GENERAL PHARMACOLOGY

1. Pharmacy

It is the science of identification, Selection, Preservation, Standardization, Compounding, and

Dispensing of medicinal substances

2. Pharmacology

Origin from two Greek words “pharmacon” means drug and “logos” means science.

Pharmacology is the study of interaction of drugs with living organisms. It also includes history,
source, physicochemical properties, dosage forms, and methods of administration, absorption,
distribution, mechanism of action, biotransformation, excretion, clinical uses and adverse effects
of drugs.

3. Clinical pharmacology

Clinical pharmacology is "that discipline that teaches, does research, frames policy, gives
information and advice about the actions and proper uses of medicines in humans and
implements that knowledge in clinical practice". The main aim of clinical pharmacology is to
generate data for optimum use of drugs and the practice of 'evidence-based medicine'.

It evaluate the pharmacological action of drug preferred route of administration and safe dosage
range in human by clinical trials

In clinical pharmacology studies, most frequently in early stage development, mainly healthy
subjects or well-defined patient populations are involved.

4. Pharmacotherapeutics

It deals with the proper selection and use of drugs for the prevention and treatment of disease.

In pharmacotherapy studies, the focus is on the use of medicinal products in daily patient care
(both ambulatory and in a hospital setting).

5. Drug

“Drug is any substance or product which exerts a biochemical or physiological effect on the cell,
tissue, organ, or organism that is used or is intended to be used to modify physiological systems
or pathological states for the benefit of the recipient”

Drugs are chemicals that alter functions of living organisms. Drugs are generally given for the
diagnosis, prevention, control or cure of disease.
6. Toxicology

It’s the science of poisons. Many drugs in larger doses may act as poisons. Poisons are
substances that cause harmful, dangerous or fatal symptoms in living substances.

7. Chemotherapy

It’s the effect of drugs upon microorganisms, parasites and neoplastic cells living and
multiplying in living organisms.

8. Pharmacopoeia

An official code containing a selected list of the established drugs and medical preparations with
descriptions of their physical properties and tests for their identity, purity and potency e.g. Indian
Pharmacopoeia (I.P), British Pharmacopoeia (B.P)

9. Sources of drugs

1. Minerals: Liquid paraffin, magnesium sulfate, magnesium trisilicate, kaolin, etc.

2. Animals: Insulin, thyroid extract, heparin and antitoxin sera, etc.

3. Plants: Morphine, digoxin, atropine, castor oil, etc.

4. Synthetic source: Aspirin, sulphonamides, paracetamol etc.

5. Microorganisms: Penicillin, streptomycin and many other antibiotics.

6. Genetic engineering: Human insulin, human growth hormone etc.

10. Ligand

The ligand is a molecule that binds to another molecule called a receptor to send signals within
or between cells. Ligand biology depends on the receptors they attach to.

11. Receptor

Receptor is a macromolecule in the membrane or inside the cell that specifically (chemically)
bind a ligand (drug). These protein molecules can cause changes within the cell that stop or start
a cellular process.
Receptors are protein molecules present either on the cell surface or with in the cell e.g.
adrenergic receptors, cholinoceptors, insulin receptors, etc

12. Affinity

The extent to which a drug bind with receptor. It determines the potency of a drug.
13. Potency

The relative measure of the amount of a drug required to produce a specified level of response
compared with other drugs that produce the same effect via the same receptor mechanism.

14. Efficacy
The ability of a drug to elicit the pharmacologic response.

15. Therapeutic index

The ratio of the dose that produces a toxic effect in half of the population to the dose that
produces the desired effect in half of the population. TD50/ED50

16. Drug ceiling effect

It refers to a particular phenomenon in pharmacology where a drug’s impact on the body
plateaus. At this point, taking higher doses does not increase its effect. It has, in essence, hit a
ceiling. This happens with many types of drugs, including aspirin and opioids. On the one hand,
this is partially responsible for many people overdosing on drugs that they are already building
up a tolerance against. Still, it can also be used to treat opioids with the help of agonists.

