• Inactivated by P-lactamase.
2. Anti-Staph Penicillins2: e.g. oxacillin, cloxacillin, flucloxacillin &nafcillin.

• Narrow spectrum as natural penicillins.
• Stable to gastric acidity.
• Stable to P-lactamase.
3. Extended- -spectrum penicillins, e.g. ampicillin & amoxicillin.

• Broad-spectrum (as natural penicillins plus some Gram -ve bacilli).
• Stable to gastric acidity (amoxicillin orally; ampicillin orally & parenterally).
• Inactivated by p-lactamase.
4. Antipseudomonal penicillins3, indanyl carbenicillin, piperacillin (most potent)

• Broad-spectrum including Pseudomonas & many Gram-ve bacilli.
• Indanyl carbenicillin is acid stable (oral); piperacillin is unstable (parenteral).
• Inactivated by P-lactamase.
2 Methicillin isthe la preparation in this group. It is notused now due to its nephrotoxicity.
1Pseudomonas aeruginosa has restrictive porins, making this organismintrinsically resistantto

many antimicrobial agents.
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Chemotherapy
5. Long acting penicillins, e.g. benzathine penicillin - procaine penicillin

• Insoluble salts of Penicillin G —• allow slow drug absorption with long
duration of action (penicillin G is short acting; 6 hours):
- Procaine penicillin: given every 12 hours.
- Benzathine penicillin: given once/ month.
NJB.:
- Oxacillin or Methicillin Resistant Staph Aureus (ORSA or MRSA) do not respond

to other P-lactams because they acquire penicillin-binding proteins with low
affinity for P-lactams (respond to vancomycin or rifampicin).
Routes of Administration
Depend on stability to gastric acidity & severity of infection:

1. Oral: in moderate infection and acid-stable preparations:
e.g. Penicillin V & ampicillin.
2. Parenteral (IV or IM) in severe infections or acid-unstable preparations.
• Penicillin G is preferred in severe infections with susceptible organisms.
• Depot M preparations: procaine penicillin (given/12-24 h), benzathine
penicillin (long-acting given monthly as prophylactic against Rh. fever).
Pharmacokinetics Advantages of Amoxicillin

Absorption over Ampicillin
Most preparations are incompletely Better absorption (almost
completely absorbed).
Absorbed orally, e.g. ampicillin.
Higher plasma level.
Distribution
Less GIT disturbances &
• Penicillins can cross placenta. diarrhea.
• Cross BBB when inflamed in case of meningitis.
Excretion
• Renal elimination (nafcillin & oxacillin, hepatic metabolism, biliary excreted).

• Probenecid inhibits renal tubular secretion of penicillin by competing with it
for acid secretory mechanism. Thus, it prolongs penicillin action.
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Chemotherapy
Therapeutic Uses
1. Streptococcal infections:
• Acute throat infections, wound sepsis, puerperal fever.
• Bacterial endocarditis: penicillin is given plus 2 separate IV
an aminoglycoside (facilitate penetration of bolus injections,
to avoid
aminoglycosides by interfering with bacterial interaction)
cell wall synthesis -»synergistic bactericidal effect),
2. Staphylococcal infections.
3. Pneumococcal infections.
4. Syphilis & gonorrhea. (Alternative: fluorinated quinolones).

5. Meningococcal meningitis: penicillin G or ampicillin IV plus chloramphenicol.
6. Typhoid & paratyphoid fever: amoxicillin & ampicillin.
7. Diphtheria, tetanus & gas gangrene (penicillin plus specific antitoxins).
8. Prophylaxis against:
a. Recurrence of rheumatic fever: benzathine penicillin (1.2 million units/month ).

b. Bacterial endocarditis (plus an aminoglycoside).
Adverse Effects (one of the safest antibiotics)

1. Hypersensitivity (most important): rashes & phlebitis (direct effect) or
angioedema4& anaphylaxis (immunological due to antigenic metabolite
penicilloic acid). Cross-allergy may occur between p-lactam antibiotics.
2. Diarrhea: due to disruption of normal balance of intestinal flora; more with
incompletely absorbed & broad spectrum agents eg. ampicillin.
3. Neurotoxicity: seizures if injected intrathecally or with t blood level.
4. Cation disturbance: K+ in penicillin G —> hyperkalemia.
5. Decreased coagulation: with high doses of piperacillin.
4Angioedema: marked swelling of lips, tongue, periorbital area.

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Chemotherapy
CEPHALOSPORINS & CEPHAMYCINS
• p-Lactams: similar mechanism to penicillins but more resistantto P-lactamase.
Classification according to Antibacterial Spectrum
1st Generation (cephalexin, cefazolin)

Spectrum:
• G +ve cocci (Strept - Staph).

• Some G -ve organisms (E coli - Klebsiella).
Special features
• Cephalexin: oral, broad spectrum in upper respiratory & urinary infections.

• Cefazolin :_lsl choice in surgical Prophylaxis & Orthopedic surgery:
• Parentral
• Penetrates bone well.
• Penicillinase resistant (Staph).
2nd Generation ( cefuroxime, cefaclor, cephamycins)

Spectrum:
• Less active on G +ve than 1- generation.

• Extended spectrum on G -ve organisms.
• Cephamycins: aerobic & anerobic G -ve bacilli.
Special features
• Oral agents are used in sinusititis - otitis.

• Cefuroxime: also used in community acquired pneumonia (H. influenza).
• Cephamycins (cefoxitin - cefotetan cefmetazole): structurally related to
cephalosporins, parentral in mixed anerobic infections , B. fragillis, peritonitis.
3rd Generation (cefoperazone, cefotaxime, ceftriaxone, ceftazidime)

Spectrum: t Activity against resistant G -ve organisms (e.g. Pseudomonas).
Special features:
• Used in serious infections.
• Most agents can cross BBB (used in meningitis)
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Chemotherapy
Ceftriaxone (Parenteral, longest tYl)

• Used in gonorrhea (single injection) - typhoid (resistant cases).
• Bone: good penetration into bone.
• BBB: crosses BBB, so can be used in meningitis.
• Bile: excreted in bile (40%), used in biliary infection & in renal dysfunction.
4th Generation (Cefepime: parentral)
• Similar spectrum to 3rd gen. on gram negative & crosses BBB well.
• Effective on penicillin resistant streptococci & staphylococci.
5th Generation (Ceftarolene fosamil)
• Broad spectrum pro-drug of active metabolite ceftarolene.
• Sectrum: MRSA, VRSA, H influenza, gram negative (plus amino glycosides).
• Used in: skin infections and community acquired pneumonia.
• Requires dose adjustment in renal impairment.
Pharmacokinetics
• Some members are absorbed orally but most are given parentrally.
• Agents of 1- & 2— generations cannot cross BBB while 3--generation agents
(except cefoperazone) can cross -» useful in meningitis.
• Elimination is mainly renal -* adjust dose in renal dysfunction.
• Cefoperazone & ceftriaxone are excreted mainly in bile5 -» can be used in
biliary infection & patients with renal dysfunction.
Adverse effects
1. Hypersensitivity: avoid in pts with serious penicillin allergy (cross-allergy).

2. Nephrotoxicity especially if used with aminoglycosides.
3. Local irritation -* severe pain after IMI and thrombophlebitis after IVI.
4. Hypoprothrombinemia & bleeding (cefoperazone).
5. Intolerance to alcohol -* disulfiram-like reaction.
6. Cross-resistance with penicillins: avoided in penicillin- resistant infections.
5Cefoperazone (75 %)& ceftriaxone (40 %)are excreted in bile

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Chemotherapy
Other P-Lactam Antibiotics

I
_£ 1
CARBAPENEMS MONOBACTAMS
Imipenem Aztreonam
(Given IV) (Given IV & IM)
• Broadest-spectrum P-lactams. • Narrow spectrum.

• Effective against Gram +ve, -ve • Effective against aerobic gram -ve
organisms and anaerobes. organisms (as aminoglycosides).
• Resistant to P-lactamase. • Resistant to P-lactamase.
• tttcross-allergy with penicillin • No cross-allergy with P-lactams.
• t Risk of Toxicity: • Relatively non-toxic:
1. Metabolized in kidney to • Similar to P-lactams with

an inactive nephrotoxic less risk of hypersensitivity.
metabolite -*has to be
given with cilastatin to

inhibit renal metabolism.
2. t risk of convulsion -*
avoided in meningitis
Meropenem & Ertapenem
• Similar to imipenem with less renal degradation (cilastatin is not required)

&i risk of convulsions.
B-Lactamase Inhibitors: Clavulanic acid & Sulbactam
• They do not have significant antibacterial effect.

• Irreversibly inhibit p-lactamase, -» protect antibiotics inactivated by it.
• Combined with P-lactam antibiotics for P-lactamase-producing organisms.:
o Amoxicillin + clavulanic acid (Augmentin)
o Ampicillin + sulbactam (Unasyn)
o Cefoperazone + sulbactam (Sulperazone)
o Piperacillin +tazobactam (Zosyn)
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Chemotherapy
VANCOMYCIN
Mechanism of Action (Bactericidal)

• Inhibits cell wall synthesis at an earlier stage than P-lactam antibiotics.
Uses (Gram +ve organisms)

1. Staph resistant to penicillin (ORSA orMRSA): drug of choice: used inSerious
infections as Staph pneumonia, endocarditis & osteomyelitis.
2. Severe staph infections in patients allergic to penicillins or cephalosporins.
3. Pseudomembraneous colitis following antibiotic use, e.g. clindamycin.
Pharmacokinetics
• Given by IV infusion.
• Given orally in antibiotic-induced pseudomembraneous colitis due to Clostridium
difficile (not well absorbed; acts locally).
• Excreted renally: dose adjustment is required in renal dysfunction.
Adverse effects
1. Fever, chills, rigors and phlebitis.

2. Shock with rapid infusion -» red man syndrome (due to histamine release),
avoided by slow infusion & pretreatment with antihistamines.
3. Ototoxic.
4. Nephrotoxic.
Drug-induced Pseudomemberaneous Colitis: Kill intestinal

• Clindamycin. flora-*
• Broad-spectrum antimicrobials flourishing of
Tetracyclines, co-trimoxazole, chloramphenicol [ Clostridium
Treatment difficile (G +ve
1. Metronidazole or vancomycin. anerobe) & its
2. Cholestyramine to bind toxins. toxins -» colitis.
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Chemotherapy
TELAVANCIN (synthetic derivative ofvancomycin)

Mechanism of action (bactericidal)
• Inhibits bacterial cell wall synthesis.
• Disruption of cell membrane.
Spectrum (grampositive)
• MRSA,VRSA, daptomycin & linezolid resistant infections.
Adverse effects
1. Metallic taste.
2. Red man syndrome, allergy.

3. Nephrotoxic.
4. Prolongs QT interval.
TEICOPLANIN
• Similar to vancomycin in mechanism, spectrum & renal elimination.
• Has the advantage of once daily administration by IM as well as IV routes.
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Chemotherapy
lANTIMICROBIALS DISRUPTING CELL MEMBRANESl
DAPTOMYCIN
Mechanism of action
• Binds to & depolarizes cellmembrane causing rapid cell death.
Spectrum
• Similarto vancomycin on Gram+ve organisms
Advantages
• More rapidly bactericidal.

• Effective against vancomycin resistant organisms.
Uses (IV & IM)
1. Skin & soft tissue infections
2. Bacteremia & endocarditis.
Adverse effects
1. GIT upset & elevated liver enzymes.

2. Myopathy —> avoid with statins.
N.B.: Daptomycin is inactivated by pulmonary surfactants; CI in pneumonia.
77-
Chemotherapy
["INHIBITORS OF PROTEIN SYNTHESIS

• Tetracyclines • Aminoglycosides • Chloramphenicol
• Macrolides • Clindamycin
TETRACYCLINES
Members
• Tetracycline: short acting.

• Demeclocycline: intermediate
• Doxycycline
line 1
M. „line J| Long-acting (Lipophilic); given once/d
Mechanism of Action (Bacteriostatic)

• Bind to 30S ribosomal bacterial subunits -»inhibition of binding of tRNA -»
inhibition ofprotein synthesis.
Spectrum & Uses
1. Tetracyclines are broad-spectrum antibiotics used in:

• Amebiasis - Acne.
• Brucellosis - Biliary infection (doxycycline & minocycline).

• Chlamydial infections - Cholera (doxycycline + fluid replacement).
• Mycoplasma pneumonia - Meningococcal carriers (Minocycline; cone, in saliva).
• Rickettsial infection.
2. Demeclocycline is used in treatment of Syndrome of Inappropriate Secretion of

Antidiuretic Hormone (by antagonizing effect of ADH on renal tubules).
78-
Chemotherapy
Pharmacokinetics
Absorption
• Incomplete oral absorption.
Absorption is decreased by food due to formation of non-absorbable

chelates oftetracycline with Ca2+, Mg2*, Al3+ (in antacids) and iron.
Distribution
• Penetrate BBB in insufficient concentration for therapeutic effect.
Tetracyclines are concentrated in bone & teeth -» deformities.

Tetracyclines can cross the placenta and affect fetal bones.
Metabolism & Excretion
• Metabolized in part in liver & metabolites & parent drug are excreted in bile,
undergo enterohepatic circulation (especially doxycycline).
• Excreted in urine (| tm in renal dysfunction)-* CI in renal dysfunction
exceptdoxycycline which is eliminated mainly in bile
Adverse Effects & Contraindications
1. Epigastric pain due to gastric irritation (non-compliance) -»|if taken with non-
dairy food (to avoid chelation with Ca2+ in milk).
2. Teeth discoloration & bone hypoplasia-»CI: pregnancy, lactation & child < 8 y.
3. Hepatotoxicity (in renal failure or pregnancy).
4. Phototoxicity (sensitivity of skin to sun light).
5. Superinfection with Candida, C. difficile or resistant Staph in intestine.
6. Fanconi-like syndrome: renal tubular dysfunction with outdated tetracyclines.
7. Contraindicated in renal dysfunction.
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Chemotherapy
TIGECYCLINE
• Similar to tetracycline in mechanism of action & adverse effects (structurally

similar).
• Effective against grampositive, gramnegative & anerobes
• Given by slow iv infusion (adjust dose in liver impairment).
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Chemotherapy
AMINOGLYCOSIDES
Members
• Streptomycin • Gentamycin • Tobramycin

• Amikacin • Netilmicin • Neomycin

Irreversibly bind with 30S ribosomal bacterial subunits leading to inhibition of
protein synthesis by:
• Inhibition of formation of the initiation complex.
• Misreading of mRNA leading to formation of abnormal protein.
• Breaking down of polysomes to nonfunctional monosomes.
Spectrum and Activity
• Effective against aerobic organisms.

• Ineffective against anaerobes (requires 02 for transport into cells).
• Act mainly against Gram -ve organisms, e.g. E-coli, Pseudomonas, cholera.
• Gentamycin is also effective against Staph infections.
• Amikacin resists bacterial enzymatic inactivation, thus it is the most effective
aminoglycoside against Gram -ve bacilli.
Pharmacokinetics
Absorption
• Not absorbed orally thus have to be given parenterally.

Distribution
• They do not cross BBB even when meninges are inflamed.

• Aminoglycosides are concentrated in renal cortex, perilymph & endolymph of
inner ear -» nephrotoxicity & ototoxicity.
Excretion
• Aminoglycosides are excreted unchanged through the kidney, so precaution

should be taken in patients with renal dysfunction.
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Chemotherapy
Adverse Effects
1. Nephrotoxicity
Acute tubular necrosis (may be irreversible). Risk t by dehydration, old age, t
dose, t treatment duration orconcurrent use ofnephrotoxic drugs.
2. Ototoxicity
May be irreversible. Coadministration of loop diuretics orquinidine -*t risk.
3. Neuromuscular paralysis (inhibits Ach release)
Especially after intraperitoneal or intrapleural infusion oflarge doses ().
4. Allergy
Contact dermatitis with topically applied neomycin.
Therapeutic Uses (toxic, reserved for serious infections, plus penicillins)

1. Peritonitis, septicemia, pneumonia.
2. Bacterial endocarditis.
3. Complicated urinary tract infection.

4. Streptomycin is used in TB.
5. Amikacin & netilmicin are reserved for resistant cases.
6. Neomycin (too nephrotoxic for systemic use): used orally in hepatic coma &
intestinal antiseptic before surgery (not absorbed) & topically in infected
wounds.
Spectinomvcin: (structurally related to aminoglycosides)

• It inhibits protein synthesis at 30 S subunit.
• Its use is limited to gonorrhea in patients allergic to penicillin or patients with
penicillin-resistant gonococcal infection (single deep IMI).
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Chemotherapy
MACROLIDES
Members
• Erythromycin
• Clarithromycin
New members
• Azithromycin
Semisynthetic derivatives of erythromycin
• Roxithromycin.
Erythromycin

• Binds to 50S ribosomal subunits preventing translocation -înhibition of
protein synthesis (bacteriostatic at low cone & bactericidal at high cone).
Spectrum & Uses
• Chlamydia, Mycoplasma, Spirochetes, Gram +ve cocci & bacilli as an

alternative to penicillins & tetracyclines: Drug of choice for
- Patients with allergy to p-lactam antibiotics.
- Urogenital Chlamydia infection in pregnancy.
- Mycoplasma pneumonia in children (tetracyclines are contraindicated).
Pharmacokinetics
• Erythromycin is destroyed by gastric acidity, so given as enteric-coated tablets,

stable salts or esters (clarithromycin is not destroyed by gastric acidity).
• Food decreases absorption of erythromycin, but t clarithromycin absorption.
• Poor penetration to CNS.
• Metabolized in liver & inhibits oxidation of other drugs (enzyme inhibitor).
Adverse Effects
1. Epigastric pain & GIT distress (increases bowel motility).

2. Cholestatic jaundice (erythromycin estolate). CI: in liver disease.
3. Ototoxicity and may lead to transient deafness.
4. Thrombophlebitis if injected intravenously (erythromycin).
5. Prolongation of QT interval.
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Chemotherapy
Drug Interactions
1. Enzyme inhibitor: t level of theophylline, warfarin, carbamazepine.

2. t digoxin level (inhibits intestinal flora that inactivate digoxin).
Advantages of new generation macrolides over erythromycin :

a. Gastric acid stability.
b. Better absorption.
c. Long ti/,.
Azithromycin
• Less effective on Gram +ve, more effective on

Gram-ve micro-organisms than erythromycin.
• Potent against Chlamydia.
• Long ty„ allowing once-daily dosing.
• Excreted through bile.
Clindamycin
• Similar to macrolides (bacteriostatic).

• It is used specifically against anaerobic infections.
• It is effective against Gram +ve organisms: Staph & Strept infections.
• It is used in bone infection (good penetration into bone).
Adverse Effects
1. Pseudomembraneous colitis.
2. Skin rash.
3. Diarrhea.
4. Liver dysfunction.
84-
Chemotherapy
CHLORAMPHENICOL

• It binds with 50S ribosomal subunits inhibiting transpeptidation -» inhibiting
peptide chain elongation -»inhibition of protein synthesis.
Spectrum
• It is a broad-spectrum drug (affecting bacteria & rickettsia).
Uses of Chloramphenicol
• Because of its toxicity, its use is restricted to:

1. Typhoid fever (not carrier), but replaced by fl. quinolones.
2. Bacterial meningitis (e.g. H. influenza) plus penicillin.
3. Topically in eye infections.
4. Anaerobic infection, e.g. anaerobic brain abscess.
Pharmacokinetics
1. It is completely absorbed orally.

2. Distributed all over the body reaching the CSF.
3. Metabolized in liver. It inhibits microsomal enzymes.
4. Excreted via kidney.
Adverse Effects
1. GIT upsets and superinfection.

2. Bone marrow depression: may bedose-independent or idiosyncratic.
3. Grey baby syndrome in neonates (J. drug clearance due to undeveloped
liver & kidney functions).
4. Optic neuritis.
5. Enzyme inhibitor : t warfarin, phenytoin &oral hypoglycemics level.
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Chemotherapy
STREPTOGRAMINS
Quinupristin / Dalfopristin6
Mechanism of Action
• Complex with bacterial 50S ribosomal subunits to inhibit protein synthesis
Spectrum & Uses (iv infusion)

• Serious infections with resistant Gram +ve organisms e.g. MRSA &
streptococcus pneumonia when vancomycin cannot be tolerated
Adverse Effects
1. Arthralgia & myalgia.
2. Thrombophlebitis.
3. Enzyme inhibitor -> drug interactions (similar to erythromycin)
OXAZOLIDINONES
Linezolid
Mechanism of Action
•Binds to a unique site on 50S subunit -» inhibits initiation complex & proteinsynthesis.
Spectrum & Uses (iv = oral7)

• Restricted to serious G +ve infections resistant to vancomycin or MRSA in
patients intolerant to vancomycin or if iv access is unavailable.
Adverse Effects
1. Thrombocytopenia.
2. GIT: Nausea, vomiting & diarrhea.
3. Mild MAOI-+ avoid with SSRIs & pseudoephedrine in cold remedies -*t BP
6Given in combination as they are less active ifgiven separately: 7.5 mg/Kg every 8-12hrs.
7 100% bioavailability: 600mg twicedaily oral or iv
-86-
Chemotherapy
INHIBITORS OF NUCLEIC ACH) SYNTHESIS |
I
Quinolones Rifampicin
QUINOLONES

• Inhibit DNA gyrase (topoisomerase II) enzyme, which is responsible for
unwinding of double-stranded DNA leading to inhibition of DNA replication.
• Also inhibits topoisomerase IV responsible for cell division.
Classification
I. Nonfluorinated Quinolones II. Fluorinated Quinolones

1st Generation 2nd —• 4th Generation
Nalidixic Acid
» Not used in systemic infections Newer Fluorinated derivatives
90% of drug is bound to achieving systemic levels

plasma proteins —*• insufficient
plasma cone.
» Was used only in urinary tract
!
infections with G-ve bacilli. Used in Systemic Infections
» Rapid resistance limits its use.
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Chemotherapy
II. Generations of Flouroauinolones
• Fl.quinolones were effective mainly against aerobic G -ve organisms ,

weak against G +ve & ineffective against anerobes.
• Newer generations have âctivity on Gram +ve cocci & anerobes.
2nd Generation: norfloxacin - ciprofloxacin - ofloxacin - pefloxacin

•Excellent on Gram-ve: pseudomonas, E. coli, H. influenza, proteus, salmonella
& penicillinase-producing gonococci (ciprofloxacin is superior to all specially
against pseudomonas).
•Moderate on G+ve: staph (not MRSA), weak on strepto- & pneumo-cocci.
N.B.: Norfloxacin is used in urinary tract infections only as it does not

achieve systemic levels.
3rdGeneration: Levofloxacin
•Effective against G-ve organisms.
•Greater effect on G +ve (pneumococci) than ciprofloxacin.
4th Generation: Moxifloxacin - Clinafloxacin

• Gram-ve activity < ciprofloxacin (poor against pseudomonas).
• Improved activity against G +ve cocci esp. S pneumonia & some staph.
• Active against anerobes (clinafloxacin most potent).
Uses of quinolones
1. Typhoid &infective diarrhea (ciprofloxacin: 1st choice for empiric therapy).

2. Active against anerobes (clinafloxacin: the most potent).
3. Urinary tract infections (Gram -ve bacilli) & prostatitis.
4. Gonorrhea (ofloxacin single dose, levofloxacin ).
5. Respiratory infections resistant to P-lactams & atypical pneumonia due to
chlamydia, mycoplasma, legionella (levofloxacin- moxifloxacin).
6. Bone & soft tissue infection.
7. Resistant TB.
8Derivative of ofloxacin replaced it in treatment of gonorrhea
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Chemotherapy
Adverse Effects and Contraindications (CI)
1. GIT: Nausea, vomiting & diarrhea (most common).

2. CNS: Headache, dizziness, insomnia, convulsions in susceptible patients.
3. Phototoxicity.
4. Hepatotoxicity.
5. Reversible arthropathy (children < 18 years).
6. Drug interactions
a. Enzyme inhibitor -» | serum level of theophylline, warfarin and cyclosporin

(ciprofloxacin).
b.tQT interval -* arrhythmias (trisk with hypokalemia & with drugs that t QT
interval e.g., erythromycin, class IA & III antiarrhythmics & TCAs.
c. Cations (in antacids) —>| absorption of quinolones.
• Quinolones are contraindicated in pregnancy & lactation.

• Not routinely recommended in patients <18 years (-ârthropathy).
89
Chemotherapy
RIFAMPICIN (Rifampin)
Mechanism:
• Binds & inhibits DNA-dependent RNA polymerase -» inhibits RNA synthesis.

Antimicrobial spectrum:
• Potent broad spectrum bactericidal. Effective against ORSA (or MRSA).

• Effective against mycobacteria at all sites & leprosy.
• Antiviral effect.
Kinetics:
• Well absorbed after oral administration.
• Widely distributed in body tissues & fluids & can reach TB cavities & sputum
& penetrate macrophages killingslowly growing TB bacilli inside.
• Crosses BBB.
• Metabolized in the liver & it is a potent enzyme inducer.

• Excreted mainly in bile (enterohepatic recycling) & slightly in urine.
Uses:
1. Mycobacteria: TB (main use), leprosy.

2. Meningitis Prophylaxis.
3. MRSA (ORSA).
4. Brucellosis; plus doxycycline (1st choice).
Adverse effects:
1. Skin rash, fever and GIT upset (Most common).

2. Liver damage and jaundice.
3. Enzyme induction (serious drug interactions); rifabutin is a less potent enzyme
inducer thus induces less drug interaction.
4. An influenza-likesyndrome (malaise, headache and fever,..).
5. Red discoloration of urine, tears, sputum and soft contact lenses.
6. Resistance9: rapid (but no cross resistance with other anti-TB drugs).
9Due to modification of DNA-dependent RNA polymerase bychromosomal mutation

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Chemotherapy
FOLATE-ANTAGONISTS
Sulfonamides Trimethoprim
(-) (-)
Dihydropteroate Dihydrofolate
Synthetase Reductase
PABA • folic acid •*• folinic acid DNA & RNA
SULFONAMIDES
Members
• Sulfadiazine - sulfamethoxazole - sulfadoxine.
• Sulfacetamide (topical eye preparation).

• Sulfonamides are structural analogs of PABA-»compete with it for
dihydropteroate synthetase -» inhibition of folate synthesis-* inhibition of
DNA & RNA synthesis.
NJB.: Human cells utilize already-formed folic acid (explains selectivity of
sulfonamides to bacteria).
Therapeutic Uses
1. Antibacterial: Sulfamethoxazole + trimethoprim (Co-trimoxazole).

