General Pharmacology

By Dr Arya Raveendran
PG Scholar
Dept of RSBK
MVRAMC
Introduction
 Pharmacology as a science had its beginning in the later half of the 19 th century.
 Oswald Schmiedberg considered to be the founder of Modern pharmacology.
 In India, Sir R N Chopra was responsible for the development of pharmacology as a well defined
discipline. He is called as the Father of Pharmacology in India.
 The term Pharmacology is derived from the Greek words ‘Pharmakon’ and ‘logos’.
Pharmakon – drug
Logos – reasonable or rational discussion
 Pharmacology deals with the properties and effects of drugs.
 Definition
 Pharmacology is the science that deals with the study of drugs and their
interaction with the living systems.
 It also includes physicochemical properties, methods of administration,
absorption, distribution, mechanism of action, biotransformation, excretion,
clinical uses and adverse effects of drugs.
 Drug :
derived from French word ‘drogue’ which means a ‘dry herb’
Acc to WHO, a drug is any substance or product that is used to modify or explore
physiological systems or pathological states for the benefit of recipient.
In the context of medicine, it means a chemical used in the prevention, diagnosis
or treatment of diseases.
 Two main division of pharmacology are:
1. Pharmacokinetic : what the body does to drug
2. Pharmacodynamic: what the drug does to body

Pharmacokinetics is the study of the time course of absorption, distribution, metabolism and excretion
of drugs and their metabolites in the intact organism.
The major processes include (ADME)
Absorption
Distribution
Metabolism
Excretion
Pharmacodynamic is the study of drug action in animals or humans
 Types of drug action: 1. Stimulation 2. Depression 3. Irritation 4. Replacement 5. Cytotoxic action

