General

Pharmacology

• INTRODUCTION AND SOURCES OF DRUGS

• ROUTES OF DRUG ADMINISTRATION
• PHARMACOKINETICS
• PHARMACODYNAMICS
• ADVERSE DRUG REACTIONS
• DRUG INTERACTIONS
• GENE THERAPY

INTRODUCTION AND SOURCES OF DRUGS like’ and dilution enhances the action of drugs.
Thus, several systems of therapeutics were
Pharmacology is the science that deals with the introduced, of which only few survived. The basic
study of drugs and their interaction with the living reason for failure of many systems is that man’s
systems. concepts about diseases were incorrect and
Early man recognized the benefits and toxic baseless in those days. By the end of the 17th
effects of many plants and animal products. century the importance of experimentation and
India’s earliest pharmacological writings are from observation became clear and many physicians
the ‘Vedas.’ An ancient Indian physician Charaka applied these to the traditional drugs. Francois
and then Sushruta and Vagbhata described many Magendie and Claude-Bernard popularized the
herbal preparations included in ‘Ayurveda’ use of animal experiments to understand the
(meaning the science of life). James Gregory effects of drugs. The development of physiology
recommended harsh and dangerous remedies like also helped in the better understanding of
blood-letting, emetics and purgatives to be used pharmacology. The last century has seen a rapid
until the symptoms of the disease subsided (such growth of the subject with new concepts and
remedies often resulted in fatality). This was called techniques being introduced.
‘Allopathy’ meaning the other suffering. This
word, still being used for the modern system of
DEFINITIONS
medicine, is a misnomer. To counter this system,
Hannemann introduced the system of Homoeo- The word pharmacology is derived from the Greek
pathy meaning similar suffering in the early 19th word—Pharmacon meaning an active principle or
century. The principles of this include ‘like cures drug and logos meaning a discourse or study.
 2 Pharmacology for Physiotherapy

Drug (Drogue—a dry herb in French) is a substance SOURCES OF DRUGS

used in the diagnosis, prevention or treatment of
The sources of drugs could be natural or synthetic.
a disease. WHO definition—“A Drug is any
substance or product that is used or intended to
be used to modify or explore physiological systems Natural Sources
or pathological states for the benefit of the Drugs can be obtained from:
recipient.” 1. Plants, e.g. atropine, morphine, quinine, and
Pharmacodynamics is the study of the effects of digoxin.
the drugs on the body and their mechanisms of 2. Animals, e.g. insulin, heparin, gonado-
action, i.e. what the drug does to the body. trophins and antitoxic sera.
3. Minerals, e.g. magnesium sulphate, alumi-
Pharmacokinetics is the study of the absorption,
nium hydroxide, iron, sulphur and radio-
distribution, metabolism and excretion of drugs,
active isotopes.
i.e. what the body does to the drug (in Greek
4. Microorganisms—antibacterial agents are
Kinesis = movement).
obtained from some bacteria and fungi. We
Therapeutics deals with the use of drugs in the thus have penicillin, cephalosporins, tetra-
prevention and treatment of diseases. cyclines and other antibiotics.
5. Human—some drugs are obtained from
Toxicology deals with the adverse effects of drugs
human beings, e.g. immunoglobulins from
and also the study of poisons, i.e. detection,
blood, growth hormone from anterior
prevention and treatment of poisonings
pituitary and chorionic gonadotrophins
(Toxicon = poison in Greek).
from the urine of pregnant women.
Chemotherapy is the use of chemicals for the
treatment of infections. The term now also includes Synthetic
the use of chemical compounds to treat
malignancies. Most drugs are now synthesized, e.g. quinolones,
omeprazole.
Pharmacopoeia (In Greek Pharmacon = drug;
Many drugs are obtained by cell cultures, e.g.
poeia=to make) is the official publication con-
urokinase from cultured human kidney cells.
taining a list of drugs and medicinal preparations
Some are now produced by recombinant DNA
approved for use, their formula and other
technology, e.g. human insulin, tissue plasmi-
information needed to prepare a drug; their
nogen activator.
physical properties, tests for their identity, purity
and potency. Each country may follow its own
pharmacopoeia to guide its physicians and ROUTES OF DRUG ADMINISTRATION
pharmacists. We thus have the Indian Pharma-
Drugs may be administered by various routes. The
copoeia (IP), the British Pharmacopoeia (BP) and
choice of the route in a given patient depends on
the United States Pharmacopoeia (USP). The list
the properties of the drug and the patient’s
is revised at regular periods to delete old useless
requirements. A knowledge of the advantages and
drugs and to include newly introduced ones.
disadvantages of the different routes of adminis-
Pharmacy is the science of identification, tration is essential.
compounding and dispensing of drugs. It also The routes can be broadly divided into:
includes collection, isolation, purification, • Enteral
synthesis and standardization of medicinal • Parenteral
substances. • Local.
 General Pharmacology 3