2. Eye infections: topical sulfacetamide.
3. Burns: topical silver sulfadiazine.
4. Ulcerative colitis: sulfasalazine.
5. Malaria: sulfadoxine + pyrimethamine (Fansidar).
91-
Chemotherapy
Adverse Effects
1. Crystalluria & nephrotoxicity

• Sulfonamides metabolites formed in liver precipitate in acidic urine -»
crystalluria &nephritis (avoid by | fluid intake &urine alkalinization).
2. Hypersensitivity reactions.
3. Hematopoietic disturbances.
a Granulocytopenia & thrombocytopenia
• Hemolytic anemia inpatients with G-6-PD deficiency.
4. Kernicterus (Jaundice & CNS affection)
• Displace bilirubin from plasma protein. Free bilirubin crosses BBB
(immature in newly-born) & reaches CNS.
5. Interactions
a t level of oral hypoglycemics & anticoagulants (displacement from plasma

proteis).
TRIMETHOPRIM
Mechanism of Action
• Inhibition of dihydrofolate reductase enzyme, which converts folic acid to

tetrahydrofolic acid (folinic acid), which is essential for DNA synthesis.
Adverse Effects
1. Megaloblastic anemia (folate deficiency).
2. Granulocytopenia & leucopoenia.
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Chemotherapy
CO-TRIMOXAZOLE
• It is a combination of: sulfamethoxazole (400 mg) + trimethoprim (80 mg).
Mechanism of Action
• See sulfonamides & trimethoprim.
Advantages
1. Synergistic combination.
2. Less and delayed bacterial resistance
3.More potent (Bactericidal) & wider-spectrum including Proteus,
Salmonella, Shigella, H. influenza & Gonococcus.
Therapeutic Uses
1. Urinary tract infections, gonococcal urethritis and prostatitis.

2. Salmonella & Shigella infections.
3. Respiratory tract infection due to H. influenza & S. pneumonia.
4. MRSA
Adverse Effects
• See sulfonamides and trimethoprim
Urinary antiseptics: for urinary tract infections (UTI)
• UTI ( E coli & staph) are treated with antimicrobials & urinary antiseptics, including:
Nitrofurantoin
Mechanism : reduced by bacteriato a highly active intermediate-* DNA damage.

Spectrum: E coli & staphylococci.
Adverse Effects: GIT upset- neurological disturbances - acute pneumonitis & fibrosis
Methenamine
Mechanism : decomposes in acidic urine to formaldehyde-*toxic to bacteria.

Uses: chonic suppressive therapy to reduce frequency of urinary tract infections.
Adverse Effects: GIT upset- albuminuria, hematuria, and rash.
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Chemotherapy
lANTI-TUBERCULOUS DRUGS
• TB bacilli grow slowly.They are intracellular (inactive), extracellular (active) or
present in necrotic TB tissues.
Problems with TB theranv:
1. Emergence of resistant bacilli as the organisms grow slowly, so combination of

drugs is required.
2. Slowly growing organisms -> disease has to be treated for a long period
(minimum of 6 months up to 2 years) to prevent relapse.
3. Poor compliance when multidrug therapy lasts for 6 months or more -> to
ensure completion of therapy use "directly observed therapy" (DOT) in which
patients take drugs under supervision & observation.
Anti-TB drugs include:
1.1 line drugs (tefficacy, accepted degree of toxicity):

1. Rifampicin: affects the organisms at all sites.
2. Isoniazid (INH): affects intracellular & extracellularorganisms.
3. Pyrazinamide:affects mainly intracellular organisms(resistant strains).
4. Ethambutol.
II. 2 line drugs (used in resistance/ intolerance to 1st line drugs)10:

1. Streptomycin: affects only the extracelular organisms.
2. Ceftriaxone.
3. Fluoroquinolones (ciprofloxacin, levofloxacin & moxifloxacin).

4. Cycloserine -* peripheral neuritis & CNS dysfunction.
5. Ethionamide -^peripheral & optic neuritis
6. Capreomycin -* nephrotoxic & ototoxic.
7. Clarithromycin.
10 Other secondline drugs: aminosalicylic acid.

-94-
Chemotherapy . .
General principles for treatment of TB
1. Bactericidal drugs are preferred.

2. Treatment involves 2 phases :
a- Initial intensive phase: For 2 months
• 4 drugs are used to l the number ofbacilli to avoid resistance.

• Drugs used: Rifampicin + INH + pyrazinamide + ethambutol or
streptomycin.
b- Continuation phase: minimum of 4 months.
• 2 drugs are used: INH & rifampicin.
INDIVIDUAL DRUGS
I. ISONIAZID (INH)
• Affects the enzyme responsible for assembly of mycotic acid in mycobacteria

cell wall (unique structure).
Pharmacokinetics:
• Readily absorbed from GIT & widely distributed into all body tissues and fluids
(CSF, pleural and ascitic fluids, sputum, saliva, and caseous tissue).
• Metabolized in the liver mainly by acetylation which is genetically determined;
individuals are either rapid orslow acetylators11 (respond better).
Adverse effects
2. Neurotoxicity with slow acetylators (B6 deficiency12): peripheral neuritis, optic
neuritis, memory impairment & convulsions -* Vit. B6supplements.
3. Hepatitis: rare but fatal, risk is increased with age.
4. Enzyme inhibitor:tphenytoin & carbamazepine serum level.
" T 1/2 is one hour with rapid &3 hours with slow acetylators.
12 INH metabolites inhibit pyridoxine phosphokinase, which converts pyridoxine (B-6) to active
form, which is required for GABA synthesis. INH overdose-* jpyridoxal-5-phosphate &
iGABA-* CNS stimulation
-95
Chemotherapy
II- RIFAMPICIN: see before
III- PYRAZINAMIDE
• Mechanism : the drug targets mycobacterial fatty acid synthase -I gene

involved in mycotic acid synthesis.
• Bactericidal against resistant intracellular bacilli.
• Given orally, penetrates CSF-> valuable intuberculous meningitis
• Resistance develops rapidly.
• Adverse effects: hepatitis - hyperuricemia &arthralgia - GIT upset.
IV- ETHAMBUTOL
• Bacteriostatic; enters active mycobacteria-* inhibit RNA synthesis.

Side effects:
• Optic neuritis -* red/green colour blindness - ^visual acuity.
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Chemotherapy
Antileprotic Drugs
Management:
Drugcombinations are used to ^resistance:

• Paucibacillary13 leprosy : dapsone + rifampicin (for 6 months).
• Multibacillary leprosy: dapsone + rifampicin + clofazimine (for 2 years).
I. Rifampicin: the most active agent (see before)
II. Dapsone
• A bacteriostatic related to sulfonamides achieves high skin concentration.

• Antagonist to PABA-* inhibits folate synthesis.
Adverse effects:
1. Hemolysis (esp. in G-6-PD def.) - methemoglobuinemia.

2. Peripheral neuropathy.
3. Erythema nodosum leprosum -> suppressed by corticosteroids.
III. Clofazimine (oral)

• A dye accumulating in phagocytes & skin -» bactericidal effect through:
- Binding to DNA, preventing template formation & DNA replication.
- Formation of cytotoxic oxygen radicals.
• Anti-inflammatory: used in patients developing erythema nodosum leprosum
with dapsone.
Adverse effects:
• Skin discoloration (red - brown).

• Enteritis.
13 Paucibacillary = few bacilli.
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Chemotherapy
I CLINICAL ASPECTS OF ANTIMICROBIALS |
• Empirical therapy: It is the use of antimicrobial agents before identification of

causative organism or availability of susceptibility testresults.
• Definitive therapy: It involves the use of antimicrobial agent after
identification/susceptibility tests of causative organism responsible for the disease.
• In severe infections, empirical therapy with antimicrobial drug combination
should be initiated depending on the clinical diagnosis. Later, the antimicrobial
agent should be selected according to the type of organism, culture and sensitivity
reports.
• Bacterial resistance to antimicrobial agent and cross-resistance should also be

considered while selectingdrugs.
Antibiotic Pharmacodynamic Categories
I. II. HI.
Cone. -Dependent Time- Dependent Time-Dependent
With With minimal or no With enhanced
Post antibiotic effect Post antibiotic effect Post antibiotic effect
• Aminoglycosides • P-lactams • Erythromycin

• Quinolones • Vancomycin • Tetracycline
• Clindamycin
• Streptogramins
• linezolid
N.B.: post antibiotic effect (PAE): persistence of antibiotic effect for a period of
time after its level falls below the minimum inhibitory concentration (MIC).
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Chemotherapy
I. Concentration -Dependent antibiotics with PAE:

Maximize drug Cone
• Bactericidal effect depends on drug concentration
• Large infrequent
(increased effectwith increased concentration).
doses are as effective
• Optimum effect is achieved with concentration as small frequent
10 times MIC. doses & may be less
• Trough drug cone, may fall below MIC during toxic.
dosing interval without loss of efficacy as bacterial

regrowth is inhibited by the PAE->|resistance
II. Time- Dependent antibiotics with Minimal/ no PAE :
• Bactericidal effect depends on the duration Maximize duration
during which the drug level exceeds MIC14. of exposure to drug
• Small frequent doses

• Concentrations should be maintained at 2 to 4
& IV infusions are
times MIC throughout the dosing interval as
superior to large
bacterial re-growth starts very soon after trough
infrequent doses.
falls below MIC since drug has no PAE.
HI. Time-Dependent Antibiotics with enhanced PAE:
• Drugs have both time -dependent & concentration - dependent effects.
14 Time above MIC( T> MIC) isanimportant parameter

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Chemotherapy
Antimicrobial Drug Combinations

Indications
1. To provide broad spectrum empirical therapy in severely ill patient.

2. To treat polymicrobial infection such as intra-abdominal abscess.
3. To Xdevelopment of resistant strains e.g. in cases of TB infection.
4. To I dose-related toxicity by reducing doses ofone ormore ofthe combined drugs.
5. To obtain enhanced inhibition or killing (Synergism).
Examples of useful combinations & their mechanisms
1. Penicillins + aminoglycosides in bacterial endocarditis (t antimicrobial effect

& aminoglycosides uptake).
2. Augmentin = Amoxacillin + clavulanic acid (p-lactamase inhibitor) (Inhibition
of enzymatic inactivation).
3. Co-trimoxazole = Sulfamethoxazole + trimethoprim (Blockade of sequential
steps in a metabolic sequence).
4. Anti-TB drugs e.g. INH + rifampicin + ethambutol or pyrazinamide (J, resistance)
Disadvantages of unnecessary use of antimicrobial combinations

1.1 Toxicity.
2. tCost.
3. May I efficacy due to antagonism:

• Inhibition of bactericidal activity by bacteristatic drugs (tetracycline
—•ipenicillin efficacy).
• Induction of enzymatic inactivation e.g. P-lactams ( imipenem, cefoxitin &
ampicillin) are potent inducers of P-lactamase.
4. Increased risk of superinfection.
5. Irrational combination can lead to development of resistance.
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Chemotherapy
Choice of Antimicrobials
Antimicrobials against penicillinase-producing Staph.

• Antistaph penicillins: e.g., cloxacillin, cloxacillin, nafcillin or
amoxicillin + clavulanic acid.
• Cephalosporins: cephalexin, cefazolin, cefuroxime.

• Clindamycin - Co-trimoxazole
♦ Antimicrobials against ORSA (or MRSA):

• Vancomycin & Rifampicin.
• Daptomycin (if resistant to vancomycin & can be given IM).
• Quinupristin/Dalfopristin (if resistant to vancomycin (VRSA).
• Linezolid (if resistant to vancomycin (VRSA); can be given orally).
• Telavancin (MRSA & VRSA, daptomycin & linezolid resistant cases).
• Ceftarolene fosamil (MRSA & VRSA).
• Co-trimoxazole.
Antimicrobials against gram negative organisms:

• Anti-psuedomonas penicillins, e.g., piperacillin+tazobactam
• Cephalosporins: ceftazidime, cefepime.
• Quinolones: ciprofloxacin.
• Meropinem.
• Aminoglycosides (combined with other agents in the immuno-compromized).
Antimicrobials for anaerobic infections:
• Metronidazole.
• Clindamycin
• Cefoxitin
• Imipenem.
• Chloramphenicol (brain abscess).
Antimicrobials for bone infection:
• Agents against staph & gram negative organisms (see above).

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Chemotherapy
♦ Antimicrobials for bacterial endocarditis:
• Gentamycin plus penicillin (or vancomycin).
♦ Antimicrobials for pharyngitis (streptococci)15

• Penicillins: penicillin V, amoxicillin, penicillin G (severe cases).
• Cephalosporins: cefuroxime, cefaclor,....
• Macrolides: erythromycin, azithromycin, clarithromycin.
♦ Antimicrobials for otitis media (streptococci, H influenza)

• Amoxicillin (high dose, plus clavulanic acid in case of lactamase-
producing H influenza).
• Cephalosporins: cefuroxime, cefaclor, ceftriaxone (resistant cases)
• Macrolides (if allergic to B lactams).
♦ Antimicrobials for sinusitis (streptococci, H influenza, anerobes)

• Same drugs as for otitis media.
• Doxycycline (broad spectrum, good penetration into sinuses).
• Clindamycin (for anerobes).
♦ Antimicrobials for dental infections:
• Amoxicillin (empirical treatment)

• Metronidazole —*• added to penicillins if no improvement in 72 hours (in
mixed infections dominated with anerobes)
• Erythromycin/Azithromycin (in patients allergic to penicillins).
• Clindamycin (third choice).
♦ Antimicrobials for bacterial meningitis16:

• Cephalosporins: cefotaxime- ceftriaxone, cefepime.
• Penicillin G.
• Rifampicin.
• Chloramphenicol (brain abscess).
15 Mostcasesare viral requiring no treatment. Streptococci maybe involved.

16 Gentamycin may also beused in meningitis.
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Chemotherapy
♦ Antimicrobials for biliary tract infection17:

• Cefoperazone - ceftriaxone- cefazolin.
• Rifampicin -Doxycycline.
• Ampicillin or amoxicillin.
♦ Antimicrobials for brucellosis18:

• First choice: Doxycycline + Rifampicin or aminoglycosides.
♦ Antimicrobials for typhoid fever:

• Ciprofloxacin (adults).
• Ceftriaxone (children).
• Others: Co-trimoxazole - amoxicillin - chloramphenicol.
♦ Antimicrobials for urinary tract infections (E coli (mainly), staph):

• Fluoroquinolones - Cotrimoxazole.
• Amoxicillin+ clavulanic acid.
• Urinary antiseptics: nitrofurantoin & methenamine.
♦ Antimicrobials for gonorrhea:

• Penicillins.
• Ceftriaxone (single dose).

• Fluorinated quinolones (ofloxacin & levofloxacin).
• Spectinomycin (single dose).
♦ Antimicrobials in pregnancy:
• Penicillins - Cephalosprins - Erythromycin.
♦> Antimicrobials contraindicated in infants & children:
• Tetracyclines -» teeth discolouration & bone deformity.

• Chloramphenicol -* grey-baby syndrome.
• Sulfonamides -» kemicterus in newly-born.
• Quinolones -* arthropathy (not routinely used below 18 years).
17 Gentamycin may also be used in biliary infections.

"Alternative drugs for brucellosis: chloramphenicol +aminoglycosides orco-trimoxazole.
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Chemotherapy
DRUG THERAPY OF AMEBIASIS|
• Amebiasis is an infection produced by ingestion of cysts (non-invasive

form) of E. histolytica. This organism can cause:
A. Bowel lumen amebiasis: Asymptomatic (carriers or cyst passers),
may become symptomatic if left untreated.
B. Tissue amebiasis: cysts develop into trophozoites which feed on
intestinal bacteria or invade submucosa of large intestine, resulting in:
1. Intestinal infection: mild to moderate (no dysentery) or severe
(dysentery).
2. Amebic granuloma (ameboma) in intestinal wall.
3. Extra-intestinal amoebiasis: liver abscess, pulmonary amoebiasis...
Antiamebic Drugs
Antiamebic drugs are classified into:
A. Luminal amebecides —• eradicate the cysts (source of infection).

B. Tissue amebecides —> effective against the trophozoites in tissues.
A. Luminal amebecides
Diloxanide - Iodoqinol - Paromomycin

I- Diloxanide
• 1st choice luminal amebicide used for asymptomatic luminal infections &
with tissue amebicides in tissue amebiasis to eradicate source of infection.
Kinetics
• 90% of diloxanide is absorbed & the unabsorbed 10% is the active
amebicide.
Side effects
1. Flatulence - nausea - abdominal cramps.
2. Teratogenic: CI in pregnancy & children.
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Chemotherapy
II- Paromomycin
• Aminoglycoside antibiotic. Not absorbed & remains in GIT lumen.

• Direct luminal amebicide alternative to diloxanide.
• Also acts indirectly by | intestinal bacterial flora (nutrients for amebae).
Side effects: GIT upset, e.g. diarrhea.
III- Iodoqinol
• 90% of the oral dose is retained in intestine (poorly absorbed).

• Luminal amebicide (toxic drug; alternative to other luminal amebecides).
• Also used in giardiasis.
Adverse effects:
1. GIT upset: nausea, vomiting, diarrhea.

2. Neurotoxicity: subacute myelo-optic neuropathy (SMON).
3. Thyroid enlargement.
Tetracyclines: kill intestinal bacterial flora which are nutrients for amebae.
B. Tissue amebecides
Metronidazole - Tinidazole
Chloroquine - Emetine - Dehydroemetine
I- Metronidazole (Flagyl) nitroimidazole
- It is a prodrug activated by reduction of its nitro group in anerobes &

sensitive protozoa-* disruption of DNA structure & function —> cell death.
- Highly effective tissue amebicide & partially effective luminal amoebicide

affect trophozoites not cysts (due to J. luminal concentration as it is
completely absorbed).
105-
Chemotherapy
Uses of metronidazole:
1. Anaerobic protozoal infections:

a. Amebiasis (all forms except asymptomatic cyst passers).
b. Others: Giardiasis - Urogenital trichomoniasis.
2. Anaerobic bacterial infections:
- Pseudomembranous colitis due to Clostridium difficile.
- Brain abscess, ulcerative gingivitis & dental infections- leg ulcers.

Adverse effects:
1. GIT: unpleasant metallic taste, glossitis, stomatitis,nausea & vomiting.

2. CNS (serious): dizziness - vertigo - ataxia - neuropathy - convulsions
3. Dark urine - dysuria.
4. Neutropenia.
5. Enzyme inhibitor: | warfarin level.
6. Disulfiram- like reaction with alcohol.
7. Teratogenic (CI in pregnancy).
II- Tinidazole (Fasigvn):
• Similar to metronidazole but more effective, longer t >/, & less teratogenic.
III- Chloroauine
Mechanism: tissue amoebicide used mainly in hepatic amoebiasis.
Adverse effects
1. GIT: nausea, vomiting, dyspepsia & abdominal pain.

2. Skin: pruritis, rash & discoloration. (CI. in psoriasis).
3. Eye: retinal degeneration - corneal opacities.
4. C.V.S.: quinidine like action (hypotension & arrhythmias if given IV).
5. Hemolytic anemia: in G6PD-deficient subjects.
Uses:
• Anti-amebic- anti-malarial.
• Rheumatoid arthritis.
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Chemotherapy
IV- Dehvdroemetine & emetine (more toxic)

• Tissue amebicide used in cases of severe intestinal or extraintestinal
amoebiasis if metronidazole cannot be used.
Adverse effects: limit its use
1. Cardiotoxic: arrhythmia - CHF (given in hospital —*• ECG monitoring)

2. Severe pain at site of injection.
3. Neuromuscular weakness & fatigue.
Treatment of specific forms of amebiasis
A. Asymptomatic lumen amebiasis (cyst carriers):

Luminal amebicide: should be used to eradicate cysts1
1. Diloxanide (1st choice).
2. Paromomycin.
Alternatives
3. Iodoquinol.
B. Tissue amebiasis
• A course of luminal amebicide is always given with tissue amebicides to

eradicate the source of infection.
Plus
1. Intestinal infection2
Luminal
1. Metronidazole or tinidazole (1st choice).
Amebicide
2. Tetracyclines3 (alternative in moderate cases)
2. Extra-intestinal infections4 (liver abscess...)

Plus
1. Metronidazole or tinidazole (1st choice).
Luminal
2. Metronidazole + chloroquine (liver abscess
Amebicide
only); ifabove drugs fail5.
1 As carriers may become symptomatic or a source of infection:.

2 Dehydroemetine or emetine (alternatives in severe cases).
3 Orerythromycin
*Dehydroemetine or emetine (alternatives if relapse occurs).
5Aspiration ofabscess-chloroquine is given only inliver abscess.
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Chemotherapy
|DRUG THERAPY OF MALARIA|
• Malaria is caused by 4 species of plasmodia (P): P. ovale, P. vivax, P. malaria

& P. falciparum.
Life cycle of malaria
1. Primary tissue phase (pre-ervthrocvtic).
• Infected mosquito6 injects sporozoites into victim's blood which develop

into shizonts in liver cells forming thousands of merozoites.
2. Erythrocytic phase (responsible for clinical picture)

• Merozoites invade RBCs & develop into shizonts which form more
merozoites.
•Infected RBCs rupture releasing merozoites —> clinical attack.
• Merozoites re-enter fresh RBCs to repeat the erythrocytic phase.
3. Secondary tissue phase (exoerythrocytic)
• Some parasites remain inactive in liver cells for months or years (dormant
form). Re-activation of dormant forms in hepatic cells —> relapse (in P
ovale & P vivax only).
4. After several cycles parasites in RBCs may develop into male & female
gametocytes that are infectious to mosquitoes.
5. Mosquitos pick up gametocytes that develop into sporozoites & are stored
in salivary glands.
6. Life cycle is repeated when infected mosquitoes inject sporozoites into the
blood of a new victim.
6 Infection may result from blood contaminated needles.

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Chemotherapy
2.1" tissue phase
Schizonticides
1. Mosquito injects sporozoites Primaquine
into victim's blood

1
"Causal prophylaxis"
1 Liver
2ry Tissue Phase 3. Erythrocytic phase

Dormant form
Re-activates—»
relapse §4 Schizont Blood schizonticides
4-aminoquinolines
2ry Tissue Merozoites '\
Antifolates
schizontocide
Artemisinin
Primaquine
Schizont Atovaquone
i
Prevents relapse 1
"Radical cure" 1. Clinical cure
4. Gametocytes 2. Suppressive prophylaxis

(Prevent attack)
Sporontocides
i
Antifolates Gametocides
Primaquine
I 5. Mosquito
Taken up in sucked blood I
sucks
& kill sporozoites in Prevent
gametocytes
mosquito transmission of
that develop
Eradicate disease in infection to
into
endemic areas mosquito
sporozoites
- 109-
Chemotherapy
Drug therapy
Problems
• Chloroquine resistance: Chloroquine is the mainstay of anti malarial

therapy but resistance to dmg (geographically distributed) is a major problem
especially with P. falciparum (most dangerous —• encephalopathy & renal
failure).
• Relapse: Re-activation of dormant form in hepatic cells —• relapses in P.
ovale & vivax not in P. falciparum.
INDIVIDUAL DRUGS
4-aminoquinolines
Chloroquine - Quinine - Mefloquine
1. Chloroquine
• Blood schizonticide.
• Moderately effective gametocidal in all species except falciparum..
Mechanism of action: highly concentrated in infected RBCs

• Inhibitsparasite hemoglobin digestion -> I nutrient amino acids for parasite.
• Inhibits parasite heme polymerase —• accumulation oftoxic heme .
Therapeutic uses
1. Prophylaxis & treatment of chloroquine-sensitive malaria:

• Radical cure in falciparum & clinical cure in ovale & vivax (followed
by primaquine to eradicate dormant form—* prevent relapse).
2. Amoebic hepatitis and amoebic liver abscess.
3. Rheumatoid arthritis (anti inflammatory effect).
Adverse effects: see anti-amebic dmgs.
7Parasite splits HB into globin (nutrient amino acids for parazite) & heme. Heme
polymerase polymerizes toxic free heme to hemozoin, rendering it harmless.
-110-
Chemotherapy
2. Quinine8
• Blood schizonticide with unknown mechanism of action.
• Treatment of chloroquine resistant falciparum but not in prophylaxis (too toxic).
Adverse effects:
1. Quinidine like action -> hypotension & arrhythmias.

2. Eye -> blurred vision and blindness.
3. Cinchonism: tinnitus - headache - dizziness and visual disturbances.
4. Black water fever &hemolysis9.

5. Oxtytocic on uterus—*• abortion
3. Mefloquine
Mechanism: Same as quinine but more effective- longer acting - less toxic.
Uses: Treatment & prophylaxis of chloroquine resistantfalciparum.
Artemisinin & Derivatives
• Rapidly acting blood schizonticidal against all human malaria parasites.
Mechansm of action:
•Cleavage of the drug's endoperoxide bridge —• free radicals.
Therapeutic uses
•Treatment of multidrug resistance P. falciparum.

Adverse effects:
•Nausea, vomiting, diarrhea.

•Prolonged QT interval.
Derivatives: Oral, rectal, IM; artesunate is also available rv
• Artemether (combined with lumifantrene 10to decrease resistance).
• Artesunate (may be given with fansidar or combined with mefloquine).
8 Weak antipyretic - weak muscle relaxant (used in muscle cramps).

9Allergic reaction to dmg: marked hemolysis—• hemoglobinuria —* black colour of urine
10 Lumifantrene: related to halofantrinc (blood schizonticide, active in all types. Cardiac problems limit its
use to chloroquine resistant falciparum.
-Ill-
Chemotherapy
Atovaauone
• Active against tissue and erythrocytic schizonts.
Mechansm of action:
•Inhibits mitochondrial electron transport, ATP & pyrimidine biosynthesis.
Therapeutic uses: oral
•Prevention & treatment of choloroquineresistant falciparum (plus proguanil).

Adverse effects:
1. Headaches, nausea, vomiting, diarrhea.

2. Fever, rash.
8-aminoquinolines
Primaquine
• Tissue schizonticide & gametocide (unknown mechanism of action).
Therapeutic uses:
1. Radical cure of relapsing malaria (tissue schizonticide given after a blood

schizonticide to eradicate dormant form).
2. Terminal prophylaxis of relapsing malaria (given after leaving the endemic
area to ensure that dormant forms are eradicated)
3. Prevents transmission of disease to mosquito (gametocide).
Adverse effects:
1. Haemolytic anemia (in G6PDD)- methaemoglobinaemia .

