Pharmacology

lecture (1)
Dr. Marvit Jazzar
Lecturer
Department of pharmacology
UGC
— Pharmacology is Science of DRUGS
— Study of the interaction of chemicals (drugs) with living systems or
is an experimental science which is the study of changes brought
about in living organisms. whether used for therapeutic purposes or
not.
— A DRUG is a chemical that act on living systems at the chemical
(molecular) level
— WHO definition: any substance or product that is used or intended
to be used to modify or explore physiological systems or
pathological states for the benefit of the recipient.
— The major subdivision of PHARMACOLOGY:
— PHARMACOTHERAPEUTIC: is the study of drugs used for the
diagnosis, prevention, and treatment of disease.
— TOXICOLOGY: is the study of the untoward effects of chemical
agents on living systems. It is an area of pharmacology.
— CHEMOTHERAPY.
— PHARMACODYNAMIC & PHARMACOKINETIC.

Introduction to Pharmacology
— Drugs vs medicines
— NOMECLATURE OF THE MEDICINES:
— Chemical names: gives the complete
description of the molecule
— Generic names: the official or legal name of the
drug, specify chemicals and are used in public
domain
— Brand name: specifies a particular formulation
assigned by the manufacturer of a generic
product (trade or brand name). The brand name
is restricted to the original copyright holder
— Pharmacology contributes to
— development of drugs
— Understanding of their mechanisms of action
and the description of their conditions of use
— Assessment of their efficiency through clinical
trials
— Their safety (through pharmacovigilance)
— Pharmacology is a guide for therapeutics and
contributes to the evidence-based medicine

…..2
— Pharmacogenetics: Study of genetic influences
on responses to drugs
— Pharmacogenomics: use of genetic information
to guide the choice of drug therapy on an
individual basis.
— Pharmacoepidemiology: Study of drug effects
at the pooulation level. Mainly concerned with
the variability of drug effects between individuals
in a population.
— Pharmacoeconomics: To quantify cost and
benefit of drugs used therapeutically.
— Pharmacovigilance :observation of the effects
of drugs after their release and use in practice.
— Pharmacodynamics :This describes the action
of the drug on the body, including receptor
interactions, dose response phenomena, and
mechanisms of therapeutic and toxic action
— Pharmacokinetics: Describe the action of the
body on the drug, including absorption,
distribution, metabolism and excretion
(Elimination of a drug may be achieved by
metabolism or by excretion.)

Pharmacology
FACTORS AFFECT DRUGS RESPONSE:
— The nature of drugs
— SIZE:The great majority of drugs lie in the range from
molecular weight 100 to 1000.Drugs in this range are
large enough to allow selectivity of action and small
enough to allow adequate movement within the various
body compartments
— Chemistry and reactivity: Drugs may be small simple
molecules, amino acids, amines, organic acids, alcohols,
esters, ions …etc or Carbohydrates, polysaccahrides,
lipids or proteins.
— Binding of drugs to proteins target such
as(RECEPTORS ).
— SHAPE: is very important for the drug molecule to fit into
the receptor (Chiral enantiomers Levo or dextro).
PHARMACODYNAMIC
(How drugs act)
PROTEINS TARGET:
— Enzymes
— Carrier proteins (membrane transporters)
— Ion channels
— Receptors
DRUG SPECIFICITY:
— Drugs act selectively on particular cells and
tissues
— Show high degree of binding site SPECIFIVITY
— Proteins that act as drug targets generally show
high degree of LIGAND specificity.
— It is not absolute.
— No drugs are completely specific in their actions
— Increasing the dose, in many cases, will cause
undesirable effects by acting on targets other
than the PRINCIPAL one
— This can lead to SIDE EFFECTS

Specificity
— A drug molecule BINDS to a receptor , this
occupation May or MAY NOT result in
ACTIVATION of the receptor i.e. produce a
RESPONSE.
— If a drug binds to a receptor and produce a
response, this drug is termed AGONIST
— If a drug binds to a receptor and does not
produce a response, this drug is called
ANTAGONIST.

