Basic Principles of General

Pharmacology

Shashi Bhushan
Scientist C
1
Division of Cancer Pharmacology
The term pharmacology comes from the Greek words:
•Pharmakon - drug or medicine
•Logos - the truth about or a rational discussion
…………Truth about medicine

• Pharmacology is the study of how

drugs exert their effects on living
systems.
• More specifically it is the study of
the interactions between a living
organism and drugs that alter normal
biochemical function. 2
 History of Pharmacology

Early pharmacology
focused on natural
substances, mainly plant
extracts.

3
 Modern approach
• Pharmacology is a discipline as a bridge, not only to
connect pharmacy with medicine, but also to link
foundational medicine to clinical medicine

Foundational
FoundationalMedicine
Medicine Clinical
ClinicalMedicine
Medicine

Pharmacy
Pharmacy Pharmacology Medicine
Medicine

Research
Researchof
ofDrugs
Drugs Manufacture
Manufactureof
ofDrugs
Drugs

4
 Subdivisions of Pharmacology

Neuropharmacology: study of the effect of
drugs oncomponents of the nervous
system (brain, spinal cord, nerves)
Example: treatment of Alzheimer's

Cardiovascular Pharmacology: study of the effects of

drugs on heart, vasculature and kidney that participate in
cardiovascular function.
Example: treatment of high blood pressure
(hypertension) e.g. atenolol

Molecular Pharmacology: study of the

biochemical and biophysical characteristics
of drug molecules
Example: Drug-Receptor Interaction
……..Subdivisions of Pharmacology

Clinical Pharmacology:
application of pharmacodynamics
and pharmacokinetics to human.

•Toxicology -Study of
harmful effects of drug

•Posology- How medicines are

dosed or calculation of dose

•Pharmacognosy-
Development of medicinal
substances obtained from
plants
 Division of Pharmacology:
Two important and interrelated areas:

Pharmacokinetics: Study of the absorption,
distribution, metabolism and excretion of drugs
(ADME).
……………..what the body does to the drug

Pharmacodynamics: Study of the molecular,
biochemical and physiology effects of drugs on
cellular systems and their mechanisms of action.
……………..what the drug does to the body

Plasma Site of
Dosage Effects
Concen. Action

Pharmacokinetics Pharmacodynamics
 (I) Pharmacokinetics
……………..what the body does to the drug

• Absorption (A)

• Distribution or Disposition (D)

• Metabolism (M)

• Elimination or Excretion (E)

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 Drug Absorption
• Absorption is the process by which
a drug enters the bloodstream
without being chemically altered

• The movement of a drug from

its site of application into
the blood or lymphatic system

• Mathematically it is define in
terms of Bioavailability (Rate
and extent of absorption).
 Bioavailability
Definition: Rate and extent of absorption
i.e. Ka (Absorption constant)………. Rate of absorptio
Area under curve (AUC)………. extent of absorp
• for i.v.: 100%
• for non i.v.: ranges from 0-100%
e.g. lidocaine bioavailability is 35% due to
destruction in gastric acid and liver metabolism
 Process of Absorption
• In order for a drug to be absorbed, it must be able to pass
through cell membranes (which is a lipid barrier)

• Lipid soluble drugs would be ideal to pass through the

membrane easily.

• There are 4 main ways drugs can be absorbed:

1. Lipid diffusion

2. Aqueous diffusion

3. Coabsorption with lipids

4. Facilitated diffusion/active transport

 ………………….Process of Absorption

1. Lipid diffusion
Highly lipid soluble drugs are able to pass across cell membranes
quite easily driven by passive diffusion.

2. Aqueous diffusion
Drugs which are small and easily dissolved in solution will be
able to pass through the cell membrane via aquaporins – special
protein channels designed for the movement of water into cells.

3. Coabsorption with lipids

Some drugs can be absorbed in conjunction with lipids via
micelles formation . e.g. Vitamin A, digitoxin.

4. Facilitated diffusion/active transport

Transport systems which allow the active (require energy) uptake
of materials which are structurally similar to the transporter
compound. e.g. Levadopa
Factors which influence the rate of
absorption

– Routes of drug administration

– The physicochemical properties of the drug
– Dosage forms
– Circulation at the site of absorption
– Concentration of the drug
 Routes of Drug Administration
• The route of administration (ROA) have a profound effect upon
the speed and efficiency of drug’s action.

• Parentral: Drug delivered in the systematic circulation

without crossing intestinal mucosa
– Intravascular
– Intramuscular
– Subcutaneous
– Inhalation
– Local/ Topical
 Enteral Routes
(1) Sublingual - Some drugs are taken as smaller tablets which
are held in the mouth or under the tongue. e.g. sorbitrate
Advantages
• Rapid absorption
• Drug stability

• Avoid first-pass effect :

- Drugs which absorbed orally

are initially transported to the
liver via portal vein. The
greater the first-pass effect, the
less the agent will reach the
systemic circulation and less
drug action
 (2) Oral Route (swallowing)
• The most common route of drug administration.
Drug is given through oral cavity.

