BASIC PRINCIPLES OF PHARMACOLOGY 3.

Describe how drugs are metabolized

1. Differentiate pharmacokinetics from pharmacodynamics A. Drug Metabolism as a Mechanism of Activation or
Termination of Drug Action
Pharmacokinetics - describes the effect of the body on Conversion to an inactive metabolite is a form of elimination.
drugs (example: absorption, excretion) In contrast, prodrugs (eg, levodopa, minoxidil) are inactive
Pharmacodynamics: -denotes the actions of the drug on the as administered and must be metabolized in the body to become
body (example: mechanism of action. toxic effects) active. Many drugs are active as administered and have active
metabolites as well (eg, morphine, some benzodiazepines).
B. Drug Elimination Without Metabolism
2. List and discuss the common routes of drug
Some drugs (eg, lithium, many others) are not modified by
administration and excretion
the body; they continue to act until they are excreted.
Phase I Reactions: Oxidation, Reduction, Deamination
and Hydrolysis
75% of drugs are metabolized by the enzymes CYP3A4 and
OP CYP2D6.
Phase II Reaction: addition (conjugation) of subgroups to —
OH, —NH2, and —SH, Glucuronidation, Acetylation,
Glutathione conjugation, Glycine conjugation, Sulfation,
Methylation

4. Differentiate first-order elimination from zero-order

elimination.

A. First-Order Elimination
The term first-order elimination indicates that the rate of
elimination is proportional to the concentration (ie, the higher
the concentration, the greater the amount of drug eliminated per
unit time). The result is that the drug’s concentration in plasma
decreases exponentially with time. Drugs with first-order elimination
have a characteristic half-life of elimination that is constant
regardless of the amount of drug in the body. The concentration of
such a drug in the blood will decrease by 50% for every half-life. Most
drugs in clinical use demonstrate first-order kinetics.
B. Zero-Order Elimination
The term zero-order elimination implies that the rate of
elimination is constant regardless of concentration. This occurs
with drugs that saturate their elimination mechanisms at
concentrations of clinical interest. As a result, the
concentrations of these drugs in plasma decrease in a linear
fashion over time.
Such drugs do not have a constant half-life. This is typical of
ethanol (over most of its plasma concentration range) and of
phenytoin and aspirin at high therapeutic or toxic
concentrations.

