GENERAL PRINCIPLES OF PHARMACOLOGY

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 Introduction
• Pharmacology came from the Greek words “Pharmacon”
meaning drug or medicine and “logos” meaning the truth
about or a rational discussion.
• Pharmacology
>> Is the study of drugs and their interaction with living systems.

• Medicine
>> Are chemicals that alter functions of living organisms given for
the diagnosis, prevention, control or cure of disease.
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 Cont’ed
• Drug names
– For written and verbal communications about drugs
– To put labels to identify the medications present in containers

Type of drug name Examples

Chemical name N-acetyl-para-aminophenol
Generic name Paracetamol
Trade name Panado, Tylenol, Dapa, Valadol,
Valorin, Helenol, etc
 Cont’ed

• Which name to use?

Generic names should be used except for drugs with

a low therapeutic index and known differences in
bioavailability among marketed products

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 Basic Principles of pharmacology
 Pharmacokinetics
- Pharmacon------------ drugs or poison
- Kinesis------------------ motion
 The four major pharmacokinetic processes are:
 Drug absorption
- The movement of drugs from the site of administration into
the blood.
 Drug distribution
- Drug movement from the blood to the interstitial space of
tissues and from there into cells.
 Drug metabolism
- Enzymatically mediated alteration in drug structure.
 Drug excretion
- Movement of drugs (& their metabolites) out of the body.
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The four basic pharmacokinetic processes.

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 Cont’ed
• Determine the concentration of a drug at its sites of
action.
• All phases of pharmacokinetics involve drug movement
• Factors that determine the passage of drugs across
membranes have profound influence on all phases.

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 Passage of drugs across membranes

• It is translocation of a drug from one side of the biological

barrier to the other.
• Structure of biological membrane: The outer surface of
the cell covered by a very thin structure known as plasma
membrane

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 Passage of drug
Drugs can cross cellular membranes by:

(A). Passive transfer

(1). Simple passive diffusion

(2). Filtration
(B). Specialized transport
(1). Facilitated diffusion
(2). Active transport
(3). Endocytosis 9
 Passive diffusion
 Also called non-ionic diffusion, is the major
(more than 90%) mechanism for absorption of
drugs.
 The driving force for this process is the
concentration gradient or electrochemical
gradient (defined as the difference in the drug
concentration on either side of the membrane).
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 Cont’ed
• Passive diffusion is best expressed by Fick’s first law of
diffusion, which states that drug molecules diffuse
from a region of higher concentration to one of lower
concentration until equilibrium is attained and that
the rate of diffusion is directly proportional to the
concentration gradient across the membranes.
 Carrier mediated transport
 Involves binding of the drug to specific receptors
on the membrane for translocation into the
cytoplasm
 Characteristics of carrier mediated transport
 Selectivity (structure specific)
 Competitive inhibition by chemical congeners
 Saturability
 Movement against electrochemical gradient (active
transport)
 Along concentration gradient (Facilitated diffusion)

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 Absorption

• The movement of drugs from the site of

administration into the blood.
• The rate determines how soon its effects will begin
• The amount determines the intensity of a drug
effects .

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 Factors affecting drug absorption

 The route of administration

 Physico-chemical properties of drug
 Nature of the dosage form
 Physiological factors
 Pharmacogenetic factors
 Disease states

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 Characteristics of Commonly Used Routes of
Administration
 ROA of administration affects rate of absorption.

1. Parentral
Intravenous (IV)
 Advantages—Absorption is instantaneous and complete;
rapid onset; precise control over levels; can use large
volumes of fluids; used for irritating drugs.
 Disadvantages—High cost; cannot self-administer; cannot
reverse injection; could cause fluid overload; increased risk of
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 Intramuscular (IM)
• Advantages—Only barrier is capillary wall; used for
poorly soluble drugs; for depot preparations to
decrease number of injections.
• Disadvantages—Inconvenience; discomfort with
administration.

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 Subcutaneous (SC)—Almost identical to IM for
advantages and disadvantages.
2. Enteral—Via gastrointestinal tract
Oral(PO); must cross GI tract and capillary wall; highly
variable absorption.
• Advantages—Administration is easy, convenient, and
inexpensive.
• Disadvantages—High variability, inactivated by pH and
first-pass effect; requires compliance; local irritation.

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Comparing oral administration with parenteral
administration

Oral route preferred to parenteral except for

certain situations (i.e., emergencies, drugs
destroyed by gastric acidity, when drug levels are
to be tightly controlled, when severe irritation
would occur, for depot preparations, and when
patients cannot take oral drugs).