III. Pharmacokinetics
Pharmacokinetics deals with the absorption, distribution, metabolism and excretion drugs in the
body.
A. Biotransport of drug: It is translocation of a solute from one side of the biological barrier to
the other.
1. Structure of biological membrane: The outer surface of the cell covered by a very thin
structure known as plasma membrane. It is composed of lipid and protein molecules.
The membrane proteins have many functions like
(a) contributing structure to the membrane
(b) acting as enzyme
(c) acting as carrier for transport of substances
(d) acting as receptors.
The plasma membrane is a semipermeable membrane allowing certain chemical substances to
pass freely e.g. it allows water, glucose, etc. but it won’t allow sucrose until it is converted into
glucose and fructose.
 2. Passage of drug across membrane.
(a) Passive transfer
i) Simple diffusion
ii) Filtration
(b) Specialized transport
i) Facilitated diffusion
ii) Active transport
iii) Endocytosis.
(a) i) Simple diffusion: Movement of a solute through a biological barrier from the phase of
higher concentration to phase of lower concentration. No need of energy e.g. highly lipid
soluble drugs.
ii) Filtration: Is the process by which water soluble drug of relatively low molecular
weight crosses the plasma membrane through pores as a result of hydrodynamic pressure
gradient across the membrane e.g. urea and ethylene glycol.
(b) i) Facilitated diffusion: It means the passage of drug across the biological membrane
along the concentration gradient by the protein carrier mediated system also called as
carrier mediated diffusion. It depends on number of carrier e.g. tetracycline, pyrimidine.
ii) Active transport: The process by which drugs pass across the biological membrane
most often against their concentration gradient with the help of carriers along with the
expenditure of energy e.g. alpha methyl dopa, levodopa, 5-fluoro-uracil, 5 bromouracil.
iii) Endocytosis: It is the process by which the large molecules are engulfed by the cell
membrane and releases them intracellularly e.g. protein, toxins (botulinum, diphtheria)

B. Drug absorption: Absorption is the process by which the drug enters in to the systemic
circulation from the site of administration through biological barrier. In case of intravenous or
intra-arterial administration the drug bypasses absorption processes and it enters into the
circulation directly.
2. Bioavailability: It is the rate and amount of drug that is absorbed from a given dosage form
and reaches the systemic circulation following non-vascular administration. When the drug is
given IV, the bioavailability is 100%. It is important to know the manner in which a drug is
absorbed. The route of administration largely determines the latent period between
administration and onset of action. Drugs given by mouth may be inactive for the following
reasons:

a) Enzymatic degradation of polypeptides within the lumen of the gastrointestinal tract e.g.
insulin, ACTH.

b) Poor absorption through gastrointestinal tract e.g. aminoglycoside antibiotic.

c) Inactivation by liver e.g. testosterone during first passage through the liver before it reaches
systemic circulation.

3. Factors affecting drug absorption and bioavailability:

a) Physico-chemical properties of drug

b) Nature of the dosage form

c) Physiological factors

d) Pharmacogenetic factors

e) Disease states.

a) Physico-chemical properties of drug:

i) Physical state: Liquids are absorbed better than solids and crystalloids absorbed better than
colloids.

ii) Lipid or water solubility: Drugs in aqueous solution mix more readily than those in oily
solution. However at the cell surface, the lipid soluble drugs penetrate into the cell more rapidly
than the water soluble drugs.

iii) Ionization: Most of the drugs are organic compounds. Unlike inorganic compounds, the
organic drugs are not completely ionized in the fluid. Unionized component is predominantly
lipid soluble and is absorbed rapidly and an ionized is often water soluble component which is
absorbed poorly. Most of the drugs are weak acids or weak bases. It may be assumed for all
practical purposes, that the mucosal lining of the G.I.T is impermeable to the ionized form of a
weak organic acid or a weak organic base. These drugs exist in two forms.

Acidic drugs: rapidly absorbed from the stomach e.g. salicylates and barbiturates.
Basic drugs: Not absorbed until they reach to the alkaline environment i.e. small intestine when
administered orally e.g. pethidine and ephedrine.

b) Dosage forms:

i) Particle size: Small particle size is important for drug absorption. Drugs given in a dispersed
or emulsified state are absorbed better e.g. vitamin D and vitamin A.

ii) Disintegration time and dissolution rate.