Drug Receptor Interactions

— The tendency of a drug to bind to a receptor is
governed by its AFFINITY
— The tendency of the drug-receptor complex to
produce a response is termed EFFICACY
— Therefore, an agonist has affinity and efficacy
— The antagonist has affinity but not efficacy
— The drug receptor interactions seems to follow
the Law of Mass Action:
— D+R DR (response)
— Drugs with intermediate levels of efficacy, i.e.
they produce a submaximal response are called
PARTIAL AGONISTS
— Full agonists produce a maximal response that
the tissue is capable of producing.
— Inverse agonists: this when activation of a
receptor may exist even when no ligand is
present
— Such drugs include, Benzodiazepines and
Cannabinoids
— Inverse agonists produce a negative efficacy
— Full agonists produce positive efficacy
— Antagonists have zero efficacy.
— Many agonists are capable of producing
maximal responses at very low receptor
occupancies (less than 1%)Therefore, there is
substantial receptor reserve, called SPARE
RECEPTORS Example(Drugs that cause
smooth muscle contraction)

Spare receptors
— These are graphical representation of the effect
of drugs on targets in the body.
— We measure a response that is produced by a
drug using various methods
— We can measure a rise in blood pressure or a
contraction or relaxation of smooth muscle
— Activation or inhibition of an enzyme

Dose Response Curves

— This response is plotted as concentration or
dose response curve.
— Such curves allow us to estimate the maximal
response that the drug can produce (Emax)
— And we can also find the dose needed to
produce 50% maximum response called EC50
or ED50.
— This value is useful for comparing potencies of
different drugs that produce similar effects
(quantitatively)

DRC
— Remember, drug response is not directly related
to ability of the drug to bind to a receptor
— That means other reactions might happen after
drug binding that affect the drug response
— It is not a direct measure of receptor occupancy
— Several factors may be involved in producing
the final drug-induced effect.

DRC
 Competitive Antagonism:
This a situation whereby one drug binds selectively to a
receptor without activating it, but prevent the binding of
an agonist to this receptor.The two drugs compete with
each other, since the receptor can bind one drug at a
time.The agonist concentration will be reduced by the
presence of the antagonist.
However, because the two are in competition, raising
the agonist concentration can restore the agonist
occupancy of the receptor. Hence the agonist response
can also be restored Therefore, the antagonism is
SURMOUNTABLE

TYPES OF ANTAGONISM
— In the presence of the antagonist, the agonist log
concentration response curve is shifted to the right. (Fig)
with no change in maximum or slope.
— Extent of the shift is a measure of the DOSE RATIO.
— Dose ratio s the ratio by which the agonist concentration
has to be increased in the presence of the antagonist in
order to restore a given level of response
— Dose ratio increases linearly with antagonist
concentration
— The slope of this relationship is a measure of the affinity
of the antagonist for the receptor
Non-competitive antagonism:
— The antagonist blocks a step in the events that
leads to the production of the response.
— E.g. Verapamil and Nifedipine prevent the entry
of calcium into the cell, and eventually block
smooth muscle contraction
— They reduce the maximum and slope of the
DRC.
Chemical antagonism:
— The competing substances combine in solution.
The effect of the active drug will be lost.
— Chelating agents; dimercaprol for Hg
— EDTA for heavy metals
— Neutralising antibodies against protein
mediators (Cytokines, growth factors)
— Pharmacokinetic antagonism:
— Antagonism at the site of action
— Warfarin and barbiturates or rifampicin
(metabolism)
— Reduction in the rate of absorption; antacids or
milk and tetracycline
— Reduction or increase in rate of excretion
— Penicillin and Probenecid, Quinidine and digoxin
— Physiological antagonism:
— Antagonism by two drugs giving opposing
actions.
— Adrenaline and acetylcholine
— Histamine and Omperazole
— Histamine acts of H-2 receptors in the parietal
cells to increase acid secretion
— Omperazole inhibits the proton pump, therefore
blocks hydrogen ions.
— Drugs should be able to reach their intended site of
action after administration by a convenient route.
— Direct: very few site, mainly topical application.
— Intravenous route: drug will circulate in blood before it
produces an effect
— BUT most drugs are given by the oral route where it
passes into another compartment.
— This requires absorption into blood and distribution to
its site of action, permeating through various barriers
that separate these compartments.
— After the drug brings about its effect, the drug should be
eliminated from the body (Metabolism and excretion).

