Introduction to Pharmacology

Pharmacology: Pharmacology is the study of substances (drugs) and

their interaction with living systems through chemical processes,
especially by binding to regulatory molecules and activating or inhibiting
normal body processes. Most times, these substances are administered
to achieve a beneficial therapeutic effect on some process within the
patient or for their toxic effects on regulatory processes in parasites
infecting the patient. Pharmacology involves the study of the origin or
source, physicochemical properties/chemistry, dosage forms, methods
of administration, absorption, distribution mechanism of action,
biotransformation, excretion, clinical uses and adverse effects of drugs.

Specialties in Pharmacology

Toxicology - Toxicology is the branch of pharmacology that deals with

the undesirable effects of chemicals on living systems, from individual
cells to humans to complex ecosystem

Pharmacogenomics - (pharmacogenetics): It is the study of the genetic

variations that cause differences in drug response among individuals or
populations. Some patients respond to certain drugs with greater than
usual sensitivity to standard doses due to a very small genetic
modification that results in decreased activity of a particular enzyme
responsible for eliminating that drug. The study is concerned with the
genetically mediated variations in drug responses. Some examples of
genetically mediated variations are: Acetylation and hydroxylation of
drugs: The rate of acetylation of INH, dapsone, hydralazine
procainamide and some sulfonamides is controlled by an autosomal
recessive gene and the dosage of these drugs depends up on the
acetylator status of individuals.
Chemotherapy – It is the study of the drugs that are used in the
management and cure of infectious diseases.

Pharmacognosy – The study of drugs from natural products

Ethno-pharmacology – Study of the various therapeutic products e.g.

drugs used by different ethnic groups.

MAIN BRANCHES OF PHARMACOLOGY

Pharmacokinetics:

Study of the absorption, distribution metabolism and excretion (ADME)

of drugs (“i.e what the body does to the drug”).

Pharmacodynamics:

The study of the biological and therapeutic effects of drugs (i.e, “what
the drug does to the body”).

Pharmacokinetics

Pharmacokinetics refers to the process of absorption, distribution,

metabolism and elimination.

ABSORPTION

Drugs are absorbed from their sites of administration into the blood,
distributed via the blood to the tissues and then eliminated. The
concentrations of drugs at their sites of interaction with receptors is
determined by these pharmacokinetic properties. Drugs usually enter
the body at sites remote from the target tissue and are carried by the
circulation to the intended site of action. Before a drug can enter the
bloodstream, it must be absorbed from its site of administration. The
rate and efficiency of absorption differs depending on the route of
administration.
Routes of administration of drugs:

Oral - Maximum convenience but may be slower and less complete than
parenteral (non-oral) routes. Dissolution of solid formulations (e.g.,
tablets) must occur first. The drug must survive exposure to stomach
acid. This route of administration is subject to the first pass effect
(metabolism of a significant amount of drug in the gut wall and the liver,
before it reaches the systemic circulation) Unpredictable absorption
due to degradation by stomach acid and enzymes. However, the oral
route is easier, does not require special equipment and is mostly
preferred by patients. Slow-release preparations may be available to
extend duration of action. Drugs can be formulated in such a way as to
protect them from digestive enzymes, acid, etc. it is unsuitable in
patients who are vomiting or have ileus.

Sublingual – Sublingual administration involves placing a drug under the

tongue. This route permits direct absorption into the systemic venous
circulation thus avoiding the first pass effect. There are connective
tissues beneath the epithelium containing a profusion of capillaries, thus
when a drug is placed under the tongue, the substance will diffuses
through into the venous circulation bypassing "first-pass metabolism" in
the liver. Sublingual administration produces faster absorption.
Nitroglycerin is administered by this route in the treatment of angina.

Rectal - Same advantages as sublingual route; larger amounts are

feasible. Useful for patients who cannot take oral medications (e.g.
because of nausea and vomiting). The haemorrhoidal veins drain directly
into the inferior vena cava, avoiding hepatic first pass metabolism. It
may not be suitable after rectal or anal surgery, also some patients
dislike suppositories.

Intramuscular - Absorption is sometimes faster and more complete than

after oral administration. Large volumes (e.g. 5 - 10 mL) may be given.
Requires an injection. Y6Generally more painful than subcutaneous
injection. Vaccines are usually administered by this route. Absorption
may still be unpredictable if peripheries are poorly perfused. Injections
are painful and may cause bruises, needle phobics and children in
particularly are frightened with the sight of needles.