2. Teratogenic.
N.B.: tetracycline & doxycycline are blood schizonticides (not used alone).
-112-
Chemotherapy
Antifolate Antimalarial drugs

Proguanil - Pyimethamine - Sulfadoxine.
• Blood schizonticides (mainly)- sporontocides.
Mechanism of action
• Inhibit folate pathway at 2 sequential steps—• inhibit DNA& RNA synthesis

Sulfonamides Pyrimethamine - proguanil
(-) ,,|
Dihydropteroate Dihydrofolate
Synthetase Reductase
PABA * Folic acid » Folimc acid ». DNA & RNA
Therapeutic uses:
1. Chloroquine resistant falciparum:

• Atovaquone- proguanil.
• Artesunate plus pyrimethamine + sulfadoxine (fansidar ).
2. Toxoplasmosis: pyrimethamine + sulfadiazine.
Side effects:
1. GIT upset - hypersensitivity.

2. Megaloblastic anemia - haemolytic anemia (in G6PDD).
Treatment & Prevention of Malaria
Treatment Prophylaxis
Chloroquine Chloroquine
Sensitive +
Primaquine (in vivax & ovale to prevent relapse)

Chloroquine • Atovaquone-proguanil. • Atovaquone-proguanil.
Resistant
Falciparum • Artemether/ lumifantrene
OR
• Mefloquine • Mefloquine
• Quinine + doxycyline . • Doxycyline
-113-
Chemotherapy
ANTIFUNGAL DRUGS
Fungal infections could be classified into:
A. Superficial fungal infections:

I. Dermatophytes:
Tinea: Capitis (scalp), Corporis (body), Inguinum (nails) & Pedis (foot)
II. Candida:
a. Cutaneous, vaginal, oropharyngeal and gastrointestinal candidiasis.

b. Mucocutaneous candidiasis in severely immunodefecient patients &
can spread to deep tissues (disseminated).
B. Deep fungal infections:
Fungal pneumonia, gastroenteritis, endocarditis or meningitis.
Classification of Antifungal drugs

I- Drugs for systemic (deep) fungal infections:
1. Amphotercin-B.
2. Flucytosine.
3. Azoles: ketoconazole- fluconazole - itraconazole.
4. Caspofungin.
II. Drugs for superficial infections:
A. Drugs given systemically:

1. Griseofulvin.
Dermatophytes
2. Terbinafine.
3. Azoles (ketoconazole, fluconazole, itraconazole): dermatophytes-candida.
B- Drugs given topically:
1.Nystatin (Candida).
2.Terbinafine - naftifine (dermatophytes).
3.Azoles:ketoconazole - miconazole- clotrimazole1'(dermatophytes-candida).
4.Gentian violet (candida) - whitfield ointment (dermatophytes).
11 Miconazole- clotrimazole are used only topically, tootoxic for systemic use.
-114-
Chemotherapy
N.B.: Superficial fungal infections are treated first with topical agents.
Systemic therapy is used in:
1. Resistance to topical therapy.

2. Wide or inaccessible area.
3. Severe infections of hair- skin and nails.
4. Decrease immunity of patient
I. © Synthesis of a glucose
polymer necessary for Caspofungin
Cell
maintaining cell wall
Wall
Terbinafine
II.
Azoles Naftifine
Ergosterol
Cell membrane e
Lanosterol Squalene
Polyenes
Form pores CYP-450 Squalene
Dependent
Epoxidase
14-a-
Demethylase
III.
Nucleus
Microtubules
Flucytosine Griseofulvin
Site of Action of Antifungal Drugs
N.B.: Polyenes: amphotericin & nystatin
-115-
Chemotherapy
INDIVIDUAL DRUGS
Amphotericin-B
Mechanism of action: fungicidal

• Binds to ergosterol of cell membrane -> formation of artificial pores -»
leakage of important cell constituents -» cell death.
Indications: Most important antifungal in deep infections especially:

p Severe life threatening (rV- not absorbed orally).
• Meningitis (intrathecal- does not reach CSF after IVI).
Side effects & toxicity:
• Fever, rigor, vomiting, hypotension & shock after rVT - convulsions

(intrathecally)
• Nephrotoxic -> I erythropoietin -> anemia.
• Hypokalemia and cardiac arrhythmias.
N.B.: liposomal amphotericin (in lipidbilayer) -»less nephrotoxic, used in

patients intolerant to drug.
Flucytosine
• Cytotoxic, transformed to 5-flurouracil -> inhibits nucleic acid synthesis.
Indications: given orally with amphotericin in

1. Cryptococcal meningitis. 2. Disseminated Candida.
Adverse effects: cytotoxic drag

1. Bone marrow depression. 3. Hair loss.
2. Enterocolitis. ^ 4. Hepatotoxic.
Advantages of combination of flucytosine with amphotericin B:
1. i Resistance to flucytosine.
2. 1 Amphotericin nephrotoxicity (lowerdoses of amphotericin are used).
116
Chemotherapy
AZOLES
Ketoconazole - fluconazole - Itraconazole
Mechanism of action: fungistatic

• Inhibition of ergosterol synthesis of cell membrane by inhibiting CYP450
dependent 14- a- demethylase that converts lanosterol to ergosterol.
1. Ketoconazole
• 1st oral broad spectum antifungal for:

1. Deep fungal infections (mild - non meningeal) 2nd line to amphotericin
2. Candidal infection.
3. Dermatophytes resistant to griseofulvin & terbinafine (oraland topical).
Avoid combination with:
1. Antacids or H2 blockers —>4 gastric acidity -» 4 ketoconazole absorption.

2. Amphotericin B : ketoconazole -+-1 amphotericin effect by -lergosterol
(target for amphotericin).
Adverse effects
1.Nausea - vomiting - rash (common).

2. Hepatotoxic (serious).
3. Inhibition of human cytochrome P45o (serious)
i) 4 Steroid synthesis which depends oncytochrome P450:
• i Corticosteroids -> adrenal suppression (used inCushing's disease).
• ^Testesterone -» gynecomastia, impotence (used in cancer prostate).
• -l Female sex hormones -> menstrual irregularities, infertility.
ii) i Metabolism of drugs -> drug interactions:
• t Level of astemizole & terfenadine ->• arrhythmias.
• tLevel of oral anticoagulants, antiepileptics
N.B: Ketoconazole was discontinued in many countries as systemic antifungal.
The less toxic & generally more effective triazole antifungal agents fluconazole
and itraconazole are usually preferred.
-117-
Chemotherapy
2. Itraconazole and fluconazole (oral -IV)

• These drugs are azoles that are more specific to fungal cytochrome P450
than to human cytochrome P450 compared to ketoconazole.
Advantages of fluconazole and itraconazole over ketoconazole
1. Less toxic (less effect on human cytochrome P450): less hepatotoxic - less
adrenal suppression - less drug interactions.
2. More effective.
Advantages of fluconazole over ketoconazole and itraconazole
1. Absorption is better and does not depend on acidity of stomach, therefore

antacids or H2 blockers could be taken safely with fluconazole.
2. Reaches CSF—> unlike ketoconazole it could be given in fungal meningitis.
3. Single dose -> increases patient compliance.
Caspofungin
Mechanism:
• Inhibits synthesis of a glucose polymer that is necessary for maintaining

structure of fungal cell wall—* loss of cell integrity—• lysis & death.
Uses (W)
• Candidiasis & invasiveaspergillosis refractory to amphotericin.

Adverse Effects (well tolerated): GIT upset - flushing.
Griseofulvin
Mechanism: Fungistatic
• Concentrated in newly formed keratin preventing its infection by:
1. Interfering with microtubular function—• interfere with mitosis.
2. Inhibiting nucleic acid synthesis.
• When infected keratin is shed it is replaced by uninfected one.
Indications
• Dermatophyte infections (orally; f absorption byhigh fat diet).
-118-
Chemotherapy
Adverse effects (largely replaced by itraconazole & terbinafine)

1. Nausea-vomiting.
2. Headache - mental confusion
3. Hepatotoxic.
4. Enzyme inducer -> -l warfarin level.
Terbinafine
Mechanism
• Inhibition of squalene epoxidase enzyme which is essential for ergosterol

synthesis of cell membrane-* accumulation of toxic squaline.
Advantages over Azoles
1. Squalene epoxidase enzyme is not present in human.

2. No inhibition of cytochrome P450 (no serious adverse effect of azoles).
Indications:
• Systemic (oral) & topical for dermatophytes. More effective than

griseofulvin.
Side effects (safe): GIT and taste disturbances.
Nystatin
Mechanism
• Binds to ergosterol of fungal cell membrane -> formation of artificial pores-*

damage of membrane -»leakage of important cell constituents -* cell death.
Indications: (too toxic for systemic use)

Used locally in:
1. Oropharyngeal and GI Candida: oral (not absorbed).

2. Cutaneous Candida: topical (nonirritant- rarely causes allergy).
3. Vaginal Candida: It is given both topically and orally because quite
often vaginal Candida is associated with gastrointestinal Candida which
acts as a source of reinfection ofvagina.
-119-
Chemotherapy
ANTIVIRAL DRUGS}
• Viruses consist of nucleic acid (RNA or DNA) enclosed in a protein coat.
Types of viruses:
1. DNA viruses: herpes, hepatitis B, cytomegalovirus (CMV)

2. RNA viruses: influenza, mumps, measles, HCV & poliomyelitis viruses...
3. RNA Retrovirus : Hrv (contains reverse transcriptase enzyme)...
Steps of Virus replication & enzymes involved (targets for drug therapy)
1. Adsorption- penetration & uncoating: viruses have no metabolic machinery

& have to enter host cell & use its metabolic processes to replicate.
2. Early protein synthesis: e.g., synthesis of viral RNA & DNA polymerases.
3. Synthesis of RNA & DNA & coat proteins: by RNA & DNA polymerases in
RNA & DNA viruses respectively. In Hrv, reverse transcriptase makes a
DNA copy of viral RNA.
4. Late structural protein synthesis by viral protease—• viral protein processing

—• mature virion core.
5. Assembly of the formed nucleic acid & coat proteins into new viral particles.
6. Release of new viral particles from host cell; facilitated by neuroaminidase.
Immunoglobulins (v-globulin)
• Pooled immunoglobulins (IgGs) containing antibodies against virus

envelope —• inhibition of viral adsorption & penetration.
• Used before symptoms (viremia) —*• attenuates or prevent measles,
infectious hepatitis, & poliomyelitis (passive immunization; offers 3weeks
protection).
Viral replication occurs before symptoms —• antivirals must be used chemoprophylactically.
-120-
Chemotherapy
Mechanism of Action & Indications of Antiviral Drugs
Drug Mechanism Indications
Amantadine Inhibits penetration & uncoating Influenza A -parkinsonism.

Acyclovir Inhibits DNA polymerase Herpes: H. simplex.
H. zoster - chicken pox.
Ganciclovir Inhibits DNA polymerase CMV pneumonia & retinitis
(in immune-compromized).
Ribavirin Inhibits RNA dependent - HCV (in combinations).
polymerase -Respiratory syncytial Virus
& -InfluenzaA &B.
m - RNA synthesis
Zidovudine Inhibit reverse transcriptase —> HIV (ATDs).
inhibition of replication
Ritonavir Inhibits protease —> inhibition of Anti Hrv (+zidovidine)
viral protein processing
Rifampicin. Inhibit viral particles assembly Vaccinia lesions.
Zanamivir Inhibition of neuraminidase Influenza A (Avian) &

Oseltamivir —•inhibition of viral release Influenza B
Prophylaxis - treatment.
Adverse effects of Antiviral Drugs
1. Amantadine: Insomnia - hallucination - livido reticularis.
2. Acyclovir: N&V, headache, confusion, Seizures, renal Stones, eye Stinging.
3. Ganciclovir: myelosupression - retinal detachment (withintraocular implants).
4. Ribavirin : Anemia - upper airway irritation (withaeroSol) - teratogenic.

5. Zidovudine: myelosupression -flu like syndrome - cholestatic hepatitis.
6. Ritonavir: GIT upset, metallic taste, paresthesias, hyperlipidemia.

7. Zanamivir/ Oseltamivir: N& V - nose & throat irritation (inhaled zanamivir).
-121-
Chemotherapy
0
y-globulin Penetration & •+ Amantadine
e Uncoating of Virus Rimantadine
Penetration
Early protein synthesis of

RNA- DNA polymerases
Acyclovir,
Ganciclovir
\
Ribavirin
0DNA
Polymerase ©RNA
dependent
©
Zidovudine polymerase
©Reverse
Transcriptase
/ &
m-RNA
Nucleic acid
synthesis synthesis
Ritonavir
I
Protease Protease
Inhibitor ©
Late Protein synthesis &

processing
Neuraminidase
1 ©
Viral " Packaging

Release © &
Zanamivir assembly
/
of virus
Oseltamivir
Particles
Viral Replication in Host Cell & Mechanism of Action

of Antiviral Drugs
-122-
Chemotherapy
Anti-viral agents for HCV
1. Interferon (see below)
2. Ribavirin (in combinations).

• Inhibits RNA dependent polymerase & m - RNA synthesis.
• Side effects: anemia - upper airway irritation (with aerosol) - teratogenic.
Newer agents:
• Anti HCV therapy progressed toward simpler IFN-free or IFN- & ribavirin-free
regimens with shorter treatmentdurations & improved efficacy & safety.
• Targets for newer anti HCV drugs include
o NS3, NS4A, NS4B, NS5A, and NS5B involved in synthesis of new viral RNA.
o NS3- 4A (complex of NS3 & NS4A protein): a protease involved in viral protein
synthesis.
1. Sofosbuvir (pro drug, nucleotide analog)l3

• Inhibitor of NS5B polymerase (RNA-dependent RNA polymerase).
Side effects
1. Fatigue, headache, irritability

2. Nausea and rash.
N.B.: Mainly renal elimination—> dose adjustment in renal impairment.
2. Siminrevir
• Inhibitor of NS3- 4A protease.

• Side effect: rash, pruritis.
3. Ledinasvir
• Inhibitorof NS 5A (involved in replication & assembly of viral particle).

• Side effect: Fatigue, headache.
13 400mg, once/day. Covers allgenotypes (12 weeks for genotypes 1,2 ,4;24weeks for type 3).
-123-
Chemotherapy
4. Others
• Daclatasvir: NS5A inhibitor
• Ombitasvir: NS5A inhibitor .
• Dasabuvir : NS5B polymerase inhibitor.

• Paritaprevir: NS3-4A protease inhibitor.
Combinations prescribed '4

• Sofosbuvir/ Ledipasvir (Harvoni).
• Sofosbuvir (Sovaldi) plus ribavirinwith or without peg-interferon.
• Sofosbuvir plus simprevir (Olysio); sometimes given with ribavirin.
• Sofosbuvir plus daclatasvir (Daklinza)
• Ritonavir- paritaprevir, ombitasvir (Technivie) plus ribavirin.
N.B.:
• Paritaprevir is metabolised primarily by CYP3A4 thus it is given with a

low dose of the CYP3A inhibitor ritonavir; this enables once daily
administration and lowering the dose.
• Most side effects are due to ribavirin or interferon containing regimens .
Fatigue, headache , influenza-like symptoms are reduced and
neutropenia is absent in interferon-free treatment.
Ritonavir- paritaprevir, ombitasvir tablet and dasabuvir tablet (Viekera pack), sometimes
given with ribavirin. Indicated in genotype 1 but is contraindicated in genotype 4.
-124-
Chemotherapy
Interferons
• Interferons (IFN) are endogenous proteins released by virally infected cells

-> I susceptibility of neighboring cells to various DNA & RNA viruses.
• Purified interferons are prepared by recombinant DNA technology.
Types
• IFN - a & IFN-B: produced by B & T lymphocytes, macrophages &

fibroblasts in response to viruses & cytokines —> antiviral effect.
• IFNy: produced by T lymphocytes in response to viruses, rickettsiae,
protozoa —*• immunostimulant effect.
• Pegylated IFN- a15: f efficacy & longer acting than IFN - a -* SC once/wk.
Mechanism of action
• Bind to specific cell membrane receptors —* inhibition of viral penetration,

translation, transcription, protein processing, maturation & release.
• t Phagocytic activity of macrophages.
• 1" Proliferation of cytotoxic T cells.
Therapeutic uses of IFN - a
1. Hepatitis B&C.
2. Herpes: Disseminated infections in cancer patients.
3. HIV infection (AIDs).
4. Hairy cell leukemia (cytotoxic)
Adverse effects:
1. Flu like syndrome: fever, chills, myalgia & GIT upset.

2. CNS effects: dizziness - headache- confusion.
3. CVS effects: hypotension- arrhythmias.

4. Bone marrow depression.
5. Alopecia.
15 Polyethylene glycol is attached to IFN- a—• large molecule

-125-
Chemotherapy
DRUG THERAPY OF HELMINTHIC INFECTIONS
Mechanism of Action of Anthelmintics
I
Paralysis Other Mechanisms
1. Pyrantel Pamoate: 1. Benzimidazoles

• Depolarizing NMB -> spastic paralysis Inhibit microtubules
-»worm expulsion. synthesis —>interfere

2. Levamisole. with glucose uptake.
• Depolarizing NMB & immunostimulant. 2. Niclosamide
3. Ivermectin Inhibits glucose uptake

• t GABA transmission (|C1" influx ) & oxidative
phosphorylation -*
4. Praziquantel
scolex loosening &
• t Permeability of worm cell membrane to
worm expulsion.
Ca2+ -» contraction followed by spastic
paralysis, dislodgement & death. 3. Diethylcarbamazine
Alters surface
5. Metrifonate
structure of
• Organophosphorus choline esterase
microfilariae
inhibitor —> worm paralysis.
displacing them from
6. Oxamniquine
tissues -> T
• Unkown mechanism —> worm paralysis—*
destruction by host
hepatic shift & death.
defense mechanisms.
N.B.: In nematodes cholinergic receptors at NMJ are ganglionic nicotinic.
-126-
Chemotherapy
Indications of Anthelminthics
A. Drugs for Nematodes
L Benzimidazoles
1. Mebendazole (ascaris, ancylostoma, enterobius, trichurius).

1. Enterobiasis: single 100-mg chewed tablet, repeated after 2 & 4 weeks.
• All family treatedat the same time + general hygienic measures
• Local application of white precipitate ointment around the anal canal.
2. Other nematode infections: 100 mg twice daily for 3 successive days.

• Fe is given in ancylostomiasis to correct the associated anemia.
2. Flubendazole: similar to mebendazole but also effective in strongyloides
3. Albendazole (broad spectrum for nematodes & cestodes)
1. Nematode infection (ascaris, ancylostoma, enterobius, trichurius):

• Single oral dose 400 mg (repeat for 3 days for ascaris & in 2 wks
for enterobius).
2. Cestode infection 1st choice in
a. Hydatid disease.
b. Neurocysticercosis: plus corticosteroids to înflammatory reaction
to dieing parasites.
4. Thiabendazole
1. Strongyloides (25 mg/kg twice/ day for 2 days). Chewed

2. Trichinosis (for 5 days). tablets given
3. Cutaneous larva migrans (for 2 days). after meal
II. Pyrantel Pamoate
• Alternative to mebendazole in ancylostoma, ascaris & enterobius.
HLLevamisole
• Broad spectrum for nematodes.
-127-
Chemotherapy
IV. Antifilarial Drugs
1. Diethylcarbamazine
• Effective on blood microfilaria of Wuchereria bancrofti & loa loa.
2. Ivermectin: well tolerated
• 1 choice for onchocerciasis - strongyloidiasis.

• Lice - scabies.
B. Antibilharzial Drugs
1. Praziquantel (broad-spectrum for trematodes & cestodes)
1. Schistosomiasis: 1- choice in all species.

20 mg/kg /4-6 hrs (3 doses).
2. Cestodes
- Taeniasis: 1- choice (single dose of 5-10 mg/kg).

- H. nana and D. latum infection (Is' choice).
- Neurocysticercosis (2~ choice to albendazole) plus corticosteroids.
- Hydatid disease as an adjunct to albendazole pre- and post-surgery.
2. Oxamniquine (in mansoni) - metrifonate (in haematobium); rarely used.
C. Drugs for Cestodes: Praziquantel - niclosamide - albendazole
Niclosamide
• 2nd line to praziquantel for T. saginata &solium, D. latum &H. nana.

• Dose: 2 g (4 chewed tablets), single dose on empty stomach.
Precaution
In T. solium infection, a purgative is given to avoid cysticercosis; as
damaged segments release ova which are not affected by drug.
-128-
Chemotherapy
Adverse effects (CI: GIT ulcers)
Drug Adverse effect
1. Mebendazole/ flubendazole 1. GIT pain & diarrhea.

2. Teratogenic (mebendazole).
< 10 % absorbed
2. Albendazole
2. Headache - dizziness -insomnia.
3. Hepatotoxicity - pancytopenia &

alopecia (in ttt of hydatid cyst).
1. Anorexia, nausea & vomiting
3. Thiabendazole
2. Fatal skin reactions
Complete absorption —>more
3. CNS effects
toxic
4. Teratogenic (CI in pregnancy)
4. Pyrantel Pamoate • Nausea, vomiting &diarrhea (mild).
5. Levamisole • GI upset - allergy -CNS effects.

1. GIT upsets (taken after meals).
6. Diethylcarbamazine
2. Headache, arthralgia.
3. Allergic reactions to dying parasites:
fever, rash, leukocytosis.
7. Niclosamide
• Nausea & vomiting (rare)
(Minimal absorption).
8. Praziquantel
2. Rash & pruritus & malaise.
(Well tolerated)
3. Low-grade fever -eosinophilia.
4. Headache, dizziness, drowsiness
5.Teratogenic (CI in pregnancy)
-129-
Chemotherapy
CYTOTOXIC DRUGS
Cell Cycle Kinetics
• All cells undergoing division (cycling) pass through a group of phases of

synthesis of RNA, DNA, mitosis and rest.
Classification of cytotoxic drugs according to phases of cell division
A- Cell cycle specific (CCS) —• given to rapidly growing tumors:

• Antimetabolites - Vinca alkaloid - antibiotics as Bleomycin.
B- Cell cycle nonspecific (CCNS) —> given to slowly growing tumors:

• Alkylating agents - antibiotics as dactinomycin, adriamycin.
I. Alkylating agents
Examples: cyclophosphamide, busulphan - nitrosoureas - cisplatin.

Mechanism:
• They are chemical substances containing highly reactive groups (alkyl).

• They transfer these active groups to various cellular constituents (mainly
DNA, proteins and enzymes decreasing their synthesis &/ or functions.
• They are CCNS; effective against slowly growing tumours
II. Antimetabolites
Mechanism:
• They are structural analogues of naturally occurring metabolites

competing with them for enzyme systems -> J, DNA & RNA synthesis.
• They are cell cycle specific (CCS) effective in highly growing tumours
A. Methotrexate (folic acid antagonist)

• Inhibits dihydrofolate reductase -» -l tetrahydrofolate synthesis -» i
DNA & RNA synthesis.
B. 6- mercaptopurine (purine antagonist).

• Decreases purine synthesis -> I DNA and RNA synthesis.
130-
Chemotherapy
III. Natural products
A. Plant alkaloids: (Vinblastine, Vincristine)

• They are mitotic spindle poisons -» mitotic arrest.
• They are CCS used in rapidly growing tumors.
B. Antibiotics (adriamycin, methramycin and bleomycin)

• Bind to DNA -> fragmentation of itsstrands -> -l DNA synthesis
C. Enzymes (L- asparaginase)
• i blood asparagine —• deprives tumor cells ofthis amino acid which
is essential for protein synthesis.
D. Interferons
IV. Hormones
They are used to suppress growth of hormone dependent tumours:

• Corticosteroids in leukemia and lymphomas
• Testesterone in Cancer breast.
• Estrogen in cancer prostate.

• Hormone receptors agonists & antagonists: (estrogen/tamoxifen),
(testosterone/cyproterone, flutamide).
• Gonadotropin-releasing hormone agonists (leuprolide and goserelin) for
prostate and breast tumors.
V. Radioactive isotopes
• Radioactive iodine (I131), Phosphorus (P32), Gold198 and Cobalt60.

Mechanism:
• Emit P irradiations which cause destruction of the exposed tissues.
Uses:
1. Cancer thyroid.
2. Lymphomas.
-131-
Chemotherapy
Combination chemotherapy in cancer
Advantages:
1. Synergism: Each drug attacks tumour cells at different phases of growth cycle
2. Decrease incidence of resistance
3. Decrease incidence of adverse effects due to use of small optimal doses.
Adverse effects of cytotoxic drugs
A. General adverse effects:
1. Bone marrow depression: leucopenia, thrombocytopenia or pancytopenia.

2. Immunosuppression: liability to infections & delayed healing of wounds.
3. GIT disturbances: vomiting, diarrhea and GIT ulcers.
4. Hair loss.
5. Gonadal damage: sterility, amenorrhea and azospermia

6. Teratogenicity and mutagenicity.
7. Secondary malignancy
8. Hyperuricaemia (due to destruction of "[number of tumor cells)
B. Specific adverse effects:
© Cyclophosphamide: haemorrhagic cystitis.

© Busulphan: interstitial pneumonitis and pulmonary fibrosis
© Methotrexate: mouth ulcer,hepatotoxic, pneumonitis, folate deficiency,
© Vinca alkaloids: peripheral & autonomic neuropathy.
© Bleomycin: pulmonary fibrosis - skin pigmentation.
• Radiation: skin reactions, necrosis, fibrosis, and fistula.
-132
III. Immunomopharmacology
Intended Learning outcomes
• Identify the major classes of immunosuppressant and immuno-stimulant

drugs.
• Identify the mechanism of action , uses & adverse effects of different

agents.
• Recognize the importance of the various uses of the newely introduced

monoclonal antibodies (MAbs).
• Discuss choices of drugs used in rheumatoid arthritis according to the

guidelines.
• Recognize the importance of methotrexate in rheumatoid arthritis.
• List the different therapeutic agents for autoimmune diseases.