Disintegration time: The rate of break up of the tablet or capsule into the drug granules.

Dissolution rate: The rate at which the drug goes into solution.

iii) Formulation: Usually substances like lactose, sucrose, starch and calcium phosphate are
used as inert diluents in formulating powders or tablets. Fillers may not be totally inert but may
affect the absorption as well as stability of the medicament. Thus a faulty formulation can render
a useful drug totally useless therapeutically.

c) Physiological factors:

i) Gastrointestinal transit time: Rapid absorption occurs when the drug is given on empty
stomach. However certain irritant drugs like salicylates and iron preparations are deliberately
administred after food to minimize the gastrointestinal irritation. But some times the presence of
food in the G.I tract aids the absorption of certain drugs e.g. griseofulvin, propranolol and
riboflavin.

ii) Presence of other agents: Vitamin C enhances the absorption of iron from the G.I.T.
Calcium present in milk and in antacids forms insoluble complexes with the tetracycline
antibiotics and reduces their absorption.

iii) Area of the absorbing surface and local circulation: Drugs can be absorbed better from the
small intestine than from the stomach because of the larger surface area of the former. Increased
vascular supply can increase the absorption.

iv) Enterohepatic cycling: Some drugs move in between intestines and liver before they reach
the site of action. This increases the bioavailability e.g. phenolphthalein.

v) Metabolism of drug/first pass effect: Rapid degradation of a drug by the liver during the
first pass (propranolol) or by the gut wall (isoprenaline) also affects the bioavailability. Thus a
drug though absorbed well when given orally may not be effective because of its extensive first
pass metabolism.

d) Pharmacogenetic factors: Individual variations occur due to the genetically mediated reason
in drug absorption and response.
e) Disease states: Absorption and first pass metabolism may be affected in conditions like
malabsorption, thyrotoxicosis, achlorhydria and liver cirrhosis.

C) Distribution of drugs

1. Definition: Penetration of a drug to the sites of action through the walls of blood vessels from
the administered site after absorption is called drug distribution. Drugs distribute through various
body fluid compartments such as (a) plasma (b) interstitial fluid compartment (c) trans-cellular
compartment.

Apparent Volume of distribution (VD): The volume into which the total amount of a drug in
the body would have to be uniformly distributed to provide the concentration of the drug actually
measured in the plasma. It is an apparent rather than real volume.

Factors determining the rate of distribution of drugs:

1. Protein binding of drug: A variable and other significant portion of absorbed drug may
become reversibly bound to plasma proteins. The active concentration of the drug is that part
which is not bound, because it is only this fraction which is free to leave the plasma and site of
action.

a) Free drug leave plasma to site of action

b) binding of drugs to plasma proteins assists absorption
c) protein binding acts as a temporary store of a drug and tends to prevent large fluctuations
in concentration of unbound drug in the body fluids
d) protein binding reduces diffusion of drug into the cell and there by delays its metabolic
degradation e.g. high protein bound drug like phenylbutazone is long acting. Low protein
bound drug like thiopental sodium is short acting.

2. Plasma concentration of drug (PC): It represents the drug that is bound to the plasma
proteins (albumins and globulins) and the drug in free form. It is the free form of drug that is
distributed to the tissues and fluids and takes part in producing pharmacological effects. The
concentration of free drug in plasma does not always remain in the same level e.g.

i) After I.V. administration plasma concentration falls sharply

ii) After oral administration plasma concentration rises and falls gradually.
iii) After sublingual administration plasma concentration rise sharply and falls gradually.

3. Clearance: Volume of plasma cleared off the drug by metabolism and excretion per unit time.
Protein binding reduces the amount of drug available for filtration at the glomeruli and hence
delays the excretion, thus the protein binding reduces the clearance.

4. Physiological barriers to distribution: There are some specialized barriers in the body due
to which the drug will not be distributed uniformly in all the tissues. These barriers are:
 a) Blood brain barrier (BBB) through which thiopental sodium is easily crossed but not
dopamine.
b) Placental barrier: which allows non-ionized drugs with high lipid/water partition
coefficient by a process of simple diffusion to the foetus e.g. alcohol, morphine.

