PHARMACOKINETICS AND

PHARMACODYNAMICS
CONTENTS
1) INTRODUCTION

2) PHARMACOKINETICS
(i) Absorption
(Ii) Drug Distribution
(Iii) Metabolism
(Iv) Drug Elimination

3) PHARMACODYNAMICS
(i) Mechanism of Drug action
(ii) Receptor
(iii) Dose Response Relationship
(iv) Drug Synergism and Antagonism
(v) Factors that modify the effects of drugs
 INTRODUCTION

Purpose of studying:-

Pharmacokinetics and pharmacodynamics is to understand

the drug action, therapy, design, development and evaluation
 Pharmacokinetics v Pharmacodynamics

If Pharmacokinetics is what the body does to the

drug then Pharmacodynamics is what the drug
does to the body
PHARMACOKINETICS
 PHARMACOKINETICS

• Pharmacokinetics is currently defined as the study of the

time course of drug absorption, distribution, metabolism,
and excretion.

• The movement of the drugs into, within and out of the body.
It involves Four Processes

ABSORPTION

DRUG DISTRIBUTION

METABOLISM

DRUG ELIMINATION
Once drug is administered, it is absorbed, i.e enters the
blood, it is distributed to different parts of the body, reaches
the site of action, is metabolized and excreted.
• All these processes involve passage of the drug
molecules across various barriers - like the intestinal
epithelium, cell membrane, renal filtering membrane,
capillary barrier.
• Drugs may be transported across the membrane by
passive or active transport.
Passive transport ; the drug moves across a membrane
without any need for energy.
 ACTIVE TRANSPORT

• Transfer of drugs against a concentration of drugs against a

concentration gradient and needs energy.

• Only drugs related to natural metabolites are transported by

this process.

e.g Levodopa, iron, amino acids, penicillin and probenecid

are given together, the excretion of penicillin is delayed by
probenecid.
 ABSORPTION

Defined as the passage of the drug from the site of

administration into the circulation.

In order for a drug to reach its site of action, it must pass

through various membranes depending on the route of
administration.
 ABSORPTION

Absorption occurs by one of the processes i.e .passive

diffusion or active transport.

Thus except for IV route, absorption is important for all

other route of administration
 ABSORPTION

• Factors influence the rate and extent of absorption of a

drug are:-

Disintegration and dissolution time :

The drug taken orally should break-up into individual particles

to be absorbed ,then it has to dissolve in the GI fluids.

In case of drugs given SC or IM ,the drug molecules have to

dissolve in the tissue fluids, liquids are absorbed faster than
solids.
 ABSORPTION

• Delay in disintegration and dissolution result in delayed

absorption.

• Formulation : Inert substance used with drugs as

diluents like starch and lactose may sometimes interfere
with absorption.
 ABSORPTION

• Particle size: small particle size is important for better

absorption of drugs.

• Drugs like corticosteroids digoxin ,asprin and

tolbutamide are well absorbed when given as small
particles.

• Lipid solubility: lipid soluble drugs are absorbed faster

and better by dissolving in the phospholipids of the cell
membrane.
 ABSORPTION

• pH and ionization : Ionized drugs are poorly absorbed

while unionized drugs are lipid soluble and are well
absorbed.

• Acidic drugs remain unionized in acidic medium of the

stomach and are rapidly absorbed, e.g aspirin,
barbiturates.

• Basic drugs are unionized when they are reach the

alkaline medium of intestine from where they are rapidly
absorbed, e.g pethidine, ephedrine.
 ABSORPTION

• Strong acid and bases are highly ionized and therefore

poorly absorbed ,e.g heparin, streptomycin.

Area and vascularity of the absorbing surface :

Larger area of the absorbing surface and more the

vascularity – better is the absorption.

Thus most of the drug absorbed from the small intestine.

 ABSORPTION

• Gastrointestinal motility: Gastric emptying time-if

gastric emptying is faster ,the passage of the drug to the
intestines is quicker and hence absorption is faster.

• Intestinal motility – when motility is highly increased as in

diarrhea, drug absorption is reduced.
 ABSORPTION

• Presence of food: Drugs may form complexes with

food, Such complexes are poorly absorbed .e.g.
Tetracycline chelate Ca2+ present food ,so absorption
reduced.

• Metabolism: Some drugs may be degraded in stomach,

e.g. nitroglycerin, insulin.