ENTERAL ROUTE (ORAL INGESTION) minimizes chances of the drug getting into larynx
or behind the epiglottis. Recumbent patient
This is the most common, oldest and safest route
should not be given drugs orally as some drugs
of drug administration. The large surface area of
may remain in the esophagus due to the absence
the gastrointestinal tract, the mixing of its contents
of gravitational force which facilitates the passage
and the differences in pH at different parts of the
of the drug into the stomach. Such drugs can
gut facilitate effective absorption of the drugs given
damage the esophageal mucosa, e.g. iron salts,
orally. However, the acid and enzymes secreted
tetracyclines.
in the gut and the biochemical activity of the
bacterial flora of the gut can destroy some drugs
Enteric Coated Tablets
before they are absorbed.
Some tablets are coated with substances like
Advantages cellulose-acetate, phthalate, gluten, etc. which are
1. Safest route. not digested by the gastric acid but get disinte-
2. Most convenient. grated in the alkaline juices of the intestine. This
3. Most economical. will:
4. Drugs can be self-administered. 1. Prevent gastric irritation.
5. Non-invasive route. 2. Avoid destruction of the drug by the stomach.
Disadvantages 3. Provide higher concentration of the drug in
1. Onset of action is slower as absorption needs the small intestine.
time. 4. Retard the absorption, and thereby prolong
2. Irritant and unpalatable drugs cannot be the duration of action. But if the coating is
administered. inappropriate, the tablet may be expelled
3. Some drugs may not be absorbed due to certain without being absorbed at all. Similarly,
physical characteristics, e.g. streptomycin. controlled-release or sustained-release
4. Irritation to the gastrointestinal tract may lead preparations are designed to prolong the rate
to vomiting. of absorption and thereby the duration of
5. There may be irregularities in absorption. action of drugs. This is useful for short-acting
6. Some drugs may be destroyed by gastric juices, drugs.
e.g. insulin. Advantages
7. Cannot be given to unconscious and unco- • Frequency of administration may be reduced.
operative patients. • Therapeutic concentration may be maintained
8. Some drugs may undergo extensive first pass specially when nocturnal symptoms are to be
metabolism in the liver. treated.
To overcome some of the disadvantages,
Disadvantages
irritants are given in capsules, while bitter drugs
• There may be ‘failure of the preparation’
are given as sugar coated tablets. Sometimes drugs
resulting in release of the entire amount of the
are coated with substances like synthetic resins,
drug in a short-time leading to toxicity.
gums, sugar, coloring and flavoring agents
• It is more expensive.
making them more acceptable.
Certain precautions are to be taken during oral
PARENTERAL ROUTE
administration of drugs—capsules and tablets
should be swallowed with a glass of water with Routes of administration other than the enteral
the patient in upright posture either sitting or stan- (intestinal) route are known as parenteral routes.
ding. This facilitates passage of the tablet into the Here the drugs are directly delivered into tissue
stomach and its rapid dissolution. It also fluids or blood.
 4 Pharmacology for Physiotherapy

Advantages can be enhanced by the addition of the enzyme

• Action is more rapid and predictable than oral hyaluronidase.
administration.
Disadvantages
• These routes can be employed in an
• As SC tissue is richly supplied by nerves,
unconscious or uncooperative patient.
irritant drugs can cause severe pain. Hence
• Gastric irritants can be given parenterally and
such drugs cannot be injected.
therefore irritation to the gastrointestinal tract
• In shock, absorption is not dependable
can be avoided.
because of vasoconstriction.
• It can be used in patients with vomiting or
• Repeated injections at the same site can cause
those unable to swallow.
lipoatrophy resulting in erratic absorption.
• Digestion by the gastric and intestinal juices
and the first pass metabolism are avoided. Hypodermoclysis is the SC administration of large
Therefore, in emergencies parenteral routes are volumes of saline employed in pediatric practice.
very useful routes of drug administration as the
Drugs can also be administered subcu-
action is rapid and predictable and are useful in
taneously as:
unconscious patients.
1. Dermojet In this method, a high velocity jet of
Disadvantages drug solution is projected from a fine orifice
• Asepsis must be maintained. using a gun. The solution gets deposited in
• Injections may be painful. the SC tissue from where it is absorbed. As
• More expensive, less safe and inconvenient. needle is not required, this method is painless.
• Injury to nerves and other tissues may occur. It is suitable for vaccines.
2. Pellet implantation Small pellets packed with
Parenteral routes include: drugs are implanted subcutaneously. The
1. Injections. drug is slowly released for weeks or months to
2. Inhalation. provide constant blood levels, e.g. testosterone.
3. Transdermal route. 3. Sialistic implants The drug is packed in sialistic
4. Transmucosal route. tubes and implanted subcutaneously. The
drug gets absorbed over months to provide
INJECTIONS constant blood levels, e.g. hormones and
contraceptives. The empty non-biodegradable
Intradermal
implant has to be removed.
The drug is injected into the layers of the skin
raising a bleb, e.g. BCG vaccine, tests for allergy or Intramuscular (IM)
by multiple punctures of the epidermis through a
drop of the drug, e.g. smallpox vaccine. Only a Aqueous solution of the drug is injected into one
small quantity can be administered by this route of the large skeletal muscles—deltoid, triceps,
and it may be painful. gluteus or rectus femoris. As the muscles are
vascular, absorption is rapid and quite uniform.
Drugs are absorbed faster from the deltoid region
Subcutaneous (SC) Injection
than gluteal region especially in women. The
Here the drug is deposited in the SC tissue, e.g. volume of injection should not exceed 10 ml. For
insulin, heparin. As this tissue is less vascular, infants, rectus femoris is used instead of gluteus
absorption is slow and largely uniform making which is not well-developed till the child starts
the drug long-acting. It is reliable and patients walking. If the drug is injected as an oily solution,
can be trained for self-administration. Absorption absorption is slow and steady.
 General Pharmacology 5