Immunopharmacology
llmmunomopharmacology]
The Immune System
• The immune system protects the body from invading pathogens &eliminates
disease, while still capable of recognizing and toleratating "self antigens.
Components of Immune System:
I. Innate (Natural):
• Physical —> skin, mucus membrane (epithelial barrier)

• Biochemical —*• complement, lyzosyme, epithelial natural antibodies.
• Cellular -* macrophages, neutrophils.
II. Adaptive (Acquired): 2nd line defense if innate immune response is inadequate
• Humoral immunity: -> B- lymphocytes ->Ig antibodies -»eliminate

extracellular microbes & toxins.
• Cell Mediated immunity :-*• T-lymphocytes (Kill bacteria, tumorcell&

virus infected cell) -+eliminate intracellular microbes.
N.B.: Antibodies mediate their functions by acting as opsonins to enhance

phagocytosis and cellular cytotoxicity andby activating complement to
elicit an inflammatory response —abacterial lysis.
Major Steps in Immune Responses

1- Antigen recognition.
2- IL-1 production.
3- IL-2 and other cytokine expression.
4- Lymphocyte proliferation & differentiation.
-135-
Immunopharmacology
Abnormal Immune Responses
I. Hypersensitivity (see general pharmacology)

• Immediate hypersensitivity: usually Ig-mediated. (Type LType II, Type III)
• Delayed hypersensitivity (Type IV ): cell-mediated
II. Autoimmunity:
• Activation of self-reactive T and B lymphocytes —> cell-mediated or humoral
immune responses against self antigens e.g Rheumatoid arthritis, systemic
lupus(SLE), multiple sclerosis (MS), DM type I, etc
III. Immunodeficiency diseases:
• These are diseases resulting from inadequate function in the immune system -* f
susceptibility to infections and prolonged duration & severity of disease.
• Immunodeficiency diseases may be either congenital (DiGeorge's syndrome) oi
secondary to bacterial or viral infections (AIDS) or drug treatment.
Opsonized
bacteria
Lysosoma
^jty Blymphocyte
Class II MHC
Peptide
IFNy
TNFp
Proliferation
® ~<sp
Activated Activated Activated
macrophage NK cell cytotoxic T cell
(Kills bacteria) (k«s vtius- (kills tumor Memory B cells
Injected cells cells and
Cl.i-.m.i €••»:,
and tumor vtrus-lnfected
cello l cells)
-136-
Immunopharmacology
Drugs Acting on the Immune System
• Drugs affecting immune function are used for treatment of abnormal immune
responses. They may be classified into:
I. Immunosuppressants
II. Immunostimulants
Immunosuppressants
I. Glucocorticoids (see Corticosteroids)

II. Calcineurins inhibitors: Cyclosporine- tacrolimus
A. Cyclosporine
• Binds to an immunophyllin forming a complex that inhibits calcineurin

(a protein necessary for activation of a T cell-specific transcription
factor involved in synthesis of interleukins, e.g. IL-2) ->J,cytokine
production by T lymphocytes.
Adverse Effects1:
1. Nephrotoxicity (T with CYP450 inhibitors). 3. Hypertension

2. Hepatotoxicity. 4. Hyperglycemia
Uses
1. Organ transplantation &allogenic stem cell trasplantation2.

2. Psoriasis
3. Rheumatoid arthritis.
4. Asthma
1Other side effects ofcyclosporine: seizures , hirsutism, hypertrophy ofgum, hperkalemia, cancers.
2Cyclosporine is used in treatment of host versus gaft disease following transplantation.
-137-
Immunopharmacology
B. Tacrolimus
Mechanism of action & adverse Effects: similar to cyclosporine.

Uses
1. Organ transplantation. 2. Atopic dermatitis. 3. Psoriasis.
III. Proliferative signal inhibitors: Sirolimus
• Binds to immunophyllin forming a complex that blocks mTOR3 which is

involved in cell proliferation & angiogenesis.
Adverse Effects
1. Bone marrow depression. 3. Hypertriglyceridemia.
2. Hepatotoxic. 4. Headache.
Uses
1. Solid organ transplantation & stem cell transplantation.
2. Dermatological disorders.
3. Sirolimus eluting stent: prevent restenosis by its antiproliferative effect.
IV. Mvcophenolate Mofetil & mycophenolic acid:

• Prodrug —> mycophenolic acid —înhibits purine synthesis —> selective

reduction in T & B lymphocyte responses.
Adverse Effects:
1. Bone marrow suppression 2. Hepatitis. 3. Nausea, vomiting, diarrhea.

Uses
1. Hemopoietic stem cell transplantation. 3. Rheumatoid arthritis.

2. Lupus nephritis. 4. skin disorders
*mTOR: molecular target ofrapamycin. It is akey component ofacomplex signalling pathway involved
in cell growth, proliferation and angiogenesis.
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Immunopharmacology
V. Cytotoxic agents
1. Methotrexate: see rheumatoid arthritis
2. Azathioprine:
• Metabolized to 6-MP -> inhibits purine synthesis -> inhibits DNA

synthesis -^cytotoxic effect on proliferating lymphocytes-înhibits
cellular & humoral responses.
Adverse Effects.:
1. Bone marrow suppression. 3. Nausea & vomiting.

2. Hepatic dysfunction. 4. Rash.
Uses4
1. Organ transplantation 3. SLE
2. Rheumatoid arthritis 4. Multiple sclerosis
3. Cyclophosphamide:
• Alkylating cytotoxic agent: cross links DNA-»inhibits cell replication

-> inhibits T cell & B cell function.
Adverse Effects:
1. Hemorrhagic cystitis.
2. Adverse effects of cytotoxic dmgs: e.g., bone marrow depression,etc.
Uses
1. Rheumatoid arthritis.:for extra-articular manifestations as pericarditis.

2. SLE.
3. Multiple sclerosis.
4. Cytotoxic
4Other uses of azathioprine: chrons disease, idiopathic thrombocytopenic purpura, autoimmune

hemolytic anemia.
-139-
Immunopharmacology
VI. Monoclonal antibodies (MAbs) and immunoglobulin-based agents:

1. Adalimumab -Etanerceot & Infliximab: TNF-a blockers
2. Rituximab:. Targets CD20 -> depletion of P lymphocytes see
Rheuma
3. Abatacent:. Binds CD80 & CD86 of antigen presenting cell toid
4. Anakinara: Interleukin-1 receptor antagonist Arthritis
5. Basiliximab (Anti-CD25): Anti-IL-2 Receptor

6.Muromonab-(CD3): Binds to CD3—> internalization of
^_ used in
T-cell receptor —• prevents antigen Renal
recognition, signalling & proliferation. Transplantation
7. Abciximab: blocks gpllblla platelet receptor—• prevents platelet
aggregation and re-stenosis after coronary angioplasty
8. Omalizumab: Anti-IgE (used in treatment of bronchial asthma).
9. RhfD) immune globulin: to Rh (-ve) mother after delivery.
10. Thvmoglobulin: Anti-Thymocytes Polyclonal Globulin —• removal of
T-cell from the circulation —*•[ cytokine response.
Therapeutics uses of Immunosuppressants
I. Organ transplantation & stem cell transplantation:
1. Corticosteroids 2. Azathioprine. 3.Mycophenolate Mofetil.

4. Cyclosporin 5. Tacrolimus. 6. Sirolimus.
7. Muromonab-CD3 8. Basiliximab. 9. Thymoglobulin
II. Cancer: e.g. Rituximab in B cell non-Hodgkin's lymphoma
III. Autoimmune & inflammatory diseases:
1. Rheumatoid Arthritis, SLE, Multiple sclerosis (see below)

2. Psoriasis: Corticosteroids, tacrolimus, cyclosporin plus Sirolimus.
3. Bronchial asthma: corticosteroids, omalizumab, sirolimus, cyclosporin.
IV. Angioplasty:
1. Sirolimus - eluted stent.
2. Abciximab: to prevent re-stenosis after angioplasty
140-
Immunopharmacology
II. Immunostimulants
Therapeutic uses: Immunodeficiency disorders, chronic infectious diseascs& cancer.
Drug Mechanism Indications Adverse effect
1. BCG vaccine5 • Activation of • Intravesical • Hypersensitivity.

macrophages "superficial • Shock, chills, fever.
—•more effective bladder • Malaise.
killer cells cancer" • immune complex
2.Thalidomide • Immunomodulator: • Erythema • Teratogenicity,
Favors TH2 over TH1. nodosum • Peripheral neuropathy.

• Suppress TNF-a leprosum • Constipation.
(antiinflammatory). (ENL). • Rash.
• Antiangiogenesis: • Multiple • Hypothyroidism.

teratogenicity & Myeloma • Thrombosis( DVT).
anticancer (MM).
3. Levamisole • Restores depressed • Given with 5- • Fatal Agranulocytosis
(antihementhic) immune function of FU in class C Replaced by: 5-FU-
B-&T- colorectal leucovorin (more effective
lymphocytes, cancer(only) & less mortality)
monocytes &
macrophages.
4. Interleukin-2 • T cell proliferation. • Malignant • Capillary leak
(aldesleukin) • TH, NK, LAK cell Melanoma. syndrome .
activation • Renal cell • | Disseminated

carcinoma. infection
5. Interferons
See Antiviral Drugs.
"IFNs"
5Bacillus Calmcttc-Gucrin-Vaccine (BCG):viablc strain of M.bovis used for TB immunization .

6Capillary leak syndrome : loss ofvascular tone —» leak ofplasma protein & fluid into
extravascular space—* hypotension, j. organ perfusion, —> death.
-141-
Immunopharmacology
JDrug Therapy of Rheumatoid Arthritisl

Rheumatoid arthritis is an autoimmune disease characterized by joint
inflammation &subsequent tissue damage -» progressive deformities &joint
damage.
Immune complexes (IgM) activate complement & release cytokines (TNF-a

& interleukin-1) which are chemotactic for neutrophils. These inflammatory
cells release lysosomal enzymes -^damage cartilage & erode bone.
•
PGs released during the process-* vasodilation &pain.
• Drug Theranv
A. Nonsteroidal anti-inflammatory dmgs (NSAIDs).

B. Disease-Modifying antirheumatic drugs (DMARDs)
•Methotrexate (drug of choice).
•Hydroxychloroquine.
•Leflunomide.
•Sulphasalazine -penicillamine.
•Cyclosporine - -cyclophosphamide (see immunosuppressants)
•Azathioprine- gold (less commonly used due to f toxicity & I efficacy).
• Biological agents (monoclonal antibodies):
1. TNF-a Inhibitors: adalimumab- etanercept - infliximab.
2. Interleukin-1 inhibitors: anakinra.
3. Anti CD 20 : rituximab.
4. T- cell co-stimulation modulator: Abatacept.

C. Corticosteroids: e.g., Prednisolone
Guidelines for drug theranv of rheumatoid arthritis

1. Goal oftherapy is to relieve pain, inflammation, swelling, stiffness and joint
destruction thus avoiding joint replacement surgery.
-142-
Immunopharmacology
2. Start therapy with NSAIDs: analgesic anti-inflammatory; reduce pain and

swelling but do not prevent progression ofdisease &joint damage.
3. DMARDs therapy is started early once diagnosis is made to suppress the
immune system -»delay disease progress -^prevent joint damage.
4. The onset of DMARDs therapeutic effects is delayed therefore NSAIDs or
corticosteroids are given concurrently to relieve pain & inflammation until
therapeutic effect of DMARDs is achieved.
5. Combinations of DMARDs are usedas they loseeffectiveness overtime.
6. Corticosteroids are too toxic for chronic use and should be reserved for
temporary control ofsevere exacerbation of inflammatory joint condition or
for patients intolerant to DMARDs.
7. Monitor hepatic, renal &bone marrow function regularly to avoid drag toxicity.
Disease-Modifying Antirheumatic Drugs

(DMARDs)
1. Methotrexate
• Main effect Inhibits aminoimidazole carboxamide ribonucleotide (AICAR)

transformylase & thymidalate synthetase -> 2^ effects on
polymorphonuclear chemotaxis.
• Folic acid antagonist: competitively inhibits dihydrofolate reductase-*
ipurine synthesis -» J.DNA -» affects lymphocyte &macrophage function.
• Direct effect: [ cytokines -J, inflammatory cell proliferation &t apoptosis .
Adverse Effects (best tolerated DMARDs)
• Nausea-mucosal ulcers (mostcommon,I by folic acid).
• Bone marrow suppression (Regular bloodcount).
• Hepatotoxicity (Regular liver function tests).
-143-
Immunopharmacology
• Pneumonitis (Regular chest radiology).

• Drug interaction: trimethoprim & sulfonamides:-*tantifolate effect on
bone marrow (add folinic acid).
CI.: pregnancy- renal & liver disease
Uses: (Immunosuppressant, anti-inflammatory &cytotoxic7)

1. Rheumatoid arthritis (ofchoice, most effective).
2. Psoriasis -SLE- Crohn's disease.
3. Leukemias, lymphomas, solid tumors.
2. Hydroxychloroquine
Mechanism of action: accumulates in lymphocytes, macrophages,

polymorphs &fibroblasts-* inhibit phagocytosis (unknown mechanisms).
Proposed mechanisms:
•
Inhibit T lymphocyte response to mitogens.
1Decrease leucocyte chemotaxis.
• •Stabilize lysosomal enzymes.
Adverse Effects
1. GIT: nausea, vomiting, dyspepsia &abdominal pain.

2. Skin: pruritis, rash &discoloration (CI. in psoriasis)
3. Eye: retinal degeneration - corneal opacities (ophthalmic monitoring/6 m).
4. C.V.S.: quinidine like action (hypotension &arrhythmias ifgiven IV).
5. Hemolytic Anemia: in G6PD-deficient subjects.
Uses
1. Rheumatoid arthritis.
2. Systemic lupus.
3. Stem cell transplantation.
4. Malaria
Doses for rheumatoid arthritis are lower than those for malignant tumors.
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Immunopharmacology
3. Leflunomide8:
• Inhibits dihydro-orotate dehydrogenase (DHODH) necessary for

pyrimidine synthesis -> prevents T cell proliferation & production of
auto-antibodies by B cells .
Adverse Effects:
1. Diarrhea 3. Alopecia.
2. Hepatoxicity 4. Teratogenic.
Uses; rheumatoid arthritis
4. Sulfasalazine
Mechanism of action & Uses:
It is split by colonic bacteria into:

• Sulfapyridine: antifolate -» J, cytokines release (interlukins & TNF-
a) by monocytes -» immunomodulator in rheumatoid arthritis
• 5-amino salicylic acid~> anti-inflammatory in inflammatory bowel
disease.
Adverse Effects
1. GIT upset. 2. Neutropenia. 3. Allergy to sulfonamides.
5. Penicillamine
• Îmmune response & IL-1generation.

• Prevents maturation of new collagen
Adverse Effects:
1. Skin rash. 3. Proteinuria.
2. Stomatitis, taste disturbance. 4. Nausea & vomiting.

5. Thrombocytopenia.
1Leflunomide is convertedto its active metabolite in intestine & plasma& is as effective as methotrexate.
-145-
Immunopharmacology
6. Gold compounds (auranofin, sodium aurothiomalate)

Mechanism of action: (unclear)
• Auranofin inhibits induction of IL- 1 and TNF-a.
Adverse Effects: (less with auranofin)
1. Skin rash & mouth ulcers. 3. Proteinuria.
2. Flu like symptoms. 4. Blood dyscrasias.
7. Cyclosporine - -cyclophosphamide & azathioprine: see immunosuppressants

8. Biological agents (Monoclonal antibodies; MAbs)
1. Adalimumab -Etanercept & Infliximab

• Monoclonal anti TNF-a antibodies -> combine with soluble TNF-a,

preventing its interaction with receptor-* inhibit T cells & macrophages.
Adverse Effects- (more with infliximab )
1. Immunosuppression; respiratory infections (reactivation of TB ).

2. Infusion reaction (infliximab)
2. Anakinara
Mechanism of action: (less effective than TNF-ainhibitors)

• Interleukin-1 receptor antagonist -> prevents IL1 binding and
suppresses inflammatory process in synovium.
Adverse Effects: Immunosuppression; respiratory infections.
3. Rituximab:.
• Monoclonal antibody -targets CD20 on p lymphocytes -» depletion of p

lymphocytes ->l presentation of antigen to lymphocyte &| release of
proinflammatory cytokines-*! inflammation.
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Immunopharmacology
Adverse Effects:
1.Infusion reaction: urticaria , hypotension, fever, chills & subsequent

hypersensitivity reaction .
2. Exacerbates CVS disease (rare).
4. Abatacept:.
• Monoclonal antibody: selectively binds to CD80 &CD86 of antigen presenting

cell, blocking its binding to CD28 of T cell, preventing T cell activation.
Adverse Effects:
• Increase risk of infections (specially upper respiratory).

• Infusion reaction, hypersensitivity and anaphylaxis (rare).
Avoid infusion reaction with rituximab by pre-treatment withcorticosteroid orantihistamine.
-147-
Immunopharmacology
Management of SLE
Hydroxychloroquine: mild cases

Azathioprine- methotrexate - mycophenolate mofetil: potency > H.chloroquine.
Corticosteroids: in flares & severe cases (nephritis).
Cyclophosphamide severe cases (nephritis).
Rituximab: moderate &severe cases in young and child bearing period.
Disease-Modifying Treatment of Multiple Sclerosis (MS) 10
Glucocorticoids.
Interferons11: INF-p-la and INF-P-lb (Avonex, Betaferon).

Glatiramer acetate12: immunosuppressant, shifts T-cells from pro
inflammatory Thl cells -> regulatory Th2 cells that suppress inflammation.
Natalizumab (Ig against integrin on leucocytes).
Mitoxantrone, Fingolimod.
Azathioprine-cyclosporine-cyclophosphamide-methotrexate-sulfasalazine.
Inflammatory disease: demyeUnation & scarring of fatty myelin sheaths around axons in brain
& spinal cord -> neurological, cognitive, psychological...signs and symptoms.
" IFN-y used for treatment ofchronic granulomatous disease
12 Copaxone
-148-
IV. NONSTEROIDAL ANTI
INFLAMMATORY DRUGS
Drug Therapy of Gout
Recognize the advantages ofNSAIDS over opioid analgesics.
Explain why aspirin is used as an antiplatelet drug while other NSAIDS are
not.
List the indications of aspirin at different dose levels.

Recall the adverse effects specific to aspirin &those common with other
NSAIDs.
Explain why NSAIDS are nephrotoxic specially in hypovolemic patients.

Explain why aspirin increases bleeding tendencies.
Compare between different members ofNSAIDS regarding efficacy &side
effects.
Explain why indomethacin is reserved for serious joint diseases.

Discuss the possible drug interactions of NSAIDs.
Explain why COX 2inhibitors are dangerous in patients with ahistory of
transient ischemic attacks.
Explain why paracetamol has weak anti-inflammatory effect.
Explain why paracetamol is preferred to aspirin in patients with gout
Discuss the advantages of paracetamol over aspirin.
Explain why the dose ofparacetamol should not exceed 4g/day.
Recall the advantages & uses of intravenous paracetamol.
Discuss the strategy for gout therapy.
Describe the mechanism of action of antigout drugs.
Recall the most common adverse effect of colchicine.
Explain why allopurinol and uricosurics have to be combined with anti

inflammatory drugs in the first 2 months of treatment.
Nonsteroidsal Antiinflammatory Drugs
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

& Drug Therapy of Gout
• Nonsteroidal anti-inflammatory dmgs (NSAIDs) are a heterogeneous group

having anti-inflammatory, analgesic &antipyretic effects. They include:
I. Prototype NSAID: acetylsalicylic acid (aspirin).
II. Non selective NSAIDs: (ibuprofen, naproxen, diclofenac, piroxicam,
indomethacin).
III. Selective COX-2 Inhibitors: Celecoxib.
• Paracetamol is an analgesic-antipyretic with weak anti-inflammatory action.
Cvclooxvpenase Enzymes
• COX-1: Mainly constitutive (present normally in tissues regulating its
physiologic functions), responsible for forming protective PGs in GIT &
kidney.
• COX-2: Inducible in inflammation, constitutive in endothelium & kidney.
• COX-3: Newly discovered (its role is still under investigation)
Mechanism of Action of NSAIDs & Paracetamol

• Acetylsalicylic acid, irreversibly inhibits (acetylates) cyclooxygenase
enzymes (COX-1, COX-2) -» inhibits conversion of arachidonic acid to
endoperoxides -* inhibits PG & TXA2 production.
• Other NSAIDs cause competitive reversible inhibition of COX enzymes.
• Celecoxib is a selective inhibitor of COX-2 enzyme.
• Paracetamol:. Inhibits PG synthesis mainly in CNS -» analgesic &
antipyretic effects (may act on COX-3). Weak anti-inflammatory effect
(poorly inhibits COX enzyme in the presence of excess peroxides in inflamed
tissue). Its action may involve interaction with the serotonergic and
endogenous opioid systems.
151-
I. ACETYLSALICYLIC ACID (Aspirin)

Pharmacological Actions & Therapeutic Uses
£
Low-Dose High-Dose(4-8 g/d)
Prophylactic Anti-inflammatory
1. Antiplatelet' (0 TXA2 synthesis). 4PGE2 & PGI2 -*4VD &
Main use2: prophylaxis for transient edema of inflammation.
ischemic attacks, unstable angina, Uses
1. Rheumatic fever.
acute myocardial infarction (but 300
2. Rheumatoid arthritis & other
mgin acute attack).
inflammatory joint diseases
2. 4 Risk ofcolorectal cancer.
(NSAIDs replaced aspirin).
Intermediate dose
(325 ms tab) 1-2 tab/4 h
Analgesic Antipyretic
a) Peripheral effect: I PGs (that are released 4 pyrogen-induced PGE2 in fever3

during inflammation & sensitize nerve -* resetting of hypothalamic
endings to kinins) -» t pain threshold. thermostat to normal -» ©
b) Central effect: 4- PGs -» 9 pain temperature-regulating
transmission at subcortical sites. mechanisms -» VD & sweating
Use -» 4- temperature (no effect on
1. Mild to moderate pain 2ry to inflammation , normal temperature).
e.g. arthritis, dental pain (ineffective in Uses
severe visceral pain). Antipyretic in fever
2. Headache, dysmenorrhea. (paracetamolpreferred).
3. Postpartum pain, postoperative & cancer
pain (added to opioids to 1 their dose).
There is nodifference in efficacy between doses of 75 to 150mg/day and 160to 325 mg/day.
2Use ofaspirin in l17 prevention ofCV disease is weighed against risk ofbleeding on individual basis.
3PGE2 generated by inflammatory pyrogens -»t hypothalamic set point for temperature control in fever.
-152-
Pharmacokinetics
• Aspirin is given orally & is rapidly absorbed partly from stomach (largely
nonionized in acidic medium) & mostly from upper small intestine.
• Bound to albumin -» displaces warfarin potentiating its effect.
• Rapidly hydrolyzed into acetic acid & salicylate by tissue & blood esterases
(t>/2 15 min), followed by conjugation (saturable) -» follows dose dependent
elimination (t>/, varies from 2 hrs in low doses up to 30 hrs in toxic doses).
• Alkalinization of urine t its excretion (useful in toxicity).
Adverse Effects
A. Effects Common to all NSAIDs (particularly in the elderly)
1. GIT (most common; directmucosal irritation & ^protective PGs)

Dyspepsia, nausea, vomiting, gastritis, ulceration with | risk of bleeding.
Reduced by co-administration of misoprostol or omeprazole.
2. Nephrotoxicity4 (less frequent with aspirin)

hi renal insufficiency or in hypovolemic patients whose GFR depends on
vasodilator PGs (e.g. heart failure or extensive diuretic therapy),
•l vasodilator PGs by NSAIDs -* I renal blood flow resulting in:
a. Salt & water retention (edema), t BP.
b. Hyperkalemia.
c. Acute renal insufficiency
3. Hypersensitivity reactions: Skin rash, rhinitis, asthma especially in

asthmatics & patients with nasal polyps (diverts arachidonate metabolism
from cyclooxygenase to lipooxygenase pathway -* t chemotactic LTB4
& spasmogenic LTs).
3Aspirin should not be added to anticoagulant therapy except in specific conditions e.g. recent
acute coronary syndrome or stent placement.
Analgesic nephropathy: irreversible chronic intersdtial nephritis due to abuse of mixed
analgesics.
-153
4. t Bleeding tendency (stop aspirin 1 week before surgery)

• Antiplatelet effect.
• Displacement of warfarin from plasma proteins potentiating its effect.
5. CV. events (except with low dose aspirin)
There is an increased risk of adverse cardiovascular events: (MI, stroke,
HF, AF and cardiovascular death), naproxen seems to have the least risk.
6. Hepatotoxicity: Idiosyncratic reaction

• Severity vary from asymptomatic elevations in liver tests to fulminant
hepatic necrosis resulting in death
• On an individual patient level, NSAIDs do not pose a very large risk
of hepatotoxicity.
B. Effects Specific to Aspirin
1. Hypoprothrombinemia:t bleeding risk(> 5 g/d competes with vit. K).

2. Hyperuricemia (low-dose aspirin in gout): competes with uric acid for
excretion by organic acid secretory mechanism in renal tubules.
3. Reye's syndrome: encephalopathy and liver damage in patients with
fever due to viral infection (CI as antipyretic in viral infections).
4. Chronic toxicity (salicylism): prolonged administration of large doses
-» dizziness, tinnitus, nausea & vomiting.
5. Acute toxicity: respiratory alkalosis (hyperpnea —> washing out of C02)
followed by respiratory acidosis (respiratory depression—*• C02 retention)
& metabolic acidosis (accumulation of acidic metabolites).
Advantages over opioid analgesics:
i. No dependence.
ii. No respiratory depression (in therapeutic doses)
154-
II. Non selective NSAIDs
• Possess analgesic, antipyretic &anti-inflammatory effects (see aspirin).

• They are increasingly used in inflammatory joint diseases (osteoarthritis,
rheumatoid arthritis & gouty arthritis), dysmenorrhea, renal colic &
postoperative pain; in patients not responding to aspirin orintolerant to it.
• They are ineffective as antiplatelets since they inhibit COX reversibly -»
short antiplatelet effect. If taken with low dose aspirin they may attenuate
its antiplatelet effect.
Adverse Effects: see before
Individual NSAIDs (differentiated by cost-effectiveness, efficacy & safety)

Ibuprofen
• First-choice in inflammatory joint disease: less effective than others but

better tolerated (4- incidence of side effects than other NSAIDs).
• May be used as antipyretic besides paracetamol, if needed.
Naproxen
• Related to ibuprofen: more potent, with moderate risk of adverse effects.

• Longer-acting (given twice daily) -* t patient compliance.
• Least risk of CV events.
Diclofenac
• Combines good efficacy (stronger than ibuprofen) with relatively low

incidence of side effects (more than ibuprofen but less than indomethacin).
• A combination of diclofenac and misoprestol is available in some countries.
Piroxicam
• Strong anti-inflammatory with t risk of GIT bleeding.

• Long-acting (t% 45 h), given once daily.
-155-
Indomethacin
• Strong anti-inflammatory.
• Due to serious adverse effects its use is limited to:
1. Acute gouty arthritis.
2. Rheumatoid arthritis, ankylosing spondylitis.
3. Postoperative pain.
4. Patent ductus arteriosus (inhibits PG synthesis closing the ductus).
Adverse Effects
1. Adverse effects common with other NSAIDs (see before).

2. CNS: dizziness, confusion, ataxia, severe headache (cerebral VD).
3. Aplastic anemia.
Drug interactions of NSAIDs
l.| Effects of ACEIs (| BK - induced PG production).