 Majority of the drugs produce their effect by interacting with a discrete target biomolecule. There
are four major target of drug: 1. Enzymes 2. ion-channel 3. Transporters 4. receptors.
ABSORPTION
 The passage or transfer of drug molecules from the site of administration into the blood or body fluids is
called absorption.
 It involves passage of drugs across biomembranes
 Basic examples of drug transfer are absorption from GIT, capillary transfer, cellular penetration and renal
tubular reabsorption.
MECHANISM:
 Cell or biological membranes have a mosaic structure consisting of a bilayer of lipid molecules with
intermingled protein molecules. The smaller components of lipoproteins or glycoproteins are embedded
in the lipid matrix, with iconic and polar groups protruding from one or both sides of the membrane.
 Local changes in this lipid protein mosaic may result in the formation of ion channels or pores, and the
membrane become less restrictive to the passage of substances into the cells.
 The cell membrane also provides a matrix to a variety of enzymes and drug receptors. Because of the
lipoid nature of the biomembranes, lipid soluble substances readily permeate into the cells.
 Adjacent epithelial or endothelial cells have tight junctions between them and also contain water filled
channels through which water soluble substances of small molecules enter.
 Factors influencing drug absorption are:
1.Physiochemical properties:
• Physical state: liquids better absorbed than solids
• Lipid soluble and unionized form better absorbed than water soluble and ionized form
• Particle size: smaller particle sized are absorbed better.
• Disintegration time: time taken by the formulation to break up and its variation may affect the
bioavailability.
• Dissolution time: time taken by the particles to go into solution, shorter the time better the absorption.
• Formulations: agents added to the formulation like the binding agents may affect the absorption
2.Route of drug administration
3. pH and ionization: strongly acidic and strongly basic drugs usually remain ionized at all pH, hence they are
poorly absorbed.
4.Food: presence of food in the stomach can affect the absorption of some of the drugs. Food decreases the
absorption of rifampicin, levodopa etc. hence they are poorly absorbed.
5.Presence of other drugs: concurrent administration of two or more drugs may affect their absorption of oral
iron. Antacids reduce the absorption of tetracyclines.
6.Area of absorbing surface: drugs are better absorbed in the small intestine because of larger surface area.
7.Gastrointestinal and other diseases: increased peristaltic movement that decreases drug absorption, in CCF
there is GI mucosal oedema that reduces absorption of drugs.
 The passage of drugs across biological membranes involves complex natural processes like:
 Filtration
 Diffusion
 Carrier mediated transport
 pinocytosis
Filtration
 Filtration is passage of drugs through aqueous pores in the membrane or
through paracellular spaces.
 Depends on the molecular size and weight of the drug.
 Filtration through porous membrane refers to the flow of solvent along with
the dissolved substance/solute, except molecules which are larger than the
size of pores.
 Glomerular membrane of kidney is a good example of filtering membrane.
 Majority of cells in the body have very small pores (4 Å ) and drugs with MW
>100 or 200 are not able penetrate.
 Capillaries (except in the brain) have large paracellular spaces (40 Å) and
most drugs ( even albumin ) can filter through these.
DIFFUSION
 Most important method in drug
absorption and distribution.
 Substances move from an area of
high concentration to low
concentration areas.
 Simple diffusion of a substance
across a membrane is characterized
by rate of transfer which is directly
proportional to the concentration
gradient across a membrane.
 The rate of diffusion is dependent on
the lipid water partition coefficient,
ie distribution between the
membrane phase and aqueous
environment.
 For ionic compounds, factors like pH
and degree of ionization play an
important role in drug permeation
through membranes.
Specialized transport
 The passage of many substances across the
cell membrane cannot be explained on the
basis of filtration or diffusion alone. Some
substances are taken up against the
concentration gradient.
 Such phenomena are usually performed with
the help of specific ‘carrier’ molecules.
 Active transport : the drug molecules move
from a region of lower to higher
concentration against the concentration
gradient. It is an energy dependent process
and makes use of specific carrier protein
molecules.
 Facilitated diffusion : this is a type of carrier-
mediated transport and does not require
energy. The drug attaches to a carrier in the
membrane, which facilitates its diffusion
across the membrane. Here transport of
molecule is from higher to lower
concentration.
Pinocytosis
 pinocytosis, a process by which liquid droplets are ingested
by living cells.
 Pinocytosis is one type of endocytosis, the general process
by which cells engulf external substances, gathering them
into special membrane-bound vesicles contained within
the cell.
 In pinocytosis, rather than an individual droplet of liquid
traveling passively through the cell membrane, the droplet
first becomes bound, or adsorbed, on the cell membrane,
which then invaginates (forms a pocket) and pinches off to
form a vesicle in the cytoplasm.
 It is believed that a vesicle may carry extracellular fluid to
the opposite side of the cell, where it undergoes exocytosis.
A droplet of fluid could thus be transported through the cell
without disturbing its cytoplasm. Alternatively, the contents
of the vesicle may be released to mix with the cytoplasm.
Distribution
 Drug distribution: refers to the reversible transfer of a drug between the blood and the extra vascular fluids and tissues
of the body (for example, fat, muscle, and brain tissue).
 Dissemination of the drug to various sites after absorption constitutes delivery of drug from systemic circulation to the
tissues.
 After the drug reaches the plasma, it must cross several barriers before it reaches the target tissue or site of action.
 The processes of filtration, diffusion, and specialized transport are put to use to carry the drug molecules across the
lipid biological membrane.
 Lipid soluble substances pass through the endothelium whereas the hydrophilic molecules use the aqueous channels in
the ‘tight junction’.
 Larger molecules are transferred at a slower rate.
 Factors which affect drug distribution:
o Plasma protein binding
o Cellular binding
o Rate of blood flow into various organs
o Concentration in fatty tissue
o Blood-brain barrier
 Plasma protein binding