• Diseases: The disease of the stomach like

malabsorption and achlorhydria result in reduced
absorption of drugs.
 First Pass Metabolism

• First pass metabolism is the metabolism of the drug

during its passage from the site of absorption to the
systemic circulation. It is also called presystemic
metabolism or first pass effect

• Drugs given orally maybe metabolized in the gaster wall

and in the liver before reaching the systemic circulation.
The extent of FPM differs from drug to drug and person
to person.
 First Pass Metabolism

• FPM may result in partial to total inactivation of the drug.

When it is partial , it can be compensated by giving
higher dose of particular drug, e.g nitroglycerin,
salbutamol.
 First Pass Metabolism

• After a drug reaches the systemic circulation ,it gets

distributed to various tissues . It should be cross several
barriers before reaching the site of action.

• Like absorption, distribution also involves the same

process, i.e filtration, diffusion and specialized transport.
 First Pass Metabolism

• Various factors determine the rate and extent of

distribution, they are lipid solubility, ionization, blood flow
and binding to plasma proteins and cellular protein.

• Unionized and lipid soluble drugs are widely distributed

through out the body.
 Plasma Protein Binding

• Upon reaching the circulation, most of the drug bind to

plasma protein; acidic drug mainly bind with albumin and
basic drugs to α-acid glycoprotein.

• The free or unbound fraction of the drug is the only form

available for action, metabolism and excretion.
 Plasma Protein Binding

• The protein bound form serves as a reservoir . PB

prolongs the duration and action of drug. e.g warfarin
99%,morphine 35%,ethosuximide and lithium 0%.

• One drug may displaces another binding site and result

in displacement interaction, warfarin 99% PB
indomethacin reduces its binding to 95%

• Free warfarin level increased it produce toxicity.

 Tissue Binding

Tissue binding : some drugs get bound to certain tissue

constituent because of special affinity for them. TB delays
excretion and thus prolongs the duration of drug.

Lipid soluble drug like thiopentone sodium are bound to

adipose-tissue,bone-tetracycline,retina-chloroquine,
thyroid-iodine.
 Blood brain barrier (BBB)

• The endothelial cells of the brain capillaries have tight

junctions. Moreover glial cells envelope the capillaries
and together these form the BBB.

• Only lipid soluble and unionized drugs can cross BBB.

E.g. Penicillin readily penetrates BBB.

 Placental barrier

• Lipid soluble, unionized drugs readily cross the placenta

 Metabolism

• Metabolism or biotransformation is the process of

biochemical alteration of the drug in the body.

• Body treats most of the drugs as foreign substance and

tries to inactivate and eliminate them by various
biochemical reactions.

• These processes convert the drugs into more polar ,water

soluble compounds so that they are easily excreted
through the kidneys.
 Metabolism

• Some of the drugs are largely unchanged in urine, e.g

frusemide, and atenolol.

• Mainly drugs are metabolized in liver some are

metabolized in kidneys, lungs, blood and skin.
 Metabolism

• The chemical reactions of biotrasformation can take

place in two phases:

• Phase I (Non-synthetic reactions) : convert the drug to

more polar metabolite by oxidation, reduction, or
hydrolysis.

• If the metabolites are not water soluble it undergoes

phase II reactions.
 Metabolism

• Phase II (Synthetic reaction) : in this reactions water

soluble substance present in the body like glucuronic
acid, sulfuric acid or an amino-acid combine with the
drug to form a highly polar compounds it excreted by the
kidneys

• Large molecules are excreted through the bile

 Excretion

The major organs of excretion are the kidneys, intestine,

biliary system and the lungs.

Drugs of small amounts are excreted in saliva, sweat and

milk.
 Renal Excretion

• Kidney is the most important organ of drug excretion.

• Highly lipid soluble drugs are reabsorbed in the renal

tubules ,so their excretion is slow.

• Unabsorbed portion of the orally administered drugs are

eliminated through the feces.

• Large water soluble conjugates are excreted in the bile.

• The lungs are the main route of elimination for gases
and liquids, e.g. GA , Alcohol.
• Plasma half-life is the time taken for the plasma
concentration of a drug to be reduced to half its value.

• Minimum dose is the smallest dose required to produce

a desired therapeutic effect of the drug.