The most important organ for drug metabolism is the liver

FIGURE: Comparison of first-order and zero-order elimination. For drugs with first-
Elimination of Drugs: Usually through the kidneys order kinetics (left), rate of elimination (units per
hour) is proportional to concentration; this is the more common process. In the case of
zero-order elimination (right), the rate is constant and
independent of concentration.
 - However, the exogenous folic acid does not correct the
BLOOD & GOUT DRUGS neurologic defects of vitamin B12 deficiency
- Administration of folic acid to patients with vitamin B12
1. Name the 2 most common types of nutritional anemia, deficiency helps refill the tetrahydrofolate pool and partially or
and, for each, describe the most likely biochemical fully corrects the anemia.
causes. - However, the exogenous folic acid does not correct the
neurologic defects of vitamin B12 deficiency.
Iron deficiency and vitamin deficiency anemia - The 2 available forms of vitamin B12— hydroxocobalamin
- Microcytic hypochromic anemia and cyanocobalamin—have equivalent effects.
- Caused by iron deficiency - The major application is in the treatment of naturally
- Most common type of anemia occurring pernicious anemia and anemia caused by gastric
Pernicious anemia resection.
-The most common type of vitamin B12 deficiency anemia - Because vitamin B12 deficiency anemia is almost always
-Caused by a defect in the synthesis of intrinsic factor, a caused by inadequate absorption, therapy should be by
protein required for efficient absorption of dietary vitamin replacement of vitamin B12, using parenteral therapy.
B12, or by surgical removal of that part of the stomach that
secretes intrinsic factor. 4. Name 3 types of anticoagulants and describe their
mechanisms of action.
2. Identify the iron and folic acid requirements for Heparin
pregnant women. acts by binding to endogenous antithrombin III via a key
pentasaccharide sequence; the resulting complex irreversibly
30 mg to 60 mg of elemental iron and inactivates thrombin and factor Xa.
400 µg (0.4 mg) folic acid In the presence of heparin, ATIII proteolyzes thrombin and
factor Xa approximately 1000-fold faster than in its absence
3. Explain how folic acid and B12 deficiency affects the body and how
they can be treated.
Direct Thrombin Inhibitors
Folic acid Parenteral: Lepirudin, desirudin, bivalirudin, argatroban
- folic acid is required for normal DNA synthesis, and its Oral: Dabigatran
deficiency usually presents as megaloblastic anemia. - The protein analogs of lepirudin bind simultaneously to the
- In addition, deficiency of folic acid during pregnancy active site of thrombin and to thrombin substrates.
increases the risk of neural tube defects in the fetus - Argatroban binds solely to the thrombin- active site.
- Anemia resulting from folic acid deficiency is readily treated - Unlike the heparins, these drugs inhibit both soluble
by oral folic acid supplementation. thrombin and the thrombin enmeshed within developing
- Because maternal folic acid deficiency is associated with clots.
increased risk of neural tube defects in the fetus, folic acid - Bivalirudin also inhibits platelet activation.
supplementation is recommended before and during Rivaroxaban and apixaban; Rapid onset of action and shorter
pregnancy. half-lives than warfarin. These drugs are given as fixed oral
doses and do not require monitoring
- These small molecules directly bind to and inhibit both free
Vitamin B12 (cobalamin)
factor Xa and factor Xa bound in the clotting complex.
- a cobalt-containing molecule, is, along with folic acid, a
cofactor in the transfer of 1-carbon units, a step necessary for Warfarin
the synthesis of DNA. -acts by interfering with the normal post- translational
- Impairment of DNA synthesis affects all cells, but because red modification of clotting factors in the liver, a process that
blood cells must be produced continuously, deficiency of depends on an adequate supply of reduced vitamin K.
either vitamin B12 or folic acid usually manifests first as The drugs inhibit vitamin K epoxide reductase (VKOR), which
anemia. normally converts vitamin K epoxide to reduced vitamin K.
In addition, vitamin B12 deficiency can cause neurologic The vitamin K-dependent factors include thrombin and factors
defects, which may become irreversible if not treated VII, IX, and X.
promptly
5. Compare the pharmacokinetics, clinical uses, and toxicities of such as omeprazole and esomeprazole, should not be
the major antiplatelet drugs. administered concurrently with clopidogrel. Antagonists of
A. Aspirin ADP receptors: clopidogrel
Pharmacokinetics: When given orally, aspirin is absorbed by
passive diffusion and quickly hydrolyzed to salicylic acid in the
liver. Salicylic acid is further metabolized in the liver, and some Therapeutic use: Clopidogrel is approved for prevention of
is excreted unchanged in the urine. The half-life of aspirin atherosclerotic events in patients with a recent MI or stroke
ranges from 15 to 20 minutes and for salicylic acid is 3 to 12 and in those with established peripheral arterial disease. It is
hours. Aspirin, an IRREVERSIBLE COX inhibitor also approved for prophylaxis of thrombotic events in acute
coronary syndromes (unstable angina or non–ST-elevation MI).
Therapeutic use: Aspirin is used in the prophylactic treatment
Additionally, clopidogrel is used to prevent thrombotic events
of transient cerebral ischemia, to reduce the incidence of
associated with percutaneous coronary intervention (PCI) with
recurrent MI, and to decrease mortality in the setting of
or without coronary stenting. Ticlopidine is similar in structure
primary and secondary prevention of MI. Complete
to clopidogrel. It is indicated for the prevention of transient
inactivation of platelets occurs with 75 mg of aspirin given
ischemic attacks (TIA) and strokes in patients with a prior
daily. The recommended dose of aspirin ranges from 50 to 325
cerebral thrombotic event. However, due to life-threatening
mg daily. Aspirin is used to prevent further infarcts in persons
hematologic adverse reactions, ticlopidine is generally
who have had 1 or more myocardial infarcts
reserved for patients who are intolerant to other therapies.
Adverse effects: Higher doses of aspirin increase drug-related Prasugrel is approved to decrease thrombotic cardiovascular
toxicities as well as the probability that aspirin may also inhibit events in patients with acute coronary syndromes (unstable
prostacyclin production. Bleeding time is prolonged by aspirin angina, non–ST-elevation MI, and ST-elevation MI managed
treatment, causing complications that include an increased with PCI). Ticagrelor is approved for the prevention of arterial
incidence of hemorrhagic stroke and gastrointestinal (GI) thromboembolism in patients with unstable angina and acute
bleeding, especially at higher doses of the drug. Nonsteroidal MI, including those undergoing PCI.
anti-inflammatory drugs, such as ibuprofen, inhibit COX-1 by
Adverse effects: These agents can cause prolonged bleeding
transiently competing at the catalytic site. Ibuprofen, if taken
for which there is no antidote. Ticlopidine is associated with
within the 2 hours prior to aspirin, can obstruct the access of
severe hematologic reactions that limit its use, such as
aspirin to the serine residue and, thereby, antagonize platelet
agranulocytosis, thrombotic thrombocytopenic purpura (TTP),
inhibition by aspirin. Therefore, immediate release aspirin
and aplastic anemia. Clopidogrel causes fewer adverse
should be taken at least 60 minutes before or at least 8 hours
reactions, and the incidence of neutropenia is lower. However,
after ibuprofen. Although celecoxib (a selective COX-2
TTP has been reported as an adverse effect for both
inhibitor, see Chapter 36) does not interfere with the
clopidogrel and prasugrel (but not for ticagrelor). Prasugrel is
antiaggregation activity of aspirin, there is some evidence that
contraindicated in patients with history of TIA or stroke.
it may contribute to cardiovascular events by shifting the
Prasugrel and ticagrelor carry black box warnings for bleeding.
balance of chemical mediators in favor of thromboxane A2.
Additionally, ticagrelor carries a black box warning for
B. Ticlopidine, clopidogrel, prasugrel, and ticagrelor diminished effectiveness with concomitant use of aspirin doses
above 100 mg.
Pharmacokinetics: These agents require loading doses for
quicker antiplatelet effect. Food interferes with the absorption C. Abciximab, eptifibatide, and tirofiban
of ticlopidine but not with the other agents. After oral Pharmacokinetics: Abciximab is given by IV bolus, followed by
ingestion, the drugs are extensively bound to plasma proteins. IV infusion, achieving peak platelet inhibition within 30
They undergo hepatic metabolism by the cytochrome P450 minutes. The metabolism of abciximab is unknown. After
(CYP) system to active metabolites. Elimination of the drugs cessation of abciximab infusion, platelet function gradually
and metabolites occurs by both the renal and fecal routes. returns to normal, with the antiplatelet effect persisting for 24
Clopidogrel is a prodrug, and its therapeutic efficacy relies to 48 hours. When IV infusion of eptifibatide or tirofiban is
entirely on its active metabolite, which is produced via stopped, both agents are rapidly cleared from the plasma.
metabolism by CYP 2C19. Genetic polymorphism of CYP 2C19 Eptifibatide and its metabolites are excreted by the kidney.
leads to a reduced clinical response in patients who are “poor Tirofiban is excreted largely unchanged by the kidney and in
metabolizers” of clopidogrel. Tests are currently available to the feces. Glycoprotein IIb/IIIa receptor inhibitors: abciximab,
identify poor metabolizers, and it is recommended that other tirofiban, and eptifibatide
antiplatelet agents (prasugrel or ticagrelor) be prescribed for Therapeutic use: These agents are given intravenously, along
these patients. In addition, other drugs that inhibit CYP 2C19, with heparin and aspirin, as an adjunct to PCI for the
 prevention of cardiac ischemic complications. Abciximab is also
approved for patients with unstable angina not responding to
CARDIOVASCULAR DRUGS
conventional medical therapy when PCI is planned within 24 Drugs Used in Hypertension
hours. The glycoprotein IIb/IIIa inhibitors prevent restenosis 1. List the 4 major groups of antihypertensive drugs, and give
after coronary angioplasty and are used in acute coronary examples of drugs in each group. (Renin inhibitors are not
syndromes (eg, unstable angina and non-Q-wave acute considered an independent major group; can you name
myocardial infarction). the drug that acts by this mechanism?)