Subcutaneous - Slower absorption than intramuscular. Large volumes are

not feasible. Onset is more rapid than with oral route. Depending on
formulation can have very long duration of action, e.g. depot
antipsychotics and contraceptives. It requires an injection (Insulin is
administered by this route), the injections can be painful, and
contributes to the generation of medical waste.

Inhalation - For respiratory diseases, this route deposits drug close to

the target organ. When used for systemic administration (e.g., nicotine
in cigarettes, inhaled general anesthetics) it provides rapid absorption
because of the large surface area of the respiratory endothelium.
Bronchodilators and inhaled steroids are administered through this
route. Bioavailability depends on patient’s inhaler technique and the size
of drug particles generated by the delivery technique.

Topical - It is an easy and non-invasive means of drug administration.

Application is made to the skin or mucous membrane of the nose, throat,
airway, or vagina for a local effect. Topical drug administration can
result in significant absorption of drug into the systemic circulation. It
produces high levels of patient satisfaction. However, its limitation is
that most drugs have a high molecular weight and are poorly lipid soluble,
so are not absorbed via skin or mucous membranes, and also it exhibits
very slow absorption.

Transdermal - Application to the skin for systemic effect. Transdermal

preparations generally are patches that stick to the skin and are worn
for a number of hours or even days. To be effective by the transdermal
route, drugs need to be quite lipophilic. Transdermal delivery has a
variety of advantages compared with the oral route. In particular, it is
used when there is a significant first-pass effect of the liver that can
prematurely metabolize drugs. Transdermal delivery also has advantages
over subcutaenous injections. In addition, transdermal systems are non-
invasive and can be self-administered. They can provide release for long
periods of time (up to one week). They also improve patient compliance
and the systems are generally inexpensive. Perhaps the greatest
challenge for transdermal delivery is that only a limited number of drugs
are amenable to administration by this route. With current delivery
methods, successful transdermal drugs have molecular masses that are
only up to a few hundred Daltons, exhibit octanol-water partition
coefficients that heavily favor lipids and require doses of milligrams per
day or less. It has been difficult to exploit the transdermal route to
deliver hydrophilic drugs; the transdermal deliver of peptides and
macromolecules.

Intravenous - Instantaneous and complete absorption (by definition,

100%); potentially more dangerous because the systemic circulation is
transiently exposed to high drug concentrations and drugs administered
cannot be recalled. Dependable and reproducible effects. Entire
administered dose reaches the systemic circulation immediately - the
dosing requires a functioning cannula so as to accurately titrate. More
expensive and labour intensive than other routes. Cannulation is
distressing to some patients, especially children. Cannulae are prone to
infection. IV injection of drugs may cause local reactions.

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.

Factors affecting drug absorption and bioavailability:

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.

iv) 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. 10 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. Nature of the dosage form –

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 administered after food to
minimize the gastrointestinal irritation. But sometimes 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.

DISTRIBUTION

It involves the movement of drug molecules through various body

compartments and across the barriers separating those compartments.
Drugs distribute through various body fluid compartments such as (a)
plasma (b) interstitial fluid compartment (c) trans-cellular compartment.
The distribution of drugs from the site of absorption, through the
bloodstream and to the target tissue depends upon:

1. Blood perfusion rate: The rate at which blood perfuses to different

organs varies widely. The blood flow to the tissue is important in the rate
of uptake of a drug. Tissues that receive a high degree of blood flow
(e.g. brain, kidney) have a fast rate of uptake whereas tissues with a low
degree of blood flow (e.g. adipose tissue) accumulate drug more slowly.

2. Drug Solubility: Some tissues, e.g. brain, have a high lipid content and
dissolve a higher concentration of lipophilic agents.

3. Plasma protein binding: Binding of the drug to macromolecules in the

blood or tissue limits their distribution. Extensive plasma protein binding
will cause more drug to stay in the central blood compartment.
Therefore drugs which bind strongly to plasma protein tend to have
lower volumes of distribution. Only drugs that are unbound to proteins
and other components in the blood are free to diffuse across the cell
membranes into the tissues of the body.