2. J, Effects of diuretics.
3. Displace warfarin & oral hypoglycemics from plasma proteins.
4. | Risk of gastric ulceration with glucocorticoids.
-156-
ffl. Selective COX-2 Inhibitors
Celecoxib
• Selective COX-2 inhibitors were developed to spare COX-1 enzyme, thus

retaining their anti-inflammatory effects without the adverse effects resulting
from inhibition of constitutive COX-1 in GIT and kidney.
Uses
1. Anti-inflammatory: used inchronic inflammatory musculoskeletal

disorders (with less risk of gastric ulceration).
2. Acute pain or primary dysmenorrhea
Adverse Effects of COX-2 Inhibitors5
1. Nephrotoxicity (COX-2 is constitutive in kidney).

2. Stroke & infarction (COX-2 is responsible for endothelial PGI2 synthesis).
3. Skin rash with celecoxib (structurally relatedto sulfonamides).
PARACETAMOL (Acetaminophen)
•It is an analgesic antipyretic with weak anti-inflammatory action.

It is preferred to aspirin in:
1. Patients allergic to aspirin.

2. Peptic ulcer (no GIT disturbances).
3. Gout (aspirin may cause hyperuricemia).
4. Feverdue to viral infections (to avoid Reye's syndrome with aspirin).
5. Bleedingdisorders (does not affect platelet function).
Dose
• For Adults: 1000 mg 3-4 times daily; orally. Maximum: 4 g daily.

• For Children: 10 to 15 mg/kg/4-6 h. Maximum 5 doses/d.
'Recently, COX-2 was also found tobeconstitutive inmany tissues (kidney, endothehum...).
-157-
Kinetics
• Paracetamol is conjugated in the liver to inactive metabolites & only 5% is

converted by mixed-function oxidases to a hepatotoxic metabolite (N-acetyl-p-
benzoquinone) -» deactivated by conjugation with glutathione.
• In toxic doses saturation of conjugating enzymes results in increased
conversion of the drag to the toxic metabolite beyond the capacity of liver to
conjugate it with glutathione -» hepatotoxicity.
Adverse Effects & Toxicity
• Minimal adverse effects - well tolerated.

• Analgesic nephropathy with high doses for long periods.
• Paracetamol hepatotoxicity (in toxic doses [150 mg/kg6]: nausea and
vomiting, followed in 24-48 h by liver damage)
Treatment: Precursors for glutathione synthesis: acetylcysteine (orally or
IV) ormethionine (orally) can prevent liver damage if given early.
Intravenous paracetamol7
1. Analgesic: in mild to moderate postoperative pain -» safe with opioid
sparingeffect (4 opioid dose).
2. Antipyretic: in acute fever of infectious origin requiring IV therapy.
6Dose ismuch lower ifgiven with enzyme inducers.

7Perfalgan
-158-
DRUG THERAPY OF GOUT
• Gout is a metabolic disease associated with increased body stores of uric

acid due to increased production orreduced excretion ofuric acid orboth.
• Hyperuricemia is diagnosed ifserum uric acid is > 7 mg/dl.
• Hyperuricemia may be asymptomatic or may result in precipitation of
monosodium urate crystals injoints &kidney resulting in:
- Acute attack of gouty arthritis.
- Tophi in joints, kidney & other tissues.
- Renal stones.
Etiology
Primary hyperuricemia & gout

• Inborn defect in purine metabolism; t uric acid production or I excretion.
Secondary hyperuricemia & gout

1. Increased nucleic acid turnover: tumors - hemolytic anemias...
2. Reduced uric acid excretion: chronic renal failure.
3. Drug induced:
- Aspirin: small dose competes with uric acid for acid secretory system.
- Diuretics: competes with uric acid for organic acid secretory system.
- Alcohol: t urate production (t nucleotides catabolism) - I urate excretion.
- Cytotoxics: t uric acid production (t nucleic acid turnover).
Food increasing uric acid (avoided in gout)

• Meat (especially organ meat).
• Seafood.
• Beans.
• Alcohol.
159
- . Nonsteroidsal Antiinflammatory Drugs
Pathophysiology of goutv arthritis
• t Uric acid -» deposition ofurate crystals in joints -» pain &inflammation.

• The inflammatory reaction involves migration of leucocytes that phagocytose
urate crystals -* production of inflammatory mediators; PGs & LTB4
(chemotactic for neutrophils) and oxygen metabolites -* tissue damage.
Purines
Allopurinol
Hypoxanthines
Xanthine
Xanthines
oxidase
^ Pegloticase]
Uric acid -^ ADantoin
Deposition in tissues Renal excretion
Inflammatory Uricosuric agents

reaction Sulphinpyrazone
&
Probenicid
Leucocytes migration
PGs &timte crystals LTB4 (Chemotactic)
a phagocytosis Attracts more
leucocytes
Indomethacin Cholchicine
(non-specific anti (specific anti-inflammatory in gout)
inflammatory in gout) Inhibits mlcrotubularassembly of leucocytes
Mechanism of Action of Drugs Used in Gout
-160-
Treatment Strategies Include:
I. Decrease inflammation during acute attacks:

• NSAIDs, colchicine or glucocorticoids.
II. Increase uric acid excretion with uricosuric drugs:
• Probenecid - Sulfinpyrazone - Benzbromarone.
III. Inhibiting uric acid synthesis:
• Allopurinol (xanthine oxidase inhibitor).
IV. Conversion of uric acid to a water-soluble metabolite:
• Pegloticase
Management
A. Treatment of acute gout
•Anti-inflammatory drags: NSAIDs or colchicine (if NSAIDs are

contraindicated) or glucocorticoids (if both are contraindicated).
B. Long-term treatment
• Allopurinol.
• Probenecid - Sulfinpyrazone-Benzbromarone .
• Pegloticase.
A. Treatment of Acute Gout
I. NSAIDs (indomethacin-naproxen...)
• A potent oral NSAID, such as naproxen (500 mg twice daily) or
indomethacin (50 mg three times daily).
II. Colchicine
Mechanism of Action
1. Selective inhibitor of microtubule assembly -»4- leucocyte migration &

phagocytosis.
2. Reduces production of leukotriene B4 (chemotactic for neutrophils).
-161-
Indications
1. Acute gouty arthritis.

2. Mediterranean fever (unknown mechanism).
Dose in Acute Goutv Arthritis
• 1.2 mg then 0.6 mg one hlater on 1st day, then 0.6 mg x3/day till pain resolves.
• Dose is reduced to.0.6 mg once or twice/d for 2-3 days after complete resolution.
Toxicity (especially with high doses)

1. Nausea, vomiting, abdominal pain, and diarrhea.
2. With chronic administration: myopathy, neutropenia, aplastic anemia,
and alopecia.
III. Glucocorticoids
• Choice of route depends upon number of inflamed joints, clinician

experience with joint injection techniques & need for parenteral rather
than oral therapy.
B. Long-Term Treatment
• Patients with hyperuricemia & repeated acute attacks of gouty arthritis

or with chronic tophaceous gout (urate crystals deposited in tissues)
should be treated with allopurinol as a first choice.
• Uricosurics are added in severe cases.
• Pegloticase may be used if other measures failed.
Allopurinol, uricosurics or pegloticase mayprecipitate an acute attack

(lowering of serum uric acid causes its withdrawal from tissues initiating
an inflammatory reaction).
To avoid precipitation of an acute attack, colchicine or an NSAID is
combined with these drugs in the first 6 monthsof treatment.
-162
I. Allopurinol
Mechanism
• Inhibits xanthine oxidase which converts hypoxanthine to xanthine &

xanthine to uric acid -* I uric acid synthesis & urate pools.
Adverse Effects
1. GIT upset.
2. Precipitates acute attacks of gout.
3. Hypersensitivity8.
II. Uricosuric Agents (Probenecid - Sulphinpyrazone, Benzbromarone)
Mechanism
• Directly inhibit URAT-1 (a urate-anion exchanger located at the apical

brush border of the proximal nephron) and therefore reduce urate
reabsorption
In low doses, uricosurics may also compete with uric acid for
renal tubular secretion & can even | serum uric acid level.
To avoid urate stones: increase fluid intake + alkalinize
urine.
Adverse Effects
1. Acute attacks of gout.

2. GIT disturbances (peptic ulcer with sulphinpyrazone).
8
Febuxostat, a xanthine oxidase inhibitor isanalternative for patients intolerant ofallopurinol,
patients with moderate chronic kidney disease, orwho do not reach the target uric acid range
with maximal doses of allopurinol.
-163-
III. Pegloticase
Mechanism
• It is a recombinant form of the enzyme urate oxidase or uricase.

• Urate oxidase converts uric acid to allantoin, a water-soluble nontoxic
metabolite, which is excreted mainly by the kidneys.
• Pegloticase is used in patients with gout, who did not respond to xanthine
oxidase inhibitors.
• It is administered as an IV infusion every 2 weeks.
Adverse Effects
1. Acute attacks of gout.

• NSAID or colchicine is recommended for the first 6 months of therapy
unless contraindicated or not tolerated.
2. Infusion reactions up to anaphylaxis.

• Premedication with antihistamines & corticosteroids.
• Close monitor of patients is required.
Contraindications
• Patients with G6PD deficiency.
164-
V. CNS PHARMACOLOGY
By the end ofthis chapter, the student should be able to recognize the following ILOs:
Opioid Analgesics: the student should be able to
• Recognize the adverse effects of opioids as an extension of their widespread
pharmacological actions.
• List the 2 most serious adverse effects of opioids.
• Explain why pethidine should not be used in chronic pain.
• Explain why fentanyl is preferred in anesthesia.
• Explain why remifentanyl induces less ventillatory depression than morphine.
• Explain why methadone and buprenorphine are used in detoxification of addicts.
• Identify the advantages of partial opioid agonists over pure agonists.
• Describe the impact of tramadol's dual opioid/ nonopioid analgesic
mechanisms on its adverse effects & on management of its toxicity.
• Explain why naltrexone is used in management of chronic opioid toxicity
(addiction ) while naloxone is used in acute toxicity.
Anxiolytics and sedative-hypnotics: the student should be able to
• Describe the mechanisms of agents interacting with the GABA receptor complex.
• List the multiple actions of benzodiazepines & the uses of different members.
• Explain the advantages of selective hypnotics (e.g. Zolpidem) and selective
anxiolytics (e.g. buspirone) over benzodiazepines.
• Recognize that flumazenil antagonizes benzodiazepines & Zolpidem but not
buspirone or barbiturates.
Antidepressants
• Classify antidepressants according to their mechanism of action.
• List the adverse effects of tricyclic antidepressants and the advantages of the
newer SSRIs and NSRIs over them.
• Discuss the disadvantages of nonselective MAOIs thatrestrict theiruse.
• Recognize the advantages of the reversible selective MAO-A inhibitors.
Antipsychotics: the student should be able to
• Describe the effects of blockade of dopamine receptors in different brain areas
and the corresponding uses and adverse effects of antipsychotics.
• Discuss the differences in adverse effects between low & high potency agents.
• Discuss the advantages of the atypical agents over the older typical agents.
Antiepileptic drugs: the student should be able to
• Describe the mechanism of action of antiepileptic involving effects on brain
transmitters and/or blockade of sodium or calcium channels.
• Discuss the choices of antiepileptics according to the type of epilepsy.
• Explain why barbiturates and benzodiazepines are not first choice agents.
• List the adverse effects of antiepileptics and the necessary precautions required
during long term therapy of epilepsy.
• Discuss the lines of management of status epilepticus.
• Discuss the precautions required for antiepileptic therapy during pregnancy.
Antiparkinsonian drugs: the student should be able to
• Recognize that antiparkinsonian therapy aims to correct the imbalance

involved in the pathophysiology of the disease by the use of anticholineric
dmgs or dopaminergic agents.
• Discuss the central and peripheral adverse effects of L-dopa.
• Explain how optimization of L-dopa therapy could be achieved by its
combination with peripheral decarboxylase inhibitors (e.g. carbidopa),
COMT inhibitors (e.g. entacapone), MAO-B inhibitors (e.g. selegilene) or
dopamine agonists
• Recognize the use of apomorphine in emergency cases of sudden immobility.
Drug Abuse : the student should be able to
• List the major drugs that are commonly abused.

• Recognize that addictive drugs activate the mesolimbic dopaminergic reward
pathway.
• Recognize that drug abuse occurs more with short-acting agents & withdrawal
syndrome is more severe than that oflonger-acting agents.
• Discuss management of withdrawal syndromes by detoxification &
replacement of a short-acting agent by a longer-acting agent in the same
group.
• Discuss other measures of management of withdrawal syndromes including
aversion therapy (e.g. disulfiram for alcohol) or use of antagonists (e.g.
naltrexone for opioids) or useof partial agonists (e.g. varenicline for nicotine).
General Anesthetics: the student should be able to
• List the commonly used intravenous anesthetics & describe their
pharmacodynamic & pharmacokinetic characteristics.
• Discuss the major adverse effects of halothane & characteristics of newer
inhalation agents.
• Recall the advantages ofnitrous oxide compared to other inhalation agents.
• Recall 2 anesthetics with powerful analgesic effects.
• Describe the different anesthetic protocols e.g. conscious sedation,
neuroleptanalgesia, neuroleptanesthesia, preanesthetic medication.
Local Anesthetics: the student should be able to
• Describe the mechanism ofaction of local anesthetics.
• List important members of the ester & amide groups & compare their
characteristic features.
• Recall major adverse effects of local anesthetics. \
• Discuss the importance ofvasoconstrictors, tissue pH &drug pKa on activity
of local anesthetics.
Central Nervous System Pharmacology
CENTRAL NERVOUS SYSTEM
PHARMACOLOGY
ANALGESICS
Analgesics are drugs that relieve pain due to multiple causes.
Classification of Analgesics
l
<'
<
Nonopioid Analgesics Opioid Analgesics
• Nonsteroidal anti-inflammatory drags. • Morphine.

• Paracetamol. • Synthetic opioids.
Used in mild to moderate pain - Used in moderate to severe -

(see NSAIDs) pain
Opioid (Narcotic) Analgesics
• Opioids are drugs with morphine-like effects.
Sources
1. Plant: morphine - codeine (termed opiates; natural alkaloids; products of opium

poppy).
2. Synthetic: fentanyl - methadone - heroin - pethidine....
3. Endogenous: endorphins - enkephalins - dynorphins (opiopeptides) released in
the body, acting on opioid receptors, producing morphine-like effects.
-167-
Classification of Opioids
r 1
Opioid Analgesics Opioid Antitussives Opioid Antidiarrheals
(Less addictive than (Less addictive than
(see below)
morphine) morphine)
• Codeine • Loperamide
• Dextromethorphan • Diphenoxylate
(See Respiration) (See GIT)
Mechanism of Action
Opioid receptors
• Mu (mediate most effects of opioids), kappa & delta, are Gi protein-coupled

receptors present in the CNS and periphery (e.g. GIT).
Site of action of opioids
Opioids (directly or through release of opiopeptides) activate receptors in:

• Afferent pain-conducting fibers -* peripheral analgesia.
• Spinal cord -» spinal analgesia.
• Brain stem1, thalamus &cerebral cortex -» supraspinal analgesia.
• Limbic system -» euphoria & 4> emotional response to pain (patient
may still feel the painbut the feeling is not unpleasant).
At the cellular level
Activation of receptors -» neuronal inhibition through:

a. Inhibition ofCa2+ entry -* 4- release ofexcitatory neurotransmitters including
substance P. (Presynaptic)
b. Stimulation of K+ outflux -» hyperpolarization of neuronal membrane.
(Postsynaptic)
Activation ofopioid receptors in midbrain-* activation ofinhibitory descending pathways to raphe

nuclei in medulla-* to dorsal hom ofspinal cord—>l transmission in pain pathways ascending
from spinal cord to thalamus, limbic & somatosensory cortex.
-168-
Actions, Uses, Adverse Effects & Contraindications (CI) of Morphine

E^Â j.,„_„q nrtv.«t<- o. r'lHM
1. Analgesic in: 1. Main Effects • Masks pain

• Acute trauma. A. Analgesia CI: acute undiagnosed
• Chronic visceral pain 4- Pain perception &
abdomen
• Postoperative pain emotional response to
• Cancer pain pain
• Myocardial infarction • Sedation - Narcosis
B. Sedation
C. Euphoria(or dysphoria) • Drug dependence

2. In anesthesia
• Preanaesthesia
• CV surgery
II. Inhibitory Effects
3. Acute pulmonary
A. 0 VMC -» venular & • Hypotension
edema in LVF following
arterial VD
myocardial infarction:
• ipreload & after load B. Respiratory center • Respiratory depression
• I Respiratory distress depression—»T C02 —» & asphyxia neonatorum
• 4- Anxiety
Cerebral VD & increased • t Intracranial tension
intracranial tension CI: head injury
C. © Cough center
4. Antitussive
Replaced by
D. 0 Uterine tone -* delayed • Delayed labor
labor
Codeine
Dextromethorphan
(less addictive)
III. Stimulatory Effects
A. © Oculomotor nucleus • Miosis
"* miosis
B. © CTZ -» vomiting • Nausea - vomiting
5. Antidiarrheal C. Urinary & GI Tracts • Urine retention (alsot ADH)

Loperamide t tone of wall & (CI: enlarged prostate
Diphenoxylate sphincters (spasmogenic) • Biliary colic(CT)
j ....
(less addictive, more but 0 peristalsis -* stools

stagnate & harden due to • Constipation
widely used) fluid absorption.
• Hypotension - itching -
D. Histamine release
bronchospasm(C7: asthma)
Other effects: seizures & ri gidity in t doses. CI: age extrernes - hypothyroidism - liver
dysfunction (4-metabolism).T olerance develops to all effects except constipation & miosis.
-169-
Classification of Opioid Analgesics
ir if w
1. Strong 2. Moderate 3. Weak
A. Pure Agonists Codeine Propoxyphene

• Morphine (Oral) (Oral)
• Fentanyl(& subgroup) • Analgesic plus • Analgesic plus
• Methadone paracetamol or paracetamol or
• Pethidine aspirin in aspirin in mild
• Heroin moderate pain. to moderate
B. Partial agonists • Antitussive. pain.
• Buprenorphine
N.B.; heroin & codeine are metabolized to morphine.
I. Pure Agonists
1. Morphine (see table).

Given IV - Dvl - SC - epidurally - orally (extensive Is4 pass metabolism).
2. Pethidine [IM - Orall
• Used in ACUTE moderate & severe pain e.g, trauma, postoperative
pain, biliary colic or labor pain.
Pethidine differs from morphine in;
1. Less constipating (shorter acting).

2. Less respiratory depressant in neonates2 &does not delay labor -» preferred
during labor (4 risk of asphyxianeonatorum).
3. Atropine-like action: dry mouth, blurred vision,
4. t Risk of convulsions (withhigh dose or in renal failure due to accumulation
of toxic pethidine metabolite, norpethidine -»NOT used for more than 48
hours.
Morphine metabolism (conjugation ) is deficient in newborns -» longer depressant effect on

respiration.
-170-
3. Methadone [Oral]
Uses
1. Treatment of opioid addicts (detoxification & maintenance):

• Orally-active & long acting, thus, it is used to replace morphine or heroin in
addicts. Gradual withdrawal of methadone is associated with less severe &
smoother withdrawal symptoms.

2. Analgesic in severe chronic pain (efficacy equal to morphine).
4. Fentanvl
• More potent than morphine with rapid onset & shorter action (preferred in
anesthesia).
• High anesthetic doses—> chest wall rigidity-*J, thoracic compliance -» I
ventillation.
Uses (IV- epidural- spinal - transdermal patch - patient controlled infusion)

1. Analgesic in severe pain e.g. perioperative & cancer pain.
2. In anesthesia (for its analgesic & sedative effects):
• Preanesthetic medication.
• IV anesthetic in cardiovascular surgery (safer).

• Conscious sedation - neuroleptanalgesia - neuroleptanesthesia.
Conscious Sedation & Neuroleptanalgesia
(Amnesia, sedation & analgesia without complete loss of consciousness)

Uses: minor procedures or for diagnostic purposes (e.g. endoscopy).
Conscious Sedation
• IV benzodiazepine (e.g. midazolam) - opioid analgesic (e.g. fentanyl).

• Easily reversed by flumazenil & naloxone (advantage).
Neuroleptanalgesia
• Neuroleptic (e.g. droperidol) plus opioid analgesic (e.g. fentanyl).

• Converted to neuroleptanesthesia by adding 65% nitrous oxide in 02.
-171-
Fentanyl subgroup
• Sufentanil is more potent than fentanyl.

• Remifentanil (IV infusion): ultrashort acting as it is metabolized by blood
& tissue esterases —Mess ventilatory depression.
5. Heroin
• Diacetylmorphine converted to morphine in CNS.

• Rapid onset (greater lipid solubility -* crosses BBB more than morphine) &
short duration -* t risk of abuse (not used clinically in most countries).
Oxycodone (oral & parentral)

• Opioid agonist inducing dose dependent analgesia.
• Used in acute and chronic pain.
• Combinations with aspirin or paracetamol are widely used.
• Drug of abuse (hillbilly heroin).
Tramadol (mixed opioid/nonopioid)

• Analgesic acting by inhibiting uptake of 5- HT and NA.
• Weak Mu agonist (only partially antagonized by naloxone).
• Less constipation, respiratory depression & addiction than morphine.
• | Risk of convulsions.
Uses (oral, IM, TV)

• Analgesic in postoperative & chronic moderate pain & in neuropathic pain.
II. Partial Agonists

Buprenorphine (partial Mu receptor agonist)
Advantages over Pure Agonists
1. Less addiction (less euphoria -* less craving).

2. Respiratory depression is not t by t dose (ceiling due to antagonist effect) but if
it occurs, it is not easily reversed as it binds with t affinity to receptors.
172
Uses (parentral. sublingual)

1. Analgesic in severe pain.
2. Alternative to methadone for treatment of opioid addicts (long-acting, slowly
dissociates from receptors); given sublingually.
Drug Interactions of Opioids
1. Opioids + other CNS depressants (sedatives, alcohol, antidepressants &

antipsychotics) -» additive CNS depression.
2. Pethidine + MAOIs -» serotonin syndrome (hyperpyrexia- convulsions)3.
3. Partial agonist + pure agonist -» withdrawal syndrome & I analgesic effect.
Acute Morphine Toxicity
• Coma.
• Respiratory depression.
• Pin pointed pupil (diagnostic).
Treatment
• Support respiration.
• Naloxone (IV): opioid antagonist, repeated when necessary.
3Inhibition ofpethidine metabolism by MAOIs -* formation of the toxic metabolite,

norpethidine, by another metabolic pathway.
-173-
Pure Opioid Antagonists

I
f 1
Naloxone Naltrexone
IV & short-acting Oral & long-acting
i I
Management of acute toxicity Maintenance therapy in addicts
1. Acute opioid toxicity 1. Opioid abuse
Repeated as necessary to avoid Blocks euphoria of opioids

relapse into coma since duration —> loss of desire to take
of action is shorter than opioids. drug (prevents relapse).
2. Asphyxia neonatorum 2. Alcohol abuse
Respiratory stimulant in opioid- I Craving in chronic

induced respiratory depression alcoholics (prevents
in newborns. relapse).
N.B.:
• Addicts should be closely monitored during reversal of acute opioid toxicity

with naloxone to avoid precipitation of withdrawal symptoms.
• Naltrexone should be given to opioid addicts after full detoxification, otherwise
it would precipitate a withdrawal syndrome
Alvimopan (oral)
• Antagonist on gastrointestinal Mu receptors (does not cross BBB).

• Blocks constipation, nausea & vomiting induced by opioids.
• Used in managementof acute postoperative ileus.
174
ANXIOLYTICS AND SEDATIVE-HYPNOTICS
Anxiolytics and sedative-hypnotics are drugs used mainly in treatment of

anxiety and insomnia.
«,-
Classification According to Mechanism of Action
< r
< r i'
I. Drugs Facilitating GABA \ II. 5-HT1A II. Melatonin

Action :
Agonist/Partial (MTi & MT2)
• Barbiturates i
Agonist Receptor
• Benzodiazepines (BZDs) • Buspirone Agonists
• Zolpidem - Zaleplon. Ramelteon
• Alcohol
Other Drugs with anxiolytic or sedative-hypnotic Effects
• Antidepressants.
• Antihistamines.
• P Blockers - clonidine (sympatholytics).
GABA Receptors
GABAA receptors: mediate postsynaptic neuronal inhibition.
GABAr receptors: mediate:

• Presynaptic neuronal inhibition by inhibiting Ca2+ influx -» inhibition of
release of the excitatory neurotransmitter glutamate.
• Postsynaptic neuronal inhibition by t K+ outflux -* hyperpolarization.
-175-
Extracellular
Intracellular
GABAa Receptor CI- ion Channel Complex
• The GABAA receptor is a pentamer formed of 3 different types of subunits (two a,

two (3 & one y) surrounding a CI" ion channel.
• The GABA binding site is at the interface between a and P subunits.

• BZD binding site is on y subunit or an area on the a subunit regulated by y subunit.
located at the interface of the a subunit and the y subunit on the GABAA receptor;
• Common BZ receptor subtypes in the CNS are designated as BZl or BZ2 depending
on whether the binding site includes an al or a2 subunit, respectively.
- 176-
Mechanism of action of drugs acting at GABA-A receptor CI- ion channel
complex
• Binding of GABA to its binding site between a and P subunits of GABA- A

receptor opens a CI" channel with influx of CI* resulting in hyperpolarization
and inhibition of neuronal firing.
• Binding of BZDs to the BZD receptor site of the GABA- A receptor

complex -»T affinity of GABA to bind to its receptors. This increases the
frequency of opening of CI" channel facilitating the inhibitory effects of
GABA.
• Zolpidem binds to the BZD, receptor subtype (involved in hypnosis) -»

facilitation of GABA inhibitory effect.
• Barbiturates bind to a site near the CI' channel distinct from the BZDs
site. This results in increased duration of opening of CI' channel,

facilitating the inhibitory effects of GABA.
-177-
Barbiturates
• More powerful CNS depressants than BZDs since in addition to enhancing GABA
effect, barbiturates also have direct GABA-mimetic effects as well as inhibitory
effects on glutamate receptors.
• Formerly used as sedative-hypnotics but largely replaced by BZDs due to:
1. Narrow therapeutic index (BZDs are safer)
Barbiturates induce a dose-dependent CNS depression: sedation (at low

doses), hypnosis (at higher doses) & anesthesia, coma, cardiovascular &
respiratory depression -* death (toxic doses).
2. No specific antidote is available for barbiturates whereas, flumazenil is a

specific BZD antagonist.
3. Drug dependence is greater with barbiturates than with BZDs.
4. Enzyme induction occurs with barbiturates but not with BZDs -» drug
interactions.
5. Acute porphyria4 may be precipitated by barbiturates in susceptible patients.
Members of Barbiturates
• Long-acting: phenobarbital (antiepileptic).