5. Affinity of drugs to certain organs: The concentration of a drug in certain tissues after a
single dose may persist even when its plasma concentration is reduced to low. Thus the hepatic
concentration of mepacrine is more than 200 times that of plasma level. Their concentration may
reach a very high level on chronic administration. Iodine is similarly concentrated in the thyroid
tissue.

D. Metabolism of drugs:

Drugs are chemical substances, which interact with living organisms and produce some
pharmacological effects and then, they should be eliminated from the body unchanged or by
changing to some easily excretable molecules. The process by which the body brings about
changes in drug molecule is referred as drug metabolism or biotransformation.Enzymes
responsible for metabolism of drugs:

a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and
GIT e.g. glucuronyl transferase, dehydrogenase , hydroxylase and cytochrome P450 I.V
Sublingual Oral Plasma Concentration 0 Time 14

b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. e.g.

esterases, amidase, hydrolase.

Types of biotransformation: The chemical reactions involved in biotransformation are

classified as phase-I and phase – II (conjugation) reactions. In phase-I reaction the drug is
converted to more polar metabolite. If this metabolite is sufficiently polar, then it will be
excreted in urine. Some metabolites may not be excreted and further metabolised by phase –II
reactions.

Phase-I: Oxidation, reduction and hydrolysis.

Phase-II: Glucuronidation, sulfate conjugation, acetylation, glycine conjugation and methylation

reactions.

Phase - I reactions

a) Oxidation: Microsomal oxidation involves the introduction of an oxygen and/or the removal
of a hydrogen atom or hydroxylation, dealkylation or demethylation of drug molecule e.g.
conversion of salicylic acid into gentisic acid.
b) Reduction: The reduction reaction will take place by the enzyme reductase which catalyze
the reduction of azo (-N=N-) and nitro (-NO2) compounds e.g. prontosil converted to
sulfonamide.

c) Hydrolysis: Drug metabolism by hydrolysis is restricted to esters and amines (by esterases
and amidases) are found in plasma and other tissues like liver. It means splitting of drug
molecule after adding water e.g. pethidine undergoes hydrolysis to form pethidinic acid. Other
drugs which undergo hydrolysis are atropine and acetylcholine.

Phase - II reactions (conjugation reactions):

This is synthetic process by which a drug or its metabolite is combined with an endogenous
substance resulting in various conjugates such as glucoronide, ethereal sulfate, methylated
compound and amino acid conjugates.

Glucuronide conjugation: It is the most common and most important conjugation reaction of
drugs. Drugs which contain a) Hydroxyl, amino or carboxyl group undergo this process e.g.
phenobarbitone.

c) Sulfate conjugation: Sulfotransferase present in liver, intestinal mucosa and kidney,

which transfers sulfate group to the drug molecules e.g. phenols, catechols, etc.
d) Acetyl conjugation: The enzyme acetyl transferase, which is responsible for acetylation,
is present in the kupffer cells of liver. Acetic acid is conjugated to drugs via its activation
by CoA to form acetyl CoA. This acetyl group is then transferred to-NH2 group of drug
e.g. dapsone, isoniazid.
e) Glycine conjugation: Glycine conjugation is characteristic for certain aromatic acids e.g.
salicylic acid, isonicotinic acid, p-amino salicylic acid. These drugs are also metabolized
by other path ways. e) Methylation: Adrenaline is methylated to metanephrine by
catechol-o-methyl transferase. Here the source of methyl group is s – adenosyl
methionine.

E. Excretion of drugs

Excretion of drugs means the transportation of unaltered or altered form of drug out of the body.
The major processes of excretion include renal excretion, hepatobiliary excretion and pulmonary
excretion. The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid, nails
and hair. The rate of excretion influences the duration of action of drug. The drug that is excreted
slowly, the concentration of drug in the body is maintained and the effects of the drug will
continue for longer period.

