INTRODUCTION TO

PHARMACOLOGY
 What is Pharmacology

 What is pharmacology?

 In this introductory part, we will study

 The origin of pharmacology
 Its evolvement as a scientific discipline
 The present day state of the subject and its
relation to other areas of biomedical
sciences.
 Definition

 Pharmacology can be defined as the study of the effects of

drugs on the function of living systems (Rang and Dale, 6th
Edn., 2007)

 What is a drug?
 A drug can be defined as “a chemical substance of known
structure, other than a nutrient or an essential dietary
ingredient, which, when administered to a living organism,
produces a biological effect”. Drugs may be synthetic
chemicals, chemicals obtained from plants or animals, or
products of genetic engineering.
 Drugs
 A drug
 the substance that must be administered as such, rather than
released by physiological mechanisms. Many substances, such as
insulin or thyroxine, are endogenous hormones but are also drugs
when they are administered intentionally.
 Many drugs are not used in medicines but are nevertheless useful
research tools. In everyday parlance, the word drug is often
associated with addictive, narcotic or mind-altering substances-an
unfortunate negative connotation that tends to bias opinion against
any form of chemical therapy.
 We will deal with drugs used for therapeutic purposes but also describe
important examples of drugs used as experimental tools. Although
poisons fall strictly within the definition of drugs, they will not be
covered.
 Medicine

 Medicine
a chemical preparation, which usually but not
necessarily contains one or more drugs,
administered with the intention of producing
a therapeutic effect.
 usually contain other substances (excipients,
stabilisers, solvents, etc.) besides the active
drug, to make them more convenient to use.
Biotechnology and Pharmacology
 1980s, biotechnology also emerged as a major source of new
therapeutic agents in the form of antibodies, enzymes and various
regulatory proteins, including hormones, growth factors and
cytokines
 Although such products (known as biopharmaceuticals) are generally
produced by genetic engineering rather than by synthetic chemistry, the
pharmacological principles are essentially the same as for conventional
drugs.
 Looking further ahead, gene- and cell-based therapies although still in
their infancy, will take therapeutics into a new domain.
 The principles governing the design, delivery and control of functioning
artificial genes introduced into cells, or of engineered cells introduced
into the body, are very different from those of drug-based therapeutics
and will require a different conceptual framework, which texts such as
this will increasingly need to embrace if they are to stay abreast of
modern medical treatment.
 Pharmacology today

 Biotechnology - Originally, this was the production of

drugs or other useful products by biological means
(e.g. antibiotic production from microorganisms or
production of monoclonal antibodies).

 Pharmacotherapeutics - use of drugs to treat

disorders; the emphasis is on clinical management
 Pharmacoepidemiology- This is the study of drug
effects at the population level
 Pharmacology today contd…
 Pharmacogenetics - This is the study of genetic influences on
responses to drugs.

 Pharmacogenomics - This recent term overlaps with

pharmacogenetics, describing the use of genetic information to
guide the choice of drug therapy on an individual basis. The
underlying principle is that differences between individuals in their
response to therapeutic drugs can be predicted from their genetic
make-up.

 Pharmacoeconomics- This branch of health economics aims to

quantify in economic terms the cost and benefit of drugs used
therapeutically.
 Pharmacology today contd…
 Pharmacodynamics
 study the mechanisms by which drugs work
 also study endogenous agents
 (What drug does to our body)

 Pharmacokinetics
 study the fate of drugs once ingested and the variability
of drug response in varying patient populations
 how the body absorbs, distributes, metabolizes, and
excretes drugs
 calculation of various rates brings a quantitative
component to assessing drug action
 (What our body does to the drug)
 Pharmacokinetics/ Drug Biochemical
metabolism Phamacology

Molecular Pharmacology Chemotherapy

Pharmacology

Ocular Clinical
Systemic Pharmacology Pharmacology
Pharmacology

Neuro Respiratory
Pharmacology Pharmacology
Immuno
Cardiovascular Gastrointestinal
Pharmacology
Pharmacology Pharmacology
 Important Terms
 Receptor - Generally the term “receptor” indicates a
recognition molecule for a chemical mediator. Hormones,
neurotransmitters, inflammatory mediators, etc.-produce their
effects. Examples such as acetylcholine receptors, cytokine
receptors, steroid receptors, and growth hormone receptors

