Introduction to Pharmacology

Dr.Riaz Hussain Unar

M,B,B,S,DPA,MAS,Mphill(Pharma)

What is Pharmacology?

From the Greek pharmakon (drug),

legein (to speak)

Broadly defined as the study of how

chemical agents affect living processes. Hormones Neurotransmitters

Growth factors Local autocrine

factors Drugs (Pharmaceuticals)

Toxic agents in the environment

The medicinal/ organic chemist may create the

candidate compound (sometimes referred to as

a new chemical entity, NCE), it is the

pharmacologist who is responsible for testing it

for pharmacological activity.

Ultimately will lead to the discovery of novel

drug targets for therapeutic intervention in

diseases where distal steps in signal

transduction have gone awry.

Pharmacology studies the effects of drugs and

how they exert their effects.

Acetylsalicylic acid (ASA) can reduce

inflammation, pain and fever

inhibit the action of a human cell membrane

enzyme known as cyclooxygenase, which is

responsible for the synthesis of a number of

inflammatory mediators.

Penicillin cures certain bacterial infections

disrupt the synthesis of cell walls in susceptible

bacterial strains by inhibiting a key enzyme.

Some Pharmacology Definitions

and Areas of Study

Pharmacotherapeutics-use of drugs to treat disorders; the emphasis is on clinical

management

Pharmacoepidemiology-study of the effect of drugs on populations; questions dealing with

the influence of genetics are particularly

important

Pharmacoeconomics-study of the cost-

effectiveness of drug treatments; the cost of

medications is of worldwide concern, particularly

among certain groups such as the elderly and

AIDS patients

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

Pharmacodynamics Study the mechanisms by which drugs work

Also study endogenous agents

Pharmacokinetics Principles Movement of drugs in the body

Absorption Distribution

Elimination Dosage regimens

PharmacodynamicPrincipl

es Receptor type Drug-receptor interactions Graded

dose-response relationships

Quantal dose-response

relationships Drug-drug

antagonism

Binding Studies Association to receptor

Dissociation from receptor

Forces of binding

Covalent

Electrostatic

Hydrophobic

Clearance

Adsorption

t1/2

Steps in Manufacture of Drugs

Scientific Research to discover/synthesize new

compounds, or improve existing compounds

(R & D) Computer simulation

Combinatorial

chemistry

Develop safe and effective applications of

promising compounds

Screen compounds in bacterial cultures or

animal subjects

Clinical trials on

humans Clinical Trials Kidneys and liver are two most important organs

In Phase I trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its

safety, determine a safe dosage range, and identify side effects.

In Phase II trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to

further evaluate its safety.

In Phase III trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness,

monitor side effects, compare it to commonly used treatments,

and collect information that will allow the drug or treatment to be

used safely.

In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

Purpose of Drug Therapy to prevent, control or cure various

disease states.

To achieve this, the right drug dose must

be delivered to the tissues

Important to know Speed of onset of drug action

Intensity of drug effect

Duration of drug action

A Graphical Example:

Time in Hours

Therapeutic

Range

Sub-

Therapeutic

Lethal

Dose

Peak Onset

Duration

How Do We Study Pharmacology?

General Concepts Drug Dose

Administration

Pharmaceutical

Pharmacokinetics

Pharmacodynamics

Pharmacotherapeutics

Disintegration

of Drug

Absorption/distribution

metabolism/excretion

Drug/Receptor

Interaction

Drug Effect

or Response

Routes of Drug Delivery

Parenteral

(IV)

Inhaled

Oral

Transdermal

Rectal

Parenteral

( SC, IM )

Topical

What Happens After Drug

Administration?

Drug at site

of administration

Drug in plasma

Drug/metabolites

in urine, feces, bile

Drug/metabolites

in tissues

1 . Absorption

2 . Distribution

4 . Elimination

3 . Metabolism

Modified from Myceket al. (1997)

Movement of Drug in the Body

Passive diffusion Occurs across lipid membranes Requires some degree of

lipid solubility

Lipid solubility is determined in part by the

electrical charge on the molecule. Majority of

drugs are weak acid or weak bases.