Adverse effects: The major adverse effect of these agents is

bleeding, especially if used with anticoagulants

D. Dipyridamole

Dipyridamole, a coronary vasodilator, increases intracellular

levels of cAMP by inhibiting cyclic nucleotide
phosphodiesterase, thereby resulting in decreased
thromboxane A2 synthesis. The drug may potentiate the effect
of prostacyclin to antagonize platelet stickiness and, therefore,
decrease platelet adhesion to thrombogenic surfaces.
Dipyridamole is used for stroke prevention and is usually given
in combination with aspirin. Dipyridamole has variable
bioavailability following oral administration. It is highly protein
bound. The drug undergoes hepatic metabolism, as well as
glucuronidation, and is excreted mainly in the feces. Patients
with unstable angina should not use dipyridamole because of
its vasodilating properties, which may worsen ischemia
(coronary steal phenomenon). Dipyridamole commonly causes
headache and can lead to orthostatic hypotension (especially if
administered IV).

E. Cilostazol

Cilostazol is an oral antiplatelet agent that also has vasodilating

activity. Cilostazol and its active metabolites inhibit
phosphodiesterase type III, which prevents the degradation of
cAMP, thereby increasing levels of cAMP in platelets and
vascular tissues. The increase in cAMP levels in platelets and
the vasculature prevents platelet aggregation and promotes
vasodilation of blood vessels, respectively. Cilostazol favorably
alters the lipid profile, causing a decrease in plasma
triglycerides and an increase in high-density lipoprotein
cholesterol. The drug is approved to reduce the symptoms of
intermittent claudication. Cilostazol is extensively metabolized
in the liver by the CYP 3A4, 2C19, and 1A2 isoenzymes. As
such, this agent has many drug interactions that require dose
modification. The primary route of elimination is via the
kidney. Headache and GI side effects (diarrhea, abnormal
stools, dyspepsia, and abdominal pain) are the most common
adverse effects observed with cilostazol. Phosphodiesterase
type III inhibitors have been shown to increase mortality in
patients with advanced heart failure. As such, cilostazol is
contraindicated in patients with heart failure.
Inhibitors of phosphodiesterase 3: dipyridamole and cilostazol
NOTE: READ THE LECTURE NOTE
 Low-dose thiazide diuretics are often used as first-line agents Because it can cause hirsutism, minoxidil is also available as a
• Induce hypokalemia and hyperuricemia in 70 percent of topical agent for the treatment of baldness.
patients and hyperglycemia in 10 percent of patients Calcium-Channel Blockers
Renin Inhibitors: Aliskiren Moderately effective vasodilators
The newest drug in the antihypertensive group Suitable for chronic use in hypertension of any severity
Directly inhibits renin’s action on its substrate, Intracellular concentration of calcium helps maintains the tone
angiotensinogen. of smooth muscle and contraction of the myocardium.
It thus reduces the formation of angiotensin I and, in Calcium enters muscle cells through special voltage-sensitive
consequence, angiotensin II calcium channels triggers release of calcium from the
It lowers blood pressure about as effectively as ARBs, ACE sarcoplasmic reticulum and mitochondria ↑ cytosolic level of
inhibitors, and thiazides. calcium
It does not appear to cause cough Drug binds to L-type calcium channels in the heart and in
It does not show reproductive toxicity in animals but is smooth muscle of the coronary and peripheral vasculature
considered to be contraindicated in pregnancy because of the block the inward movement of calcium vascular smooth
toxicity of ACE inhibitors and ARBs. muscle relax dilation mainly of arterioles
Note: Aliskiren (newest drug) – does not cause cough
Nicardipine
Captopril (old drugs) – cause cough
Also used in hypertensive emergencies
Losartan – lower cough incidence
Can be given as an intravenous infusion
All 3 are contraindicated in pregnancy
Major limitation of nicardipine in treating hypertensive
2. List the 4 mechanisms of action of vasodilator drugs.
emergency: long half-time (approximately 8 hours), which
- release of nitric oxide
precludes rapid titration.
- opening of potassium channels (which leads to
May have unique benefits in cerebrovascular disease: crosses
hyperpolarization)
the blood-brain barrier and acts to vasorelax cerebrovascular
- blockade of calcium channels
smooth muscle
- activation of D1 dopamine receptors (causing vasodilation)
NITROPRUSSIDE
Release of nitric oxide (from the drug molecule itself) 
stimulates guanylyl cyclase  ↑ cyclic guanine
monophosphate (cGMP) concentration in smooth muscle 
prompt vasodilation with reflex tachycardia
The drug has little effect outside the vascular system, acting
equally on arterial and venous smooth muscle.
Note: Because nitroprusside also acts on the veins, it can
reduce cardiac preload