 Most drugs in the vascular compartment bind reversibly to macromolecules in the plasma.
 Acidic drugs bind mainly to albumin, whereas basic drugs frequently bind to other plasma proteins.
Free drug + protein = drug- protein complex
 The extent of binding influences drug distribution, metabolism and elimination, because only the free
drug can take part in various pharmacokinetic processes.
 Drugs thus circulate in both free and bound forms and there is a dynamic equilibrium between these two
forms.
 The free fraction of the drug is the pharmacologically active form and diffuses through capillary walls to
reach the site of action.
 Thus extensive binding reduces the intensity of drug action, and the reduction is proportional to the
fraction of the bound drug.
 Plasma protein binding provides a reservoir which can replace the free drug lost by metabolism and
excretion. Thus binding does not prevent the drug from reaching the site of action but merely delays
it( prolongs the half-life).
 Albumin is the most important plasma protein involved in drug binding.
 The amount of drug bound to plasma proteins depends on:
I. The free drug concentration
II. The affinity of the binding sites
III. The protein concentration.
Clinical importance of plasma protein binding:
1. Plasma protein binding favours drug absorption.
2. Plasma protein binding delays the metabolism of drugs.
3. Bound form is not available for filtration at the glomeruli,hence excretion of highly plasma protein bound
drugs is delayed.
4. In case of poisoning, highly plasma protein bound drugs are difficult to be removed by haemodialysis.
5. In diseases like anaemia, renal failure, chronic liver disease etc. plasma albumin levels are low .So there
will be an increase in the free form of the drug, which can lead to drug toxicity.
6. Plasma protein binding can cause displacement interactions. More than one drug can bind to the same site
on plasma protein. The drug with higher affinity will displace the one having lower affinity and may result in
a sudden increase in the free concentration of the drug with lower affinity.
Cellular binding
 Some drugs are distributed to sites other than the plasma, eg. Lipid soluble drugs may enter fat
stores.
 Tissue binding is also seen and this delays elimination from the body, thus prolongs the t 1/2 of the
drug. Eg. Digoxin binds to cardiac muscles and chloroquine binds to retina.
 Cellular binding is usually a result of increased affinity of some cellular constituents.

Rate of blood flow into various organs

 Rate of blood flow influences drug delivery to the sites of action.
 Following intravenous injection of a lipid soluble drug, the brain concentration rise rapidly due to
good tissue perfusion. The equilibrium between free and bound drug is attained much faster.
 In less perfused areas like muscles, though the fat content is appreciable , but due to restricted blood
flow the drug is absorbed at a slower rate.
Concentration in fatty tissue
 Drugs with high lipophilicity like glutethimide are stored in fat and serve as a depot.
 When plasma levels are lowered by metabolism or by excretion, the plasma levels are promptly restored
by depot storage sites.

Blood – brain barrier

 The capillaries in brain are enveloped by glial cells which form a barrier, that is impermeable to water
soluble compounds but excessively permeable to lipophilic substances. The transfer of drugs into the
brain is regulated by this blood-brain barrier.
 The blood – brain barrier is a single row of brain capillary endothelial cells joined by continuous tight
inter cellular junctions.
 Only drugs with high lipid-water partition coefficient will penetrate this blood -brain barrier.It provides
a unique example of unequal distribution of drugs.
 Drugs are selectively taken into the brain.
Criteria for the entry of drugs are:
 Lipid solubility and degree of ionization: only lipid soluble and unionized drugs have access to the brain.
 Since the pH of CSF is 7.35, weak organic bases tends to concentrate more than the weak organic acids
 Only the free form of drug is available for diffusion. Extensive plasma protein binding inhibits drug
transfer into CNS.
 Inflammation as seen in bacterial meningitis or encephalitis may disrupt the integrity of BB barier and
inverts its permeability. Thus allowing normally impermeable substance to brain.
 Some areas in the brain have weak barrier and the permeability regulations are not effective. Egs.
Neurohypophysis and the area postrema.
 Though many drugs do not reach the CSF from blood, movement in the reverse direction can be
efficient. The flow of CSF is unidirectional ie from the site of formation in the choroid plexus through
the ventricles to the arachnoid villi and secreted across the choroid plexus.
 Some drugs like penicillin will not leave the CSF in this way, and is actively transported back into the
blood.
METABOLISM
 Metabolism or biotransformation implies chemical transformation of a drug within the body. This is a major
mechanism to terminate the action of the drug.
 The metabolism of a drug usually converts lipid soluble and unionized compounds into water soluble and
ionized compounds.
 If the parent drug is highly polar (ionized), then it may not get metabolized and is excreted as such.
 SITES:liver is the main site for drug metabolism. Other sites are GI tract, kidney, lungs, blood, skin, and
placenta.
 The end result of drug metabolism is inactivation, but sometimes a compound with pharmacological activity
may be formed as :
 Active drug to inactive metabolite: most common type of metabolic transformation
eg: phenobarbitone hydroxyphenobarbitone
 Active drug to active metabolite
eg: codein morphine
 Inactive drug (prodrug) to active metabolite.
eg: levodopa dopamine, prednisone prednisolone