Advantages rate can be increased—specially for short-

• Intramuscular route is reliable. acting drugs.
• Absorption is rapid.
• Soluble substances, mild irritants, depot Disadvantages
preparations, suspensions and colloids can • Once injected into the vein, the drug cannot be
be injected by this route. withdrawn.
• Irritation of the veins may cause thrombo-
Disadvantages phlebitis.
• Intramuscular injection may be painful and • Extravazation of some drugs may cause severe
may even result in an abscess. irritation and sloughing.
• Nerve injury should be avoided near a nerve, • Only aqueous solutions can be given IV but
irritant solutions can damage the nerve if not suspensions, oily solutions and depot
injected. preparations.
• Self medication is difficult.
Intravenous (IV)
Intraperitoneal
Here, the drug is injected into one of the superficial
veins so that it directly reaches the circulation and Peritoneum offers a large surface area for absorp-
is immediately available for action. tion. Fluids are injected intraperitoneally in
infants. This route is also used for peritoneal
Drugs can be given IV as:
dialysis.
1. A bolus—where an initial large dose is
given, e.g. heparin. The drug is dissolved Intrathecal
in a suitable amount of the vehicle and
Drugs can be injected into the subarachnoid space
injected slowly.
for action on the CNS, e.g. spinal anesthetics. Some
2. Slowly—over 15-20 minutes, e.g. amino-
antibiotics and corticosteroids are also injected
phylline.
by this route to produce high local concentrations.
3. Slow infusion—when constant plasma
Strict aseptic precautions are a must.
concentrations are required, e.g. oxytocin
Drugs are also given extradurally. Morphine
in labor or when large volumes have to be
can be given epidurally to produce analgesia.
given, e.g. dextrose, saline. Generally about
one liter of solution is infused over 3 to 4 Intra-articular
hours. But the patients condition dictates
Drugs are injected directly into a joint for the treat-
the rate of infusion.
ment of arthritis and other diseases of the joints.
Advantages Strict aseptic precautions are required, e.g.
• Most useful route in emergencies as the drug hydrocortisone in rheumatoid arthritis.
is immediately available for action.
Intra-arterial
• Provides predictable blood concentrations
with 100 percent bioavailability. Here drug is injected directly into the arteries. It is
• Large volumes of solutions can be given. used only in the treatment of (i) peripheral
• Irritants can be given by this route as they get vascular diseases, (ii) local malignancies and
quickly diluted in the blood. (iii) diagnostic studies like angiograms.
• Rapid dose adjustments are possible—if
unwanted effects occur, infusion can be Intramedullary
stopped; if higher levels are required, infusion Injection into a bone marrow—now rarely used.
 6 Pharmacology for Physiotherapy

INHALATION application. The drug slowly diffuses through the

membrane and percutaneous absorption takes
Volatile liquids and gases are given by inhalation,
place. The rate of absorption is constant and
e.g. general anesthetics. In addition, drugs can be
predictable. Highly potent and short acting drugs
administered as solid particles, i.e. solutions of
are suitable for use in such systems.
drugs can be atomized and the fine droplets are
Sites of application are chest, abdomen, upper
inhaled as aerosol, e.g. salbutamol. These inhaled
arm, back or mastoid region, e.g. hyoscine,
drugs and vapors may act on the pulmonary
nitroglycerine, fentanyl transdermal patches.
epithelium and mucous membranes of the
respiratory tract and are also absorbed through Advantages
these membranes. • Duration of action is prolonged
Advantages • Provides constant plasma drug levels
• Almost instantaneous absorption of the drug • Patient compliance is good.
is achieved because of the large suface area of Inunction This route where a drug rubbed into the
the lungs. skin gets absorbed to produce systemic effects is
• In pulmonary diseases, it serves almost as a called inunction.
local route as the drug is delivered at the
Iontophoresis In this procedure, galvanic current
desired site making it more effective and less
is used for bringing about penetration of lipid
harmful.
insoluble drugs into the deeper tissues where its
• First pass metabolism is avoided.
action is required, e.g. Salicylates.
• Blood levels of volatile anesthetics can be
conveniently controlled as their absorption Jet injection As absorption of drug occurs across
and excretion through the lungs are governed the layers of the skin, dermojet may also be
by the laws of gases. considered as a form of transdermal drug
administration (description on page 4).
Disadvantages
• Irritant gases may enhance pulmonary
TRANSMUCOSAL
secretions-should be avoided.
• This is an important route of entry of certain Drugs are absorbed across the mucous mem-
drugs of abuse. branes. Transmucosal administration includes
sublingual, nasal and rectal routes.
TRANSDERMAL
Sublingual
Highly lipid soluble drugs can be applied over
the skin for slow and prolonged absorption, e.g. Here, the tablet or pellet containing the drug is
nitroglycerine ointment in angina pectoris. placed under the tongue. It dissolves in the saliva
Adhesive units, inunction, iontophoresis and jet and the drug is absorbed across the sublingual
injection are some forms of transdermal drug mucosa, e.g. nitroglycerine, nifedipine,
delivery. buprenorphine.
Adhesive units (transdermal therapeutic systems) Advantages
are adhesive patches of different sizes and shapes • Absorption is rapid—within minutes the drug
made to suit the area of application. The drug is reaches the circulation.
held in a reservoir between an outer layer and a • First pass metabolism is avoided.
porous membrane. This membrane is smeared • After the desired effect is obtained, the drug
with an adhesive to hold on to the area of can be spat out to avoid the unwanted effects.
 General Pharmacology 7