 Ligand – Anything that binds to the receptors with high affinity

 Agonist
 Antagonist

 Binding
 Activation
 Summary
 Targets for drug action : A drug is a chemical applied to a physiological system
that affects its function in a specific way.
 With few exceptions, drugs act on target proteins, namely:
 receptors
 enzymes
 carriers
 ion channels.
 The term receptor is used in different ways. In pharmacology, it describes protein
molecules whose function is to recognise and respond to endogenous chemical
signals. Other macromolecules with which drugs interact to produce their effects
are known as drug targets.
 Specificity is reciprocal: individual classes of drug bind only to certain targets, and
individual targets recognize only certain classes of drug.
 No drugs are completely specific in their actions. In many cases, increasing the
dose of a drug will cause it to affect targets other than the principal one, and this
can lead to side effects.
Drug Antagonism
 Definition
 DRUG ANTAGONISM : When the effect of one
drug is diminished or completely abolished in the
presence of another.

 chemical antagonism
 pharmacokinetic antagonism
 antagonism by receptor block
 non-competitive antagonism, i.e. block of receptor-
effector linkage
 physiological antagonism.
 Agonist and Antagonist
 Binding and activation represent two distinct steps in the
generation of the receptor-mediated response by an
agonist .
 Occupation of a receptor by a drug molecule may or may
activation
not result in of the receptor. By activation,
we mean that the receptor is affected by the bound
molecule in such a way as to elicit a tissue response.
This is known as a agonist.
 If a drug binds to the receptor without causing
activation and thereby prevents the agonist from
binding, it is termed a receptor antagonist.
 Agonist and Antagonist
 The tendency of a drug to bind to the receptors is
governed by its affinity, whereas the tendency for
it, once bound, to activate the receptor is denoted
by its efficacy.

 Drugs of high potency will generally have a high

affinity for the receptors and thus occupy a
significant proportion of the receptors even at low
concentrations. Agonists will also possess high
efficacy, whereas antagonists will, in the
simplest case, have zero efficacy.
DRUG RECEPTOR INTERACTIONS
Definitions
Agonist:
Interacts with a receptor  Effect changes  Response

Antagonist:
Binds to a receptor  blocks agonist from interacting
with the receptor  No response
 Definitions
Agonist potency is governed by 2
parameters:
- Affinity : Tendency to bind to a
receptor
-Efficacy : Ability, once bound to
initiate changes in the receptor
 DRUG RECEPTOR INTERACTIONS
Schematic representation

Drug

Pharmacological
1 2 3
Receptor Response

1.
2.
3.
Desensitization and Tachyphylaxis
 Often, the effect of a drug gradually diminishes
when it is given continuously or repeatedly.
Desensitisation and tachyphylaxis are synonymous
terms used to describe this phenomenon, which
often develops in the course of a few minutes.
- Tolerance – gradual decrease in
responsiveness to a drug (weeks and months)
- Refractoriness – Loss of therapeutic efficacy
- Drug resistance – Loss of effectiveness of
antimicrobial or antitumour drugs
 Reasons for desensitization:

 change in receptors
 loss of receptors

 exhaustion of mediators

 increased metabolic degradation of the

drug
 physiological adaptation

 active extrusion of drug from cells (mainly

relevant in cancer chemotherapy;

 Drug effects
Drug + Target

Physiological SLOW
Altered gene
response expression

SLOW

Delayed
responses
DRUG SELECTIVITY
 DRUG SELECTIVITY
In pharmacology, the extent to which a
dose of a drug produces the desired
(beneficial) effect in relation to adverse
(side) effects.

Side effects may be predictable,

unpredictable, toxic and sometimes
desirable too.
 DRUG SELECTIVITY
Therapeutic (Beneficial) Effects:
Aspirin  Analgesic, Antipyretic, Anti-inflammatory

Side Effects (Predictable):

Aspirin  Upset stomach, Gastric ulcers

Side Effects (Unpredictable):

Aspirin  Asthma attack, Abdominal pain

Side Effects (Desirable):

Aspirin  Reduced pain sensation, Euphoria
 DRUG SELECTIVITY
Therapeutic and Undesirable Effects:
Antihistamines  Drowsiness (Undesirable)
Sleep aids  Drowsiness (Desirable)

Antibiotics (selected)  Diarrhea (Undesirable)

Laxative  Diarrhea (Desirable)

Caffeine  Diuresis (Undesirable)

Diuretic  Diuresis (Desirable)
 DRUG SELECTIVITY

Active ingredients in Tylenol allergy sinus®:

Acetaminophen  Analgesic
Pseudoephedrine  Decongestant
Diphenhydramine  Antihistamine

Drug 2 is an agonist
Drug 3 is an antagonist
 RELATIONSHIP BETWEEN THERAPEUTIC
& TOXIC EFFECTS
Same Receptor and Organ:
Th
D+R [DR]  X Tx

Examples-
1. Anti-arrhythmic drugs:
Therapeutic effects- Normalization of cardiac rhythm
Toxic effects- Arrhythmia (QTc prolongation, Torsade)

2. Barbiturates:
Therapeutic effects- Sedation, Hypnosis
Toxic effects- Coma, Death
 RELATIONSHIP BETWEEN THERAPEUTIC
& TOXIC EFFECTS
Same Receptor but different Organs:
X  Th
D+R [DR]
Y  Tx

Examples-
1. Estrogen Replacing agents (at estrogen receptors):
Therapeutic effects- Decrease in bone loss (bone)
Toxic effects- Breast cancer (breast)

2. Angiotensin-converting enzyme (ACE) inhibitors:

Therapeutic effects- Lowering blood pressure (kidney)
Toxic effects- Cough (lungs)
 RELATIONSHIP BETWEEN THERAPEUTIC
& TOXIC EFFECTS
Different Receptors and Organs:
R1 [DR1]  X  Th
D+
R2 [DR2]  Y  Tx

Examples-
1. Anti-asthmatic (Bronchodilators):
Therapeutic effects- Bronchodilation (2 receptors in lungs)
Toxic effects- Increase in heart rate (1 receptors in heart)

2. Clonidine:
Therapeutic effects- Lowering BP (2 receptors in brain)
Toxic effects- Urinary retention (1 receptors in bladder)
 USE OF DRUGS IN TREATMENT OF DISEASES
(PHARMACOTHERAPEUTICS)

Symptomatic treatment:
Treats symptoms of a disease but does not cure the disease itself
- Hypertension
- Parkinson’s disease
- Diabetes
- Depression

Chemotherapy:
Targeted towards attacking the disease with a chemical
- Infection (antibiotics or antiviral targeted towards bacteria or virus)
- Cancer (anticancer agents)
 USE OF DRUGS IN TREATMENT OF DISEASES
BIOLOGICAL VARIATIONS

Body Size and Weight:

Age-Sex:

Genetic Factors:

Psychological Factors (Placebo Effect):

 USE OF DRUGS IN TREATMENT OF DISEASES
BIOLOGICAL VARIATIONS

Food in the stomach:

Drug-drug interactions:

Food-drug interactions:
PRINCIPLES OF DRUG
ACTION
Pharmacokinetics
 Pharmacokinetics

Movement of Drugs, or,

In simpler terms – Dispersion of Drugs

 Pharmacokinetics
 Pharmacokinetics is the movement of drug
- First step in the movement of the drug is absorption of the
drug into blood stream
- What happens after that?
- Once it reaches blood what is the fate of the drug now?
 There are several critical steps even after the drug has reached
the blood that decide its action
 First of all the drug should be in a free or unbound state:
some drugs because of their chemical structure can bind to
plasma proteins. If bound they are not going to act. So for any
action to happen the drug should be in free state. It will also
facilitate the metabolism of that drug, which usually converts
an active drug into an inactive metabolite.
 Similarly drug in free or unbound state can be easily excreted
from the body.
 Drug action
 The drug when reaches the site of action,
act at the cellular level; mainly by binding
to a receptor and produces action.
 The intensity of pharmacologic effect
depends on
 - receptor occupancy: if something is wrong with
receptor no matter how high dose of drug is given,
or however high the concentration of the free drug
is in the blood it is not going to act.
 PHARMACOKINETICS
General Scheme- Absorption, Distribution, Metabolism, Excretion
(ADME)
Drug Dosage
Binding to Absorption
plasma Metabolism
protein Free Drug in Bloodstream

Storage in Tissue Excretion

Drug Concentration at Site of Action

Receptor Occupancy

Intensity of Pharmacologic Effect

Important Definitions
Cmax - it is defined as the maximal blood concentration
achieved after a single dose of drug
Tmax - is the time at which the plasma concentration of
a drug is maximal

MEC - the minimum concentration of the drug in the

blood, that shows effectiveness (therapeutic effect)