Prodrug
 It is an inactive form of a drug, which is converted to an active form after metabolism.
 Uses of Prodrugs (advantage)
• To improve bioavailability: parkinsonism is due to deficiency of dopamine. Dopamine itself cannot
be used since it does not cross the blood brain barrier (BBB) So it is given in the form of a prodrug.
Dodecarboxylase
• LEVADOPA LEVADOPA DOPAMINE

BBB

• To prolong the duration of action: phenothiazines have a short duration of action, whereas esters
of phenothiazine have a longer duration of action.
• To improve the taste: Clindamycin has a bitter taste, so clindamycin palmitate has been
developed for a paediatric use .
• To provide site- specific drug delivery:
Acidic pH of urine
methanamine formaldehyde
Pathways of drug metabolism

Phase Ⅰ reaction Phase Ⅱ reaction

Oxidation: Addition of oxygen or removal  Consists of conjugation reaction

of hydrogen. It is the most important and
 If phase Ⅰ metabolite is polar, it is
common metabolic reaction.
excreted in urine or bile.
 Oxidation reactions are mainly
carried out by cytochrome.  Many metabolites are lipophilic and
undergo subsequent conjugation with an
Reduction: removal of oxygen or
endogenous substrate, such as glucuronic
addition of hydrogen.
acid, sulphuric acid, acetic acid or amino
Hydrolysis: breakdown of compound by acid.
addition of water.
 These conjugates are polar, usually water
Cyclization: conversion of a straight chain
soluble and inactive.
compound into ring structure.
Decyclization: breaking the ring structure
of the compound. ⸭Not all drugs undergo phase Ⅰ and Ⅱ reactions in
 At the end of phase Ⅰ, the metabolite that order, sometimes phase Ⅱ can preceed phase Ⅰ
may be active or inactive
Factors affecting drug metabolism
1. Age : neonates and elderly metabolize some drugs to a lesser extent than adults. (due to diminished
activity of hepatic microsomal enzymes)
2. Diet: poor nutrition can decrease enzyme function.
3. Diseases: chronic diseases of liver may affect metabolism of some drugs.
4. Genetic factors( pharmacogenetics)
5. Simultaneous administration of drugs: can cause increased or decreased metabolism of drugs.
Enzyme induction: repeated administration of certain drugs increase the synthesis of microsomal
enzymes. This is known as enzyme induction.
Enzyme inhibition: drugs which inhibit the action of metabolizing enzymes.
Inhibition of one drug by another one occurs when both these drugs are metabolized by the same enzyme.
Enzyme inhibition is a rapid process compared to enzyme induction.
EXCRETION
 Removal of drug and its metabolite from the body is known as drug excretion.
 Drugs are eliminated from the body after conversion into water soluble metabolites or even in the
unmetabolised form.
 The principal organs of excretion are the kidneys, intestine, biliary system, and the lungs.
 The physiological principles and procedure involved are similar to that of absorption,ie, passage of
drugs across biological membrane.
1. Kidney: most important route of excretion.
The 3 basic processes involved are: (a) glomerular filtration
(b) Active tubular secretion.
(c) passive tubular reabsorption.
rate of renal excretion = (rate of filtration + rate of secretion) – rate of reabsorption
A) Glomerular filtration: extent of filtration is directly proportional to the GFR and to the fraction of the
unbound drug in plasma.
B) Active tubular secretion: it is a carrier mediated transport(energy required). Active secretion is
unaffected by changes in pH of urine and protein binding.
 Passive tubular reabsorption: main factors that affect passive reabsorption is the pH of renal tubular fluid
and degree of ionization.
 strongly acidic and strongly basic drugs remain in ionized form at any pH of urine, hence excreted in
urine.
 Weakly acidic drugs in acidic urine remain mainly in unionized form so they are reabsorbed into the
circulation.( if urine becomes alkanine – excreted )