The most important proteins in the blood that can affect the
distribution of a drug include the plasma protein albumin, the alpha-1
acid glycoprotein, and lipoproteins. Acidic drugs commonly bind to
albumin, while basic drugs often bind to alpha1-acid glycoproteins and
lipoproteins. Many endogenous substances, steroids, vitamins, and metal
ions are bound to globulins. However, binding of drugs to plasma proteins
assists absorption, 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; also 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.

4. Physiological barriers: 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

The distribution of pharmaceutical substances to the brain and central

nervous system (CNS) is limited by the blood-brain barrier, which
inhibits the entry of most foreign substances. Some drugs that are lipid-
soluble are able to cross the blood-brain barrier, whereas polar
compounds are not able to enter. Still other pharmaceutical substances
may be able to penetrate the CNS via the brain capillaries and
cerebrospinal fluid.

Of special concern is the ability of drugs to distribute to breast milk in

lactating women, and the ability of drugs to cross the placenta (the
specialized tissue connecting a pregnant woman and her fetus) and
affect the developing fetus. A number of drugs are known to be
teratogens (drugs that cause abnormal fetal development) and should be
avoided in pregnancy. Women taking drugs that are considered unsafe
for infants and that achieve appreciably high concentrations in breast
milk should not breast-feed their infants.

METABOLISM

This is otherwise known as ‘Drug Biotransformation’.

It refers to the metabolic breakdown of xenobiotics usually through

specialized enzymatic systems. At the subcellular level, these enzymes
may be located in the endoplasmic reticulum (ER), mitochondria, cytosol,
lysosomes, or even the nuclear envelope or plasma membrane.

Although every tissue has some ability to metabolize drugs, the liver is
the principal organ of drug metabolism. The liver plays a key role in the
metabolism, digestion, detoxification and elimination of substances from
the body. The family of liver isoenzymes known as Cytochrome P-450 are
responsible for transforming drug components into metabolites. Other
tissues that display considerable activity include the gastrointestinal
tract, the lungs, the skin, the kidneys, and the brain.

Foreign chemicals, drugs and toxins usually require metabolism, a

process that makes them more hydrophilic and usually also destroys
their pharmacologic activity, for elimination.

In general, lipophilic xenobiotics are transformed to more polar and

hence more readily excreted products. For example, lipophilic
barbiturates such as thiopental and pentobarbital would have extremely
long half-lives if it were not for their metabolic conversion to more
water-soluble compounds. As a general principle, metabolic products are
often inactive or less pharmacodynamically active than the parent drug
and may even be inactive. However, some biotransformation products
have enhanced activity or toxic properties. In some cases, with
metabolism of so-called prodrugs, metabolites are actually the active
therapeutic compounds. The best example of a prodrug is
cyclophosphamide, an inert compound which is metabolized by the liver
into a highly active anticancer drug.

These metabolic or transformation reactions are either Phase I and

phase II reactions.

Phase I: These reactions usually convert the parent drug to a more polar
metabolite by introducing or unmasking a functional group (−OH, −NH2,
−SH). These reactions are either hydroxylation, deamination,
epoxidation, dehalogenation, desulfuration e.t.c catalyzed by
cytochrome P450 s. If phase I metabolites are sufficiently polar, they
may be readily excreted. Often these metabolites are inactive, but in
some instances, activity is only modified or even enhanced.

Phase 2: Many phase I products are not eliminated rapidly and undergo
a subsequent reaction in which an endogenous substrate such as
glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with
the newly incorporated functional group to form a highly polar conjugate.
Such conjugation or synthetic reactions are the hallmarks of phase II
metabolism. In general, conjugates are polar molecules that are readily
excreted and often inactive. Conjugate formation involves high-energy
intermediates and specific transfer enzymes.
Glucuronide conjugation: It is the most common and most important
conjugation reaction of drugs. Drugs which contain Hydroxyl, amino or
carboxyl group undergo this process e.g. phenobarbitone.

Sulfate conjugation: Sulfotransferase present in liver, intestinal mucosa

and kidney, which transfers sulfate group to the drug molecules e.g.
phenols, catechols, etc.

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.

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.

Methylation: Adrenaline is methylated to metanephrine by catechol-o-

methyl transferase. Here the source of methyl group is s – adenosyl
methionine.