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 Bioavailability(F)
• Bioavailability is the amount of drug which enters
the plasma or site of action.
• For an IV infusion, all the drug administered appears
in the plasma, and so bioavailability = 100%
• Bioavailability is often expressed as fractional
bioavailability, F, where

• AUC = area under the curve of a plasma 19

 Distribution
• Drug movement from the blood to the interstitial
space of tissues and from there into cells.
• Distribution controls onset, duration actions, efficacy
and side effect.
• Distribution of drugs is rarely uniform.
• Drugs are simultaneously being eliminated and
distributed, but distribution is usually faster.
• Tissue distribution is determined by the partitioning of
drug between blood and the particular tissue

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 Distribution

• The distribution of any given drug is determined by:

– Blood flow
• Blood flow varies as a result of the unequal
distribution of cardiac output to the various organs
– Capillary permeability,
• Presence of barriers protects some sensitive tissue
from noxious stimuli in the circulation. E.g BBB,
– The degree of binding of the drug to plasma and tissue
proteins
• Albumin is a major carrier for acidic drugs; 1-acid
glycoprotein binds basic drugs.
– The relative hydrophobicity of the drug.
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• Non polar drug distribute throughout the body unlike
Volume of distribution (Vd)
• Defined as volume in which the total amount of
drug in the body would be required to be dissolved
in order to reflect the drug concentration attained in
plasma
Vd = Amount of drug in body
Plasma concentration
 METABOLISM
• It is also called as biotransformation.
• Drug biotransformation is a process by which
drugs are chemically changed in the body as a
result of their interaction with cells or tissues.
• The purpose of biotransformation is to facilitate
excretion of drugs by rendering lipid soluble drugs
more polar (water soluble) or by conjugating it
with highly polar molecules.

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 Metabolism (Biotransformation)

Metabolism of drug occur in all body parts

Lung, GIT, kidney, liver, blood….
But mainly take place in liver ; b/c it contain
large amount of metabolizing enzyme
 The primary sites for metabolism is liver!

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 First-Pass Metabolism
• Following nonparenteral administration of a drug, a
significant portion of the dose may be metabolically
inactivated in either the intestinal endothelium or the
liver before it reaches the systemic circulation
• Limits oral availability of highly metabolized drugs
 Types of biotransformation
Classified as phase-I & phase – II
• In phase-I reaction the drug is converted to more polar
metabolite.
– Oxidation, reduction and hydrolysis.
– Some metabolites may not be excreted and further
metabolised by phase –II reactions.
• Phase-II: Glucuronidation, sulfate conjugation, acetylation,
glycine conjugation and methylation reactions.

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Therapeutic Consequences of Drug Metabolism

1) Promotion of renal excretion,

2) Reduction of therapeutic action,
3) Activation of a prodrug,
4) Enhancement of therapeutic action
5) Alteration of toxicity

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 Factors affecting drug biotransformation

 Genetic polymorphism
 Disease conditions especially of the major drug
metabolizing sites.
 Age
 Predisposing factors to enzyme induction or inhibition.
• Diet :- eg. grape fruit juice (inhibit cyp3A4)
• Sex:- eg. Alcohol

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 Induction & inhibition of drug metabolism

Enzyme ↑ synthesis of
microsomal ↑metabolism ↑excretion
duction enzyme

Enzyme ↓liver
enzyme ↓metabolism ↓excretion-
hibition function

toxicity
 Excretion
• Drug excretion is the elimination (passage
out) of a systemically absorbed drug from the
body in the form of metabolites or unchanged
drug.
– It is a process of drug transfer from the
internal to the external environment
The kidneys are the main organ of excretion
of drugs and their metabolites.

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 Renal excretion
• Principal organ for most drug removal
especially for water soluble (responsible for
excreting water soluble substances) and
non volatile drug
• The amount of drug or its metabolites
ultimately present in urine is the
cumulative effect of:
– Glomerular filtration
– Tubular secretion
– Tubular reabsorption
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Generally the rate of urinary drug excretion will
depend on:
Drug volume of distribution
Degree of protein binding
Glomerular filtration rate
Tubular fluid PH
Extent of back-diffusion of unionized form of drug
Extent of active tubular secretion of compound
Possibly, extent of tubular reabsorption

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 Excretion
• Removal of drugs from the body

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 Time Course of Drug Responses
A. Plasma Drug Levels
Clinical significance of plasma drug levels—there is usually direct
correlation between therapeutic and toxic responses and plasma
drug levels.
 Two plasma drug levels defined
A. Minimum effective concentration (MEC) –
> Is defined as the plasma drug level below which therapeutic
effect will not occur.
B. Toxic concentration – the plasma drug level
> At which toxic effects begin is termed as toxic concentration.
 Drug Half-Life - Time required for amount of drug in the body to
decrease by 50 %.

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Therapeutic range—Objective of drug dosing (between
MEC and toxic levels).

B. Single-Dose Time Course

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 Pharmacodynamics

• The study of the biochemical & physiological effects of

drugs
• The molecular mechanisms by which these effects are
produced.
• Is the study of what drugs do to the body and how
they do it.
• Most drug produce their effect by binding on receptor
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What are receptors?