The charge is determined by the pH of the

medium according to the

HendersonHasselbalch equation: Log (protonated form/unprotonated form) = pKa - pH

Movement of Drug in the Body

Passive diffusion Log (protonated form/unprotonated form) = pKa - pH

Protonated form of a weak acid Uncharged, more lipid soluble form

Unprotonated form of a weak base

Uncharged, more lipid-soluble form

Active transport Requires special carrier molecules Drugs should be

structurally related to

Movement of Drug in the Body

endogenous molecules such as amino acids or

sugars

Some very large or very polar drugs (vitamin

B12, Iron) are complexed with proteins and

actively transported into cells by endocytosis.

Very small molecules (lithium, alcohols,

gases) diffuse rapidly.

Drug Absorption First-pass effect

Bioavailability

First-pass effect Refers to the

elimination that

occurs when a

drug is first absorbed from the intestine and

passes through the liver via the portal

circulation.

Because the liver is the primary drug-

metabolizing organ of the body, drugs are

easily metabolized have a large first-pass effect

and low bioavailability.

Drug Absorption Bioavailability (F ) Describe the fraction of an

administered dose of unchanged drug that reaches

the systemic circulation.

By definition, when a medication is administered

intravenously, its bioavailability is 100%.

However, when a medication is administered via

other routes (such as orally), its bioavailability

decreases (due to incomplete absorption and first-

pass metabolism).

Bioavailability is one of the essential tools in

pharmacokinetics, as bioavailability must be

considered when calculating dosages for non-

intravenous routes of administration.

An Important Concept:

BIOAVAILABIITY Definition: Fraction of a drug that

reaches systemic

circulation after a particular

route of administration

Affected by: 1st pass metabolism

(eg: Lidocaine,

propranolol)

Solubility

Instability

(eg: Penicillin G, insulin) Time

Injected Dose

Oral Dose

An Important Concept:

BIOAVAILABIITY

Factors Affecting Drug

Absorption Transport Active vs. passive

pH

Physical factors Blood flow

Surface area

Contact time

A-

BH

Drug Distribution

Blood flow to the tissue Size of the

organ

Solubility of the drug Binding

Volume of distribution

Blood flow to the tissue Tissues with high blood flow (viscera, brain, muscle) receive

significant amount of drug on a short time.

Organs with low perfusion (fat, bone) receive

Drug Distribution

the drug more slowly.

Size of the organ Very large organs (eg., skeletal muscle) can take up large quantities of

drug if allowed to reach steady state.

Binding Drugs that bind to macromolecules in a tissue

may be restricted in distribution. For example, drugs that bind avidly to plasma

albumin (eg. Warfarin) may be effectively restricted to the

Drug Distribution

vascular compartment. Volume of distribution

(Vd) Vd of a drug is a proportionality constant

defined as: Vd = amount of drug in the body/plasma concentration

Volume of Drug Distribution

Drugs may distribute Plasma

into any or all of the (4 litres)

following compartments: Plasma Interstitial Fluid

(10

litres)

Interstitial Fluid

Intracellular Fluid Intracellular

Fluid

(28

litres)

What Factors Affect Distribution?

Blood flow Brain vs. fat

Capillary

permeability Differences in

capillary

structure

Binding to proteins Role of albumin

More So What? It takes time for a drug to distribute in the

body

Drug distribution is affected by elimination

Time 0

0.5

1.0

1.5

0

Elimination Phase

Distribution Phase Drug is eliminated

Drug is not eliminated

Albumin Affects Distribution Drugs bind

differentially to

albumin

2 drug

classifications: Class I: dose less Drug X than available binding

sites (eg: most drugs)

Class II: dose greater

than binding sites

(eg: sulfonamide) The

problem:

One drug may out-

compete the other Sulfonamide

Albumin

Drug Metabolism

First pass Metabolism of drugs may occur as they cross

the intestine or transit the liver eg: Nitroglycerin

Other drugs may be destroyed before

absorption eg: Penicillin

Such reactions decrease delivery to the

target tissues

Drug Metabolism (contd)

Two Phases: I and II Drug

Phase I: conversion to Phase I lipophilic compoundsOxidation

Phase II: conjugationReduction

Phase I involves the Hydrolysis cytochrome

P-450 Activation/Inactivation system

Phase II

Ultimate effect is to

Glucuronidation facilitate elimination

Conjugation Products

Example of First Pass Effect

Drug Elimination

Most important route is the kidney

May also involve bile, intestine, lung, breast

milk

What clinical scenarios may affect drug

elimination?