Disadvantage Evacuant enema In order to empty the bowel,

Buccal ulceration can occur. about 600 ml of soap water is administered per
rectally. Water distends and thus stimulates the
Nasal rectum while soap lubricates. Enema is given prior
to surgeries, obstetric procedures and radiological
Drugs can be administered through nasal route
examination of the gut.
either for systemic absorption or for local effects,
Retention enema The drug is administered
e.g.
with about 100 ml of fluids and is retained in the
• Oxytocin spray is used for systemic absorption.
rectum for local action, e.g. prednisolone enema
• For local effect
in ulcerative colitis.
– Decongestant nasal drops, e.g. oxymeta-
zoline;
– Budesonide nasal spray for allergic rhinitis. TOPICAL
Drugs may be applied on the skin for local action
Rectal as ointment, cream, gel, powder, paste, etc. Drugs
Rectum has a rich blood supply and drugs can may also be applied on the mucous membrane as
cross the rectal mucosa to be absorbed for systemic in the eyes, ears and nose, as ointment, drops and
effects. Drugs absorbed from the upper part of the sprays. Drugs may be administered as suppository
rectum are carried by the superior hemorrhoidal for rectum, bougie for urethra and pessary and
vein to the portal circulation (can undergo first douche for vagina. Pessaries are oval shaped
pass metabolism), while that absorbed from the tablets to be placed in the vagina to provide high
local concentrations of the drug at the site, e.g.
lower part of the rectum is carried by the middle
antifungal pessaries in vaginal candidiasis.
and inferior hemorrhoidal veins to the systemic
circulation.
Special Drug Delivery Systems
Some irritant drugs are given per rectally as
suppositories: In order to improve drug delivery, to prolong
Advantages duration of action and thereby improve patient
• Gastric irritation is avoided. compliance, special drug delivery systems are
• Can be administered by unskilled persons. being tried. Drug targeting, i.e. to deliver drugs at
• Useful in geriatric patients and others with the site where it is required to act is also being
vomiting and those unable to swallow. aimed at, especially for anticancer drugs. Some
such systems are ocusert, progestasert, trans-
Disadvantages
dermal adhesive units, prodrugs, osmotic pumps,
• Irritation of the rectum can occur.
computerized pumps and methods using
• Absorption may be irregular and unpredic-
monoclonal antibodies and liposomes as carriers.
table.
• Drugs like—indomethacin, chlorpromazine, Ocusert systems are thin elliptical units that
diazepam and paraldehyde can be given contain the drug in a reservoir which slowly
rectally. releases the drug through a membrane by
diffusion at a steady rate, e.g. pilocarpine ocusert
Drugs may also be given by this route as
used in glaucoma is placed under the lid and can
enema.
deliver pilocarpine for 7 days.
Enema is the administration of a drug in a
liquid form into the rectum. Enema may be Progestasert is inserted into the uterus where it
evacuant or retention enema. delivers progesterone constantly for over one year.
 8 Pharmacology for Physiotherapy

Transdermal Adhesive Units (See page 6). site-specific delivery of drugs may be possible with
the help of liposomes.
Prodrug is an inactive form of the drug which gets
metabolized to the active derivative in the body. A
prodrug may overcome some of the disadvantages PHARMACOKINETICS
of the conventional forms of drug administration, Pharmacokinetics is the study of the absorption,
e.g. dopamine does not cross the BBB; levodopa, a distribution, metabolism and excretion of drugs,
prodrug crosses the BBB and is then converted
-

i.e. the movement of the drugs into, within and

to dopamine in the CNS. Prodrugs may also be out of the body. For a drug to produce its specific
used to have longer duration of action, e.g. response, it should be present in adequate
Bacampicillin (a prodrug of ampicillin) is longer concentrations at the site of action. This depends
acting. on various factors apart from the dose. Once the
drug is administered, it is absorbed, i.e. enters the
Osmotic pumps are small tablet shaped units blood, is distributed to different parts of the body,
consisting of the drug and an osmotic substance reaches the site of action, is metabolized and
placed in two chambers. The osmotic layer swells excreted (Fig. 1.1). All these processes involve
and pushes the drug slowly out of a small hole. passage of the drug molecules across various
Iron and prazosin are available in this form. barriers—like the intestinal epithelium, cell memb-
rane, renal filtering membrane, capillary barrier
Computerized miniature pumps: These are
and so on. To cross these barriers the drug has to
programmed to release drugs at a definite rate
cross the cell membrane or pass in-between the
either continuously as in case of insulin or
epithelial or endothelial cells.
intermittently in pulses as in case of GnRH.
The cell membrane/biological membrane is
Various methods of drug targeting are tried
made up of two layers of phospholipids with
especially for anticancer drugs to reduce toxicity.
intermingled protein molecules (Fig. 1.2). All lipid
Monoclonal antibodies against the tumor specific soluble substances get dissolved in the cell
antigens are used to deliver anticancer drugs to membrane and readily permeate into the cells. The
specific tumor cells. junctions between epithelial or endothelial cells
have pores through which small water-soluble
Liposomes are phospholipids suspended in molecules can pass. Movement of some specific
aqueous vehicles to form minute vesicles. Drugs substances is regulated by special carrier proteins.
encapsulated in liposomes are taken up mainly The passage of drugs across biological
by the reticuloendothelial cells of the liver and membranes involves processes like passive
are also concentrated in malignant tumors. Thus, (filtration, diffusion) and active transport.