3. List the major antihypertensive vasodilator drugs and

describe their effects.
HYDRALAZINE
Acts through the release of nitric oxide from endothelial cells
Used to treat moderately severe hypertension
Rarely used at high dosage because of its toxicity
Hydralazine-induced lupus erythematosus with high dosage
4. Describe the differences between the 2 types of
-reversible upon stopping the drug
angiotensin antagonists.
-lupus is uncommon at dosages below 200 mg/d.
MINOXIDIL Angiotensin Converting Enzyme (ACE) Inhibitors
Reserved for severe hypertension – Captopril (benazepril, enalapril)
a prodrug; its metabolite, minoxidil sulfate, is a potassium - Decrease Angiotensin II and increase bradykinin =
channel opener that hyperpolarizes and relaxes vascular vasodilation
smooth muscle.
 ↓ angiotensin II levels, ACE inhibitors  ↓ secretion of
aldosterone  ↓ sodium and water retention Nitrate (Nitroglycerin)
Useful in heart failure and diabetes as well as in hypertension - 10 – 20min Short duration of action (sublingual
Slow the progression of diabetic nephropathy administration; for Acute angina)
ACE inhibitors are also effective in the management of patients - 8 – 10 hours Long duration of action (transdermal; for
with chronic heart failure. prophylaxis of angina)
ACE inhibitors are a standard in the care of a patient following - Intermediate duration of action (oral; for prophylaxis of
a myocardial infarction. Therapy is started 24 hours after the angina)
end of the infarction. Atherosclerotic Angina is relieved within 5–10 min by rest
- Reduce peripheral resistance w/o increasing cardiac output and/or sublingual nitroglycerin
- TOXICITY: Cough, Renal damage in renal disease patient and - Nitrate also treats acute coronary syndrome
Fetus, and Fetal renal toxicity -Contraindicated in pregnancy - MOA: Nitrates release nitric oxide (NO) within smooth
muscle cells which stimulate Guanylyl cyclase and then
Angiotensin II Receptor Blockers (ARBs) – Losartan increase cGMP (secondary messenger)
(valsartan,irbesartan) cGMP induces smooth muscle relaxation.
Smooth muscle relaxation  venodilation  reduced
Competitively inhibit angiotensin II at its AT1 receptor site preload  reduced cardiac size and cardiac output
Appear to be as effective in lowering blood pressure as the Venodilation leads to decreased diastolic heart size and
ACE inhibitors fiber tension.
Also produce arteriolar and venous dilation and block Relaxation of arterial smooth muscle  increase flow
aldosterone secretion  ↓ blood pressure and ↓ salt and through partially occluded epicardial coronary vessels.
water retention Reduced afterload, from arteriolar dilation of resistance
TOXICITY: Fetal renal toxicity – contraindicated in pregnancy vessels  increase in ejection and a further decrease in
cardiac size.
5. List the major toxicities of the prototype Arteriolar dilation leads to reduced peripheral resistance
antihypertensive agents. and blood pressure.
Thiazide – hypokalemia, hypovolemia, hyperuricemia and - Toxicities: tachycardia, orthostatic hypotension, flushing,
hyperglycemia, INSULIN RESISTANCE, INCREASED throbbing headache, convert the ferrous iron in hemoglobin
CHOLESTEROL to the ferric form, yielding methemoglobin. significant reflex
Furosemide – hypokalemia, hypovolemia and ototoxicity tachycardia and increased force of contraction
Prazosin (alpha 1 blocker) – orthostatic hypotension
especially with the first few doses. Beta blockers
Propranolol (beta blocker) – bronchospasm in asthma Used only for prophylactic therapy of angina
patients, cardiac depression and sexual dysfunction They are of no value in an acute attack
• Bradycardia Effective in preventing exercise-induced angina
• CNS side effects: fatigue, lethargy, insomnia, and Ineffective against the vasospastic form
hallucinations The combination of β blockers and nitrates is useful because
• Hypotension the adverse undesirable compensatory effects evoked by the
• Decreased libido nitrates (tachycardia and increased cardiac force) are
• Impotence prevented or reduced by β blockade.
Clonidine and methyldopa (CNS agonist/ alpha2 seletive
agonists) – rebound hypertension due to Sudden
Calcium blockers
discontinuation (drug should therefore be withdrawn slowly)
Calcium influx is increased in ischemia because of the
Most common SE: drowsiness membrane depolarization that hypoxia produces
Methyldopa: Cardiac output is not decreased. Used in  promotes the activity of several adenosine
hypertensive pregnant patients and in px with renal triphosphate-consuming enzymes  depleting energy
insufficiency stores and worsening the ischemia
Captopril – feto renal toxicity The calcium-channel blockers protect the tissue by inhibiting
the entrance of calcium into cardiac and smooth muscle cells of
the coronary and systemic arterial beds

Drugs Used in the Treatment of Angina Pectoris

- All are arteriolar vasodilators
 - Reduce blood pressure in the reduction of both sodium and calcium currents and the
- Verapamil – affects myocardium (Decrease BP, heart rate, suppression of abnormal pacemakers.
contractility and oxygen demand). Avoided in patients with The AV node is particularly sensitive to β blockers and the PR
congestive heart failure interval is usually prolonged by group 2 drugs.
- Nifedipine – affects peripheral vasculature (minimal effect on
cardiac conduction and heart rate) GROUP 3 ANTIARRHYTHMICS/ POTASSIUM IK CHANNEL
- Diltiazepine – is intermediate in its action BLOCKERS prolong the duration of the action potential
Relieve coronary artery spasm (variant angina) without altering Phase 0 of depolarization or the resting
Antiarrhythmic Drugs membrane potential
Instead, they prolong the effective refractory period.
1. Enumerate the 4 major types of antiarrhythmic drugs and list All Class III drugs have the potential to induce arrhythmias.
2-3 important drugs under each group. DOFETILIDE and IBUTILIDE are typical group 3 drugs.
SOTALOL is a chiral compound
Amiodarone is usually classified as a group 3 drug because it
blocks the same K channels and markedly prolongs AP duration
as well as blocking sodium channels
DRONEDARONE is a new drug, similar to amiodarone but less
efficacious and less toxic.
hallmark of group 3 drugs is prolongation of the AP
duration

GROUP 4 ANTIARRHYTHMICS/CALCIUM L-TYPE CHANNEL

BLOCKERS They decrease the inward current carried by
calcium, resulting in a decreased rate of Phase 4 spontaneous
depolarization.
Major effect of calcium-channel blockers is on vascular
smooth muscle and the heart
- Verapamil is the prototype.
- Diltiazem is also an effective antiarrhythmic drug
- AV conduction velocity is decreased, and effective
refractory period and PR interval are increased by
these drugs

List the major toxicities of those drugs

Class I (Na channel blockers)