• Advantages
– Convenient - self- administered, pain free
and easy to take
– Absorption - takes place along the whole
length of the GI tract
– Economical - compared to other parentral
routes
• Disadvantages
– Sometimes inefficient - only part of the drug may be
absorbed
– First-pass effect – Due to Biotransformation
– Irritation to gastric mucosa - nausea and vomiting
 (3) Rectal Route
• Drugs that are administered rectally as a suppository.
• In this form, a drug is mixed with a waxy substance that
dissolves or liquefies after it is inserted into the rectum.

Advatages:
1. Unconscious patients and children
2. If patient is nauseous or vomiting
3. Easy to terminate exposure
4. Good for drugs affecting the bowel like laxatives, pile etc.
 Parenteral Routes
 Direct delivery of drug in to systemic circulation
without intestinal mucosa

– Intravascular (IV)-
placing a drug directly
into the blood stream
– Intramuscular (IM) -
drug injected into
skeletal muscle
– Subcutaneous -
Absorption of drugs
from the subcutaneous
tissues
 Local/ Topical Route
Use of drug for external part of the body like skin, eye , nose etc.

 Mucosal membranes
• Eye drops
• Antiseptic cream and lotion
• Sunscreen lotion
• Nasal drops etc.

 Skin
a. Dermal - Oil or ointment for
local action
b. Transdermal Patches:
Nicotine, Hyoscine etc
Factor affecting absorption……
Physico-chemical properties of
Molecular weight
drug
· Drugs with a small M.W. are absorbed well
· Drugs which are large (often proteins) are absorbed poorly.

Chemical and enzymatic stability

· The drug should be stable in gastric acid and in gut enzymes.
e.g. Penicillin G is highly acid labile, or unstable in acid.

Aqueous and lipid solubility

· For better absorption a drug must have optimum water and
lipid solubility or a optimum partition coefficient. If it is highly
lipid soluble it would not dissociate in the circulation i.e. Ion
trapping. On the other hand, if it is highly water soluble then it
will not cross the biological membrane.
Factor affecting absorption……
pH and lipid solubility:

Most drugs are either weak acids or weak bases and can
exist in either the ionised (less lipid soluble) or unionised
(more lipid soluble) form depending on the pH of the
surrounding environment.

REMEMBER THAT A DRUG IS

ABSORBED BETTER IN THE
UNIONISED FORM (Lipophillic drug
can cross cell membrane)
Factor affecting absorption……
Ion Trapping
Body fluids where a pH difference will favor trapping of highly
lipophillic drugs: e.g. Breast milk , Aqueous humor (eye) ,
Vaginal secretions , Prostatic secretions
 Aspirin is an acidic drug
(pKa=5) and exist in the un-
ionised form in stomach (pH 2.0)

 In this form, it can enter the

cells of the stomach lining
(pH=7.4) where it is ionized
and, in this form, it cannot leave
the cell.

 The concentration of ionized

aspirin inside the cell continues to
rise until it saturates and
precipitates as crystals, which lead
to gastric bleeding. 22
Factor affecting absorption……

Drug dosage forms

 Different dosage forms have different rate and extent of
absorption.

 A syrup have fast rate of absorption as compare to tablet

 A capsule have fast rate of absorption than tablet

 Controlled-release, timed-release, sustained-release dosage

form have a uniform absorption and less side effects
Drug distribution
or
Disposition
Drug distribution
• After absorption drug will distributed throughout the body and it
depends on the blood circulation.
• Distribution controls drug actions, efficacy and side effect.
• Distribution of drugs is rarely uniform.
• Drugs are simultaneously being eliminated and distributed, but
distribution is usually faster.

Steps of drug distribution

1.Dilution in blood- The drug has to reach equilibrium with itself in

the blood.
2. Movement into extracellular fluid - Drugs need to be able to get out
from vascular system.
3. Uptake into cells- The drug must be able to cross the cell
membrane.
Factors affecting drug distribution

• Protein binding- More protein binding less distribution

• Ability of the drug to cross cell membranes -depend on drug lipid

solubility

• Extent of blood perfusion - If a tissue is well perfused, the drug is

able to get there faster. e.g. Adipose tissue has a low blood
perfusion so drugs will not be able to reach these places very
quickly.

• pH differences across membrane barriers- A drug will pass

through the membrane better if it is unionised (lipophilic). An
acid drug will be unionised in an acid environment, a basic drug
will be unionised in a basic environment.
 Metabolism
or
Bio-transformation
of drug

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 Drug metabolism

• Metabolism or Biotransformation involves the modification of a

drug by endogenous metabolic enzymes like CYP-450.

• Reduces the drugs effect

• Often inactivates the drug
• Makes the drug more polar so that it can be excreted

Site of metabolism:
• Occurs mainly in the liver but also occur in other sites
like Kidney, Lungs, GIT and Skin.