Fig. 1.1: Schematic representation of movement of drug in the body

 General Pharmacology 9

Fig. 1.2: Cell/biological membrane (schematic)

Mechanisms of Transport of Drug Across occurs in the direction of the concentration

Biological Membranes gradient. The carrier facilitates diffusion and is
Passive Carrier-mediated Endocytosis highly specific for the substance, e.g. uptake of
transfer transport glucose by cells, vitamin B12 from intestines.
— Simple — Active
diffusion transport Endocytosis

Movement — Filtration — Facilitated

diffusion Endocytosis is the process where small droplets

ofsolute
are engulfed by the cell. Some proteins are taken

Passive Transfer almost

all durrecess
The drug moves across the membrane without any
up by this process (like pinocytosis in amoeba).

ABSORPTION

Fighto need for energy either by simple diffusion in the

direction of its concentration gradient, i.e. from
higher concentration to a lower concentration or
by filtration through aqueous pores in the
Absorption is defined as the passage of the drug
from the site of administration into the circulation.
For a drug to reach its site of action, it must pass
through various membranes depending on the
Low membrane. Most drugs are absorbed by simple route of administration. Absorption occurs by one
diffusion. of the processes described above, i.e. passive
diffusion or carrier-mediated transport. Except for
Carrier-mediated Transport intravenous route, rate and extent of absorption
by all other routes of administration is influenced
Active transport is the transfer of drugs against a
by several factors (Fig. 1.3). They are:
concentration gradient and needs energy. It is

7
1. Disintegration and dissolution time The
carried by a specific carrier protein. Only drugs
drug taken orally should break up into indivi-
related to natural metabolites are transported by
dual particles (disintegrate) to be absorbed.
this process, e.g. levodopa, iron, amino acids.
dependent It then has to dissolve in the gastrointestinal
Facilitated diffusion is a unique form of carrier fluids. In case of drugs given subcutaneously
transport which differs from active transport in or intramuscularly, the drug molecules have
that it is not energy dependent and the movement to dissolve in the tissue fluids. Liquids are

Drug trasport=>
Mose absorption
* Lipid Soluble -

* Water Soluble -

Less absorption
M
10 Pharmacology for Physiotherapy

Fig. 1.3: Factors affecting absorption of drugs

absorbed faster than solids. Delay in should be kept large, e.g. anthelmintics like
disintegration and dissolution as with poorly bephenium hydroxynaphthoate.
water-soluble drugs like aspirin, result in 4. Lipid solubility Lipid soluble drugs are
delayed absorption. absorbed faster and better by dissolving in
2. Formulation Pharmaceutical preparations the phospholipids of the cell membrane.
are formulated to produce desired 5. pH and ionization Ionized drugs are poorly
absorption. Inert substances used with drugs absorbed while unionized drugs are lipid
as diluents like starch and lactose may soluble and are well absorbed. Most drugs
sometimes interfere with absorption. are weak electrolytes and ionise according
3. Particle size Small particle size is important
for better absorption of drugs. Drugs like
to pH. Thus acidic drugs remain unionized -
in acidic medium of the stomach and are Aspirin
corticosteroids, griseofulvin, digoxin, aspirin rapidly absorbed, e.g. aspirin, barbiturates.
and tolbutamide are better absorbed when Basic drugs are unionized when they reach >
Diazepam
-

given as small particles. On the other hand, the alkaline medium of intestine from where
when a drug has to act on the gut and its they are rapidly absorbed, e.g. pethidine,
absorption is not desired, then particle size ephedrine.
 General Pharmacology 11

Strong acids and bases are highly ionized glycerine, propranolol, salbutamol. But for drugs
and therefore poorly absorbed, e.g. strepto- that undergo extensive first pass metabolism, the
mycin. route of administration has to be changed, e.g.
6. Area and vascularity of the absorbing isoprenaline, hydrocortisone, insulin.
surface: The larger the area of absorbing
First pass metabolism
surface and more the vascularity—better is
• is metabolism of a drug during its first passage
the absorption. Thus most drugs are
through gut wall and liver
absorbed from small intestine because it has
• reduces bioavailability
a large surface area for absorption and good
vascularity. • extent of metabolism depends on the drug and
7. Gastrointestinal motility: individuals
Gastric emptying time—if gastric emptying is • consequences:
faster, the passage of the drug to the intestines — dose has to be increased for some drugs like
is quicker and hence absorption is faster. propranolol
— route has to be changed for some others like
Intestinal motility—when highly increased as
hydrocortisone
in diarrheas, drug absorption is reduced.
8. Presence of food: In the stomach delays • Examples: morphine, chlorpromazine, nitro-
glycerine, verapamil, testosterone, insulin,
gastric emptying, dilutes the drug and delays
lignocaine
absorption. Drugs may form complexes with
food constituents and such complexes are
poorly absorbed, e.g. tetracyclines chelate Bioavailability
calcium present in food. Moreover, certain Bioavailability is the fraction of the drug that
drugs like ampicillin, roxithromycin and reaches the systemic circulation following
rifampicin are well-absorbed only on empty administration by any route. Thus for a drug given
stomach. intravenously, the bioavailability is 100 percent.
9. Metabolism: Some drugs may be degraded On IM/SC injection, drugs are almost completely
in the GI tract, e.g. nitroglycerine, insulin. absorbed while by oral route, bioavailability may
Such drugs should be given by alternate be low due to incomplete absorption and first pass
routes. metabolism. Infact all the factors which influence
10. Diseases of the gut like malabsorption and the absorption of a drug also alter bioavailability.
achlorhydria result in reduced absorption of
drugs. Bioequivalence
First pass metabolism is the metabolism of a Comparison of bioavailability of different
drug during its passage from the site of absorption formulations of the same drug is the study of
to the systemic circulation. It is also called bioequivalence. Often oral formulations con-
presystemic metabolism or first pass effect and is taining the same amount of a drug from different
an important feature of oral route of administ- manufacturers may result in different plasma
ration. Drugs given orally may be metabolized in concentrations, i.e. there is no bioequivalence.
the gut wall and in the liver before reaching the Such differences occur with poorly soluble, slowly
systemic circulation. The extent of first pass absorbed drugs mainly due to differences in the
metabolism differs from drug to drug and among rate of disintegration and dissolution. Variation
individuals, from partial to total inactivation. in bioavailability (nonequivalence) can result in
When it is partial, it can be compensated by giving toxicity or therapeutic failure in drugs that have
higher dose of the particular drug, e.g. nitro- low safety margin like digoxin and drugs that need
 12 Pharmacology for Physiotherapy