Different routes of drug excretion

a) Renal excretion: A major part of excretion of chemicals is metabolically unchanged or

changed. The excretion of drug by the kidney involves.
i) Glomerular filtration
ii) Active tubular secretion
iii) Passive tubular reabsorption.

The function of glomerular filtration and active tubular secretion is to remove drug out of the
body, while tubular reabsorption tends to retain the drug.

i) Glomerular filtration: It is a process, which depends on

(1) the concentration of drug in the plasma

(2) molecular size, shape and charge of drug
(3) glomerular filtration rate.

Only the drug which is not bound with the plasma proteins can pass through glomerulus. All the
drugs which have low molecular weight can pass through glomerulus e.g. digoxin, ethambutol,
etc.

In congestive cardiac failure, the glomerular filtration rate is reduced due to decrease in renal
blood flow.

ii) Active tubular secretion: The cells of the proximal convoluted tubule actively transport
drugs from the plasma into the lumen of the tubule e.g. acetazolamide, benzyl penicillin,
dopamine, pethidine, thiazides, histamine.

iii) Tubular reabsorption: The reabsorption of drug from the lumen of the distal convoluted
tubules into plasma occurs either by simple diffusion or by active transport. When the urine is
acidic, the degree of ionization of basic drug increase and their reabsorption decreases.
Conversely, when the urine is more alkaline, the degree of ionization of acidic drug increases
and the reabsorption decreases.

b) Hepatobiliary excretion: the conjugated drugs are excreted by hepatocytes in the bile.
Molecular weight more than 300 daltons and polar drugs are excreted in the bile. Excretion of
drugs through bile provides a back up pathway when renal function is impaired. After excretion
of drug through bile into intestine, certain amount of drug is reabsorbed into portal vein leading
to an enterohepatic cycling which can prolong the action of drug e.g. chloramphenicol, oral
estrogen are secreted into bile and largely reabsorbed and have long duration of action.
Tetracylines which are excreted by biliary tract can be used for treatment of biliary tract
infection.

c) Gastrointestinal excretion: When a drug is administered orally, a part of the drug is not
absorbed and excreted in the faeces. The drugs which do not undergo enterohepatic cycle after
excretion into the bile are subsequently passed with stool e.g. aluminium hydroxide changes the
stool into white colour, ferrous sulfate changes the stool into black and rifampicin into orange
red.
d) Pulmonary excretion: Drugs that are readily vaporized, such as many inhalation anaesthetics
and alcohols are excreted through lungs. The rate of drug excretion through lung depends on the
volume of air exchange, depth of respiration, rate of pulmonary blood flow and the drug
concentration gradient.

e) Sweat: A number of drugs are excreted into the sweat either by simple diffusion or active
secretion e.g. rifampicin, metalloids like arsenic and other heavy metals.

f) Mammary excretion: Many drugs mostly weak basic drugs are accumulated into the milk.
Therefore lactating mothers should be cautious about the intake of these drugs because they may
enter into baby through breast milk and produce harmful effects in the baby e.g. ampicillin,
aspirin, chlordiazepoxide, coffee, diazepam, furosemide, morphine, streptomycin etc.

Clearance of a drug: It is the volume of plasma cleared of the drug by metabolism (hepatic)
and excretion (renal) and other organs. Total clearance will be calculated by Ct = Ch + Cr + C
others

Ct = total clearance Ch = hepatic clearance Cr = Renal clearance

Half life: Half life (t1/2) of a drug is the time taken for the concentration of drug in the blood or
plasma to decline to half of original value or the amount of drug in the body to be reduced by
50%. It has two phases i.e half-life of distribution and half-life of elimination.

A half-life value can be readily determined for most drugs by administering a dose of the drug to
a subject, taking blood samples at various time intervals and then assaying the samples., For
example if a blood level of drug A is 8.6 mg/ml at 10 minutes and 4.3 mg/ml at 60 minutes, so
the half – life of that drug is 50 minutes. In most of the cases the rate of disappearance of a drug
from the body is reflected in the rate of lowering of its plasma concentration following a single
intravenous dose, the plasma concentration of the drug is focused to fall exponentially. With
drugs whose elimination is exponential, the biological half – life is independent of the dose, the
route of administration and the plasma concentration. It depends on VD as well as on the
metabolism and renal excretion of the drug.