IA – procainamide, quinidine: hypotension, lupus

erythematosus (procainamide)
torsades de pointes and cinchonism – headache, vertigo,
Group 1A agents (prototype procainamide) prolong the AP. tinnitus (quinidine)
Group 1B drugs (prototype lidocaine) shorten the AP in some IB – lidocaine: convulsions and cardiovascular depression, may
cardiac tissues. precipitate, hyperkalemia increase cardiotoxicity
IC – flecainide: greater mortality and hyperkalemia increase
Group 1C drugs (prototype flecainide) have no effect on AP cardiotoxicity
duration.
Class III (K channel blockers)
All group 1 drugs slow conduction in ischemic and depolarized
Amiodarone - interstitial pulmonary fibrosis, gastrointestinal
cells and slow or abolish abnormal pacemakers wherever these
tract intolerance, tremor, ataxia, dizziness, hyper- or
processes depend on sodium channels.
hypothyroidism, liver toxicity, Photosensitivity, Neuropathy,
GROUP 2 / BETA BLOCKERS (Propranolol and esmolol) are muscle weakness, blue skin & corneal discoloration
prototypic antiarrhythmic β blockers. caused by iodine accumulation
Their mechanism in arrhythmias is primarily cardiac β-
adrenoceptor blockade and reduction in cAMP, which results
 Class IV (Ca channel blockers) excessive depression of o Inc. ventricular ejection
cardiac contractility, AV conduction, and blood pressure. o Dec. end-systolic and end- diastolic size
These agents should be avoided in ventricular o Inc. cardiac output
tachycardias. o Inc. renal perfusion
- ECG effects:
o Increases PR interval
o Flattening of the T wave

Drugs Used in Heart Failure - Toxicity:

o Increased automacity caused by intracellular calcium
1. Describe the strategies and list the major drug groups overload
used in the treatment of acute heart failure and o Extrasystoles, tachycardia, fibrillation
chronic failure. o Extrasystoles are recognized as premature ventricular
Therapeutic strategies: beats
- Removal of retained salt and water with diuretics
o Chronic: abnormal automaticity and arrhythmias
- Reduction of afterload and salt and water retention by
means of ACE inhibitors o Severe, acute: cardiac depression leading to cardiac
- Reduction of excessive sympathetic stimulation by arrest rather than tachycardia or fibrillation
means of B blockers
- Reduction of preload or afterload with vasodilators Digitalis is no longer considered as the first line therapy for
- Systolic failure: direct augmentation of depressed cardiac chronic heart failure because too much inhibition of Na/K
contractility with positive inotropic drugs such as digitalis glycosides ATPase can cause dysrhythmias. Moreover, careful clinical
studies indicate that while digitalis may improve functional
Therapeutic strategies: acute heart failure status (reducing symptoms), it does not prolong life.
- Loop diuretics
- Very severe HF: a prompt acting positive inotropic agent such as B
agonist or phosphodiesterase inhibitor, and vasodilators should be
used as required to optimize filling pressures and blood pressure. CNS DRUGS
- Nesiritide
- recombinant form of brain natriuretic peptide Sedative-Hypnotics Drugs
- Has vasodilating and diuretic properties
Benzodiazepine:
Therapeutic strategies: chronic heart failure
Alprazolam
- Best treated with diuretics (often a loop agent plus spironolactone)
plus an ACE inhibitor and if tolerated, a B blocker Chlordiazepoxide
- Digitalis may be helpful id systolic dysfunction is Clorazepate
prominent. Flurazepam
Midazolam
2. Describe the mechanism of action of digitalis and its major effects. Clonazepam (Longacting)
Indicate why digitalis is no longer considered a first-line therapy for
chronic heart failure.
Diazepam (LA)
Digitalis- inhibition of Na/K ATPase of the cell membrane Lorazepam (LA)
Free cytosolic calcium concentrations at the end of
contraction must be ↓ for cardiac muscle to relax. MOA: Bind GABA-a receptor subunits to facilitate chloride
The Na+/Ca2+-exchanger plays an important role in this channel opening and increase frequency (which leads to an
process by extruding Ca2+ from the myocyte in exchange increase in chloride conductance)
for Na+ •membrane hyperpolarization
Inhibition of Na+/K+ ATPase  small ↑ in intracellular Na Therapeutic uses:
 alters the driving force for Na-Ca exchange by the -Anxiety disorders - useful in treating the anxiety that
exchanger, NCX  less calcium is removed from the cell accompanies some forms of depression and schizophrenia
↑intracellular calcium is stored in the sarcoplasmic -Reserved for continued severe anxiety, and then should only
reticulum and upon release increases contractile force be used for short periods of time because of their addiction
potential.
Increases force of contraction of the heart\ Increase in
contractility results in:
-panic disorders, alprazolam is effective for short- and
long-term treatment MOA:
Bind to GABA-a receptor sites (distinct from benzodiazepines)
-Diazepam is useful in the treatment of skeletal muscle • facilitate chloride channel opening and increase duration
spasms. DOC terminating grand mal epileptic seizures. • Can block excitatory glutamate receptors
• Anesthetic concentrations of pentobarbital also block high-
-Midazolam is an injectable-only benzodiazepine also used frequency sodium channels.

for the induction of anesthesia

Therapeutic uses
-Diazepam and lorazepam are the drugs of choice in Anesthesia: thiopental, are used intravenously
terminating grand mal epileptic seizures and status Anxiety: barbiturates have been used as mild sedatives to
epilepticus relieve anxiety, nervous tension, and insomnia.