precise dose adjustment like anticoagulants and example, indomethacin displaces warfarin
corticosteroids. For such drugs, in a given patient, from protein binding sites leading to increased
the preparations from a single manufacturer warfarin levels.
should be used. 5. Chronic renal failure and chronic liver disease
result in hypoalbuminemia with reduced
DISTRIBUTION
protein binding of drugs.
After a drug reaches the systemic circulation, it
Some highly protein bound drugs
gets distributed to other tissues. It should cross
several barriers before reaching the site of action. Warfarin Tolbutamide Phenytoin
Like absorption, distribution also involves the Frusemide Clofibrate Sulfonamides
same processes, i.e. filtration, diffusion and Diazepam Salicylates Phenylbutazone
Indomethacin
specialized transport. Various factors determine
the rate and extent of distribution, viz lipid solu-
bility, ionization, blood flow and binding to Tissue Binding
plasma proteins and cellular proteins. Unionized
lipid soluble drugs are widely distributed Some drugs get bound to certain tissue consti-
throughout the body. tuents because of special affinity for them. Tissue
binding delays elimination and thus prolongs
Plasma Protein Binding duration of action of the drug. For example, lipid
soluble drugs are bound to adipose tissue. Tissue
On reaching the circulation most drugs bind to binding also serves as a reservoir of the drug.
plasma proteins; acidic drugs bind mainly
albumin and basic drugs to alpha-acid glyco- Redistribution
protein. The free or unbound fraction of the drug
When highly lipid soluble drugs are given intra-
is the only form available for action, metabolism
venously or by inhalation, they get rapidly
and excretion while the protein bound form serves
distributed into highly perfused tissues like brain,
as a reservoir. The extent of protein binding varies
heart and kidney. But soon they get redistributed
with each drug, e.g. warfarin is 99 percent and
into less vascular tissues like the muscle and fat
morphine is 35 percent protein bound while
resulting in termination of the action of these
binding of ethosuximide and lithium is 0 percent,
drugs. The best example is the intravenous
i.e. they are totally free.
anesthetic thiopental sodium which induces
anesthesia in 10-20 seconds but the effect stops in
Clinical Significance of Plasma Protein Binding
5-15 minutes due to redistribution.
1. Only free fraction is available for action,
metabolism and excretion. When the free drug Blood-brain Barrier (BBB)
levels fall, bound drug is released.
The endothelial cells of the brain capillaries lack
2. Protein binding serves as a store (reservoir) of
intercellular pores and instead have tight
the drug and the drug is released when free
junctions. Moreover, glial cells envelope the
drug levels fall. capillaries and together these form the BBB. Only
3. Protein binding prolongs duration of action lipid soluble, unionized drugs can cross this BBB.
of the drug. During inflammation of the meninges, the barrier
4. Many drugs may compete for the same binding becomes more permeable to drugs, e.g. penicillin
sites. Thus one drug may displace another from readily penetrates during meningitis. The barrier
the binding sites resulting in toxicity. For is weak at some areas like chemoreceptor triggor
 General Pharmacology 13

zone (CTZ), posterior pituitary and parts of hypo- are easily excreted through the kidneys. Some
thalamus and allows some compounds to diffuse. drugs may be excreted largely unchanged in the
urine, e.g. frusemide, atenolol.
Placental Barrier
Site
Lipid soluble, unionized drugs readily cross the
placenta while lipid insoluble drugs cross to a The most important organ of biotransformation is
much lesser extent. Thus drugs taken by the mother the liver. But drugs are also metabolized by the
can cause several unwanted effects in the fetus. kidney, gut mucosa, lungs, blood and skin.

Volume of Distribution (Vd) Result of Biotransformation

Apparent volume of distribution is defined as the volume Though biotransformation generally inactivates
necessary to accommodate the entire amount of the the drug, some drugs may be converted to active
drug, if the concentration throughout the body were or more active metabolites (Table 1.1).
equal to that in plasma. It relates the amount of the When the metabolite is active, the duration of
drug in the body to the concentration of the drug in action gets prolonged. Prodrug is an inactive drug
plasma. It is calculated as which gets converted into an active form in the
Amount of drug in the body body (Table 1.1).
Vd = ________________________________
Plasma concentration
ACTIVE DRUG
For example, if the dose of a drug given is 500 mg
and attains a uniform concentration of 10 mg in the Metabolism
body, its Vd = 50 liters. Inactive → active → INACTIVATION ← active ← Active
The knowledge of Vd of drugs is clinically drug metabolite metabolite drug
important in the treatment of poisoning. Drugs (Prodrug) (Prolongs
with large Vd like pethidine are not easily removed duration
of action)
by hemodialysis.
Enzymes in Biotransformation
BIOTRANSFORMATION (Metabolism)
The biotransformation reactions are catalyzed by
Biotransformation is the process of biochemical
alteration of the drug in the body. Body treats most specific enzymes located either in the liver
drugs as foreign substances and tries to inactivate microsomes (microsomal enzymes) or in the
and eliminate them by various biochemical cytoplasm and mitochondria of the liver cells and
reactions. These processes convert the drugs into also in the plasma and other tissues (non-
more polar, water-soluble compounds so that they microsomal enzymes).