Receptors are the macromolecular component of the

cell to which a drug bind to produce its effect.
Are mainly protein molecule whose function is to
recognize and respond to endogenous chemicals and
xenobiotics
Receptor, should have ligand binding and message
propagation (i.e., signaling)

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Receptor families
 Action of drug
• Most drugs (free drug) act by forming chemical
bonds with specific receptor sites within the body to
stimulate and/or inhibit a response.
• Some drug act trough simple physical or chemical rxn
with out interacting with receptor
– Receptors: cimetidine + histamine receptor
– Enzyme--- eg acetylcholinesterase ---neostigmine
– Structural proteins: colchicine + tubuline
– Ion channel---Ca2+ channel ----calcium channel
blocker (verapamil)

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 – Carrier molecule –proton pump inhibitor---
omeoprazole
• Site of drug action
– Extracellularly e.g osmotic diuretics
– On the cell surface e.g digitalis
– Inside the cell e.g anticancer drugs
Drug & receptor
 Affinity: ability of a ligand (the drug) to bind to receptors
 Intrinsic activity (efficacy): ability of a ligand to activate
(cause change in receptor conformation) upon binding
and produce the response.

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In view of binding, ligands can be
 Agonists: It binds to the receptors and it will activate the
receptor.
 Has both affinity and intrinsic activity (A=1 & IA=1). Eg.
morphine, epinephrine
 Antagonist: binds to the receptor but it will not activate the
receptor.
 Has affinity but no intrinsic activity (A=1 & IA=0). Eg :
atenolol, metoprolol, Prazosin
 Partial agonist/antagonist: It activates the receptor and
produce sub maximal response.
 Has affinity but with sub maximal intrinsic activity (A=142&
Dose response relation ship
 Is the relationship between intensity of drug effect and
drug dosage (drug level)
 Has two components

 Dose-plasma concentration relationship

 Plasma concentration-response relationship

 Quantification of drug level at the site of action is difficult

and hence either the dose administered or its plasma
concentration are considered during quantification. 43
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 Dose response relation ship
• Grade response
– Dose administered to single subject
– The relationship between dose and response is a continuous
one
– Used to characterization of the action of drug (potency & IA)
• Quantal response
– Influence of the magnitude of the dose on the proportion of
a population that responds.
– Is all or none phenomena
– Employed to study toxicity of a drug
– Useful for determining doses to which most of the
population responds. 45
 Potency & Intrinsic activity

 Potency
• It refers to the amount of drug needed to produce
the response.
 Intrinsic activity (IA) (Efficacy)
• It refers to the maximum response of the drug.

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 Drug-drug interaction

• Drug-drug interaction – modulation of pharmacological activity one drug by

concomitant/prior administration of another drug.
• Interaction occurs at two stages:
 At pharmacokinetic level
 At the level of absorption, distribution, biotransformation or excretion
 At Pharmacodynamic level
 At the level of receptors and beyond
• Type of interaction
– Additive (e.g carbachol + acetyl choline)
– Synergetic (e.g ethanol + carbon tetrachlorid)
– Potentiation (e.g isopropanol + carbon tetrachlorid)
– Antagonism ( e.g insulin + glucagon)
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At Pharmacodynamic level
• Types of agonist- antagonist interaction at receptors
A. Reversible antagonism
1. Competitive antagonism
2. Non-competitive antagonism
B. Irreversible antagonism

Reversible antagonism
-Is reversible since week bond b/n receptor & antagonist

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Agonist- antagonist interaction at receptors

• Competitive antagonist
– Agonist & antagonist compete for same receptor
site
– Do not produce effect by themselves but ↓
agonist potency
– ↑ dose of agonist reverse antagonist effect
– Dose-response curve shift to the right

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 Agonist- antagonist interaction at receptors
• Non-competitive antagonism
– Binding site for antagonist is different from agonist
– Antagonist cannot be overcome by ↑ increasing
agonist concentration
– ↓ maximal response
• Irreversible antagonist
– Strong covalent bond
– Irreversibly inactivate the receptor
– Shift the dose response curve to right & ↓ maximal
response
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Drug adverse effects and drug toxicities

 These are effects not favorable to the patient

 Expected adverse effects
 Side effects: effects observed at therapeutic dose
 Toxic effects: effects observed at larger
concentrations
Acute toxicity: acute administration of larger
doses.
Chronic toxicity: usually with prolonged and
repeated use of a drug.

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 Unexpected adverse effects
 Hypersensitivity reactions: abnormal response
due to antigenic nature of some drugs
Allergy
Anaphylaxis: extreme sensitivity to antigenic
substance and subsequent circulatory collapse
 Idiosyncratic reactions: an abnormal reactivity to
a chemical that is peculiar to a given individual.
 General procedures in the management of
poisoning
o Life support
 The first step is to recognize and treat life threatening
conditions (ABCD)
o Drug identification
 More detailed evaluation to make a specific diagnosis
o Decontamination
 Should be undertaken simultaneously with initial
stabilization, diagnostic assessment, and laboratory
evaluation

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  Termination of exposure to the toxic substance
 Allowing to fresh air
 Washing of the eyes and skin
 Prevention of further absorption of ingested poison
 Induction of emesis
 Use of adsorbent
 Induction of purgation
o Specific antidotes
– e.g. Atropine antidote Anticholinesterases
o Enhancing elimination of toxins
- Hemodialysis or urinary alkalinization