when used as hypnotics, they suppress REM sleep more than

-chlordiazepoxide, clorazepate, diazepam, and oxazepam are
other stages.
useful in the acute treatment of alcohol withdrawal and
reducing the risk of withdrawal-related seizures Adverse effects
CNS: drowsiness, impaired concentration, and mental and
Adverse effects
physical sluggishness
-Drowsiness and confusion: The two most common side Drug hangover - occasionally, nausea and dizziness occur
effects of the benzodiazepines induce the P450 system and, therefore, may decrease the
-Ataxia occurs at high doses, don’t drive duration of action of drugs
-Cognitive impairment (decreased long-term recall and increase porphyrin synthesis  contraindicated in patients
acquisition of new knowledge) with acute intermittent porphyria.
-Triazolam, with the most rapid elimination, often shows a Abrupt withdrawal from barbiturates may cause tremors,
rapid development of tolerance, early morning insomnia, and anxiety, weakness, restlessness, nausea and vomiting,
daytime anxiety, along with amnesia and confusion. seizures, delirium, and cardiac arrest.
-Avoid in patients with acute narrow-angle glaucoma
-Alcohol and other CNS depressants enhance the sedative-
hypnotic effects Zolpidem
- acts on a subset of the benzodiazepine receptor family, BZ1.
Benzodiazepine Antagonist (Management - shows few withdrawal effects, and exhibits minimal rebound
for Overdose):
insomnia, and little or no tolerance occurs with prolonged use
Flumazenil: - Adverse effects of zolpidem include nightmares, agitation,
A GABA-receptor antagonist that can rapidly reverse the headache, gastrointestinal upset, dizziness, and daytime
effects of benzodiazepines (“olam”) drowsiness.

Buspirone Ramelteon
- treatment of generalized anxiety disorder Novel hypnotic drug that activates melatonin receptors in
MOA: mediated by serotonin (5-HT1A) receptors the suprachiasmatic nuclei of the CNS decreases the latency of
Causes hypothermia and Can increase prolactin and growth sleep onset with minimal rebound insomnia or withdrawal
hormone. Advantage of minimal sedation. symptoms.
Adverse effect: Most common effects: headaches, dizziness,
adverse effects of the drug include dizziness, fatigue, and
nervousness, and light-headedness
endocrine changes including decreased testosterone and
increased prolactin.
Barbiturates
Amobarbital
Butabarbital
Pentobarbital
Phenobarbital
Secobarbital
Thiopental
 4. Describe Fetal alcohol syndrome
Alcohol Fetal alcohol syndrome: Ethanol use in pregnancy is associated
with teratogenic effects that include mental retardation (most
1. RELATE BLOOD ALCOHOL LEVEL IN A NONTOLERANT common), growth deficiencies, microcephaly, and a
PERSON TO CNS DEPRESSANT EFFECTS OF ACUTE ALCOHOL characteristic underdevelopment of the midface region (facial
INGESTION abnormalities)
In nontolerant persons, impairment of driving ability is thought to
ANTISEIZURE DRUGS
occur at ethanol blood levels 60 and 80 mg/dL. (i.e from 60mg/L
Liver microsomal mixed function oxidase system is active) 1. LiSt the drugS of choice for partial SeizureS,
Blood levels of 120 to 160 mg/dL are usually associated with gross
drunkenness. generalized tonic-clonic SeizureS, absence
Levels greater than 300 mg/dL may lead to loss of and myoclonic SeizureS, and Statu epilepticus
consciousness, anesthesia, and coma sometimes with fatal
respiratory and cardiovascular depression.
Blood levels higher than 500 mg/dL are usually lethal.

2. Identify the toxic effects of chronic ethanol ingestion

1. Tolerance and dependence: Tolerance occurs mainly as a

result of CNS adaptation and to a lesser extent by an
increased rate of ethanol metabolism

2. Liver: Liver disease is the most common medical complication

of chronic alcohol abuse.
3. Gastrointestinal system: Irritation, inflammation, bleeding,
and scarring of the gut wall occur after chronic heavy use of Phenytoin ,Carbamazipine and Valporic Acid
ethanol - is the DOC Generalize Tonic-Clonic seizure
4. CNS: Peripheral neuropathy is the most common neurologic Phenytoin, Carbamazipine and Lamotrigine
abnormality in chronic alcohol abuse. DOC for Partial Seizure
More rarely, thiamine deficiency, along with alcohol abuse, Ethosuximide or Valproic acid
leads to Wernicke-Korsakoff syndrome, which is characterized - DOC for Absence Seizure
by ataxia, confusion, and paralysis of the extraocular muscles. Diazepam or Lorazepam
- DOC for Status Epilepticus
5. Endocrine system: Gynecomastia, testicular atrophy, and salt
retention can occur, partly because of altered steroid 2. Describe the main pharmacokinetic features, and list
metabolism in the cirrhotic liver the adverse effects of carbamazepine, phenytoin, and
6. Cardiovascular system: Excessive chronic ethanol use is valproic acid
associated with an increased incidence of hypertension,
Subclass Pharmacokinetics Adverse Effect
anemia, and dilated cardiomyopathy.
Phenytoin Variable absorption, Variable absorption,
Methanol is metabolized to formaldehyde and formic acid, dose-dependent dose- dependent
which causes severe acidosis, retinal damage, and blindness elimina- tion; elimina- tion; protein
protein binding; binding; many
3. Describe the Treatment for Ethanol overdosage many drug drug interactions
Treatment for Ethanol interactions
long-acting benzodiazepine (eg, diazepam, chlordiazepoxide) is
preferred unless the patient has compromised liver function, in
which case a short-acting benzodiazepine with less complex
Carbamazepine Well absorbed, Ataxia, diplopia,
metabolism (eg, lorazepam) is preferred active headache, nauseav
- Naltrexone metabolite • many
Nonselective competitive antagonist of opioid receptors drug
- Acamprosate interactions
Poorly understood NMDA receptor antagonist and GABAA Valproate Extensive protein Nausea, alopecia,
agonist effects binding and weight gain,
- Disulfiram metabolism; many teratogenic
drug interactions
Inhibits aldehyde dehydrogenase • causes aldehyde accumulation
during ethanol ingestion. Drug for treat chronic alcohol abuse
 DRUGS OF ABUSE withdrawal from opioids is rarely fatal (unlike withdrawal from
sedative-hypnotics). Treatment involves replacement of the
1. IDENTIFY THE MAJOR DRUGS THAT ARE COMMONLY ABUSED illicit drug with a pharmacologically equivalent agent (eg,
methadone), followed by slow dose reduction.
sedative-hypnotic drugs: are responsible for many cases of Buprenorphine, a partial agonist at μ opioid receptors and a
drug abuse includes ethanol, barbiturates, and longer acting opioid (half-life >40 h), is also used to suppress
benzodiazepines. withdrawal symptoms and as substitution therapy for opioid
addicts. The administration of naloxone to a person who is
Opioids analgesics: most commonly abused drugs in this using strong opioids (but not overdosing) may cause more
group are heroin, morphine, codeine, oxycodone, and among rapid and more intense symptoms of withdrawal (precipitated
health professionals,meperidine and fentanyl withdrawal). Neonates born to mothers physiologically
dependent on opioids require special management of
Stimulants: Caffeine (in beverages) and nicotine (in tobacco withdrawal symptoms.
products), Amphetamines, Cocaine