TABLE 1.1: Result of biotransformation

Active drug to Active drug to active Inactive drug to active
inactive metabolite metabolite metabolite (prodrug)
e.g. Morphine e.g. Primidone → e.g. Levodopa →
Chloramphenicol Phenobarbitone Dopamine
Digitoxin → Digoxin Prednisone → Prednisolone
Diazepam → Oxazepam Enalapril → Enalaprilat
 14 Pharmacology for Physiotherapy

The chemical reactions of biotransformation enzymes can be enhanced by certain drugs and
can take place in two phases (Fig. 1.4). environmental pollutants. This is called enzyme
1. Phase I (Non-synthetic reactions) induction and this process speeds up the meta-
2. Phase II (Synthetic reactions). bolism of the inducing drug itself and other drugs
metabolized by the microsomal enzymes, e.g.
Phase I reactions convert the drug to a more polar phenobarbitone, rifampicin, alcohol, cigarette
metabolite by oxidation, reduction or hydrolysis. smoke, DDT, griseofulvin, carbamazepine and
Oxidation reactions are the most important phenytoin are some enzyme inducers.
metabolizing reactions, mostly catalyzed by Enzyme induction can result in drug inter-
mono-oxygenases present in the liver. If the actions when drugs are given together because
metabolite is not sufficiently polar to be excreted, one drug may enhance the metabolism of the other
they undergo phase II reactions. drug resulting in therapeutic failure.

Phase II reactions are conjugation reactions Therapeutic application of enzyme induction

where water-soluble substances present in the Neonates are deficient in both microsomal and
nonmicrosomal enzymes. Hence their capacity to
body like glucuronic acid, sulfuric acid,
conjugate bilirubin is low which results in
glutathione or an amino acid, combine with the
jaundice. Administration of phenobarbitone—an
drug or its phase I metabolite to form a highly enzyme inducer, helps in rapid clearance of the
polar compound. This is inactive and gets readily jaundice in them by enhancing bilirubin
excreted by the kidneys. Large molecules are conjugation.
excreted through the bile. Thus, phase II reactions
invariably inactivate the drug. Enzyme Inhibition
Glucuronide conjugation is the most
Some drugs like cimetidine and ketoconazole
common type of metabolic reaction (Table 1.2). inhibit cytochrome P450 enzyme activity. Hence,
metabolism of other drugs get reduced and can
Enzyme Induction result in toxicity. Therefore, enzyme inhibition by
Microsomal enzymes are present in the micro- drugs is also the basis of several drug interactions.
somes of the liver cells. The synthesis of these Chloramphenicol, cimetidine, erythromycin,

Fig. 1.4: Phases in metabolism of drugs. A drug may be excreted as phase I

metabolite or as phase II metabolite. Some drugs may be excreted as such
 General Pharmacology 15

TABLE 1.2: Important drug biotransformation reactions

Reactions Examples of drugs
Oxidation Phenytoin, diazepam, ibuprofen,
Amphetamine, chlorpromazine, dapsone
Reduction Chloramphenicol, halothane
Hydrolysis Pethidine, procaine
Conjugation reactions
Glucuronide conjugation Chloramphenicol, morphine
Acetylation Sulfonamides, isoniazid
Methylation Adrenaline, histamine
Glutathione conjugation Paracetamol
Sulfate conjugation Paracetamol, steroids

ketoconazole, ciprofloxacin and verapamil are Drugs may compete for the same transport system
some enzyme inhibitors. resulting in prolongation of action of each other,
e.g. penicillin and probenecid.
EXCRETION
Passive tubular reabsorption: Passive diffusion
Drugs are excreted from the body after being of drug molecules can occur in either direction in
converted to water-soluble metabolites while some the renal tubules depending on the drug
are directly eliminated without metabolism. The concentration, lipid solubility and pH. As highly
major organs of excretion are the kidneys, the lipid soluble drugs are largely reabsorbed, their
intestines, the biliary system and the lungs. Drugs excretion is slow. Acidic drugs get ionized in
are also excreted in small amounts in the saliva, alkaline urine and are easily excreted while bases
sweat and milk. are excreted faster in acidic urine. This property
Renal Excretion is useful in the treatment of poisoning. In
poisoning with acidic drugs like salicylates and
Kidney is the most important route of drug barbiturates, forced alkaline diuresis (Diuretic +
excretion. The three processes involved in the sodium bicarbonate + IV fluids) is employed to
elimination of drugs through kidneys are hasten drug excretion. Similarly, elimination of
glomerular filtration, active tubular secretion and basic drugs like quinine and amphetamine is
passive tubular reabsorption. enhanced by forced acid diuresis.
Glomerular filtration: The rate of filtration through Fecal and Biliary Excretion
the glomerulus depends on GFR, concentration
of free drug in the plasma and its molecular weight. Unabsorbed portion of the orally administered
Ionized drugs of low molecular weight (< 10,000) drugs are eliminated through the faeces. Liver
are easily filtered through the glomerular transfers acids, bases and unionized molecules
membrane. into bile by specific acid transport processes. Some
drugs may get reabsorbed in the lower portion of
Active tubular secretion: Cells of the proximal the gut and are carried back to the liver. Such
tubules actively secrete acids and bases by two recycling is called enterohepatic circulation and it
transport systems. Thus, acids like penicillin, prolongs the duration of action of the drug;
salicylic acid, probenecid, frusemide; bases like examples are chloramphenicol, tetracycline, oral
amphetamine and histamine are so excreted. contraceptives and erythromycin.
 16 Pharmacology for Physiotherapy