 Weakly basic drugs in alkaline urine remain in unionized form, hence reabsorbed.(if urine is made acidic –
excreted).
2. Lungs: Alcohol and volatile general anaesthetics , such as ether, halothane are excreted via lungs.
3.Faeces: drugs that are not completely absorbed from GIT are excreted in faeces eg purgatives like senna.
4. Bile: some drugs are excreted via bile but after reaching the intestine they are reabsorbed liver
bile and the cycle is repeated. Such recycling is called enterohepatic circulation, it increases the
bioavailability as well as the duration of action of the drug, eg. Morphine
5. Skin: metals like arsenic and mercury are excreted through skin.
6. Saliva: certain drugs like metronidazole, phenytoin are excreted through saliva.
7.milk: drugs taken by lactating women may appear in milk. It has acidic pH, hence basic drugs like
tetracycline,morphine, diazepam etc are excreted through milk.
PHARMACODYNAMICS
 It is the study of drugs – their mechanism of action, pharmacological actions and adverse effects.
 TYPES OF DRUG ACTION:
1. Stimulation: some drugs act by increasing the activity of specific organs/system eg.adrenaline stimulates
the heart resulting in an increase in heart rate and force of contraction.
2. Depression: some drugs act by decreasing the activity of specific organ/ system eg.alcohol, general
anaesthetics depress the CNS.
3. Irritation: some agents on topical application can cause irritation of the skin and adjacent tissues. When
an agent on application to the skin relieves deep seated pain, it is known as counterirritants. Eg.
Eucalyptus oil, methyl salicylate etc. They exert their action by
 reflexly increasing local circulation in deeper structures.
 Blocking impulse conduction in the spinal cord.
4. Replacement: when there is a deficiency of endogenous substances, they can be replaced by drugs, eg.
Insulin in DM, thyroxine in cretinism and myxedema.
5.Cytotoxic: Drugs are selectively toxic for the infecting organ/cancer cells, eg. Antibiotics/anticancer
drugs.
 Mechanism
of drug
action

Non-
Receptor
receptor
mediated
mediated
Non-Receptor- Mediated
 By physical action:
a)Osmosis: some drugs act by exerting an osmotic effect.Eg. 20% mannitol in cerebral oedema
b)Adsorption: activated charcoal adsorbs toxins, hence it is used in the treatment of drug poisoning
c) demulcent: cough syrup produces a soothing effect in pharyngitis by coating the inflamed mucosa.
d) Radioactivity: radioactive isotopes emit rays and destroys the tissues, eg. 131
I in hyperthyroidism.
 By chemical action:
a) antacids are weak bases, they neutralize gastric acid and hence useful in peptic ulcer.
b) metals like iron, copper, mercuryetc are eliminated from the body with the help of chelating agents.
These agents trap metals and form water soluble complexes, which are rapidly excreted from the body.
Eg.Dimercaprol in arsenic poisoning.
 Through enzymes: some drugs act by inhibiting the enzyme activity.
a) drug action via enzyme inhibition:
Ⅰ. Angiotensin converting enzymes (ACE) inhibitors such as captopril act by inhibiting ACE. They are used in
the treatment of hypertension.
Ⅱ. Xanthine and Hypoxanthine are oxidised to uric acid by the enzyme xanthine oxidase, is inhibited by
allopurinol.
 Through ion channels: some drugs directly bind to ion channels and alter the flow of ions, eg. Local
anaesthetics block sodium channels in neuronal membrane to produce local anaesthesia.
 Through antibody production: vaccines produce their effect by stimulating the formation of antibodies,
eg. Vaccine against tuberculosis
 Transporters: selective serotonin reuptake inhibitors binds to 5-HT transporter and block 5-HT reuptake
into neurons and causes antidepressant effect.
 Others: anticancer drugs like cyclophosphamide produce their effect by binding to nucleic acids.
RECEPTOR – MEDIATED MECHANISM
 Receptors are macromolecules, present either on the cell surface, cytoplasm or in the nucleus with
which the drug binds and interacts to produce cellular changes.