Hallucinogens: phencyclidine
sedative-hypnotics
Acute overdoses commonly result in death through
Marijuana: Marijuana (“grass”), Cannabis sativa (hemp), depression of the medullary respiratory and cardiovascular
Hashish, cannabinoids centers. Management of overdose includes maintenance of a
patent airway plus ventilatory support. Flumazenil can be used
2. Describe the signs and symptoms of overdose with, and to reverse the CNS depressant effects of benzodiazepines,
withdrawal from, CNS stimulants, opioid analgesics, and but there is no antidote for barbiturates or ethanol.
sedative-hypnotics, including ethanol. Flunitrazepam (Rohypnol), a potent rapid-onset
3. .. benzodiazepine with marked amnestic properties, has been
4. .. used in “date rape.” Added to alcoholic beverages, chloral
hydrate or f-hydroxybutyrate (GHB; sodium oxybate) also
CNS stimulants renders the victim incapable of resisting rape. The latter
Toxicity—Acute toxicity from overdosage of caffeine or compound, a minor metabolite of GABA, binds to GABAB
nicotine includes excessive CNS stimulation with tremor, receptors in the CNS. When used as a “club drug,” GHB causes
insomnia, and nervousness; cardiac stimulation and euphoria, enhanced sensory perception, and amnesia.
arrhythmias; and, in the case of nicotine, respiratory paralysis. Withdrawal
Severe toxicity has been reported in small children who ingest Physiologic dependence occurs with continued use of
discarded nicotine gum or nicotine patches, which are used as sedativehypnotics; the signs and symptoms of the withdrawal
substitutes for tobacco products.
(abstinence) syndrome are most pronounced with drugs that
have a half-life of less than 24 h (eg, ethanol, secobarbital,
Withdrawal—Withdrawal from caffeine is accompanied by
methaqualone). However, physiologic dependence may occur
lethargy, irritability, and headache. The anxiety and mental
with any sedativehypnotic, including the longer acting
discomfort experienced from discontinuing nicotine are major
benzodiazepines. The most important signs of withdrawal
impediments to quitting the habit. Varenicline, a partial
derive from excessive CNS stimulation and include anxiety,
agonist at the α4β2 subtype nicotinic receptors, which
tremor, nausea and vomiting, delirium, and hallucinations.
occludes the rewarding effects of nicotine, is used for smoking
Seizures are not uncommon and may be life-threatening.
cessation. Rimonabant, an agonist at cannabinoid receptors,
Treatment of sedative-hypnotic withdrawal involves
approved for use in obesity, is also used off-label in smoking
administration of a long acting sedative-hypnotic (eg,
cessation.
chlordiazepoxide or diazepam) to suppress the acute
withdrawal syndrome, followed by gradual dose reduction.
Clonidine or propranolol may also be of value to suppress
opioid analgesics sympathetic overactivity. The opioid receptor antagonist
Overdose of opioids leads to respiratory depression naltrexone, and acamprosate, an antagonist at N-methyl-d-
progressing to coma and death. Overdose is managed with aspartate (NMDA) glutamate receptors, are both used in the
intravenous naloxone or nalmefene and ventilatory support. treatment of alcoholism.
Withdrawal A syndrome of therapeutic withdrawal has occurred on
Deprivation of opioids in physiologically dependent individuals discontinuance of sedative-hypnotics after long-term
leads to an abstinence syndrome that includes lacrimation, therapeutic administration. In addition to the symptoms of
rhinorrhea, yawning, sweating, weakness, gooseflesh (“cold classic withdrawal presented, this syndrome includes weight
turkey”), nausea and vomiting, tremor, muscle jerks (“kicking loss, paresthesias, and headache.
the habit”), and hyperpnea. Although extremely unpleasant
 DERMATOLOGICAL Long-term use is associated with a number of complications,
including psychiatric problems, cataracts, myopathy,
PHARMACOLOGY osteoporosis, avascular bone necrosis, glucose intolerance or
1. EXPLAIN THE USE GLUCOCORTICOIDS IN overt diabetes mellitus, and hypertension.
DERMATOLOGIC DISEASES AND THEIR TOXICITY.
Glucocorticoids (triamcinolone acetonide and triamcinolone 2. ENUMERATE IMPORTANT RETINOIDS USED IN
hexacetonide) are prescribed frequently for their DERMATOLOGICAL DISEASES.
immunosuppressive and anti-inflammatory properties. 3. DESCRIBE THEIR (RETINOID) MECHANISM OF ACTIONS,
MOA include a) apoptosis of lymphocytes, b) inhibitory effects CLINICAL USE, AND TOXICITIES.
on the arachidonic acid cascade c) depression of production of
many cytokines, and d) myriad effects on inflammatory cells.
Tretinoin
- Approved for the treatment of acne vulgaris and as an
With the development of appropriate vehicles, these agents
adjunctive agent for treating photoaging
rapidly became the mainstay of therapy for many
Reduce the hyperkeratinization that leads to microcomedone
inflammatory skin diseases. more potent drugs have a
formation, the initial lesion in acne
fluorinated hydrocortisone backbone.
- Epidermal effects include increased epidermal and granular
layer thickness, decreased melanocytic activity, and increased
Toxicity & Monitoring secretion of a glycosaminoglycan- like substance into the
Chronic use of class I topical glucocorticoids can cause skin intercellular space.
atrophy, striae, telangiectasias, purpura, and acneiform - In the dermis, blood vessel vasodilation and angiogenesis and
eruptions. increased papillary dermal collagen synthesis have been
Because perioral dermatitis and rosacea can develop after the documented. Clinically, this translates to modest attenuation