MTC - the minimum concentration of the drug in the

blood, that shows toxicity (toxic effect)
 Bioequivalent formulation

 Bioequivalence is a term in
pharmacokinetics, which is used to assess
(determine) the expected in vivo biological
equivalence of two proprietary preparations
(prepared by different manufacturers) of a
drug. If two products are said to be
bioequivalent it means that they would be
expected to be, for all intents and purposes
(therapeutic and use), the same.
 Bioequivalent formulation
 Because drug products that contain the same drug
(active ingredient) may have different inactive
ingredients, absorption of the drug from different
products may vary. Thus, a drug's effects, even at
the same dose, may vary from one drug product to
another.
 Drug products that not only contain the same
active ingredient but also produce virtually the
same blood levels at the same points in time are
considered bioequivalent. Bioequivalence makes
the two drugs therapeutic equivalent (that is,
production of the same medicinal effect), and
bioequivalent products are thus, interchangeable.
 PHARMACOKINETICS
Blood Concentration Time Profile

20 A
Blood Concentration

Formulation A B
15
(mg/ml)

Formulation B
10

0
0 1 2 3 4 5 6 7 8
Time After Drug Administration (hr.)
Peak plasma conc. (Cmax)
Maximal blood concentration achieved after a single dose of a drug
Tmax
Time at which the plasma concentration of a drug is maximal
Minimum Effective Concentration (MEC)
The lowest concentration at which effectiveness of a drug is seen
Minimum Effective Concentration (MEC)
The lowest concentration at which effectiveness of a drug is seen

Minimum Toxic Concentration (MTC)

The lowest concentration of a drug at which adverse reactions are observed
Time for Onset of Drug Action
The time required to produce the minimal effects of a drug after the administration.
This usually correlates with the time required to reach the MEC.
Duration of Drug Action
The time period during which effects of a drug are seen. This usually correlates
with the time period during which the drug concentration is above MEC.
 PHARMACOKINETICS
Distribution of Drugs

Distribution involves the delivery of the drug from the blood to various tissues,
including the drug’s site of action, e.g. the brain

• Plasma proteins (e.g. albumin, globulin etc.)

• Tissues (Adipose tissue)
• Fluids (ICF, ECF, CSF)
 PHARMACOKINETICS
Distribution of Drugs

Distribution involves the delivery of the drug from the blood to various tissues,
including the drug’s site of action, e.g. the brain

• Plasma proteins (e.g. albumin, globulin etc.)

Free Drug + Protein  Drug-Protein Complex
- Only free drug (not bound to proteins) is available to cross the blood vessel
and enter the site of action. Therefore, only free drugs are active.

Free drug that can enter the site of action (tissue)

Plasma protein
Drug (w/ 80% plasma
protein binding)

Blood vessel
 PHARMACOKINETICS
Distribution of Drugs

Distribution involves the delivery of the drug from the blood to various tissues,
including the drug’s site of action, e.g. the brain

• Plasma proteins (e.g. albumin, globulin etc.)

- An equilibrium exists between bound (inactive) and unbound (active) drug
fractions. As unbound drug is metabolized and excreted, bound drug is gradually
released, maintaining equilibrium and pharmacologic response.

Free drug that can enter the site of action (tissue)

Plasma protein
Drug (w/ 80% plasma
protein binding)

Blood vessel Dissociation after absorption of the free

drug from blood vessel to the tissue
 PHARMACOKINETICS
Drug Metabolism

Phase I and Phase II Reactions --

Phase I characteristics:
Parent drug is altered by introducing or exposing a functional group (-OH,-
NH2, -SH).
Drugs transformed by phase I reactions usually lose pharmacological activity.
Pro-drugs are converted by phase I reactions to biologically-active metabolites.
Phase I reaction products may be directly excreted in the urine and may react
with endogenous compounds to form water-soluble conjugates.

Phase II characteristics:
Parent drug participates in conjugation reactions that is formation of covalent
linkage between a parent compound functional group and:
Glucuronic acid, Sulfate, Glutathione, Amino acids, or Acetate
 PHARMACOKINETICS
Drug Metabolism

1. Biotransformation (major site is liver)

Functions :

1. Conversion of Active Drug to Inactive Drug (Metabolite).

Metabolite formed is either water soluble or forms
conjugate with water soluble compounds. This facilitates
the excretion of the drug, via Urine.

2. Sometimes conversion of the drug (which is in a pro-drug

form) to an active drug.