Metabolism of drugs and other foreign chemicals may not always be an

innocuous biochemical event leading to detoxification and elimination of
the compound. E.g. - acetaminophen-induced hepatotoxicity.
Acetaminophen, an analgesic antipyretic drug, is quite safe in
therapeutic doses (1.2 g/d for an adult). It normally undergoes
glucuronidation and sulfation to the corresponding conjugates, which
together make up 95% of the total excreted metabolites. Little or no
hepatotoxicity results as long as hepatic GSH is available for
conjugation. When acetaminophen intake far exceeds therapeutic doses,
the glucuronidation and sulfation pathways are saturated, hepatic GSH
is depleted faster than it can be regenerated, and a reactive, toxic
metabolite accumulates.

In the absence of intracellular nucleophiles such as GSH, this reactive

metabolite (N - acetyl-benzoiminoquinone) reacts with nucleophilic
groups of cellular proteins, resulting in hepatotoxicity. The chemical and
toxicologic characterization of the electrophilic nature of the reactive
acetaminophen metabolite has led to the development of effective
antidote - N- acetylcysteine.

Administration of N- acetylcysteine within 8–16 hours after

acetaminophen over-dosage has been shown to protect victims from
fulminant hepatotoxicity and death. Administration of GSH is not
effective because it does not cross cell membranes readily.

EXCRETION

Excretion is the process of removing a drug and its metabolites from

the body. It involves the transportation of unaltered or altered form of
drug out of the body. This usually happens in the kidneys via urine
produced in them. Other possible routes include bile, saliva, sweat, tears
and faeces. The major processes of excretion are as follows;

A. Kidney Excretion

The three main events that occur in the kidney are;

1. Glomerular filtration: small drug and metabolite molecules and

those not bound to plasma protein are filtered from the blood.
Large molecules or those bound to plasma protein are poorly
excreted by 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.
2. Tubular secretion: most drugs enter the kidney tubule by tubule
secretion rather than glomerular filtration. The process involves
active transport against a concentration gradient and, therefore,
requires energy and carriers to transport basic drugs such as
dopamine and histamine, and carriers for acidic drugs such as
frusemide and penicillin. 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.
3. Tubule reabsorption: Some drugs and metabolites are absorbed
back into the bloodstream. This does not require energy. It is
passive transport. 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. Bile excretion

Bile excretion involves energy expenditure in active transport across the

epithelium of the bile duct against a concentration gradient. This
transport system can also be saturated if the plasma concentrations of
the drug are high. Bile excretion of drugs mainly takes place where
their molecular weight is greater than 300 and they contain both polar
and lipophilic groups. The glucuronidation of the drug in the kidney also
facilitates bile excretion. Substances with similar physicochemical
properties can block the receptor, which is important in assessing
interactions. A drug excreted in the bile duct can occasionally be
reabsorbed by the intestines (in the entero-hepatic circuit), which can
also lead to interactions with other drugs. 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 backup 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.

Definition of Terms

Clearance - Clearance of a drug is the factor that predicts the rate

of elimination in relation to the drug concentration. Clearance, like
volume of distribution, may be defined with respect to blood (CLb),
plasma (CLp), or unbound in water (CLu), depending on the
concentration measured. Elimination of drug from the body may
involve processes occurring in the kidney, the lung, the liver, and other
organs. Dividing the rate of elimination at each organ by the
concentration of drug presented to it yields the respective clearance
at that organ. 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.

Clearance is the rate at which a drug is eliminated from the blood.

Drugs have different clearance rates. Higher doses of drugs with
high clearance rates may be needed as the drugs are removed from
the blood rapidly by the kidneys. Drugs with low clearance rates mean
that lower doses may be used to maintain the required drug
concentration in the bloodstream.

Halflife: Halflife (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%.
 Kinetics of excretion:

Generally, drug excretion is a first order kinetic process. The rate

at which a drug is excreted is directly proportional to its
concentration in blood plasma. When administering a drug, if the
times between doses are such that the drug is being replaced as
quickly as it is being excreted, a constant drug concentration is
maintained and a steady state is reached.

First order Kinetics: 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. The equation for first order excretion is rate of excretion = k [D]
where, [D] = drug concentration in blood plasma k = rate constant

A graph of log [D] against time is a straight line of gradient k. Half-life

(t½) is the time it takes for the concentration of drug in blood plasma to
halve. For a first order reaction it is a constant value, given by t½ =
0.693k

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.
 Pharmacokinetic Terms

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. Single dose bioavailability test
involves an analysis of plasma or serum concentration of the drug at
various time intervals after its oral administration and plotting a serum
concentration time curve. Bioavailability (F) = AUC= Area under curve –
which provides information about the amount of drug absorbed.