use of fluorinated compounds on the face, they should not be of fine and coarse wrinkling, smoother texture, increased
used in this site pinkness, and diminished hyperpigmentation.
- Nightly application produces maximum response within 1
year, and application one to three times weekly is said to
Systemic Glucocorticoids maintain improvement.
Systemic glucocorticoid therapy is used for severe - Treatment must be combined with a rigorous program of
dermatological illnesses. photoprotection, including sunscreens, sun avoidance, and
photoprotective clothing
In general, it is best to reserve this method for allergic contact
dermatitis to plants (e.g., poison ivy) and for life-threatening
ADAPALENE
vesiculobullous dermatoses such as pemphigus vulgaris and
Adapalene has similar efficacy to tretinoin, but unlike tretinoin,
bullous pemphigoid. it is stable in sunlight and tends to be less irritating
Chronic administration of oral glucocorticoids is problematic,
given the side effects associated with their long-term use.
Daily morning dosing with prednisone generally is preferred, Tazarotene
although divided doses are used occasionally to enhance - Treatment of psoriasis and acne vulgaris.
efficacy. - May be used as monotherapy or in combination with other
Fewer side effects are seen with alternate-day dosing, and if medications, such as topical corticosteroids, for the treatment
required for chronic therapy, prednisone is tapered to every of localized plaque psoriasis.
other day as soon as it is practical. - Side effects of burning, itching, and skin irritation are
relatively common, and patients should avoid sun exposure
Pulse therapy using large intravenous doses of
methylprednisolone sodium succinate is an option for
severe resistant pyoderma gangrenosum, pemphigus Isotretinoin
- Oral isotretinoin is approved for the treatment of severe
vulgaris, systemic lupus erythematosus with multisystem
nodulocystic acne vulgaris (numerous papules and pustules
disease, and dermatomyositis.
distributed on the whole facial area, along with developing
inflamed nodules)
Toxicity & Monitoring - normalizes keratinization in the sebaceous follicle, reduces
Oral glucocorticoids have numerous systemic effects. sebocyte number with decreased sebum synthesis, and
Most side effects are dose-dependent. reduces Propionibacterium acnes, the anaerobic, gram-
positive bacteria that produces inflammation in acne
prescribed for:
 ✓severe, recalcitrant nodular acne
✓moderate acne unresponsive to oral antibiotics
✓acne that produces scarring 6. EXPLAIN HOW TINEA CAPITIS AND TINEA PEDIS ARE
It also is used commonly for other related disorders, such as TREATED.
G(-) folliculitis, acne rosacea, and hidradenitis suppurativa
TINEA CAPITIS
- Toxicity & Monitoring: cheilitis/inflamed lip, mucous
Systemic therapy is necessary for the treatment of tinea
membrane dryness,Epistaxis/nosebleeds, dry eyes,
blepharoconjunctivitis, erythematous eruptions, and capitis.
xerosis/dry skin are all Side effects Retinoids • Oral griseofulvin has been the traditional medication for
treatment of tinea capitis.
-Systemic side effects: Transitory elevations in serum • Oral terbinafine is a safe and effective alternative to
transaminases occur rarely. Hyperlipidemia (25%), Myalgia griseofulvin in treating tinea capitis in children.
and arthralgia are common complaints for Isotretinoin
- Headaches occur and rarely are a symptom of pseudotumor TINEA PEDIS
cerebri. Topical therapy with the azoles and allylamines is effective for
- Long-term therapy may produce skeletal side effects, and tinea pedis.
premature epiphyseal closure in children. • Macerated toe web disease may require the addition of
- Teratogenicity is a major problem; it occurs if the drug is antibacterial therapy. Econazole nitrate, which has a limited
given within the first 3 weeks of gestation and is not dose- antibacterial spectrum, can be useful in this situation.
related. • Systemic therapy with griseofulvin, terbinafine, or
- Pregnancy is an absolute contraindication to the use of itraconazole is used for more extensive tinea pedis. It should
isotretinoin. be recognized that long-term topical therapy may be necessary
- Females of childbearing potential should initiate therapy at in some patients after courses of systemic antifungal therapy
the beginning of a normal menstrual period after giving
informed consent and obtaining two negative pregnancy
tests.

4. DESCRIBE THE TYPES OF UV RADIATION AND THEIR

EFFECTS
UVB (290 to 320 nm)
• The most erythrogenic and melanogenic type of radiation.
• It is the major action spectrum for sunburn, tanning, skin
cancer, and photoaging.
UVA: A-I (320 to 340 nm), and A-II (340 to 400 nm)
• The longer wavelengths of UVA are a thousand times less
erythrogenic than UVB
• However, they penetrate more deeply into the skin and
contribute substantially to photoaging and photosensitivity
diseases.
• They also enhance UVB-induced erythema and increase the
risk of skin carcinogenesis.
Psoriasis, Vitiligo – to repigment (PUVA = psoralen capsule
followed by UVA), Cutaneous T-cell lymphoma (PUVA)
• Nonmelanoma skin cancers = Photodynamic therapy
(photosensitizing drugs + visible light)

5. EXPLAIN THE CLINICAL USE OF AZOLES

The azoles miconazole and econazole and the
allylamines naftifine (gel) and terbinafine are effective
topical agents for the treatment of localized tinea
corporis (“ringworm”) and uncomplicated tinea pedis
(“athlete’s foot).
Topical therapy with the azoles is preferred for localized
cutaneous candidiasis and tinea versicolor.