Short-acting: pentobarbital, secobarbital (sedative-hypnotic).
• Ultrashort-acting: thiopental (IV anesthetic).
4Porphyrias are caused by deficiencies of specific enzymes of theheme biosynthetic pathway—*

accumulations of toxic heme precursors; protoporphyrins) —* skin or neurological complications.
Barbiturates induce ALA synthetase enzyme responsible for synthesis of the porphyrins which
accumulate sincethe enzymes responsible for their conversion into hemearedefective.
-178-
Benzodiazepines (BZDs)
Diazepam - Clonazepam - Alprazolam
Lorazepam - Midazolam
BZDs are the most widely used anxiolytics and sedative hypnotics.
Prototype: diazepam
Pharmacological Actions & Uses of BZDs
l * *
I. Anxiolytic n. Sedative (low dose) III. Anesthetic
Euphoric Hvnnotic (high dose)
Potentiate GABA in -Amnesia & sedation.

Potentiate GABA in
limbic system brainstem reticular formation - Potentiate narcotics.
Uses Uses Uses
1-Generalized anxiety 1. Insomnia: 1. Conscious sedation.

disorder & anxiety - Promote sleeponset
2. Pre-anesthesia.
with other - Tstage 2 of NREM
3. Balanced anesthesia, as
psychiatric illness 2.1 Night mares:
adjuncts.
2- Panic Disorder
[ REM sleep
3.1 Night terrors:
| Stage 3,4of NREM sleep
IV. Anticonvulsant V. Skeletal Muscle VI. Others

(Antiepileptic) Relaxant Cross tolerance with
Alcohol
(atspinal & supraspinal
> levels) (Both Potentiate GABA)
Uses
Uses
Uses
Epilepsy Alcohol withdrawal
Muscle Spasticity in
Status epilepticus (alcohol is replaced by
inflammation -trauma,
cerebral palsy. a longer acting BZD -»
smoother withdrawal
-179-
NJB.
• Above actions are shared by all BZDs but individual members differ in
selectivity:
• Alprazolam is more selective in panic attacks.
• Diazepam in muscle spasticity & alcohol withdrawal5.
• Clonazepam in long term treatment ofepilepsy.
• Midazolam, lorazepam, & diazepam in status epilepticus &in anesthesia.
Classification of BZDs according to duration of action6
1. Long-acting
• Diazepam '(prototype):
- Anxiolytic - anesthetic adjunct.
- Anticonvulsant - skeletal muscle relaxant.
• Clonazepam:
-Anxiolytic - anticonvulsant.
2. Intermediate ->short acting

• Alprazolam8:
-Anxiolytic- antidepressant.
• Lorazepam9:
- Anxiolytic - hypnotic - anesthetic adjunct- anticonvulsant.
3. Ultrashort-acting (less than 6 hours)
• Midazolam:
-Hypnotic - IV anesthetic.
5Chlordiazepoxide is a long acting BZDused in alcohol withdrawal.

6Temazepam: short acting BZD; anxiolytic - hypnotic.
7Duration of action of diazepam is 24- 48 hours.
8Duration of action of alprazolam is 24hours
9Duration of action ofof lorazepam is 14 hours. No active metabolite thus also used as ahypnotic.
-180-
Adverse Effects
1. Drowsiness - confusion - i cognitive function10 - hangover.

2. Amnesia (anterograde).
3. Ataxia & I motor skills -» difficulty in driving & t risk of falls in elderly.
4. Abuse (tolerance &dependence; most serious, but less than barbiturates).
5. Additive CNS depression with alcohol and otherCNS depressants.
6. Abnormal response: paradoxical excitement with short-acting agents.
7. Withdrawal of hypnotics -»rebound insomnia & rebound t in REM sleep .
Toxicity of Benzodiazepines
1. Prolonged sleep.
2. Respiratory & cardiovascular depression12 (rare except if given rapidly rv or
with other CNS depressants).
Antidote: Flumazenil
Flumazenil
• Competitive antagonist at BZDs receptor antagonizing BZDs & Zolpidem.
• Short t/,; readministered after 1 hour to avoid recurrence of sedation.
• Effects on respiration are unreliable -» monitor respiration.
Therapeutic Uses
1. BZDs toxicity.
2. Termination of BZDs effects in anesthesia.
Adverse Effects
1. Agitation.
2. Withdrawal syndrome or convulsions in BZDs dependent patients.
10 Ability to understand, think, leam &judge.

1Shortening ofREM sleep -* anterograde amnesia, anxiety &irritability, followed by rebound
increase with night mares on withdrawal. May occur in same night with short acting agents.
May depress vital centers in infants (passes in milk) or in neonates if given in pre-delivery period.
-181-
Zolpidem
• Non-BZDs acting on BZD] receptor subtype involved in hypnosis.

• Ultra short-acting hypnotic13 (an extended release preparation is available).
• Effects are antagonized by flumazenil.
Advantages of Zolpidem over BZDs
1. Rapid onset.
2. Less cognitive impairment.
3. Less hangover14.
4. Less tolerance & dependence with less rebound insomnia onstopping drug.
5. Less suppression ofREM sleep15.
Zaleplon:
• Similar to Zolpidem in its hypnotic action with fewer residual effects on

cognitive & psychomotor function due to its rapid elimination.
Ramelteon:
• Hypnotic; agonist atMTj &MT2 melatonin16 receptors in the brain.

• 4. Latency to persistent sleep-> useful in patients with difficulty in falling
asleep.
• Minimal abuse potential (not a controlled substance): no withdrawal symptoms
or rebound insomnia.
• Side effects: dizziness, somnolence and fatigue.
"Duration of action of Zolpidem is 4 hours.

14 Drowsiness, headache, dysphoria, mental & motor depression occurring on day following drag
intake.
15 Does notshorten REM sleep asBZD thus no REM rebound ocurrs onstopping thedrug.
16 Melatonin hormone ofthe pineal gland maintains circadian rhythm ofnormal sleep -wake cycle.
-182-
Buspirone
• Agonist/partial agonist at 5-HTiA (mechanism not fully understood).

• Differs from BZD: Selective anxiolytic (negligible sedation, no hypnotic,
anticonvulsant or muscle relaxant effects).
Advantages
•No amnesia or 4- cognitive function, or additive CNS depression with alcohol or

other sedatives.
•No ataxia or reduction of psychomotor skills.

• No abuse (delayed onset &dysphoria), useful in patients liable to abuse.
Disadvantages
1. Delayed onset (requires one to two weeks to act).

2. Does not treat insomnia or panic attacks.
-183
General Guidelines for Theranv with Sedative-Hypnotics

• Drug therapy is indicated only in severe acute anxiety or short term treatment of
acute insomnia17.
Drug therapy should be started with a small oral dose for a limited period (4-6
weeks) to avoid drug abuse &dependence (major limitation to the use ofBZDs).
Termination oftherapy should be gradual to avoid a withdrawal syndrome.
The preferred agent for insomnia in patients with difficulty in falling asleep is an
agent with rapid onset &short duration to avoid hangover; excessive sedation the
following day, e.g. lorazepam, midazolam.
Insomnic patients who complain ofearly morning awakenings &who require
anxiolytic effect during the day should receive a longer acting BZD, e.g.,
diazepam.
Chronic insomnia is usually associated with anxiety or depression thus should be
treated with an antidepressant (e.g., mirtazapine).
Acute anxiety is treated by BZDs or buspirone. Chronic anxiety is treated by
antidepressants. BZDs are added to calm the patient until the antidepressant
becomes effective.
Longer-acting BZDs are preferred as anxiolytics since shorter-acting ones result

in residual anxiety the following day.
Panic Disorder requires highly potent drugs as alprazolam (its antidepressant
effect is also useful). Buspirone is not useful.
Most BZDs are metabolized in liver —• dose adjustment is required in liver
cirrhosis to avoid accumulation to toxic levels specially of long acting agents and
those metabolized to active metabolites such as diazepam. Lorazepam has no
active metabolites thus preferred in liver dysfunction.
Dose of BZD should be reduced in elderly to avoid accumulation (reduced liver
metabolism) & to reduce risks of falling due to druginduced confusion & ataxia.
17 Dmg therapy ofanxiety should beaccompanied by psychotherapy & relaxation techniques

whereas that of insomnia should not be started except if alternative methods fail (bathing,
exercise, milk....).
-184-
ANTIDEPRESSANTS
Depression is a mood disorder. It is classified into:
1. Unipolar depression
• Major depressive Disorder (17%): a genetically determined biochemical

disorder manifested by inability to deal with normal stress of life.
2. Bipolar manic depressive disorder (4%)

• Episodes of depression alternating with episodes of mania.
• Manic attacks are characterized by decrease need of sleep, flights of ideas,
grandiosity, euphoria, talkativeness, lack ofjudgment, psychomotor agitation
& may be associated with psychotic symptoms (hallucinations, delusions).
Symptoms of Depression
• A major depressive episode is a period lasting at least two weeks, with five or
more of the following symptoms: Sadness - inability to experience pleasure
(anhedonia) - fatigue- loss of libido - disturbance in appetite & sleep (usuallyI)
- guilt - worthlessness - inability to concentrate or indecisiveness- psychomotor
agitation or retardation- recurrent suicidal ideation.
• Psychotic symptoms (hallucinations & delusions) occur in severe depression.
• Symptoms cause significant impairment of social& occupational function.
• Atypical Symptoms may occur including overeating & t sleep -anxiety -
phobias - obsessions, hypochondriasis (multiple bodycomplaints).
Monoamine Theory of Depression18

• Brain biogenic amines, norepinephrine (NE) & serotonin (5-HT) are
neurotransmitters responsible for mood. 4> Activity of these transmitters
results in depression, whereas t activity leads to mood elevation.
18 Other theories : 1.1 Brain derived neurotrophic factor essential for survival &function of
neurons. 2. Abnormalities inhypaothalamic pituitary adrenal axis & t Cortisol level. 3.
Inflammatory theory
-185-
Mechanism of Action of Antidepressants
1. Increase in brain biogenic amines (immediately within 12 hours).

2. Downregulation of brain p & 5-HT2 receptors (delayed for 2-4 weeks).
3. Affect neurotrophic factors essential for survival & function of neurons.
Mechanisms of Increase of Biogenic Amines by Antidepressants
Amine Pumo MAO Presynaptic
Inhibitors Inhibitors di Blockers

Inhibit uptake I of biogenic amines Inhibit metabolism of TNA&5-HT
into neurons resulting in their biogenic amines by MAO release into
accumulation in synaptic cleft, enzyme inside nerve endings synaptic cleft
potentiating their action at post -* t stores available for by preventing
synaptic receptors. release. ct2 auto-
inhibition.
Members Members Members
1. TCAs: Imipramine - amitriptyline 1. Nonselective Mirtazapine

Clomipramine. Tranylcypromine. (NaSSA)
2. SSRI: Fluoxetine - sertraline Phenelzine
Escitalopram. 2. Selective on MAO-A
3. NDRI: Bupropion. Moclobemide.
4. SNRI: Venlafaxine - duloxetine.
N.B.:
• TricycIics;TCAs: Block NE & 5HT uptake & autonomic receptors (Hi, M, a).
• SNRIs: SerotoninNorepinephrine Reuptake Inhibitors.
• SSRIs: Selective Serotonin Reuptakejtahibitors.
• NaSSA: Noradrenergic and Specific Serotoninergic Antidepressant
• NDRI: DA, NA reuptake Inhibitors.
-186-
Amine pump
inhibitors
Pre-synaptic Block
MAOIs
nerve ending NA & 5-HT
TNA& Reuptake
5-HT
MAO
Stores
a.2
Receptor
4» 5-HT
&NA
Serotonin
Release
is released • • • • • • • and re-uptake
Synapse • #.
ct2 Receptor
Antagonists
t 5-HT &
NA Release
Post synaptic
nerve ending Receptor sites
Mechanism of Action of Antidepressants
-187-
Adverse Effects of TCAs Advantages of Newer Antidepressants

(Limit their use) (Developed to i side effects of TCAs)
A. 1. SSRIs
Autonomic Blockade .
• No Autonomic side effects.
\ (used cautiously in elderly)'
p Less cardiotoxicity - safer in overdose.
1. Hi Blockade:
Adverse Effects
—Sedation - fatigue .
1. Nausea- Anxiety - insomnia - tremors.
2. Atropine-like actions:
2. Sexual dysfunction- suicidal tendency??
- Confusion -1 HR
3. Serotonin syndrome with MAOIs.
3. a Blockade:
- Postural hypotension.
2. Bupropion
- Reflex Tachycardia.
• Same advantages over TCAs as SSRIs. i
• Does not Asexual function--* used in
t Body weight. depressed patients intolerant to SSRIs.

• t NE/DA (4 craving) -» used in smoking
c.
.cessation.
(Used cautiously in cardiac &
• t Risk ofconvulsions.
epileptic patients):
[.Cardiotoxic
- Conduction defects. 3. Venlafaxine (SNRIs)
'.....Âjihythmias... • No Autononaic side effects.
2. Convulsions: Adverse Effects
In susceptible patients • Nausea- dry mouth- Hypertension.
S.
4. Mirtazapine
(Used cautiously in suicidal or
bipolar patients) • More rapid effect with less nausea & sexual
1. Safety margin is low. dysfunction—• useful in patients intolerant
2. Switch to mania. to sexual dysfunction of SSRIs.
3. Sexual dysfunction. • Hi antagonist —» sedation & weight gain.
4. Serious drug interactions
-188-
Drug interactions with TCA:
• Alcohol- anesthetics -* sedation.
• Hypotensive drugs (potentiate postural hypotensive effects of TCAs).

• TCAs potentiate directly acting symapthomimetics (inhibit uptake of biogenic
amines).
• Not to be given with MAOIs.
TCAs Toxicity:
• Atropine toxicity- Convulsions

• Conduction block & arrhythmia- hypotension.
Management: NaHC03 for hypotension & arrhythmia.
MAOIs
• MAOIs were among the earliest antidepressants introduced for therapy of

depression but due to their toxicity & serious food & drug interactions, their use is
limited & several precautions have to be taken during their administration.
Serious Food (cheese)19 & Drug Interactions of MAOIs

MAOIs Plus
Tyramine - Cold Remedies TCAs SSRIs ->t 5HT
rich food (sympathomimetics) (-•t CA) Pethidine —•tnorpethidine20

->t5HT
I 1 \ 4
Hypertensive Hypertensive -Hypertension "Serotonin syndrome":
crisis Crisis. -Convulsions - Convulsions
(Cheese reaction) -Hyperthermia -Hyperthermia
19 Cheese Reaction: Tyramine in food is metabolized in GIT by MAO-A &MAO-B. MAOIs

allow tyramine in tyramine-rich food (old cheese, chicken Uver, chocolate) to escape
metabolism & release 11 Tamounts ofcatecholamines from neurons -* hypertensive crisis.
20 Inhibition ofpethidine metabolism by MAOIs -»tformation ofneuro toxic metabolite, norpethidine.
-189-
Precautions with MAOIs
• Patients on nonselective MAOIs should be warned against serious drug

interactions & should be given a listof the foods they should avoid.
• Patients on MAOIs should not receive TCAs or SSRIs except after 2 weeks from
stopping MAOIs (effect persists for 2 weeks).
• Avoid in the elderly -» postural hypotension - atropine-like actions.
Reversible Inhibitors of MAO-A (RIMA)
• Antidepressant activity of MAOIs is related to inhibition of MAO-A enzyme

(responsible for NE & 5HT metabolism). Thus to reduce risk of cheese reaction,
selective inhibitors of MAO-A were developed:
Moclobemide
• Short-acting, reversible inhibitor of MAO-A (RIMA).

• Has the advantage of a reduced risk of cheese reaction due to:
• Selective MAO-A inhibitor -» allows MAO-B to metabolize tyramine.
• Short-reversible MAO-A inhibitor -» easily displaced by tyramine allowing
tyramine to be metabolized by MAO- A.
Other Antidepressants
Agomelatine
• Melatonin Ml and M2 receptor agonist and exhibits 5-HT2C antagonism (| DA

&NA).
• Used in severe depression: corrects disturbances in sleep circadian rhythm
associated with depression.
• Hepatotoxic
190
Therapeutic Uses of Antidepressants
1. Major depression disorder (main use)

2. Anxiety disorders: generalized anxiety disorder -panic disorder -phobias -
obsessive compulsive disorders (SSRIs, clomipramine).
3. Post-traumatic stress disorder.
4. Pain disorders: e.g. chronic neuropathic pain (TCA & SNRIs) .

5. Urinary incontinence (duloxetine), nocturnal enuresis (imipramine;
anticholinergic —*• contracts urethral sphincter),
6. Eating Disorders: Anorexia Nervosa &Bulimia Nervosa "(SSRIs &TCAs).
7. Smoking cessation (bupropion).
Guidelines for the use of antidepressants
• Antidepressant effect is delayed for 2 -4 weeks; treatment is continued for 4

weeks before considered unsuccessful. If partial improvement occurs continue
for another 4 weeks.
• Following remission, continue treatment for 6 months. Long term maintenance

therapy for 2 years may be needed if patient experiences recurrent episodes.
• Gradual withdrawal over 4 weeks.
• SSRIs are the most widely used initial therapy23.

• In cases resistant to initial therapy switch to a different member of same class or
to another class.
• TCAs are reserved for resistant cases due to toxicity & drug interactions.
21 Pain (in the form ofpins &needles or electrical shock), due to affection ofsensory nerves( of
pain, touch, heat & cold) e.g. trigeminal neuralgia, diabetic neuropathy or herpes zoster.
Corticospinal monoaminergic pathway is important for pain transmission; thus
antidepressants that Tmonoamines possess analgesic activity independent ofeffects onmood.
Recurrent attacks ofexcessive appetite resulting in uncontrolled overeating followed by sense
ofguilt with deliberate vomiting or using laxatives to prevent weight gain.
" Sertraline, escitalopram, followed by mirtazapine & venlafaxine have better risk benefit
profiles than otherantidepressants.
-191-
Due to toxicity & serious food & drug interactions, MAOIs are reserved for
atypical depression associated with anxiety - phobias - obsessions, panic attacks
&2nd choice in refractory major depression.
Atypical antipsychotic, lithium, or T3 may be added in resistant cases.
Antidepressants are used in anxiety disorders together with a BZD to calm the
patient until the antidepressant becomes effective.
-192-
I ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)!
• Antipsychotics are drugs used to control manifestations ofpsychosis.

Manifestations of Psychosis (mind is separated from reality)
1. Hallucinations (perception without stimulus) : e.g. auditory (most frequent),
visual, tactile....
2. Delusions (False fixed beliefs): e.g. paranoid (suspicious) persecution (people
are conspiring against him), grandeur (believes he is a genius).
3. Incoherent speech & abnormal behavior (aggression, agitation).
Schizophrenia (most common & most classic example of psychosis)
• Schizophrenia results from t DA activity inbrain mesolimbic system.
• Positive symptoms: Hallucinations, delusions and disorganized behavior.
• Negative symptoms: (4A) Affect flattening (flat emotions), Alogia (decrease
speech), Anhedonia, Amotivation & social withdrawal & intellectual
dysfunction.
Mechanism of Action of Antipsychotics
• All anti psychotics block D2 receptors in the mesolimbic system.

• Effect is delayed for several weeks -* I patient compliance.
Classification of Antipsychotic Drugs "
I I
Typical Atypical
DA Antagonists 5HT/DA Antagonists
Chlorpromazine (prototype) -Thioridazine Risperidone - Aripiprazole
Haloperidol - Trifluperazine Clozapine - Olanzapine.
24 Typical agents have ahigh DA to 5HT blocking ratio. Atypical agents block 5-HT2 receptors
withequalefficacy as D2 receptors.
Other atypical agents: quetiapine - ziprasidone.
-193-
Typical Antipsychotics
Uses Actions Side Effects

A. Blockade of Central D2 Recentors
I. Antipsychotics
1. Extrapyramidal
1.Violent patient: Side effects
calms in few hours (see next page)
2.Is1 Psychosis
(4 hallucinations &
delusions in few wks):
a. Schizophrenia
b. Mania in bipolar j Gynecomastia
depression / j Galactorrhea
c. Psychotic depression
3. 2a Psychosis Amenorrhea
Brain tumors - cocaine
Dementia
ffy Infertility
Hypothalamus
II. Antiemetic & Pituitary ,2.1 Prolactin
CTZ
3. jBody weight
B. Blockade of Autonomic Receptors
4. Sedation - |Body weight
5. Atropine side effects

Dry mouth- confusion
constipation- urine retention
* 6. Postural Hypotention
25
C. Miscellaneous 7. Cardiotoxic (TQT interval)
4Cs
8. Convulsions
9. Corneal- lens deposits.

10. Cholestatic jaundice
"tQT interval occurs especially with thioridazine which also causes retinal deposits.
-194-
Extrapyramidal Side Effects
Disorder Features Mechanism Management
l. Akathesia Motor Anticholinergics,

restlessness e.g. benztropine
Due to blockade of D2
may be given
2. Dystonia Muscle
receptors in basal
spasm, e.g.
routinely with
ganglia antipsychotics as
neck
torticollis
prophylaxis against
extrapyramidal side
3. Parkinsonism Rigidity Blockade of D2
effects but may
Hypokinesia receptors in basal
exacerbate tardive
Tremors ganglia -» relativet in
dyskinesia
cholinergic activity
4 .. f
DA ACh
Relieved by
anticholinergics
4.Tardive Abnormal Supersensitivity of DA Preventive:
dyskinesia involuntary receptors following - Least possible

(late, after 2-5 movements: chronic blockade dose of
years) - chewing antipsychotics

- sucking ttt-—-—— 1 - Minimal duration
- "fly - DA ACh • Avoid routine use
catching" Exacerbated by of anticholinergics
movement anticholinergics - Switch to atypical
of tongue agents
N.B; Neuroleptic malignant syndrome (rare)

• Muscle rigidity, fever & labile blood pressure followed by a severe form of
parkinsonism. It is due to rapid blockade of central DA receptors in patients
sensitive to extrapyramial effects of neuroleptics (idiosyncrasy).
• Management: muscle relaxants (diazepam or dantrolene)- antiparkinsonian
drugs (bromocriptine).
-195-
Classification of Typical Antipsychotics

(Equal in efficacy but differ in potency & side effects)
l
A. Low potency B. Hieh potency

Chlorpromazine - Thioridazine Haloperidol -Trifluperazine
• Less central side effects. • More central side effects.
• More autonomic & • Less autonomic & miscellaneous
miscellaneous side effects. side effects -* preferred in elderly
& cardiac patients.
II. Atypical Antipsychotics
Block 5-HT2 receptors with equal efficacy as D2 receptors.

Possess central, autonomic & miscellaneous side effects (see before).
Advantages over typical agents
1. Less central side effects (more selectivity on mesolimbic system)

• Less Parkinsonism - akathesia - dystonia - tardive dyskinesia26
• Less galactorrhea & gynecomastia (except with resperidone).
2. More efficacy (due to more 5-HT antagonism)

• Improve negative symptoms; typical agents control only positive symptoms.
• Clozapine is effective in resistant cases (30% of cases) —*• reserved for these
cases only due to t risk of agranulocytosis & seizures.
26
This advantage is lost with aripiprazole and high dose risperidone (>6mg).
-196
Special features of some important members27

Risperidone: Less extrapyramidal & autonomic side effects, less weight gain.
But, may induce galactorrhea & gynecomastia and tQT interval.
Clozapine: Less central side effects.
t Autonomic side effects.
t Body weight - insulin resistance- hyperlipidemia.

t Risk of seizures.
Agranulocytosis
Olanzapine: Similar to clozapine with no agranulocytosis.
Aripjprazole: - Has extrapyramidal side effects

-Favorable effect on cognitive function (preferred in children)
-Lesser effect on body weight & lipids (preferred in obese patients).
27 Quetiapinc: t sedation, less weight gain, tQT interval.

Ziprasidone: I autonomic effects, less weight gain, tQT.
-197-
LITHIUM CARBONATE
• Monovalent cation similar to Na.
• Mainly used in bipolar manic depression as:

1. Mood stabilizer:
4 Mood swings (maintenance therapy).

2. Anti manic:
4 Manic behavior in manic phase (antipsychotics are added for rapid control of
severe mania since the effect oflithium is delayed for several weeks).
• Other uses:
1. Recurrent endogenous depression.

2. Adjunct to antidepressants in refractory unipolar depression.
N.B.:
•The first-line treatment for bipolar depression is lithium or lamotrigine (Mood

stabilization and antidepressant effects).
•Antidepressants monotherapy is not recommended, given the risk of switch into
mania. Therefore, they are only used simultaneously with mood stabilizer
(lithium) in severe bipolardepression.
Mania
Li+ - Li+ + Antipsychotics
Mood Stabilizers
Lamotrigine -»
Depression Valproate L. Alternative mood stabilizers in case
Antidepressants carbamazepinej ofLi+ toxicity or ineffectiveness.
+Mood stabilizer
Drug Treatment of Bipolar Manic Depression
198-
Adverse Effects, Toxicity & Precautions of Lithium
Adverse Effects Precautions
1. CNS: fine tremors. •Coarse tremors & tGIT symptoms

2. GIT: nausea - vomiting - diarrhea. are early warning signs of toxicity.
3. Renal:
- Antagonizes ADH: polyuria —> thirst. •Monitor kidney function.
- Nephrogenic diabetes insipidus.
- Renal tubular damage.
4. Thyroid : Benign enlargement with •Monitor thyroid function.
or without hypothyrodism.
5. Toxic drug: •Monitor Li+ serum level.
a) Narrow TI (0.6-1.5 mEq/1). •Adjust dose inreduced Li+ excretion,
b) Long tv&. as in:
c) Cumulative. 1. Na+ depletion by diuretics.
2. Renal dysfunction.
3. Old age (J, renal function).
Lithium Toxicity
• Serum Li+ level > 2 mEq/1.
Manifestations
• Vomiting - diarrhea - coarse tremor (early signs of toxicity).

• Ataxia - arrhythmia.
• Confusion - convulsions - coma.
Management
• Fluids for dehydration- hemodialysis.

• Na HC03 -> I Li+ reabsorption28.
Li+ is excreted unchanged renally. Li+ competes with Na+ for tubular reabsorption; therefore:
Na+ depletion (e.g. by diuretics) -* t Li+reabsorption -»t serum LT level -» Li* toxicity.
-Na+ loading -» 4- Li+reabsorption -»trenal excretion -» useful in treatment oftoxicity.
-199-
| DRUG THERAPY OF EPILEPSY
Definition of Epilepsy
• Chronic disease characterized by repeated attacks (seizures or fits) of abnormal

electrical discharge of cerebral neurons resulting in EEG, motor, sensory,
autonomic or psychological changes.
Etiology
A. Primary epilepsy(unknown cause, i.e. idiopathic).