Volume of Distribution:

Volume of distribution (Vd) relates the amount of drug in the body to

the concentration of drug (C) in blood or plasma:

The volume of distribution may be defined with respect to blood, plasma,

or water (unbound drug), depending on the concentration used in
equation (1) (C = Cb, Cp or Cu).

Volume of distribution is thus defined as the volume of fluid required to

contain the total amount Q, of drug in the body at the same
concentration as that present in the plasma, Cp. it also refers to 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.
Vd can vastly exceed any physical volume in the body because it is the
volume apparently necessary to contain the amount of drug
homogeneously at the concentration found in the blood, plasma, or water.
Drugs with very high volumes of distribution (e.g. indomethacin,
Acetaminophen, Diazepam, Lidocaine) have much higher concentrations
in extravascular tissue than in the vascular compartment, i.e. they are
not homogeneously distributed; unlike drugs with low values of Vd, e.g.
0.05 – 0.2 (heparin, insulin, atenolol). It is defined as the ratio of the
drug’s number of molecules in the body (which is known from the total
dosage) divided by the plasma concentration; therefore, it varies
inversely with fraction of the drug that is present in the blood plasma.
The name of this parameter only reflects the fact that it has the
physikjcal dimension of a volume; it is not an actual volume. Indeed, some
very lipophilic drugs have Vd values that are many times greater than
the actual body volume.

PHARMACODYNAMICS

Pharmacodynamics may be defined as a study of actions of drugs on the

body. Experimentally, PDs can be studied through the following means:
i. invitro on isolated cells and tissues
ii. exvivo using cells or tissues previously exposed to a drug in the
intact animal
iii. invivo measuring the response after administration of the drug to
the live animal. Moreover, the PDs of any given drug may be studied
at many different levels from sub-molecular, molecular, cellular,
tissue/ organ system to whole body, i.e. at organism level.
In the whole animal drugs may act on many target molecules in many
tissues. These actions may lead to primary responses which, in turn, may
induce secondary responses, that may either enhance or diminish the
primary response.
When a drug, hormone or neurotransmitter combines with a target
molecule, it is described as a ligand.
Ligands are classified into two groups:
A. Agonists – They bind to the target molecule, producing a
conformational change, which activates transduction pathways
eliciting a biological response.
B. Antagonists - They bind to the target molecule, but produces no
conformational change and therefore no response. The antagonist
can compete with agonist molecules for receptor occupancy and
thereby inhibit their actions.

However, a full agonist is one that elicits the maximal response a tissue
is capable of, whilst a partial agonist has properties intermediate
between those of a full agonist and an antagonist, e.g. morphine and
fentanyl are full agonists capable of inducing strong analgesia, while
naloxone and naltrexone are antagonists producing no analgesia and
buprenorphine, butorphanol and pentazocine are partial agonists. The
latter drugs are used as analgesics, but are not capable of achieving the
level of analgesia provided by maximally effective doses of full agonists.
Indeed, at supramaximal doses the analgesic response is lessened as the
antagonist activity predominates over agonist activity.

RECEPTOR
This refers to the component of a cell or organism that interacts with a
drug and initiates the chain of events leading to the drug’s observed
effects. Receptors are the central focus of investigation of drug
effects and their mechanisms of action (pharmacodynamics).
The receptor’s affinity for binding a drug determines the concentration
of drug required to form a significant number of drug-receptor
complexes, and the total number of receptors may limit the maximal
effect a drug may produce. Thus, receptors are responsible for
selectivity of drug action.
The molecular size, shape, and electrical charge of a drug determine
whether—and with what affinity—it will bind to a particular receptor
among the vast array of chemically different binding sites available in a
cell, tissue, or patient. Accordingly, changes in the chemical structure
of a drug can dramatically increase or decrease a new drug’s affinities
for different classes of receptors, with resulting alterations in
therapeutic and toxic effects.
The forces that attract the drug to its receptor are termed chemical
bonds and they are (a) hydrogen bond (b) ionic bond (c) covalent bond (d)
Vander waals force. Covalent bond is the strongest bond and the drug-
receptor complex is usually irreversible. K1 K3 DR Biological effect D+R
K2 Where D = Drug, R= receptor DR= Drug receptor complex (affinity)
K1 = association constant K2 = dissociation constant K3 = intrinsic
activity.