Drug (D)+ Receptor (R) ↔ Drug-receptor complex response

 Receptors are primarily proteins like:

 Regulatory proteins for neurotransmitters, hormones, autacoids, growth, or transcription factors
 Enzymes in important bioregulatory pathways eg.dihydrofolate reductase
 Glycoproteins
 Structural proteins( tubulins)
 Transport proteins(Na-K-ATPase)
 Nucleic acids (for anticancer drugs)
 Ion channels (local anaesthetics)
 Drugs binds to such receptors by ionic bonds, van der Waals’ force or covalent linkages, and multiple
types of bonds may be involved in a drug-receptor interaction.
 Covalent binding is usually associated with prolonged duration of drug action.
 The nature of drug – receptor interactions also depend on the location and functional capacity of the
binding sites ie the receptors.
 The receptor concept has important pharmacological consequences:
 It expresses the quantitative relationship between dose and effect.
 It determines the selectivity of drug action
 Receptors mediate effects of specific agonists or antagonists.
 The receptor, its cellular target, and any intermediary molecules are collectively known as the signal
transduction pathway.
 Two terms are important in relation to drug/ ligand receptors interactions:
1.Affinity: the ability to combine with the receptor
2.Efficacy or intrinsic activity: the ability to produce a response.
Agonist: a drug that is capable of producing pharmacological action after binding to the receptor is
called an agonist.
Antagonist: a drug that prevents binding of agonist to its receptor or block its effect.it does not by
itself produce any effect.
 The drug action thus depends on:
 Drug has to reach the receptor site in adequate amount
 Drug has to be specific for its receptor
 Specificity depends on the chemical structure of the drug.

FACTORS MODIFYING DRUG ACTION

Drug factors:
1. Route of administration: may exhibit qualitative and quantitative variation in drug action.
Quantitative variation: oral dose of drugs is usually larger than intravenous dose. For eg. For analgesic
effect, intravenous dose of morphine is 5-10mg, oral dose is 30-60mg
Qualitative variation: eg. Magnesium sulphate administered orally produces purgative effect, parentrally –
CNS depression, Local application –reduces oedema in the inflamed area.
2.Presence of other drugs: addition, potentiation synergism or antagonistic action may take place .
3.Cumulation: when the elimination of drugs is slow,then repeated administration of the drug will result in its
accumulation in the body causing drug toxicity. Eg. Digoxin, chloroquine.
Patient factors
1.Age: in neonates, the metabolizing function of the liver and excretory functions of the kidney is not fully
developed. Eg. Chloramphenicol – gray baby syndrome.
In elderly, renal and hepatic functions progressively decline. ADR is also relatively more hence drug doses
have to be reduced accordingly.
2. Body weight and body surface: average dose of drug is calculated as
Dose = body weight (kg) × Average adult dose
70
In obese individuals and in patients with oedema or dehydration, dose calculation is based on the body
surface area( BSA).
3. Sex: drugs like β- blockers, diuretics and clonidine can cause decreased libido in males.
4.Diet and environmental factors: milk reduces absorption of tetracyclines. Cigarette smoke induces
hepatic microsomal enzymes and increase metabolism of drugs, such as theophylline.
5.Genetic factors.
6.Psychological factor:personality of the doctor as well as the patient can affect response to a drug.
( placebo—pain).
 7. pathological states:
a) GI disorders- in mal absorption syndrome, the absorption of some drugs is reduced.
b) Liver disease: in chronic liver diseases, the metabolism of drugs is highly reduced. This will increase
bioavailability of drugs having high first pass metabolism eg. Propranolol.
c) Renal failure:clearance of drugs through kidney is impaired , this will cause nephrotoxicity, ototoxicity and
aminoglycosides.
d) Absorption of iron from gut is increased in case of iron deficiency anaemia.
e) Patients with myxedema are more sensitive to morphine.
 8. Tolerance: it means need for larger doses of a drug to produce a given response. Commonly seen in
drugs like morphine, alcohol, amphetamine etc.
 9.Drug dependence: can be
psychological dependence: intense desire to continue taking drugs as the patient feels their well being
depends upon the drug.
physical dependence: repeated drug use produces physiological changes in the body, which makes continuous
presence of the drug in the body necessary to maintain normal function. Abrupt stoppage of drug may result
in imbalance and may produce withdrawal symptoms.
Dose determination and Dose response.
 Factors influencing Drug dosage:
1.Loading dose: initially, a large dose or series of doses of a drug is given with the aim of rapidly attaining