Order of kinetics

Drugs are used for the treatment of diseases but the modes of administration of drugs are
different. For example atenolol is administered once daily whereas paracetamol needs 3-4 times
administration daily. Morphine is more effective in intramuscular route, and insulin is in
subcutaneous route. The mode of administration is designed on the basis of absorption,
distribution, metabolism and excretion (ADME) of drugs. Drugs usually follow two processes
for their phamacokinetic behaviour in the body. These are first order and zero order process.
First order: This is the most common process for many drugs. The rate at which absorption,
distribution, metabolism and excretion occur are proportional to the concentration of drugs i.e.
constant fraction of this drug in the body disappears in each equal interval of time.

Zero order kinetic: It is independent of the amount of drug present at the particular sites of
drug absorption or elimination. Few drugs follow this process e.g. ethanol, phenytoin. Here
constant amount of the drug is eliminated in each equal interval of time. On repeated
administration of drug after certain stage it goes on accumulating in the body and leads to toxic
reactions.

Steady state plasma concentration: When a drug dose is given repeatedly over a given period,
a steady state is eventually reached, at which point the amount of drug absorbed is in equilibrium
with that eliminated from the body. Concentration mg/L Intravenous Oral 0 4 8 Time in hrs 19
Steady state is achieved after 4 to 5 half –lives for most of the drugs which follow first order
kinetics. For example a drug with half life of 6 hours will be expected to be at steady state after
more than 24 hours of administration. The pattern of drug accumulation during repeated
administration of drug at intervals equal to its elimination half-life. For some drugs, the effects
are difficult to measure, toxicity and lack of efficacy are both potential dangers, and/or the
therapeutic window is narrow. In these circumstances doses must be adjusted carefully to a
desired steady- state concentration by giving loading and maintenance doses.

 Loading dose: The loading dose is one or a series of doses that may be given at the
onset of therapy with the aim of achieving the target concentration rapidly.
 Maintenance dose: To maintain the chosen steady-state or target concentration, the rate
of drug administration is adjusted such that the rate of input equals to rate of loss.
 Drug intolerance: It is a quantitative deviation from the anticipated response to a given
dose of a drug. Thus drug intolerance is inability of the individual to tolerate a drug. It is
also called as hypersusceptibility
 Pharmacogenetics: The science pharmacogenetics is concerned with the
geneticallymediated variations in drug responses. Some examples of genetically
mediated variations are:

7) Drug interactions: It is usual for patients to receive a number of drugs at the same time. It is
a phenomenon which occurs when the effects of one drug are modified by the prior or concurrent
administration of another drug(s). A drug interaction may result in beneficial or harmful effects
and may be classified into:

a) Pharmaceutical drug interactions: Serious loss of potency can occur from incompatibility
between an infusion fluid and a drug that is added to it. For example diazepam if added to
infusion fluid there will be a precipitate formation → loss of therapeutic effect.

b) Pharmacokinetic drug interactions:

 1) Interaction during absorption: Drugs may interact in the gastrointestinal tract resulting in
either decreased or increased absorption. e.g. Tetracycline + Calcium → Decreased absorption of
tetracycline. 2) Interaction during distribution: A drug which is extensively bound to plasma
protein can be displaced from its binding sites by another drug or displacement from other tissue
binding sites. e.g. (i) Sulfonamide can be displaced by salicylates from plasma proteins and it
leads to sulfonamide toxicity. (ii) Quinidine displaces digoxin from binding sites in tissues and
plasma and leads to digoxin toxicity.