When first messengers like neurotransmitters, hormones, autacoids and

most of drugs bind with their specific receptors, the drug receptor
complex is formed which subsequently causes the synthesis and release
of another intracellular regulatory molecule termed as second
messengers e.g. cyclic AMP, calcium, cyclic GMP, inositol triphosphate
(IP3), diacylglycerol and calmodulin which in turn produce subcellular or
molecular mechanism of drug action.

NATURE AND CLASSIFICATION OF DRUG RECEPTORS

Most receptors are proteins, presumably because the structures of
polypeptides provide both the necessary diversity and the necessary
specificity of shape and electrical charge. Receptors vary greatly in
structure and can be identified in many ways. Most receptors are
proteins (e.g., enzymes, hormone and neurotransmitter receptors); in
addition, some DNA and RNA molecules serve as drug binding targets. A
successful receptor must distinguish between different ligands. That is,
it must bind selectively to certain ligands. In many cases, drugs bind to
a site on a protein that normally binds to an endogenous small molecule
or protein.

The best-characterized drug receptors are regulatory proteins, which

mediate the actions of endogenous chemical signals such as
neurotransmitters, autacoids, and hormones. This class of receptors
mediates the effects of many of the most useful therapeutic agents.
Other classes of proteins that have been clearly identified as drug
receptors include enzymes, which may be inhibited (or, less commonly,
activated) by binding a drug (eg, dihydrofolate reductase, the receptor
for the antineoplastic drug methotrexate); transport proteins (eg, Na +
/K + -ATPase, the membrane receptor for cardioactive digitalis
glycosides); and structural proteins (eg, tubulin, the receptor for
colchicine, an anti-inflammatory agent).
Receptors may be classified in various ways;
by location e.g. pre-synaptic,
by consequence of interaction, e.g. stimulation or inhibition of an
enzyme;
by secondary chemical messenger involved in the transduction pathway
e.g. cyclic GMP or AMP;
by structure, that is amino acid sequence.
Receptors mediate the actions of pharmacologic agonists and
antagonists.
 Agonism / Antagonism
Agonism: Some drugs and many natural ligands, such as hormones and
neurotransmitters, regulate the function of receptor macromolecules as
agonists; this means that they activate the receptor to signal as a direct
result of binding to it. Some agonists activate a single kind of receptor
to produce all their biologic functions, whereas others selectively
promote one receptor function more than another.
Antagonism: it is the binding of a molecule to a pharmacological receptor
to render that receptor unable to respond to agonists. Antagonism can
be surmountable such that an excessive concentration of agonist can
overcome the antagonism produced by a given concentration of
antagonist; this is often, but not necessarily always, the result of
competition of the agonist and antagonist for the same binding site on
the receptor. Antagonism also can be insurmountable in that no amount
of agonist is able to overcome the effects of the antagonist.

General Classes of Antagonists

Chemical Antagonists: One drug may antagonize the action of a second
by binding to and inactivating the second drug. e.g. protamine (a
positively charged protein at physiologic pH) binds (sequesters) heparin
(a negatively charged anticoagulant) making it unavailable for
interactions with proteins involved in the formation of blood clots.
Physiological Antagonists: These take advantage of physiologic
antagonism between endogenous regulatory pathways. E.g. the catabolic
actions of glucocorticoids lead to increased blood sugar - an effect
opposed by insulin. While glucocorticoids and insulin act on quite
different pathways, insulin is sometimes administered to oppose the
hyperglycemic action of glucocorticoid hormone - whether resulting
from increased endogenous synthesis (e.g. a tumor of the adrenal
cortex) or as a result of glucocorticoid therapy.
Pharmacological Antagonists: Drugs that bind to receptors but do not
alter receptor function. These antagonists may block the ability of
agonists to bind to the receptor by competing for the same receptor
site or may bind to another site on the receptor that blocks the action
of the agonist. In both cases, the biological actions of the agonist are
prevented.
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: Another type of antagonism is physiologic