Occurs in 2 phases:
· Phase I reaction
· Phase II reaction
…………..Phase-I reactions

• The most important phase I reaction is oxidation involving

·A reducing agent (NADPH)
· Molecular oxygen
· NADPH cytochrome p450 oxidase
· Cytochrome p450

• Drugs which inhibit cytochrome p450 will prevent the metabolism

of other drugs, which rely on this enzyme e.g. Cimetidine

• Alcohol and smoking induce metabolic enzymes in the liver thus

increase the metabolism or reduce the efficacy of some drugs.

• Hence, it is important to know whether a person is a smoker or not

when prescribing drugs.
 Phase II reactions
• Phase II reactions are usually the detoxification step.

• It combines some reactive group which is added to the phase-I

reaction e.g. conjugation.

• The enzymes involved in phase II reactions are tranferases. e.g.

UDP glucoronide transferase, catalyses the conjugation of a
drug with glucoronide.

• Conjugation usually allows for easier excretion since the drug

is converted into a more hydrophilic form.
Factors affecting drug metabolism
(A) Internal factors:
1· Species : Differences in drug metabolic enzymes level in
inter species.
2· Genetic polymorphism : Differences in the enzymes of
metabolism within intra species (between individuals).
e.g. Alcohol metabolism is vary from person to person due to
difference in alcohol dehydrogenase level.
3. Age: Metabolism of drugs is different in very young and old
age. Phase I reactions develop very early in the foetus,
while phase II conjugation reactions develop perinatally.
4. Gender differences: There are some differences in alcohol
and estrogen metabolism in males and females.
5. Hormonal effects: A hypothyroid person has a reduced
metabolic activity.
6· Co-existing disease: Diseases of liver will generally reduce
its metabolic capabilities e.g. cirrhosis, hepatitis
Factors affecting drug metabolism....................

External factors

1.Drug – Drug interactions:

It cause:
• Competition for the same enzyme involved in metabolism
• Induction of an enzyme involved in metabolism
• Inhibition of an enzyme involved in metabolism
e.g. Ethanol may affect the metabolism of diazepam

2. Dietary factors: A protein deficiency may affect enzyme production.

Also may affect the plasma proteins binding.

3. Lifestyle: Smokers can induce the enzymes required in the breakdown

of theophyline.
 Elimination
or
Excretion of drug
 Elimination
of drugs from the body

M KIDNEY LIVER
A
J
filtration metabolism
O secretion secretion
R (reabsorption)

M LUNGS OTHERS
I
N
exhalation mother's milk
O sweat, saliva etc.
R

Most important route of drug elimination is via the kidney

 Elimination by the kidney

• Drugs which are not metabolised by the liver rely on the kidney as
the major way of removal of the drug from the blood.
• The drugs metabolised by liver are more water soluble, less toxic
and able to be filtered through glomerulus.
 Biliary excretion
How does a drug enter the bile?

· Transport systems transport the drug from the plasma into the
bile against a concentration gradient
· Large molecular weight drugs may be subject to this type of
transport.
Drug elimination…………

Liver - After Phase I and II reactions drug will convert in to

more water soluble form and excreted in kidney

Lungs
· Can be used to eliminate gases and volatile anaesthetics

Sweat
· Drugs which are present in sweat may cause skin sensitivity

Milk
· Lactating mothers need to be aware that breast milk may
contain drugs which are being taken by the mother.
Pharmacodynamics
……………..what the drug does to the body
 How Drugs Work—An Conceptual Overview

• Most drugs (free drug) act by forming chemical bonds with specific
receptor sites within the body to stimulate and/or inhibit a
response.

• The interaction of a drug with a receptor is reversible due to

interactions via weak bonds (not covalent).

• The success of a drug’s response depends on two factors:

• Molecular fit
• Number of receptor sites it bonds to

• The better the fit and the greater number of receptor sites occupied,
the stronger the response.

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 DOSE-RESPONSE CURVE
Maximal Effect
EFFECT

EFFICACY
POTENCY

ED50

Log [Dose]

Therapeutic Index (TI) =

TxD50
Safety of drug ∝
TI 41
 Agonists and Antagonists

AGONIST
• A drug is said to be an agonist when it binds to a
receptor and causes a response or effect.
It has intrinsic activity = 1

+++ ++- ---

--- +-- +++

Depolarization 42
PARTIAL AGONIST

• A drug is said to be a partial agonist when it

binds to a receptor and causes a partial
response.
• It has intrinsic activity < 1.

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ANTAGONIST

• A drug is said to be an antagonist when it binds to a

receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the receptor.

• An antagonist itself has NO activity.

Its intrinsic activity is = 0

• They can bind both reversibly and irreversibly

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PHARMACOLOGICAL ANTAGONISTS
1. Competitive Antagonist

Similar structure with agonist and compete for the

same binding site through two ways
• Reversible
• Irreversible
A) Reversible
The effect of reversible antagonists can be
overcome by agonist.

B) Irreversible
The effect of irreversible antagonists cannot be
overcome by more drug (agonist). The antagonist
inactivates the receptors.
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Non-Competitive Antagonist

They don’t have similarity with the agonist and

can be bind elsewhere on the receptor site.
e.g. channel blockers.