3) Interactions during biotransformation: This can be explained by two mechanisms: (i)

Enzyme induction. (ii) Enzyme inhibition. (i) Enzyme induction: By this the biotransformation
of drugs is accelerated and is a cause of therapeutic failure. If the drug A is metabolized by the
microsomal enzymes, then concurrent administration with a microsomal inducer (drug B) will
result in enhanced metabolism of drug A. e.g. Warfarin (anticoagulant) + Barbiturate (enzyme
inducer) → decreased anticoagulation. Enzyme inducers: Rifampicine, phenytoin, sulfonamides,
etc. (ii) Enzyme inhibition: By this the biotransformation of drugs is delayed and is a cause of
increased intensity, duration of action and some times toxicity. e.g. Warfarin + Metronidazole
(enzyme inhibitor) → Haemorrhage. Enzyme inhibitors: Disulfiram, isoniazid, allopurinol,
cimetidine, etc. e) Interactions during excretion: Some drugs interacts with others at the site of
excretion i.e. in kidneys. e.g. Penicillin (antibiotic) + Probenecid (antigout drug) → Increases the
duration of action of penicillin (Both drugs excreted through tubular secretion).

C. Pharmacodynamic interactions:

(i) Drug Synergism: When the therapeutic effects of two drugs are greater than the effect of
individual drugs, it is said to be drug synergism.It is of two types.

(a) Additive effect: When the total pharmacological action of two or more drugs administered
together is equivalent to the summation of their individual pharmacological actions is called
additive effect. i.e A + B = AB e.g. Combination of ephedrine and aminophyllin in the treatment
of bronchial asthma. (b) Potentiation effect: When the net effect of two drugs used together is
greater than the sum of individual effects, the drugs are said to have potentiation effect. i.e AB >
A + B e.g. Trimethoprim+sulfamethoxazole

(iii) Drug Antagonism: The phenomenon of opposing actions of two drugs on the same
physiological system is called drug antagonism.

a) Chemical antagonism: In this the biological activity of a drug can be reduced or abolished
by a chemical reaction with another agent. e.g. Antagonism between acids and alkalis.

b) Competitive or reversible antagonism: In this the agonist and antagonist compete for the
same receptors and the extent to which the antagonist opposes the pharmacological action of the
agonist. Competitive antagonism can be overcome by increasing the concentration of the agonist
at the receptor site. e.g. Acetylcholine and atropine antagonism at muscarinic receptors.
c) Non competitive antagonism: In this type of the antagonism an antagonist inactivates the
receptor (R) so that the effective complex with the agonist cannot be formed, irrespective of the
agonist concentration. e.g. Acetylcholine and papaverine on smooth muscle. Acetyl choline and
decamethonium on neuromuscular junction.

d) Physiological antagonism: When the physiological effect of a drug is antagonized by another

drug by acting on two different types of receptors e.g. Acetyl choline causes constriction where
as adrenaline causes dilatation of pupil.

Importance of drug antagonism

(i) Correcting adverse effects of drugs

(ii) Treating drug poisoning. e.g. Morphine with naloxone, organophosphate compounds
with atropine.
(iii) Predicting drug combinations which would reduce drug efficacy.

Repeated administration and drug cumulation: If a drug is excreted slowly, its administration
may build up a sufficiently high concentration in the body to produce toxicity. e.g. digitalis,
emetine. To avoid cumulation.

a) One must know if a drug is eliminated slowly or rapidly,

b) Stop the drug administration at the appearance of the first warning symptoms
c) Carefully select the form in which the drug is to be administered.
d) Check liver and kidney function before and during drug administration, as even an otherwise
non-cumulative drug would produce cumulation in the presence of hepatic and renal
damage.

9) Drug tolerance: When an unusually large dose of a drug is required to elicit an effect
ordinarily produced by the normal therapeutic dose of the drug, the phenomenon is termed as
drug tolerance.

Tachyphylaxis: Rapid development of tolerance on repeated administration is called

tachyphylaxis e.g. Ephedrine, amphetamine and nitroglycerine which produce tachyphylaxis on
repeated administration.

10) Emotional factors. eg. Placebo response.

Placebo: It is a Latin word meaning” I shall please” and it is a tablet looking exactly like the
active treatment but containing no active component. It refers originally to substances merely to
please the patient when no specific treatment was available.