antagonism between endogenous regulatory pathways mediated by
different receptors. For example, several catabolic actions of the
glucocorticoid
hormones lead to increased blood sugar, an effect that is physiologically
opposed by insulin. Although glucocorticoids and insulin act on quite
distinct receptor-effector systems, the clinician must sometimes
administer insulin to oppose the hyperglycemic effects of a
glucocorticoid hormone, whether the latter is elevated by endogenous
synthesis (eg, a tumor of the adrenal cortex) or as a result of
glucocorticoid therapy. In general, use of a drug as a physiologic
antagonist produces effects that are less specific and less easy to
control than are the effects of a receptor-specific antagonist. Thus, for
example, to treat bradycardia caused by increased release of
acetylcholine from vagus nerve endings, the physician could use
isoproterenol, a β-adrenoceptor agonist that increases heart rate by
mimicking sympathetic stimulation of the heart. However, use of this
physiologic antagonist would be less rational—and potentially more
dangerous—than would use of a receptor-specific antagonist such as
atropine (a competitive antagonist at the receptors at which
acetylcholine slows heart rate).
They bind to receptors but do not activate generation of a signal;
consequently, they interfere with the ability of an agonist to activate
the receptor. The effect of a so-called “pure” antagonist on a cell or in
a patient depends entirely on its preventing the binding of agonist
molecules and blocking their biologic actions. 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
whereas adrenaline causes dilatation of pupil.
Competitive and Irreversible Antagonists
Receptor antagonists bind to the receptor but do not activate it. In
general the effects of these antagonists result from preventing agonists
from binding to and activating receptors.
Antagonists may be competitive (reversibly displaced by agonists) or
noncompetitive (not reversibly displaced by agonists). e.g. of a
competitive β-adrenoceptor antagonist - propranolol (the endogenous
adrenergic receptor agonists are norepinephrine and epinephrine
Also when propranolol is administered at moderate doses sufficient to
block the effect of basal levels of the neurotransmitter norepinephrine,
resting heart rate is decreased. However, the increase in the release of
norepinephrine and epinephrine that occurs with exercise, postural
changes, or emotional stress may suffice to overcome this competitive
antagonism. Accordingly, the same dose of propranolol may have little
effect under these conditions, thereby altering therapeutic response.

Some receptor antagonists bind to the receptor in an irreversible or

nearly irreversible fashion, either by forming a covalent bond with the
receptor or by binding so tightly that, for practical purposes, the
receptor is unavailable for binding of agonist. After occupancy of some
proportion of receptors by such an antagonist, the number of remaining
unoccupied receptors may be too low for the agonist (even at high
concentrations) to elicit a response comparable to the previous maximal
response. If spare receptors are present, however, a lower dose of an
irreversible antagonist may leave enough receptors unoccupied to allow
achievement of maximum response to agonist, although a higher agonist
concentration will be required. Therapeutically, irreversible antagonists
present distinct advantages and disadvantages. Once the irreversible
antagonist has occupied the receptor, it need not be present in unbound
form to inhibit agonist responses. Consequently, the duration of action
of such an irreversible antagonist is relatively independent of its own
rate of elimination and more dependent on the rate of turnover of
receptor molecules. Phenoxybenzamine, an irreversible α-adrenoceptor
antagonist, is used to control the hypertension caused by catecholamines
released from pheochromocytoma, a tumor of the adrenal medulla. If
administration of phenoxybenzamine lowers blood pressure, blockade
will be maintained even when the tumor episodically releases very large
amounts of catecholamine. In this case, the ability to prevent responses
to varying and high concentrations of agonist is a therapeutic advantage.
If overdose occurs, however, a real problem may arise. If the α-
adrenoceptor blockade cannot be overcome, excess effects of the drug
must be antagonized “physiologically,” ie, by using a pressor agent that
does not act via α receptors.
Antagonists can function noncompetitively in a different way; that is, by
binding to a site on the receptor protein separate from the agonist
binding site, and thereby modifying receptor activity without blocking
agonist binding. Although these drugs act noncompetitively, their actions
are reversible if they do not bind covalently. Such drugs are often called
allosteric modulators. For example, benzodiazepines bind
noncompetitively to ion channels activated by the neurotransmitter γ-
aminobutyric acid (GABA), enhancing the net activating effect of GABA
on channel conductance.
Partial Agonists - Based on the maximal pharmacologic response that
occurs when all receptors are occupied, agonists can be divided into two
classes: partial agonists produce a lower response, at full receptor
occupancy, than do full agonists.
Partial agonists produce concentration-effect curves that resemble
those observed with full agonists in the presence of an antagonist that
irreversibly blocks some of the receptor sites. Many drugs used clinically
as antagonists are actually weak partial agonists. For example,
buprenorphine, a partial agonist of μ-opioid receptors, is a generally
safer analgesic drug than morphine because it produces less respiratory
depression in overdose. Buprenorphine is effectively antianalgesic when
administered to morphine-dependent individuals, however, and may
precipitate a drug withdrawal syndrome due to competitive inhibition of
morphine’s agonist action.
However, not all the mechanisms of antagonism involve interactions of
drugs or endogenous ligands at a single type of receptor, and some types
of antagonism do not involve a receptor at all.
For example, protamine, a protein that is positively charged at
physiologic pH, can be used clinically to counteract the effects of
heparin, an anticoagulant that is negatively charged. In this case, one
drug acts as a chemical antagonist of the other simply by ionic binding
that makes the other drug unavailable for interactions with proteins
involved in blood clotting.
Drug Synergism