• Maximum dose is the largest dose of the drug that can

be safely given to a patient without producing harmful
effect.
• Toxic dose is the dose of the drug which produce
undesirable effects in majority of the patients

• Lethal dose is the dose of the drug which can cause

death. E.g lethal dose of phenobarbitone is 6-10gm.
PHARMACODYNAMICS
 Pharmacodynamics

Pharmacodynamics is the study of actions of the

drugs on the body and their mechanism of action,
i.e to know what drugs do and how they do it.
 Pharmacodynamics

• Drugs produce their effects by interacting with the

physiological system of the organisms. By such
interaction drugs can only modify the rate of function of
various systems.

• e.g Drugs may increases or decreases the secretions.

But they cannot change the basic function of any
physiological system.
Thus drugs act by:

• 1.Stimulation
• 2.Depression
• 3.Irritation
• 4.Replacement
• 5.Anti-infective or cytotoxicaction
• 6.Modification of the immune status
Stimulation is the increase in activity of the specialized
cells, e.g adrenaline stimulates the heart.

Depression is the decrease in activity of the specialized

cells, e.g quinidine depresses the heart.

Irritation : This can occur on all types of tissues in the body

and may result in inflammation, corrosion and necrosis of
cells.
Replacement : drugs may be used for replacement when
there is deficiency of natural substances like hormones
,metabolites or nutrients ,e.g insulin in diabetes, iron in
anemia ,vit C in scurvy.

Anti-infective and cytotoxic action: drugs may act by

specifically destroying infective organism, e.g penicillin
,cytotoxic effect on cancer cell
 Sites and Mechanism of drug action

Sites : drugs may produce their effects by locally or

systematically

Local : drugs may act at the site of application

e.g. antibiotics, anti-fungal agent
• Drugs may act by one or more complex mechanism of
action.

• Fundamental mechanism of drug may be:

Through receptor
• Through enzymes and pumps
• Through ion channel
• By physical action
• By chemical interaction
• By altering metabolic processes
• Through receptor
Drugs may interact specific receptor in the body.

• Through enzymes and pumps

Drugs may act by inhibition of various enzymes, thus altering the
enzyme – mediated reaction ,e.g . Allopurinal inhibits the enzyme
xanthine oxidase ; acetazolamide inhibit carbonic anhydrase.

• Through ion channel

Drugs may interfere with the movement of ions across specific
channels, e.g . Ca channel blocker , K channel blocker.
• Physical action
The action of drug could result from its physical properties.
E.g .absorption –activated charcoal in poisoning.

• Chemical interaction
Drugs may act by chemical reaction. – Antacids -
Neutralize gastric acids– Oxidising agents - KMno4
(germicidal)
• Altering metabolic processes
Drugs like antimicrobial alter the metabolic pathway in the
micro organism resulting destruction of microbe. e.g
sulfonamides interfere with bacterial folic acid synthesis.
 RECEPTORS

• A receptor is a site on the cell with which an agonist

binds to bring about a change.

• Receptor are proteins.

• Present in the cytoplasm or on the nucleus.

 FUNCTIONS OF RECEPTORS

• The receptor has to identify the compound, and when the

compound binds to the receptor ,it has convey the message
to bring about a response.

•Agonist: Substance that binds to the receptor and produce a

response.

•Antagonist: Substance that binds to the receptor and prevents

the action of agonist on the receptor.

•Partialagonist: It binds to the receptor but has low intrinsic

activity that is , produce partial response.
 DRUG SYNERGISM AND ANTAGONISM

• When two or more drugs are given concurrently ,the

effect may be additive, synergistic or antagonistic.

• Additive effect :
The effect of two or more drugs get added up and the total
effect is equal to the sum of their individual actions. e.g .
Ephedrine with theophylline in bronchial asthma.
 SYNERGISM

• Synergism : When action of one drug is enhanced or

facilitated by another drug the combination is synergistic.

• Here the total effect of the combination is greater than

the sum of their independent effect.

• It is often called ‘potentiation’ or supra-additive effect.

e.g acetylcholine + physostigmine.
 ANTAGONISM

• One drug opposing or inhibiting the action of another

drug is antagonism.

Based on the mechanism, antagonism may be :-

• Chemical antagonism,
• Physiological antagonism,
• Antagonism at the receptor level
• Reversible(competitive)
• Irreversible
• Non-competitive antagonism
 ANTAGONISM

• Chemical antagonism: Two substances chemically

interact to result in inactivation of the effect, e.g . Antacid
like aluminium hydroxide neutralize gastric acids.