B. Secondary epilepsy caused by:
1. Trauma, meningitis, brain tumors, fevers, hypoglycemia.
2. Drugs: insulin (hypoglycemia) - TCAs - cocaine- antipsychotics - Li+.
Classification of Epilepsy
• Epilepsy is caused by a group of hyper excitable neurons with excessive electrical

discharge which might be localized (partial) or spread (generalized).
f 1
A. Partial B. Generalized
1 r
1. Simple Partial 1. Tonic-clonic 2. Absence 3. Myoclonic

• Localized: sensory, motor,
psychic, or autonomic • Tonic
disturbances.; unaltered followed by • Loss of • Sudden brief
consciousness clonic consciousness single or

convulsions , abruptly for repetitive
2. Complex Partial
involving the a few seconds jerks;
(Psychomotor Epilepsy)
whole body withstaring consciousness
• Attacks of confused
with loss of or blinking is unaffected.
behavior & hallucinations
consciousness (in children).
with altered consciousness.
-200-
Antiepileptic Drugs
Members
I. Classic agents (major or older agents)

• Phenytoin (prototype) - carbamazepine - valproate (valproic acid) -
ethosuximide.
• Phenobarbital - benzodiazepines.
II. Newer agents29

• Lamotrigine - levetiracetam - oxcarbazepine.
• Topiramate - gabapentin- pregabalin.
Mechanism of Action
• Anti-epileptics block initiation or spread of seizures by I hyper-excitability of

cerebral neurons by acting on neurotransmitters or by blocking ion channels.
• Most antiepileptic drugs act by more than one mechanism:
1. Blockade ofNa* Channels 30-»4> repetitive firing ofneurons

• Phenytoin - carbamazepine- valproate.
• Topiramate - lamotrigine.
2. Blockadeof T- type Ca** Channels in thalamus -» 4» brain rhythmic
activity (effective in absence seizures)
• Ethosuximide.
• Valproate.
3. Blockade of presynaptic voltage gated Ca** Channels -» jglutamate release
• Lamotrigine.
• Gabapentin - pregabalin.
4. Binding to vesicle protein VS2A-» modify release of glutamate
• Levetiracetam.
29Ncwer agents: - lacosamide - zonisamide- rufinamide- felbamate, vigabatrin- tiagabine,

preampcncl.
Other Na channel blockers: lacosamide- zonisamide-rufinamide.
-201-
5. NMDA glutamate receptor antagonists31
• Valproate.
6. Effects on GABA
i. Facilitate GABA Action: phenobarbital -benzodiazepines -topiramate.

ii. ^ GABA Level : inhibits breakdown by transaminase: valproate.
7. Acetazolamide:
• Antiepileptic effect is due to metabolic acidosis, but tolerance occurs.
Therapeutic Uses
1. Epilepsy: (see below).

2. Mood stabilizers in bipolardepression:
• Lamotrigine - valproate - carbamazepine.
3. Neuropathic pain (trigeminal neuralgia, post herpetic & diabetic neuralgia):
• Carbamazepine- gabapentin - pregabalin.
4. Migraine:
• Valproate - topiramate.
5. Antiarrhythmic:
• Phenytoin.
31 Other NMDA antagonists: fclbamatc, preampenel.
32Tiagabin: inhibits GABA uptake, vigabatrin inhibits GABA breakdown by transaminase

-202-
Choice of Antiepileptic Drugs in Different Types of Epilepsy
Partial33 Tonic- clonic34 Absence35 Myoclonic36

First line
• Carbamazepine • Valproate. • Ethosuximide. • Valproate.

• Lamotrigine. • Lamotrigine. • Valproate
Alternatives
• Levetiracetam • Carbamazepine. • Lamotrigine. • Levetiracetam
• Valproate • Oxcarbazepine • Topiramate.
• Oxcarbazepine
N.B.:
• Valproate is preferred to ethosuximide if tonic- clonic or myoclonic seizures

coexist.
• Phenytoin is used in parial & generalized tonic-clonic (due to troublesome

pharmacokinetics & cosmetic disturbances, other agents are prefferred). Not used
in absence seizures (may exacerbate seizures).
• Oxcarbazepine:related to carbamazepine; alternative in partial & tonic clonic
seizures.
• Acetazolamide: is used in premenstrual fits (no tolerance occurs since it is used

intermittently).
• Due to sedation & tolerance, phenobarbital & BZD are used mainly in acute fits &
in status epilepticus. Phenobarbital (in tonic-clonic & partial) & clonazepam (in
absence &myoclonic) are used as 2nd line or adjuncts to other agents.
33
Adjunctive treatment (if first line treatment is not effective or not tolerated): carbamazepine, clobazam,
gabapentin, lamotrigine, levetiracetam, oxcarbazepine, valproate, topiramate
*Adjunctive treatment: clobazam, lamotrigine, levetiracetam, valproate, topiramate
Adjunctive treatment xombination ofethosuximide, lamotrigine or valproate.
"Adjunctive treatment:levetiracetam, valproate, topiramate
-203-
Adverse Effects & Precautions of Major (classic) Anti-epileptics
Phenytoin Carbamazepine Valproate

Hypersensitivity Skinrash -» stop drug
GIT Nausea - vomiting - epigastric pain (most common with valproic
Disturbances acid) -» give small dose after meals.
Neurological • Nystagmus, diplopia. • Diplopia. • Fine hand tremors.

Disturbances
• Ataxia. • Ataxia. • Ataxia.
(specially in toxic
doses) • Drowsiness. • Drowsiness. • Less sedative.
• 4- Learning in
children.
Effects on Enzyme inducer Enzyme inducer Enzyme inhibitor

Hepatic • t Metabolism of other • t Metabolism • 4 Metabolism of
Microsomal
antiepileptics. of antiepileptics antiepileptics &
Enzymes • Osteomalacia: t vitD , warfarin & other drugs.
(monotherapy is metabolism (-* vit D other drugs.
preferred) &Ca2+ supplements).
Hematological • Megaloblastic anemia • Leukopenia • Thrombocytopenia
Effects (—^regular 'supplement folic acid' • Agranulo
blood picture) • Lymphadenopathy cytosis
Teratogenicity -» • Cleftpalate & lip - • Less • Spinabifida.
give folic acid heart anomalies. teratogenic. • Neural tube defect.
Others 1. Cosmetic changes • Water • Hepatotoxicity

• Gingival hyperplasia intoxication & (rare but fatal).
(-•gum hygiene). dilutional • Hair loss.
hyponatremia
• Coarse facial
(potentiates • t Appetite.
features. • t Body weight.
ADH).
• Hirsutism - acne.
2. Unpredictable
serum level—•
monitor serum level.
N.B.: Ethosuximide (safest): GIT upset, skin rash, dizziness, drowsiness, headache.
-204-
Specific adverse effects of newer antiepileptics37

•Newer agents are generally bettertolerated with fewer drug interactions than the
older agents. Specific adverse effects include:
•Lamotrigine: rash -• fatal dermatitis (stevens Johnson syndrome), hypersensitivity.
•Topiramate: renal stones- myopia (—•glucoma)- weight loss- hypohydrosis.
•Levetiracetam: mood & behavioral changes.
•Gabapentin /Pregabalin: sedation, ataxia, weight gain- peripheral edema.
General guidelines for antiepileptic drug therapy
1. Proper diagnosis of type of epilepsy & prescribing the appropriate drug

(wrong choice may worsen the condition).
2. Monotherapy is preferred since anti-epileptics are either enzyme inducers

(phenytoin, carbamazepine & phenobarbital) or enzyme inhibitors (valproate).
Combinations could result in changes in serum level of drugs.
3. Start therapy with a small dose & a single drug and gradually t dose. If no
effect is noted, gradually substitute or add another drug.
4. Long duration of treatment: If epileptic fits are absent for 2 years, consider
terminating therapy; but if fits recur, repeat treatment for another2 years.
5. Gradual drug withdrawal: over 6 months to avoid status epilepticus or

relapse.
6. Folic acid supplements: especially in child bearing period to j teratogenic

risk.
37
Zonisamide: rash -renal stones- weight loss- hypohydrosis
Oxcarbazepine: hyponatremia, rash
205
7. Pregnancy & child bearing period: Be aware of potential effect of valproate

in pregnancy. Pregnant females should receive the lowest effective dose of the
drug (do not stop drug as seizures may be harmful to fetus).Pregnancy t
metabolism ofanti-epileptics -» adjust dose. Anti-epileptics may reduce efficacy
of contraceptives.
8. Periodic monitoring of serum level of drugs, since a drop below therapeutic

level ->loss of seizure control while an increase in level -toxicity (CNS
depression -* stupor - coma - respiratory depression).
9. The use of phenytoin is limited due to its troublesome kinetics resulting in

unpredictable serum level due to:
a. Irregular bioavailability (—>use one formula from a single manufacturer).
b. Saturation kinetics (serum cone, mayt to toxic levels —• monitor serum
level).
c. Drug interactions if combined with other antiepileptics.
10. Sedation & tolerance limit the use of phenobarbital & clonazepam.
Management ofStatus Epilepticus38:(drugs are given TV)

1. Lorazepam39, midazolam ordiazepam (rv orrectal) —• for rapid control.
2. Fosphenytoin40 orphenytoin —> long-acting, to maintain control.
3. Phenobarbital —>2nd choice to phenytoin.
4. IV anesthesia —> in resistant cases.
38 Continuous or repetitive seizures with impaired consciousness in-between fits.

39 Preferred to diazepam as its antiepileptic effect is longer &it is non irritant toi \veins.
40 Fosphenytoin: soluble, prodrug, safer than pheytoin (no need for the cardiotoxic solubilizmg agent
propylene glycol).
-206-
Antiparkinsonian I)rugs|
Definition
• Parkinson's disease is a slowly progressive neurological disease resulting from

degeneration of nigrostriatal DA neurons & characterized by tremors at rest,
rigidity, bradykinesia & postural instability.
Causes of Parkinsonism (most common in the elderly)
1. Idiopathic (Parkinsons disease):
Due to unknown neurotoxin or oxidation reactions with free radical
generation -* neuronal degeneration (environmental & genetic factors may
be responsible).
2. Viral encephalitis - CO or manganese poisoning.
3. Drug-Induced Parkinsonism:
- Antipsychotics -» block D2 receptors.
- Reserpine -* depletes DA stores.
- Methyldopa -* inhibits DA synthesis.
Substantia Nigra (DA synthesis)
1 Nigrostriatal DA neurons
Ach neurons
Corpus
Striatum
Tonic inhibition of muscle tone

&
Initiation & modulation of movement
DA /Ach Balance in Basal Ganglia
-207-
Pathophysiology of Parkinson's disease (see previous fig.)
• The basal ganglia exert a tonic inhibitory effect on muscle tone & are responsible
for proper initiation & modulation of movement.
• These effects require a normal balance in the basal ganglia between Ach & DA.
• hi the basal ganglia, DA is synthesized in the substantia nigra & reaches the
coipus striatum through the nigrostriatal DA neurons.
• In Parkinson's disease, degeneration of nigrostriatal DA neurons -» I striatal DA
& dominance of cholinergic system resulting in:
1. Bradykinesia or akinesia (failure to initiate movement).

2. Tremors.
3. Rigidity (involuntary contractions of all muscles due to loss of tonic-

inhibition of muscle tone).
Antiparkinsonian Drugs aim to restore DA/Ach balance
1.1 Dopaminergic Activity

II. I Cholinergic Activity
Dopaminergic Drugs Anticholinergics.
• Levodopa/carbidopa. • Benztropine
• Bromocriptine (ergot) • Trihcxphcnidyl
• Pramipexole- ropinirole-
rotigotinc (non-ergots)
• Amantadine.
• Entacapone.
• Selegiline.
-208-
II. Dopaminergic Drugs
Selegiline
MAO-B Inhibitors
DA Agonists MAO -B
DA
Bromocriptine •> DA metabolites
Pramipexole CNS uptake

Ropinirole
Amantadine L-dopa
Releases DA
Peripheral metabolism
COMT L-dopa
Entacapone: dccarboxvlase Carbidopa:
COMT Peripheral
Inhibitor Decarboxylase
inhibitor
Metabolites DA
Site of action of Antiparkinsonian Dopaminergic Drugs
(DA is not used as it cannot cross BBB)
-209-
Levodopa (L-dopa)
(Mainstay of Therapy)
• L- dopa is a DA precursor that crosses BBB & is decarboxylated to DA in the
CNS.
• It is given with the peripheral decarboxylase inhibitor, carbidopa, as L-

dopa/carbidopa (sinemet).
• Carbidopa prevents peripheral decarboxylation of L-dopa to DA -» 4 dose of L-
dopa by 75%. (without carbidopa, 99% of L-dopa is converted to DA peripherally
which cannot cross BBB & t peripheral side effects of L-dopa).
• L-dopa is the most effective antiparkinsonian drug; improves all features
especially bradykinesia, but benefits I in a few years due to gradual neuronal
degeneration -* better reserved till symptoms become troublesome.
Adverse Effects & Contraindications (CI) of L-dona41

A. Peripheral (due to t DA peripherally; I with carbidopa)
1. GIT: Nausea - vomiting CI: active peptic ulcer.
2. CVS: postural hypotension & arrhythmias (t CA).
B. Central (due to t DA centrally; t with carbidopa)

1. Dyskinesia (choreoathetosis; head, lip or tongue movements).
2. Confusion, hallucinations; psychosis; CI: psychosis.
C. Fluctuations in Response (due to short t ./a & fluctuation in L-dopa level??)

1. On-off effect (sudden swings from mobility to bradykinesia).
2. End-of-dose akinesia: gradual loss of effect (wearing off) before next dose.
N.B.:
• Domperidone -» I L-dopa- induced nausea &vomiting (blocks peripheral D2

receptors in CTZ (outside BBB) but not central D2 receptors in basal ganglia
(doesn't cross BBB) -» doesn't interfere with anti-parkinsonian effect ofL-
dopa).
41 Other side effects: activation ofmalignant melanoma &mydriasis; CI: narrow angle glaucoma.
-210-
Other Dopaminergic Drugs Used in Parkinsonism
Drug Mechanism of Action Adverse Effects
I. Pramipexole • Direct D2 agonists. • Simialrto L-dopa:

Ropinirole (Less fluctuation due to rapid Hallucination -dyskinesia.
Bromocriptine absorption - longert%). Nausea- postural hypotension
• Impulse control disorder42.
• Day time sleepiness.
• Vasospasm & cardiac
fibrosis (bromocriptine)
II. Amantadine • t DA release (mild effect)-» - Insomnia - hallucination.
(Given together enhances L-dopaeffect. - Ankle edema.
with other agents) • Blocks NMDA receptors43. -Livido reticularis44.
III. Selegiline'5 • Selective inhibitor of MAO- - Insomnia (selegiline)46

(Alone, modest B -» delays breakdown of - Hallucination.
benefit, or nigrostriatal DA -» prolongs - Very low risk of cheese

adjuncts to L L-dopaaction -» 4 reaction47.
dopa) fluctuation
IV. Entacapone48 • COMT inhibitor -» 4 L-dopa • Related to L-dopa /carbidopa

(adjunct to L peripheral metabolism -» t -Hallucination -dyskinesia.
dopa) itsbioavailability & prolongs -Nausea- postural hypotension
its action -> 4 fluctuations. • Orange urine.
42 Compulsive gambling &eating -hypersexuality.

43 May block glutamate receptor (NMDA) -» 4glutamate excitotoxicity -» 4neuronal degeneration
Purple spotting of skin
^Neuroprotective, antioxidant -* may I disease progress (more with the MAO B inhibitor
rasagiline).
46 Due to its metabolism to an amphetamine -like substance. Rasagiline is not metabolized to
amphetamine like substance -» no insomnia).
Selectivity of selegiline is lost at high doses.
48 Tolcapone (hepatotoxic).
-211-
N.B.:
• Non-ergot DA agonists (ropinirole, pramipexole): preferable to ergots

(bromocriptine -» vasospasm, cardiac, pulmonary & retroperitoneal fibrosis).49
• Apomorphine: DA agonist, rapid and more effective than L-dopa. For "rescue
therapy" in patients experiencing sudden akinetic episodes. Can also be given
intermittently subcutaneously -» 4'off time in advanced Parkinson's disease.
II. Anticholinergics
Benztropine - Trihexphenidyl
• Block central cholinergic activity -» restore DA/Ach balance.

• Improve tremors (mainly) & rigidity, but less effective on bradykinesia.
Used in:
i. Drug induced Parkinsonism: preferred to dopaminergic drugs, since dopaminergic

agents cannot be used in antipsychotic-induced Parkinsonism because DA
receptors are blocked by antipsychotics & dopaminergic agents may aggravate the
psychotic disorder ofthe patient.
ii. Parkinson disease (especially in the young): adjuvants to dopaminergic drugs in
cases presenting with tremors & to control sialorrhea.
NJB.: may delay gastric emptying -» 4 L-dopaabsorption.
Side Effects:
• Similar to atropine but less severe (dry mouth, constipation, confusion ).
Caution in elderly (avoid in patients over 70)

• t Memory loss & hallucinations.
• Urine retention in patients with enlarged prostate.
N.B.: beta adrenergic blockers may be used for tremors.
49 Rotigotine: non-ergot DA agonist; skin patch allows more continuous dopaminergic stimulation;
given in early Parkinsonism.
-212-
I. Choice of drugs in Early Disease50

•First choice agents in early Parkinson's disease & motor symptoms include:
• L-dopa/carbidopa.
• Non ergot dopamine agonists (oral/transdermal).
• MAO-B inhibitors.
•L-dopa is the most effective agent for motor symptoms.

•To avoid L-dopa-related motor complications, other agents are used first, in mild
cases, or when tremor is the only symptom.
•It is preferred to start therapy with a DA agonist in younger patients (<65 years) &
with levodopa in older patients (>65 years) with troublesome bradykinesia.
Amantadine: is usually used with other agents in young patients but not as first line
treatment (tolerance develops in few months).
Anti-cholinergics: should not be used as1st line treatment in Parkinson's but may be
added if tremors are troublesome, especially in young patients.
II. Management of motor complications in advanced Parkinson's disease

•L-dopa will eventually be used resulting in motor complications (dyskinesias &
fluctuations (end of dose akinesia & on/off effect), which can be managed by:
• MAO-B inhibitors.
• DA agonists (oral or transdermal) .

• Intermittent subcutaneous apomorphine (-» 4'off time).
• COMT inhibitors -» 4'off time in advanced cases with motor fluctuations.
• Amantadine.
Avoid pyridoxine: t peripheral decarboxylation of L-dopa -* 4 effect.

Diet: low in protein to 4 fluctuation in L-dopa response (NH2 acids compete with L-
dopa -» 4absorption &CNS uptake). Diet rich in fibers &fluid for constipation.
Drugs should not be started until symptoms interfere with daily activities. Therapy with 2or more
agents will eventually benecessary as disease progresses.
Management ofpsychosis &depression: Low-dose clozapine -antidepressants.
Management of dementia: Rivastigmine.
213-
[DRUG THERAPY OF ALZHEIMER'S D1SEASE|

• Alzheimer disease is the most common cause of dementia in the elderly.
• It is a neurodegenerative disorder characterized by impairment of memory &
cognitive function together with behavioral changes (psychosis, depression).
• It may lead to a completely vegetative state and early death.
Pathological changes51
• Increased deposits of beta amyloid (A0) plaques and intraneural fibrillary tangles
of hyperphosphyrlated tau protein in cerebral cortex.
• Amyloid deposits-*1"glutamate-»activates NMDA receptors -> ca2+influx into
neurons-* cell apoptosis; exocitotoxity.
• Progressive loss of cholinergic nicotinic neurons involved in cognition & memory.
Aim of therapy
• 1" Cholinergic activity.

• 4 Glutamate exocitotoxity.
Mangement
I. Symptomatic treatment:
1. Cholinesterase inhibitors52:
• Donepezil
• Rivastigmine: only agent that is available as transdermal patch
• Galantamine.
• t Cholinergic transmission inbrain by inhibiting acetylcholinestrase.

• Galantamine: also stimulates presynaptic nicotinic receptors -*fAch
release.
51Othcr mechanisms: inflammation, oxidative damage, disturbance in iron &cholesterol metabolism.

52 Tacrine was the first drug approved for AD. It is rarely used, due to hepatotoxicity.
-214-
Characteristic features
• Orally active .
• Adequate CNS penetration; some selectivity to AchE centrally compared
to periphery.
• Improve cognitive function but do not delay progress of disease.
Uses:
• Mild to moderate cases of Alzheimer disease.
• Dementia of parkinsonism (only rivastigmine )

Side effects53:
1. Cholinomimetic effects: anorexia, nausea, vomiting, diarrhea,
bradycardia, tremors, etc....
2. Drug interactions involving CYP 450 (except rivastigmine).
2. NMDA receptor Antagonists: Memantine
• Non competitive antagonist of (NMDA) receptors-* limiting influx of ca

into neurons -*protects neurons from glutamate induced excitotoxicity54.
Uses:
• Moderate to severe cases.
Side effects: (well tolerated & less toxic than cholinomimetics)

1. Confusion, dizziness, headache, hallucination.
2. Constipation.
II. Other agents (unlabeled use)

• Cholesterol-lowering agents: Statins.
• Insulin sensitizers: PPAR y agonists (rosiglitazone) - intranasal insulin.
• Anti- inflammatory (NSAIDs) & antioxidants (vitamin E &omega-3 fatty acids
(disappointing results, butresearch continues).
53 Side effects reduced by: gradual titration over >3months -transdermal rivastigmine.
54 It also blocks 5HT3 and nicotinic receptors (unknown role in dementia).
215
|DRUG ABUSE
• Drug abuse is the nonmedical use of any drug (usually psychoactive), that is
unacceptable by the society & results in health problems.
• Drug abuse reults in drug dependence due to development of:

1- Physical dependence: Adaptation of body to drug resulting in the necessity to
continue using it to avoid a physical withdrawal syndrome on drug withdrawal.
2. Craving: Severe compulsion to take a drug repeatedly to re-experience a
pleasant feeling, e.g. euphoria. Addictive drugs activate the mesolimbic
dopaminergic reward pathway -* |DA release -* euphoria
3. Tolerance: 4 Drug response following its continuous use -» larger dose is
required to produce the same initial effect -» loss of control of addict over
amount of drug used.
Classification of Drugs of Abuse
I. CNS Depressants:
1. Sedative hypnotics: barbiturates - benzodiazepines - alcohol.
2. Narcotics: heroin - morphine - pethidine - codeine.
II. CNS Stimulants: caffeine - nicotine - cocaine - amphetamine - khat.

III. Hallucinogens: LSD -mescaline -phencyclidine.
IV. Cannabis.
V. Inhalants: induce euphoria and hallucinations.

1. Solvents in glues & paints (strong dependence).
2. Anesthetics; nitrous oxide & ether (moderate dependence).
Drug abuse occurs more with short-acting agents & withdrawal

syndrome is more severe thanthat following longer-acting agents.
216-
I. Barbiturates (Strong Dependence)

BZDs (Moderate Dependence)
Acute Effects
• Euphoria - relieve anxiety and insomnia.

Risks of Chronic Abuse
• Memory loss.
Withdrawal Syndrome (severe with barbiturates - mild with BZDs)
• Insomnia - anxiety - tremors - delirium - hallucinations - convulsions.
Management of Barbiturates & BZDs Abuse
Replace short-acting agent by a longer-acting one -» less severe withdrawal:

a Phenobarbital for pentobarbital.
• Diazepam for clonazepam, alprazolam, flunitrazepam.
II. Alcohol
(Strong Dependence)
Mechanism : acts on GABA- A receptor—>| GABA effect (cross tolerance with BZDs)
Acute Effects
• Euphoria - relaxation - increased self-confidence.
Withdrawal Syndrome
• Similar to barbiturates with delirium tremens: delirium - tremors - psychosis

(visual hallucinations of crawling bugs).
Risks of Chronic Abuse (Alcoholism)

1. Withdrawn, homicidal or suicidal individual - work & family problems.
2. Liver cirrhosis - peptic ulcer- cardiomyopathy.
3. Dementia - peripheral neuropathy.
4. Thiamine deficiency -» Wernicke-Korsakoff syndrome (external eye muscles
paralysis, ataxia, confusion, psychosis).
-217-
Management of Alcohol Abuse
1. Diazepam or chlordiazepoxide (longer acting sedatives).

a. Replaces alcohol (gradual withdrawal ofdiazepam is smoother).
b. Anticonvulsant (controls convulsions ofwithdrawal syndrome).
2. Thiamine supplements.
3. Psychotherapy (group therapy) together with dmgs to avoid relapse following
detoxification:
a. Disulfiram:
• Inhibits aldehyde dehydrogenase involved in alcohol metabolism -»

accumulation of acetaldehyde -* nausea & vomiting & flushing (disulfiram -
like reaction). To avoid this reaction, patients give up drinking.
b. Naltrexone: J, craving.
c. Acamprosate: weak NMDA antagonist, GABA A receptor activator.
in. Opioids
(Very Strong Dependence)
Acute Effects
1. Euphoria (rush).
2. Apathy: drowsiness & hypo activity.
Risks of Chronic Abuse
1. Fatal overdose - homicide - suicide - accidents.
2. t Risk of infections due to syringes (hepatitis, AIDS) & 4 immunity.
Withdrawal Syndrome (sympathetic overactivity)

1. Craving for the dmg - anxiety - insomnia - tremors.
2. Piloerection - mydriasis - lacrimation - rhinorrhea.
3. Tachycardia - hypertension - hot & cold flushes.
4. Abdominal cramps - vomiting - diarrhea.
-218-
Management of Opioid Abuse
1. Methadone or buprenorphine
• Replace heroin or morphine by methadone. Gradual withdrawal of
methadone (longer-acting) is less severe.
2. Naltrexone
• Given chronically after detoxification to block opioid receptors -»

loss of euphoric effects of opioids -» loss of desire to take the dmg.
3. Symptomatic treatment of withdrawal symptoms
• Anxiolytics - antiemetics - antispasmodics.
• Clonidine: inhibits sympathetic discharge.
IV. Nicotine
(Very Strong Craving)

Mechanism : acts on central nicotinic Ach receptors —> DA release in mesolimbic
rewardpathway —• rewardexperienced upon smoking —»• craving—> dependence.
Acute Effects: euphoria - 4 anxiety -1 concentration -4appetite
Risks of Chronic Abuse: cancer, lung diseases, ischemic heart diseases.
Withdrawal Syndrome: Insomnia - anxiety - aggressiveness -1 appetite.*
Management of Nicotine Abuse
• Psychotherapy (group therapy).