When the therapeutic effect 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

DRUG CONCENTRATION & RESPONSE RELATIONSHIP

The relationship between dose of a drug and the clinically observed
response may be complex, but in carefully controlled in vitro systems,
this relationship has been described with mathematical precision. This
idealized relation underlies the more complex relations between dose
and effect that occur when drugs are given to patients.
Generally, responses to low doses of a drug increase in direct proportion
to dose. As doses increase, however, the response increment diminishes;
finally, doses may be reached at which no further increase in response
can be achieved. In idealized or in vitro systems, the relation between
drug concentration and effect is described by a hyperbolic curve.
Concentration-Response Relationship:

The therapeutic and toxic effects of drugs are determined by their

concentration in the vicinity of drug receptors. At high concentrations,
effects plateau and further increases in drug concentration do not
produce greater effects.

Site of drug action:

A drug may act:

(i) Extracellularly e.g: osmotic diuretics, plasma expanders.

(ii) On the cell surface e.g.: digitalis, penicillin, catecholamines
(iii) Inside the cell e.g.: anti-cancer drugs, steroid hormones.

Structural activity relationship

The activity of a drug is intimately related to its chemical structure.

Knowledge about the chemical structure of a drug is useful for:

(i) Synthesis of new compounds with more specific actions and

fewer adverse reactions
(ii) Synthesis of competitive antagonist
(iii) Understanding the mechanism of drug action. Slight
modification of structure of the compound can change the
effect completely.
 PHARMADYNAMIC TERMS
Affinity - Affinity is the property of attraction between a drug and a
receptor. It is usually represented as the reciprocal of the dissociation
constant of the agonist–receptor complex. A drug, which is able to fit
onto a receptor, is said to have affinity for that receptor.

Efficacy - The term efficacy, e, is used to characterize and quantify

the ability of agonists to induce a response. For a full agonist acting on
a specific receptor e = 1, as it induces the maximal response the tissue
is capable of following activation of that receptor type. For a partial
agonist e can have any numerical value greater than 0 but less than 1,
while for a pure antagonist the value of e is 0.

Thus, efficacy is the ability of a drug to produce an effect at a receptor.

An agonist has both an affinity and efficacy whereas antagonist has

affinity but not efficacy or intrinsic activity.
Potency – it is used to describe and quantify the amount of drug
(expressed in molecular units) required to elicit any given level of
response; the lower the concentration required the greater the potency.

• Minimal dose - The lowest concentration of a drug that elicits a

response
• Maximal dose – The largest concentration after which further
increase in concentration will not change the response
• EC50 or ED50 - The concentration that is required to produce 50
% of the maximum effect.
• Median lethal dose or LD50 - This is the dose (mg/kg), which would
be expected to kill one half of a population of the same species and
strain.
• Median effective dose or ED50 - This is the dose (mg/kg), which
produces a desired response in 50 per cent of test population.
• Therapeutic index: It is an approximate assessment of the safety
of the drug. It is the ratio of the median lethal dose and the
median effective dose. Also called as therapeutic window or safety.
The larger the therapeutic index, the safer is the drug. Penicillin
has a very high therapeutic index, while digitalis has a very low T.I.