B. Adverse drug reactions: The drugs that produce useful therapeutic effect may also produce
unwanted or toxic effects. It has been estimated that about 0.5% of patients who die in hospitals
do so as a result of their treatment rather than the condition for which they were treated. Serious
systemic drug toxicity may result from overdoses. If is always an exaggeration of its
pharmacological actions and some times it is predictable. e.g. Hypotension following
antihypertensive drugs. Hypoglycaemia following insulin. An adverse drug reaction is defined
as any response to a drug that is noxious and unintended and that occurs at doses used in man for
prophylaxis, diagnosis or therapy (WHO). The adverse effects are

a) 1)Side effects
b) 2)untoward effects
c) 3)allergic reactions
d) 4)idiosyncratic reactions
e) 5)teratogenic effects.

1) Side effects: Side effects are infact pharmacological effects produced with therapeutic dose
of the drug. e.g: Dryness of mouth with atropine which is troublesome in peptic ulcer patients
and useful when used as a preanaesthetic medication.

2) Untoward effects: Untoward effects develop with therapeutic dose of a drug. They are
undesirable and if very severe, may necessitate the cessation of treatment. e.g: Diarrhoea with
ampicillin and potassium loss with diuretics.

3) Allergic reactions: Most of the drugs and sera used in therapeutics are capable of causing
allergic or hypersensitive reactions. These reactions may be mild or very severe like
anaphylaxis. When an individual has been sensitized to an antigen (allergen) further contact with
that antigen can some times lead to tissue damaging reactions. These allergic reactions are 4
types.

• Type-I reactions or anaphylactic reactions (Immediate hypersensitive reaction).

• Type-II reactions or cytotoxic reactions.
• Type-III reactions or immune complex mediated reactions.
• Type-IV reactions or cell mediated reactions (Delayed hypersensitive reactions).

4) Idiosyncratic reactions: The term idiosyncrasy means one’s peculiar response to drugs. With
the increasing knowledge of pharmacogenetics, many idiosyncratic reactions have been found to
be genetically determined. e.g: Drugs like primaquine, sulfonamides and dapsone may cause
haemolysis in patients with glucose -6 phosphate dehydrogenase defeciency.

5) Teratogenic effect: Some drugs given in the first three months of pregnancy may cause
congenital abnormalities and are said to be teratogenic. The best known example is thalidomide
which results in early easily recognizable abnormalities such as absent or grossly abnormal
limbs. Other drugs with teratogenic potential are androgens, steroids, anti convulsants, anti
neoplastic drugs, cortisone, lithium, pencillamine, tricyclic antidepressants and warfarin.

Endogenous agonist: Naturally present in the body and bind to and activate the receptor
Super agonist: Capable of binding to the receptor and producing a greater maximal response
than the endogenous Agonist
Full agonist – The ligands that increase the activity of the receptors & produce the maximal
response . Ex.- Morphine ,mimics the action of endorphins at opioid receptors.
Partial agonist – These ligands partially increase the activity of the receptors but do not produce
the maximal response like full agonist even when present in excess amount. Ex.- Buspirone , is
an anxiolytic drugs , used to treat an anxiety disorder. Partial agonists have a lower intrinsic
activity at receptors than full agonists, allowing them to act either as a functional agonist or a
functional antagonist, depending on the surrounding levels of naturally occurring
neurotransmitter (full agonist).
Inverse agonist – The ligands which decrease the activity of active receptors to their inactive
state. Ex.- Flumazenil drugs acts as a inverse agonist for the GABA receptor & produce
anxiogenic effect. An inverse agonist is a ligand that binds to the same receptor-binding site as
an agonist and not only antagonizes the effects of an agonist but, moreover, exerts the opposite
effect by suppressing spontaneous receptor signaling (when present).

Irreversible agonist: binds and activates the receptor but the binding is permanent; so, this
happens only once and the receptor is essentially destroyed

A full agonist produces a maximal effect under a given set of conditions, whereas a partial
agonist produces a detectable but submaximal effect. Conversely, an inverse agonist produces an
effect opposite to that of an agonist, and inverse agonists can also be “full” or “partial”.

Dose

A dose is an amount of medication you take at one time

Dosage

A dosage is the amount of a medicine or drug that someone takes or should take, and how often
they should take it