Drug Elimination Metabolites of drugs must eventually be

excreted, but termination of action is of

greater importance.

The vast majority drugs follow first-order

elimination kinetics The rate of elimination is proportionate to plasma concentration.

Drug Elimination Only three clinically important drugs follow zero-

order elimination kinetics Ethanol

Phenytoin (high

dose) Aspirin (high

dose)

The rate of elimination is

fixed and independent of

plasma concentration.

Drug

Elimination The elimination of drugs that follow

firstorder kinetics can be characterized by

a proportionality constant, clearance, Cl. Clearance is defined as:

Cl = rate of elimination/plasma concentration

Drug Elimination For elimination half-life (t1/2) of drugs that follow

first-order kinetics is defined as the time required

(after distribution is complete) for the amount of

drug in any compartment to fall by 50%.

Half-life can be derived from graphs of plasma

concentration versus tine, ot it can also be obtained

by calculation:

T1/2 = 0.693 x Vd/Cl

After 4 half lives, elimination is 94% complete.

Concept of Half-Life

Time required to metobolize 1/2 of

the original dose of the drug

Use of this terms helps in determining

how long a drug will remain in the

body

Elimination of a drug is usually

linked to renal filtration,

secretion and reabsorption.

Example: Intravenous Infusions

Plasma concentration rises until elimination =

input

Faster infusions get

more drugs on

board, but does not

change the time to

achieve a steady

state

Time Time at which steady

state is achieved

Slow Infusion

Fast Infusion

Example: Intravenous Injection

Peak plasma

concentration of

the drug is

achieved at time =

0

There is no steady

state

concentration.

Why?

100 mg injected

50 mg injected

Time

Example: Oral Dose A single oral dose will give you a single peak

plasma concentration

The drug

concentration then

continuously

declines

Repeated doses

result in oscillations

in plasma Time

concentration

Aerosolized Agents: 7 Categories

Adrenergic Agents

Anticholinergic

Agents Mucoactive

agents

Corticosteroids

Antiasthmatics

Antiinfectives

Exogenous

Surfactants

Adrenergic Agents

Action - stimulation of sympathetically

mediated bronchorelaxation of smooth

muscle Examples: Epinephrine; Isoetharine;

Isoproterenol; Metaproterenol; Albuterol;

Pibuterol; Bitolterol; Salmeterol

Anti-cholinergic Agents

Blockage of vagally-induced

bronchospasm

This results in bronchorelaxation

Example: Iptratroprium bromide

Mucoactive Agents

Improve viscosity of mucus and enhance

clearance of secretions Examples: Acetylcysteine, Dornase

alpha

Corticosteroids

Reduce and control inflammatory

response associated with asthma and

other lung diseases Examples: Dexamethasone;

Beclamethasone; Triamcinolone;

Flunisolide

Anti-asthmatic Agents

Prevention of the inflammatory

response seen in asthma by inhibition

of chemical mediators necessary for

inflammation to occur Corticosteroids Prednisolone, Betamethasone, etc. Beta-2

agonists (bronchodilators) Samleterol, Bambuterol, etc.

Anti-asthmatic Agents

Prevention of the inflammatory

response seen in asthma by inhibition

of chemical mediators necessary for

inflammation to occur Anti-leukotrienes Montelukast, Zafirleukast

Xanthines

Theophylline

Anti-infective Agents

To inhibit or kill selected bacterial,

protozoal, fungal or viral organisms Examples: Pentamidine, Ribavirin

Exogenous Surfactants

Used by instillation in the tracheas of

premature newborns suffering from

respiratory distress syndrome Examples: Beractant, Colfosceril

palmitate

Drug dosage forms

Oral

Injectable

(parenteral)

Subcutaneous

Intramuscula

r Intravenous

Spinal

Topical

Inhalation

al

Concept of Critical Threshold

Defined as the minimum level of

drug concentration needed for the desired therapeutic effect to be present.

Other Dose-related Terms

Maximal Effect: greatest response that can

be produced by a drug, above which no

further response can be created

(sometimes called peak effect Onset: how long before a drug is able

to

exert a therapeutic effect

Duration: how long a drug effect

lasts

Agonists and Antagonists An agonistcauses a particular effect by

binding to the correct receptor

What is an antagonist?

An agent that blocks are reverses the

actions of another medication.

Concept of Potency Comparison of different drugs at the same

dose to determine which is stronger.