the target level in plasma. This is known as loading dose. A loading dose is administered if the time
taken to reach steady state is relatively more as compared to the patient’s condition.
2.Maintenance dose: the dose of a drug which is repeated at fixed intervals or given as a continuous
infusion to maintain target level in plasma or steady state concentration is known as maintenance dose.
The dose administered is equal to dose eliminated in a dosing level.
Dose – response curve
 The relationship between the dose of the drug and the clinically observed response is quite complex.
 In general with increase in dose of the drug, the pharmacological response increase proportionately.
 The change in response with alteration of dose is defined by the shape of the dose-response curve which
is conventionally plotted with dose as the abscissa and response as the ordinate.
 As the dose increases further the increment in response diminishes, and finally dose may reach a point
where no further increment in the response can be achieved.
 In contrast to this, some drugs eg loop diuretics have steep rising and prolonged curves. Such drugs have
a high ceiling of effect and are both more potent in therapeutic as well as toxic effects.
 The response to a drug is a function of the molar concentration attained in the tissue.
 In graded response- magnitude of response is proportional to the concentration of the drug. It is an
exponential or hyperbolic type of dose response curve.
 In quantal response, response is not observed till a particular threshold is reached. This is an ‘s’ or
sigmoid shaped curve .
Clinical significance of the curve
 The inclination or the slope of the curve varies from drug to drug.
 A drug with a shallow or flat dose- response curve is unlikely to show extra benefit with increment in
dose ie, a fixed low dose is appropriate.
 A drug with steep dose- response curve , adjustment and trituration of dose is necessary for optimal
therapeutic effect.
 Curve also shows which combination of dose is necessary for optimal therapeutic effect.
 In combination therapy it is beneficial to combine a drug with a similar dose- response curves as
adverse effects are likely to be additive.
 The location of the curve with respect to the abscissa expresses the potency of the drug.
 Potency of an agonist is important for determining the dose of the agonist.
 In toxicology, a similar relationship exists between the toxic dose and the response.
 LD50 is the median lethal dose which is expected to cause mortality in 50% of animals belonging to the
same species and strain.
 ED50 is the medium effective dose that produces the desired effect in 50% population / animals tested
 Progressive increase in the dose of a drug results in proportional rise in the response till a maximum
is reached.
 Beyond this point further increment in dose elicit no greater benefit but induce undesirable effect.
This is because with increase in dose from therapeutic to the toxic level, dose-response curve
becomes different.
 Therefore the utility of a drug is dependant on the extent to which these two dose responses can be
separated.
 The therapeutic index (TI) is the maximum tolerated dose divided by the minimum curative dose.
therapeutic index = LD50
ED50
 The higher the therapeutic index, the greater the margin of safety. This is a fundamental concept
which compares the usefulness of one drug with another, namely its safety in relation to its efficacy.
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