• Nicotine replacement by: nicotinegum - transdermal patch - oral inhaler- nasal spray.
• Bupropion: |DA —> decreases craving.
• Varenicline* : partial agonist at CNS cup^ nicotinic Ach receptors —> partial
stimulation while competitively inhibiting nicotine binding —• blocks ability of
nicotineto stimulate mesolimbic DA system-* | craving & withdrawal syndrome.
*Taken one week before quitting smoking & continued for 12 weeks; repeated ifnecessary.
Taken twice daily after meals with a full glass ofwater to| nausea.
Not recommended for <18 year- old smokers. May induce insomnia, mood changes or suicidal ideas.
-219-
V. Cocaine Abuse
(Very Strong Craving)
Acute effects
• Increased alertness & insomnia - decreased fatigue.

• Euphoria (due tot CA): intensity of euphoria depends upon route of
administration:
1. Intravenous -* intense euphoria (the msh) -1 risk of infections.

2. Intranasal -» less euphoria (the high) & nasal septal perforation.
3. Smoking -* intense euphoria & easy administration -» t abuse.
Withdrawal Syndrome (Crash)

• Fatigue - sleep - depression - overeating.
The Run
• Due to its short 11/2, addicts take the dmg every 30 min. to obtain the msh &
to avoid the crash until they become exhausted or run out of dmg.
Risks Associated with Cocaine Abuse
1. Overdose toxicity (during the run due to t catecholamines)

• Convulsions.
• Arrhythmia - t BP.
• Myocardial infarction - cerebral accidents.
2. Risks with Chronic Abuse
• Psychosis with hallucinations & delusions.
Manaement of cocaine abuse
1 Bupropion 55(4 cravings & also treats depressive symptoms during

withdrawal).
55 chemical structure of bupropion is similar to amphetamine

-220-
VI. Amphetamine & methamphetamine

(Strong Dependence)
Similar to Cocaine; longer acting, less addictive but t risk of psychosis.
Methylene-dioxy-methamphetamine (MDMA; ecstacy):

- CNS stimulant as amphetamine with hallucinogenic properties.
- Dance dmg in rave parties to keep pace with the beat & duration of music.
Cathinone: is found in Khat & produces similar effects to amphetamines.
VU. Lysergic Acid Diethylamide (LSD)
• Taken recreationally not regularly -» no dependence.
Acute Effects
• Euphoria & sensory changes: sights & sounds are distorted & fantastic.
• Sounds are perceived as colours & colours as sounds.
• Hallucinations, delusions, illusions.
• Philosophical & creative thinking.
Risks Associated with LSD Abuse
• Bad trips: frightening hallucinations -* homicide or suicide.

• Flashbacks: frightening hallucinations months after stopping drug.
• Psychosis: in a borderline psychotic even after a single dose.
Management of LSD Abuse
• Calm the patient during bad trips.

• BZDs - antipsychotics.
-221-
VIII. Cannabis
(Minimal Dependence)
Hashish, Marijuana & Bhang
(obtained from cannabis plant)
• THC (A9-tetrahydrocannabinol) is the most psychoactive prinicipal in cannabis.
• After inhalation, THC quickly reaches the brain to act on cannabinoid CB1
receptors and VI vanilloid pain receptors.
Acute Effects (CNS stimulation followed by depression; sleep & relaxation)

1. Euphoria - uncontrollable laughter - time passes slowly.
2. Increased perceptions (sights & sounds become more intense & fantastic).
3. 4 Motor & mental skills (cannot drive a car or finish a sentence).
4. Hallucinations & delusions (rare).
5. Philosophical & creative thinking.
Withdrawal syndrome: weak and usually mild

• Irritability, restlessness, confusion, sweating, tremor and sleep disturbances
Risks of Chronic Abuse of Cannabis
1.1 Risk of psychosis.

2. Red eyes (VD of conjunctival vessels, preceedes serious drop in BP).
3. Apathy (amotivational syndrome)
4. Sexual dysfunction (J, testosterone & sperm count)
5. Gateway dmg: opens the way to poly-drag abuse.
Management of Abuse:
•Naltrexone - buspirone - dronabinol.
N.B.: dronabilone & nabilone are synthetic analogues of THC used as antiemetics in
cancer chemotherapy.
-222-
IGENERAL ANESTHETICS
• General anesthetics are dmgs used in surgery to induce reversible loss of

consciousness, analgesia, amnesia, skeletal muscle relaxation & inhibition of
visceral reflexes.
Balanced Anesthesia
• Balanced anesthesia is used to achieve all requirements for general anesthesia

& to minimize adverse effects of individual dmgs. It includes:
1. Preanesthetic medication: preoperative administration of sedatives, opioid
analgesics, anti-muscarinics, anti-emetics and H1& H2 antagonists aimingto:
a. Induce amnesia, 4 anxiety & facilitating induction of anesthesia.
b. Suppress autonomic reflexes, 4 salivary & bronchial secretion, 4gastric
acidity.
c. Potentiate weak anesthetics.
2. IV anesthetics (for rapid induction) plus succinylcholine (for intubation).

3. Inhalation anesthetics (for maintenance) & NMBs (if needed) in operation.
Classification of General Anesthetics

I
I
I. Inhalation Anesthetics II. IV Anesthetics
(Mainly for Maintenance) (Mainly for Induction)
• Slow: provide minute to minute Rapid induction of anesthesia
control over depth of anesthesia
A. Barbiturates
• Nitrous oxide (N20). Thiopental sodium
• Halogenated agents: B. Non-barbiturates
Halothane - Isoflurane. Propofol - Ketamine.
Desflurane- Sevoflurane. Opioids- Benzodiazepines.
-223-
Mechanism of Action of General Anesthetics
• General anesthetics inhibit neuronal activity in many brain regions, specially

the midbrain reticular activating system & thalamus.
Mechanism of Neuronal inhibition

I
]
Facilitation of inhibitory effectsof GABA at • Inhibition of excitatory
GABAA receptor: effects of glutamate at
• Halogenated inhalation agents. NMDA receptor:
• Propofol. a Ketamine
a Barbiturates - Benzodiazepines. q Nitrous oxide
N.B.: other receptors involved: nicotinic Ach receptors & glycine receptors.
I. INHALATION ANESTHETICS
MAC (measures potency):

• MAC is the alveolar concentraton of anesthetic gas resulting in immobility in 50
% of patients when exposed to a painful stimulus: e.g. a surgical skin incision.
• MAC is I by anesthetic adjuvants as opioids, sedatives hypnotics , clonidine, and

in elderlypatients. It is f by drags increasing catecholamines & by alcohol abuse.
Induction & Recovery of inhalation anesthetics
•Rapid induction & recovery allow flexible control of depth of anesthesia.

• Speed of induction & recovery depends on:
i. Solubility in blood (blood: gas partition coefficient): agents with low solubility
coefficient -» rapid induction & recovery, e.g., N20, desfiurane.
ii. Fat solubility: agents with high lipid solubility accumulate in fat -* long
hangover if used for a prolonged operation.
-224-
A. Halogenated agents
Halothane
• Inhalation anesthetic for maintenance anesthesia.
• May also be used for induction (nonirritant; smooth & pleasant).

• Weak analgesic effect -> combined with N20 (powerful analgesic).
• Medium rate of induction & recovery.
Adverse Effects of halothane56

1. Hypotension: due to myocardial depression or VD.
2. Heart: bradycardia - arrhythmia (sensitize myocardium to catecholamines).
3. Hepatotoxic57.
4. Malignant Hyperthermia.
Specific featues of newer halogenated agents compared to halothane

• Due to hepatotoxicity, halothane is replaced by newer agents, which may also
induce CVS & respiratory depression & malignant hyperthermia but less than
halothane.
Isoflurane
• No risk of convulsions.
• May precipitate ischemia in patient with coronary disease.

• Respiratory irritant-* cough & laryngospasm..
Desflurane
• Similar to isoflurane with faster onset & recovery —> suitable for day surgery.
• Respiratory irritant -* cough & laryngospasm.
Sevoflurane
• Similar to desflurane with no respiratory irritation—• preferred inhalation

agent for induction of anesthesia specially in children.
• Degraded by contact with soda lime to the nephrotoxic "compound A".
Adverse effects of halothanc: respiratory depression - 4 mucociUary function -uterine relaxation-*

bleeding - tICT (cerebral VD) -^dangerous inhead injury & cerebral tumors.
Hepaic metabolism -•trifluoroacetic acid which reacts with liver proteins-* immune response.
-225-
B. Nitrous Oxide (N20)

• Rapid onset & recovery.
• Low potency: used for maintenance anesthesia, not alone, but in combination
with other inhalation agents to J, theirside effects & | their analgesic effects.
• Effective analgesic: can be used alone in subanesthetic doses in brief
procedures; e.g. dental outpatient clinic- obstetric analgesia.
• Safest inhalation agent: less cardiac or respiratory depression - less uterine
relaxation - no hepatitis - no malignant hyperthermia .
Adverse Effects ofNÔ58

1. Expands closed gas spaces -»f pressure in middle ear - CI: in bowel
obstruction & pneumothorax.
2. Hypoxia on prolonged use (mixed with 02 -* 50 - 70 % nitrous oxide).
3. Abuse: euphoria (laughing gas).
4. Megaloblastic anemia & abortion (chronic exposure of operating room staff).
58 There is a controversy about anincrease inpostoperative nausea &vomiting with nitrous

oxide.
-226-
II. INTRAVENOUS ANESTHETICS
A. Ultra Short-Acting Barbiturates:

Thiopental
Kinetics
- Rapid onset due to rapid crossingof BBB (highly lipid soluble).

- Short acting; redistributes from brain to fat & skeletal muscle.
- Slowly metabolized & liable to accumulate in body fat, thus may cause
prolonged effect if given repeatedly -» toxicity.
Clinical Uses
1. Most widely used IV anesthetic for induction followed by maintenance with

inhalation agents for major operations (the principal use).
2. Given alone in anesthesia for short procedures.
Adverse Effects (narrow safety margin)

1. Respiratory & cardiovascular depression (toxic doses).
2. Severe vasospasm if accidentally injected intra-arterially -* gangrene.
3. Can precipitate porphyria.
B. Nonbarbiturate IV Anesthetics
1. Propofol
• Widely used IV anesthetic for induction & maintenance of anesthesia.

• Rapid induction & recovery (rapid metabolism) -* given as IV bolus or
infusion without maintenance by inhalation agent -» useful in one day
surgery.
• Used in conscious59 &deep60 sedation (in intensive care).

• Advantage: antiemetic (4 risk ofpostoperative vomiting).
• Disadvantage: respiratory &CVS depression - pain at injection site.
1Amncsia;sedation &analgesia without complete loss ofconsciousness; patient responds to commands

State of I consciousness, indistinguishable from general anaesthesia.
-227-
2. Ketamine
• Short-acting IV61 anesthetic -» dissociative anesthesia62 (hypnotic state

with dissociation, amnesia & analgesia; patients are unresponsive to
commands).
• Induces profound analgesia -» used for dressings of bums & minor
orthopedic procedures in children.
• CV stimulant (t HR & BP) -* used in poor risk patients (shock states).
• Potent bronchodilator63 -» suitable for patients with j risk for bronchospasm.
Disadvantages
• t Cerebral blood flow & intracranial tension -» avoid in head injuries.

• Hallucination & disorientation (emergence phenomenon) occur on
recovery (avoided by pretreatment with diazepam).
3. Benzodiazepines (midazolam - diazepam - lorazepam)

• Midazolam is preferred due to its rapid & short action & its less irritant
effect.
• Commonly used for sedation rather than anesthesia because prolonged

amnesia & sedation may result from anesthetic doses. Used in:
1- Conscious sedation ( for minor procedures e.g. endoscopy)
2- Pre-anesthesia.
3. Balanced anesthesia, anesthetic adjuncts.

• Availability of the antidote, flumazenil, is an advantage in case of toxicity
(respiratory depression).
4. Opioid Analgesics (see before)

• Fentanyl, sufentanyl, alfentanyl, remifentanyl &morphine.
N.B.: Total intravenous anesthesia may be produced by combining
opioids with propofol rather than an inhalation agent.
61 Ketamine may also be givenIM.

62 Patients may have their eyes open, move their limbs involuntarily &breathe spontaneously.
"Ketamine is less respiratory depressant than other anesthetics
-228-
LOCAL ANESTHETICS
Definition
• A local anesthetic (LA) is a drag that induces a reversible loss of sensation in a

localized area of the body without inducing loss of consciousness or sleep.
Chemical Nature and Members

A
All LAs consist of: ester
.Tertiary
1. Hydrophilic amine group64. X, — •*• ami
amide
amine
2. Lipophilic aromatic group65.

3. Connecting group Aromatic Connecting Amine
group
(Links both groups together).
Classification of LA
I. Esters II. Amides
Connecting group is an "ester Connecting group is an "amide
• Rapidly hydrolyzed by plasma • Redistributed & metabolized by

pseudocholine esterases: liver:
1. Short duration of action. 1. Long duration of action.

2. Less liable to systemic toxicity, more 2. More liable to induce systemic
liable to allergy (PABA derivatives). toxicity.
3. Duration of action is prolonged in 3. Duration of action prolonged in
genetic enzyme deficiency. liver disease & reducedhepatic
blood flow (e.g. heart failure).
64 Provides water solubility preventing precipitation ofLA.

65 Provides lipid solubility allowing LA to cross intracellularly.
-229
Members of LA
I. Esters II. Amides
Procaine Lidocaine
• Short acting (30- 60 minutes). • Intermediate acting (2 h).

• Slow tissue penetration—* not used • Rapid penetration: 1- choice for
for surface anesthesia. surface anesthesia.
Benzocaine Bupivacaine
• Low solubility -» cannot be prepared • Long duration (3 h); due to high
in injection form -» used as a surface binding to plasma protein.
anesthetic only. • Moderate tissue penetration.
Cocaine Ropivacaine
• Used only in surface anesthesia • Long duration. More selective
(limited use due to abuse potential). on sensory than on motor nerves.
Mechanism of Action of LA
. LA bind to receptors on inner surface of Na channel in nerve membranes resulting

in their blockade -» inhibition of generation & propagation of action potential .
Factors Affecting Sensitivity of Nerves to LA
1. Rate of firing: blockade of Na+ channels by LA is use-dependent, i.e. they block

Na+ channels that are in activated (open) & deactivated states more than those in
resting state -» more effective in rapid-firing nerves (sensory).
2. Nerve size: small nerve fibers conducting pain, temperature & autonomic
activity are more sensitive to LA than large fibers conducting pressure & motor
impulses (with higher concentrations motor nerves become affected).
66 Other mechanism of action: LAs dissolve in neuronal membrane and induce swelling of
membrane &physical inactivation of Na channel.
-230-
nil and Local Anesthetic Activity
• LAs are weak bases (pKa between 7.7 and 9) . In order to increase their
solubility and stability they are prepared as acid salts (e.g. lidocaine HCI).
• The local anesthetic exists in 2 forms in equilibrium according to its pKa & to
the extracellular pH: 1. Ionized form 2. Unionized form.
• Only the unionized form can cross the nerve membrane.
• Once inside nerve cell, the amount that crossed will again re-equilibrate into
unionized & ionized forms according to the intracellular pi 1.
• The intracellular ionized form is the active form that blocks Na~ channel.
Extracellular
Ionized <- •> Unionized
Lipid bilayer Na channel
Unionized <-• Ionized

Intracellular
ionized form, cation unionized form, free

water soluble base lipid soluble
Factors affecting activity of local anesthetics
1. Plasma protein binding: affects duration of action
• Bupivacaine is 95% bound to plasma proteins thus longer acting than lidocaine
(65%).
2. Lipid solubility: affects potency

• The more lipid soluble the drug is the greater its potency. Bupivacaine is 7
times more lipid soluble than lidocaine therefore more potent.
-231-
3. PKa of drug: affects speed of onset

• The lower the PKa the greater the speed of onsetsince more drug will be non-
ionized and can cross nerve membrane. Lidocaine (PKa 7.9; 25% non-ionized)
acts more rapidly than bupivacaine (PKa 8.1; 15% non-ionized).
4. Extracellular & intracellular dH
Extracellular dH
• Infections67 or repeated injections oflidocaine Hcl -» t extracellular acidity -*

t extracellular ionized form of LA -»4 LAcrossing -*i activity.
• Adding NaHC03 to LA solution -» i extracellular acidity -» t extracellular

unionized form-* t LAcrossing -* t activity (rapid onset).
Intracellular dH
• Carbonated solutions of LA have a rapid onset since they are saturated with
CO2 which readily enters nerve cells -»t intracellular acidity -»t intracellular
ionized (active) form available to block Na+ channel.
5. Addition of vasoconstrictors: prolongs duration of action.
• LAs (except cocaine) induce VD -* t absorption -* termination of effect & t

risk of systemic toxicity.
• Vasoconstrictors are added to LA (except cocaine) to l absorption -*
t duration & I systemic toxicity.
Precautions
Vasoconstrictors are Clin anesthesia of fingers, toes & nose -» gangrene.

Felypressin is preferred in cardiac patients (no effect on HR &BP).
67 Local anesthesia is also not preferred in infections to avoid spread of infection.

-232-
Adverse Effects &Toxicitv (t systemic absorption or accidental rv injection)
1. CNS:
Low concentration:
• Sleepiness- restlessness- numbness - metallic taste.

High concentration (stimulation followed by depression)
• Tremors - convulsions68 - respiratory depression - coma - death.
2. Neurotoxicity: due to the direct local effect ofhigh concentration ofLA injected
close to nerve trunks or spinal cord.
3. CVS: hypotension (due to vasodilation) & bradycardia.
Bupivacaine is extremely cardiotoxic in high doses .
4. Allergy: with esters that are derivatives of PABA e.g. procaine.

5. Side effects of vasoconstrictoradded to LA (t BP & arrhythmia).
Drug interactions
• Lidocaine * propranolol: Propranolol by reducing hepatic bloodflow impairs

clearance of lidocaine-»toxicity.
• Procaine * sulphonamides: Procaine is hydrolysed to PABA-* reduces the

effect of sulphonamides.
• Lidocaine with adrenaline x tricyclic antidepressants-* hypertensive crisis.
• Lignocaine with adrenaline x propranolol-* dangerous rise in BP due to

unopposed alpha action of adrenaline.
Diazepam maybe given as premedication or to terminate convulsions if they occur.

69 Ropivacaine: amide with long duration ofaction. More selective on sensory than motor nerves.
Less cardiotoxic than bupivacaine.
-233-
Uses & Administration
1. Surface anesthesia (for minor surgeries):

• Applied to skin &mucous membranes of nose, mouth &cornea as a solution,
jelly or cream.
2. Infiltration (for minor surgery):

• Injected sc & in submucosal tissues to reach nerve branches & terminals.
3. Nerve block (for dentistry & surgery):
• Injected close to nerve trunks (e.g. dental nerves - brachial plexus).
4. IV regional anesthesia:
• A double cuff is applied to the arm & inflated above arterial BP & the LA
is injected IV after elevation of arm to drain the venous system.
5. Spinal anesthesia:
• Injected in subarachnoid space below L2, acts on spinal roots & spinal
cord.
• Used for surgery of abdomen, pelvis & legs when general anesthesia is
contraindicated.
Side effects:
• Headache (due to CSF leakage & traction on sensitive

structures, avoided by use of pencil point needles).
• Hypotension (sympathetic nerve block).
• Spinal root injury.
• Infection.
6. Epidural anesthesia:
• Injected outside the dura, blocks spinal roots.

• Same indications as spinal anesthesia with I risk ofside effects.
• Commonly used in obstetrics for painless labor.
N.B.: Lidocaine may be used in neuropathic pain.
-234-
Management of pain
•Pain may be nociceptive, neuropathic or psychogenic.
Drugs wth pain relieving effects
NSAUDs - paracetamol
Opioids - tramadol.
Antiepileptics (gabapentin & pregabalin, carbamazepine).
Antidepressants (amitriptyline).
Muscle relaxants: diazepam- baclofen- tizanidine.
Lidocaine.
Ketamine (NMDA antagonists).

Antihistamines.
Tetrahydrocannabinol: CBI receptor agonist, interacts with TRPVI capsaicin

receptor, synergizes with opioids.
• Bisphosphonates
Management of pain due to different origin includes
•Acute pain: NSAIDs, opioid analgesics or both.

• Chronic pain may need additional agents: antidepressants, antiepileptics. muscle
relaxants
•Pain due to inflammation secondary to infection: analgesic anti-inflammatory

agents plus antibiotics.
•Pain due to muscle spasm: muscle relaxants; diazepam- baclofen- tizanidine.
•Pain due to osteoporosis: bisphosphonates.
Topical agents have reduced systemic effects:
• NSAIDs for musculoskeletal pain.

• Capsaicin: reduces release of substance P (pain neurotransmitter).
• Antihistamines: diphenhydramine.
• Local anesthetics: lidocaine.
-235-
Neuropathic Pain
Causes of neuropathic pain
1. Trigeminal neuralgia.
2. Post herpetic neuralgia.
3. Diabetic neuropathy
Drugs used
1. Opioids (high doses): morphine- tramadol.

2. Antidepressants: amitriptyline, venlafaxine.
3. Gabapentin & pregabalin:block presynaptic Ca++Channels -* Jglutamate release.
4. Local anesthetics: lidocaine (blocks spontaneous discharge from damaged nerve
5. Anti-arrhythmics: :mexiletine-tocainide- flecainide.
6. Tetrahydrocannabinol.
NJB.:
• Neuropathic pain due to viral infection: antiviral agent plus steroids (to reduce
inflammatory degeneration of nerve).
• Neuropathic pain resistant to treatment: injection of local anesthetic in trigger

zone, alcohol, cryosurgery, or sectioning of a part of the nerve.
-236-
Step 3: Moderate to severe pain or pain uncontrolled after step 2

• Sustained release/long-acting opioid (SR oxycodone/SR
morphine/transdermal fentanyl) + short-acting opioid ±non-
opioid ± adjuvant*
Step 2: Mild to moderate pain or pain uncontrolled after step 1

• Short-acting opioid as required (morphine/oxycodone)
Step 1: Mild to moderate pain

• Non-opioid (paracetamol/NSATD) ± adjuvant*
World Health Organization analgesic ladder:

♦Adjuvants, e.g. gabapentin, amitriptyline, diazepam, etc.
-237-
REFERENCES
•Bertram G. Katzung, Suzan B. Masters and Anthony J. Trevor (2015).

Basic and Clinical Pharmacology (13th edition), Mc Graw HILL, NY.
»Whalen K, Finkel R and Panavelil TA, (2015). Lippincott's Illustrated
reviews: Pharmacology (6,h edition), Lippincott Williams and Wilkins.
•
H.P. Rang, M.M. Dale J.M. Ritter, R.J. Flower and G. Henderson (2012).
Rang and Dale's Pharmacology (7th edition), Churchill Livingstone Elsevier,
Edingburgh, UK.
'Peter N. Bennet and Morris J. Brown (2008). Clinical Pharmacology (10th

edition), Churchill Livingstone Elsevier, Edingburgh, UK.
•
Laurence L. Brunton, Keith L. Parker, Donald K. Blumenthal and Iain L.O.
Buxton (2008). Goodman and Gilman's manual of Pharmacology and
therapeutics. Mc Graw HILL, NY.
• Atkinson AJ, Abernethy DR, Daniels CE, Dedrick RL, Markey SP (2007).
Principles ofClinical Pharmacology (2nd edition), Academic Press
(ELSEVIER), Amsterdam, Netherlands.
• Walker R and Whittlesea C (Eds.) (2007). Clinical Pharmacy and

Therapeutics (4th edition), Churchill Livingstone. ELSEVIER, Edinburgh,
UK.
• http://care.diabetesjournals.Org/content/32/l/l 93.long
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Lecture Notes

Pharmacology is an ever-changing medical science. The recent, rapid

Head of Pharmacology Department

Prof. Dr. SaharKamal

Prof. Dr. Ahmed Abdel-Salam

Prof. Dr. Olfat Hassan

Prof. Dr. Hoda Sallam Prof. Dr. Mohamed Abdel-Bary

Deep appreciation for the valuable contribution of

Computer graphics &designs: Dr. Essam Ghazaly - Dr. Mohamed Bahr

2. Adrenergic Pharmacology 45- 71

4. Autacoids Pharmacology 90- 105

Target Site Therapeutic effect

Other Sites Adverse effect

Absorption Distribution Metabolism

Fate of the drug in the body

Pharmacodynamics (Greek: dynamics= power)

Pharmacokinetics (Greek: kinesis= movement)

• These are drugs or biological products for diagnosis/ treatment/prevention

• Governments offer drug companies incentives e.g. tax benefits for

EVALUATION OF NEW DRUGS

II. Evaluation in Humans

• Done on small number of healthy volunteers.

• Pharmacokinetic measurements are often done in phase I.

• Done on small number of patients to determine safety and efficacy.

• Done on large number of patients.

• The reactions unrelated to the pharmacologic effects ofadministered drug.

1. In therapeutics: in psychotherapy, sometimes a placebo does as much

• The term pharmacokinetics denotes the quantitative studying of drug

Clinical Significance of nK„

Aspirin is mostly non-ionized in the empty stomach —^crosses the cell

Bioavailability (Biological Availability)

Bioequivelance & Therapeutic equivalence:

Factors Affecting Bioavailability:

Factors affecting Absorption

I. Factors affecting drug absorption from GIT

Drugs with variable bioavailability among different dosage forms

P. First-Pass Effect fFirst-Pass Metbolism: Presvstemic Elimination)

• Reduction in portal blood flow: portal hypertension, propranolol.

Routes Bypassing the First-pass Effect

Sublingual - Parenteral - Rectal (to some extent)

Volume of Distribution (Vd)

Vd = Amount of drug inthe body/Plasma concentration

Factors affecting distribution of drugs:

•Drug distribution depends on: perfusion- diffusion- plasma protein binding-

1. Perfusion: the amount of the drug which is delivered to a particular organ

Lipophilicity facilitates drug absorption.

3It is called apparent volume since it not a real volume

3. Binding to plasma proteins:

• Bound fraction is inactive, nondiffusible, cannot be metabolized or excreted.

Significance of Binding to Plasma Proteins

4. Binding to cell and tissue constituents:

It is due to an affinity to some cellular constituents. Examples:

Passage of Drugs to CNS

Passage of Drugs to the Fetus

Many drugs cross placental barrier by simple diffusion (depending on their

Types of Biotransformation Reactions

Types of Metabolizing Enzyme Systems

Non-microsomal Enzyme Microsomal Enzyme

Plasma Enzyme Cytoplasmic Enzyme