•Physiological antagonism: Two drugs act at different

sites to produce opposing effect. E.g. Insulin and glucagon
have opposite effects on the blood sugar level.
 ANTAGONISM

• Antagonism at the receptor level

• The antagonist inhibits the binding of the agonist to the

receptor .

• Such antagonism may be reversible or irreversible.

 ANTAGONISM
• Reversible competitive antagonism :

The agonist and antagonist compete for the same receptor .

By increasing the concentration of the agonist, the antagonism
can be overcome, it is thus reversible antagonism.

Acetylcholine and atropine compete at muscarinic receptor .

The antagonism can be overcome by increasing the

concentration of Acetylcholine at the receptor
 ANTAGONISM

• Irreversible antagonism : The antagonist binds so

firmly by covalent bonds to the receptor that it is slowly
not dissociate at all.

• It block the agonist, and the blockade cannot be

overcome by increasing the dose of agonist hence it is
irreversible antagonism,

• e.g. Adrenaline and phenoxybenzamine at α- adrenergic

receptor.
 Factors Modifying the Drug Action

• Various factor modifying the drug action.

They are :-

Body weight : The recommended dose is calculated for

medium and built persons.

For the obese and underweight persons, the dose has to

be calculated individually.
 Factors Modifying the Drug Action

• Age

In the new born ,the liver and kidney are not fully mature to
handle the drugs.

E.g. barbiturates which produce sedation in adults may

produce excitation in children.
 Factors Modifying the Drug Action

• Sex: The hormonal effects and smaller body size may

influence drug response in women. Special care is
necessary while prescribing for pregnant and lactating
women during menstruation.

• Species and race: Response to drug may vary with

species and race. e.g. Rabbits are resistant to atropine
need more dose to produce mydriasis.
 Factors Modifying the Drug Action

• Diet and environment:

Food interfere with the absorption of the drugs.

E.g. tetracycline form complexes with Calcium present in

the food and are poorly absorbed.
 Factors Modifying the Drug Action

• Route of administration : route of administration may

modify the pharmacodynamic response.

• E.g. Mgso4 given orally it is a purgative, in IV it causes

CNS depression and has anti-convulsion effects.

• Applied topically it reduce local edema.

 Factors Modifying the Drug Action

• Genetic factor : the enzyme production are genetically

controlled.

• The response of the drugs differ according to the

metabolizing enzymes.

• A. Acetylation of drugs : the rate of drug acetylation differs

among individuals people may be fast or slow acetylators.
e.g. INH, sulfonamides and hydralazine.

• B.G6PD deficiency : primaquine, sulphones and quinolones

can cause hemolysis in such people.
 Factors Modifying the Drug Action

• Dose :

• Interesting to know the response of the drug, the dose is

increased the response also increased till the maximum
reached .

• Incase some drugs further increased the drug response

is lowered. e.g. Myasthenia gravis ,neostigmine enhance
the muscle power in therapeutic doses if the dose higher
it will produce muscle paralysis.
 Factors Modifying the Drug Action

• Diseases

Presence of certain disease can influence drug responses.

E.g. Malabsorption – drugs are poorly absorbed

Liver diseases- rate of metabolism reduced

 Factors Modifying the Drug Action

• Trachyphylaxis

• Rapid development of tolerance.

• When some drugs are administered repeadly at short

interval ,tolerance develops rapidly and is known as
tachyphylaxis or acute tolerance.
 Factors Modifying the Drug Action

• Repeated dosing:

• Can result in cumulation, tolerance, tachyphylaxis.

• Cumulation : Drugs like digoxin which are slowly eliminated may

cumulate resulting in toxicity.

• Tolerance :Tolerance is defined as the capacity of the body to

become less responsive to a substance.

• Lethal dose of Morphine is 250 mg, but drug addict can tolerate
morphine in gm
 Factors Modifying the Drug Action
• Psychological Factor:
The doctor patient relationship as well as the nursing care
influence the response to a large extent by acting on the patient
psychology.

The patients confidence in the doctor may be adequate enough

to relieve a suffering ,particularly the psychosomatic disorder.

Placebo is the inert dosage form with no biological activity but

only resembles the actual preparation in appearance.
 Factors Modifying the Drug Action

• Presence of other drugs :

The concurrent use of two or more drugs can influence the

response of each other
 REFERENCES

• Goodman & Gilman's The Pharmacological

Basis of Therapeutics,11th Ed., Mcgraw-hill
Medical Publishing Division, New York, 2006