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Introduction to Pharmacology

Prof. Nassiri Director, Institute of International Health Michigan State University

Medical Mission Trip May 9-16, Dominican Republic

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


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 costeffectiveness of drug treatments; the cost of medications is of worldwide concern, particularly among certain groups such as the elderly and AIDS patients

Pharmacotherapeutics - use of drugs to treat

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
Movement Absorption Distribution Elimination Dosage

Principles

of drugs in the body

regimens

Pharmacodynamic
Receptor

Principles

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:
Drug Concentration
Lethal Dose
Peak Onset

Duration

Therapeutic Range
SubTherapeutic

Time in Hours

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) Oral Transdermal Parenteral (SC, IM) Rectal Inhaled

Topical

What Happens After Drug Administration?


Drug at site of administration

1. Absorption
Drug in plasma

2. Distribution
Drug/metabolites

3. Metabolism
in tissues Drug/metabolites in urine, feces, bile

4. Elimination
Modified from Mycek et al. (1997)

Movement of Drug in the Body


Passive

diffusion

Occurs
Lipid

across lipid membranes Requires some degree of lipid solubility


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
form of a weak acid
more lipid soluble form

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

Protonated

Uncharged, Uncharged,

Unprotonated

form of a weak base

more lipid-soluble form

Movement of Drug in the Body


Active

transport

Requires

special carrier molecules Drugs should be structurally related to 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
Refers

effect

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 drugmetabolizing 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.

Definition:

An Important Concept: BIOAVAILABIITY


Serum Concentration

Fraction of a drug that reaches systemic circulation after a particular route of administration 1st pass metabolism (eg: Lidocaine, propranolol) Solubility Instability (eg: Penicillin G, insulin)

Injected Dose

Affected by:

Oral Dose

Time

An Important Concept: BIOAVAILABIITY

Factors Affecting Drug Absorption


Transport

ATP

Active vs. passive ADP + Pi

pH Physical factors

Blood flow Surface area Contact time

ABH+

Drug Distribution
Blood

flow to the tissue Size of the organ Solubility of the drug Binding Volume of distribution

Drug 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 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.

Drug Distribution
Binding
Drugs
For

that bind to macromolecules in a tissue may be restricted in distribution.


example, drugs that bind avidly to plasma albumin (eg. Warfarin) may be effectively restricted to the vascular compartment.

Volume
Vd

of distribution (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 into any or all of the following compartments:


Plasma (4 litres) Interstitial Fluid (10 litres) Intracellular Fluid (28 litres)

Plasma Interstitial Fluid Intracellular Fluid

What Factors Affect Distribution?


Blood flow

Brain vs. fat

Endothelial cells in liver capillary

Capillary permeability

Differences in capillary structure Role of albumin

Binding to proteins

Endothelial cells in brain capillary

Glial cell

More So What?

Serum Concentration

It takes time for a drug to distribute in the body Drug distribution is affected by elimination
1.5 Drug is not eliminated 1.0 0.5 Distribution Phase 0 0 Drug is eliminated Elimination Phase

Time

Albumin Affects Distribution


Drugs bind Albumin differentially to albumin 2 drug classifications:


Class I: dose less than available binding sites (eg: most drugs) Class II: dose greater than binding sites (eg: sulfonamide) One drug may outcompete the other

Drug X

The problem:

Sulfonamide

Drug Metabolism
First

pass
Nitroglycerin

Metabolism
eg:

of drugs may occur as they cross the intestine or transit the liver

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
Oxidation Reduction Hydrolysis

Phase I: conversion to lipophilic compounds Phase II: conjugation

Phase I involves the cytochrome P-450 system Ultimate effect is to facilitate elimination

Activation/Inactivation
Glucuronidation

Phase II

Conjugation Products

Example of First Pass Effect

Drug Elimination
Most May

important route is the kidney

milk

also involve bile, intestine, lung, breast

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 zeroorder 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

Plasma Concentration

Fast Infusion

Slow Infusion

Time
Time at which steady state is achieved

Example: Intravenous Injection


Plasma Concentration

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 concentration

Plasma Concentration

Time

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
This

of vagally-induced bronchospasm
results in bronchorelaxation Example: Iptratroprium bromide

Mucoactive Agents
Improve

viscosity of mucus and enhance clearance of secretions


Examples:

alpha

Acetylcysteine, Dornase

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)
Bambuterol, etc.

Samleterol,

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:

palmitate

Beractant, Colfosceril

Drug dosage forms


Oral Injectable (parenteral)


Subcutaneous Intramuscular Intravenous Spinal

Topical Inhalational

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

binding to the correct receptor

agonist causes a particular effect by

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.

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