PHARMACOKINETIC
(How body act)
DRUG ABSORPTION
— Drugs pass through membranes by diffusional
transfer, i.e. molecule by molecule.
— Ability to cross hydrophobic diffusion barriers is
strongly influenced by LIPID SOLUBILITY
— Rate of diffusion across membranes depends on,
molecular size and diffusion coefficient.
— Molecules of drugs can pass through one single
layer, e.g. from extracellular to intracellular layer
or pass through several layer to reach its target
— Many drugs are weak acids or weak bases. They exist in
solution in the body as a mixture of ionised and
unionised forms. The ratio varies with pH.
— Weak acids are highly ionised in strong alkaline solution
and weak bases are highly ionised in strong acid
solutions
— The ionised form has very low lipid solubility.
— In each compartment the ratio of ionised and unionised
forms is governed by drug pka and the pH of the
compartment.
— At equilibrium the total concentration of the drug of both
forms will be different in the two compartments.

PH & IONIZATION
— Oral, sublingual, rectal
— Inhalation
— Epithelial surfaces: skin, cornea, vaginal and
nasal mucosa
— Injection: Intravenous, intramuscular,
subcutaneous, intrathecal.

Routes of drug Administration:

— It’s a term used to indicate the proportion of drug
that passes into the systemic circulation after
oral administration.
— Therefore for bioavailability absorption and local
degradation of drugs in the gut has to be taken
into consideration.
— It is a very important parameter when comparing
generic drugs with innovators’ drugs for
bioequivalence studies

Bioavailability
— Within the body fludies compartments, drugs
exist in a free and bound form. Weak acids and
bases exists as mixture of charged and
uncharged molecules.
— The quantity of each form depends on pH.
— Equilibrium between various compartments is
governed by permeability, pH, lipid solubility and
binding in each compartment.
— Blood Brain Barrier (BBB) is a continuous layer
of endothelial cells with tight junctions. It is
highly selective for drugs that enter the CNS.

DRUGS DISTRIBUTION
VOLUME OF DISTRIBUTION:
— The apparent volume of distribution is defined
as volume of fluid required to contain the total
amount of drug in the body at the same
concentration as that present in the plasma.

— Half-life or t1/2 : is the time it takes the plasma

concentration or the amount of drug in the body
to be reduced by 50%
— I. Metabolism:
— This the system developed by animals and the
human body to detoxify foreign chemicals,
carcinogens, toxins and drugs, This process is
called Biotransformation.
— The purpose of this process is to eliminate these
foreign chemicals from the body.
— Major site is LIVER, placenta, plasma, kidney,
gut and lungs.
— Prodrugs are metabolised to active form.

Drug Elimination
— It is divided into two phases:
— Phase I reactions (functionlisation) oxidation,
reduction and hydrolysis, produce more
chemically reactive products or carcinogenic or
toxic products.
— Phase II reactions: are anabolic or synthetic
they form conjugation reactions which result in
inactive products. These products are excreted
in urine or bile. Conjugates include: sulfate,
acetyl, glucuronide, methl and glutathione.
— HEPATIC ENZYMES!!!!!
Kinetics of metabolism
— First order kinetics: the rate of metabolism is
directly proportional to the concentration of the
free drug, MOST DRUGS
— Zero-order kinetics: The rate of metabolism
remains constant over time, a constant amount
of the drug is metabolised per unit time.
— Also called presystemic metabolism of drugs.
— When the amount of drug that reaches the circulation is
less than the amount absorbed. This is due to extensive
metabolism in the liver or gut wall.
— In practice you give a much larger oral dose than when it
is given by other routes
— Individual variations occur in the extent of first pass
effect of a given drug, therefore, it becomes difficult to
predict responses or effects.
— Drugs: Propranolol, salbutamol, metoprolol, GTN
(Glyceryl trinitrate), L-dopa, Lovastatin, simvastatin,
verapamil, Aspirin, Lidocaine, isosorbide dinitrate

FIRST PASS METABOLISM

II. Renal excretion of the drugs:
— Drugs differ in the rate at which they are
excreted by the kidney.
Renal excretion is done by:
— Glomerular filtration
— Active tubular secretion
— Passive diffusion across tubular epithelium