Pulmonary Excretion body is metabolized/eliminated per unit time.

The lungs are the main route of elimination for The metabolic enzymes get saturated and
gases and volatile liquids viz general anesthetics hence with increase in dose, the plasma drug
and alcohol. This also has legal implications in level increases disproportionately resulting in
medicolegal practice. toxicity.
Some drugs like phenytoin and warfarin are
Other Routes of Excretion eliminated by both processes, i.e. by first order
Small amounts of some drugs are eliminated initially and by zero order at higher concent-
through the sweat and saliva. Excretion in saliva rations.
may result in a unique taste of some drugs, e.g.
metronidazole and phenytoin. Drugs like iodide, Plasma Half-life
rifampicin and heavy metals are excreted through and Steady State Concentration
sweat. Plasma half-life (t½) is the time taken for the
The excretion of drugs in the milk is in small plasma concentration of a drug to be reduced to
amounts and is of no significance to the mother. half its value (Fig. 1.5). Four to five half-lives are
But, for the suckling infant, it may be sometimes required for the complete elimination of a drug.
important especially because of the infant’s Each drug has its own t½ and is an important
immature metabolic and excretory mechanisms. pharmacokinetic parameter that guides the dosing
Though most drugs can be taken by the mother regimen. It helps in calculating loading and
without significant toxicity to the child, there are maintenance doses of a drug. It also indicates the
a few exceptions (Table 1.3). duration of action of a drug.
TABLE 1.3: Example of drugs that could be toxic Biological half-life is the time required for total
to the suckling infant when taken by the mother
amount of the drug in the body to be reduced to
Sulphasalazine Doxepin half.
Theophylline Amiodarone
Anticancer drugs Primidone Biological effect half-life is the time required for
Salicylates Ethosuximide the biological effect of the drug to reduce to half.
Chloramphenicol Phenobarbitone In some drugs like propranolol, the pharmaco-
Nalidixic acid Phenothiazines logical effect of the drug may last much longer, i.e.
Nitrofurantoin β-blockers
even after its plasma levels fall. In such drugs,
Drugs are metabolized/eliminated from the biological effect half life gives an idea of the
body by: duration of action of the drug.
1. First-order kinetics In first order kinetics, a If a drug is administered repeatedly at short
intervals before complete elimination, the drug
constant fraction of the drug is metabolized/
accumulates in the body and reaches a ‘state’ at
eliminated per unit time. Most drugs follow
which the rate of elimination equals the rate of
first order kinetics and the rate of metabolism/
administration. This is known as the ‘Steady-state’
excretion is dependant on their concentration or plateau level (Fig. 1.6). After attaining this level,
(exponential) in the body. It also holds good the plasma concentration fluctuates around an
for absorption of drugs. average steady level. It takes 4-5 half-lives for
2. Zero order kinetics (Saturation kinetics) Here the plasma concentration to reach the plateau
a constant amount of the drug present in the level.
 General Pharmacology 17

Fig. 1.5: Plasma concentration-time curve following intravenous dose. Plasma t½ = 4 hours

Fig. 1.6: Drug accumulation and attainment of steady state concentration on oral administration

DRUG DOSAGE Fixed dose: In case of reasonably safe drugs, a

fixed dose of the drug is suitable for most patients,
Depending on the patient’s requirements and the
e.g. analgesics like paracetamol—500 mg to
characteristics of the drug, drug dosage can be of
1000 mg 6 hourly is the usual adult dose.
the following kinds:
 18 Pharmacology for Physiotherapy

Individualized dose: For some drugs especially PHARMACODYNAMICS

the ones with low safety margin, the dose has to
be ‘tailored’ to the needs of each patient, e.g. Pharmacodynamics is the study of actions of the
anticonvulsants, antiarrhythmic drugs. drugs on the body and their mechanisms of action,
i.e. to know what drugs do and how they do it.
Loading dose: In situations when rapid action
Drugs produce their effects by interacting with
is needed, a loading/bolus dose of the drug is
the physiological systems of the organisms. By
given at the beginning of the treatment. A loading
such interaction, drugs merely modify the rate of
dose is a single large dose or a series of quickly
functions of the various systems. But they cannot
repeated doses given to rapidly attain target
bring about qualitative changes, i.e. they cannot
concentration, e.g. heparin given as 5000 IU bolus
change the basic functions of any physiological
dose. Once the target level is reached, a maintenance
system. Thus drugs act by:
dose is sufficient to maintain the drug level and to
1. Stimulation
balance the elimination.
2. Depression
The disadvantage with the loading dose is that
3. Irritation
the patient is rapidly exposed to high concent-
4. Replacement
rations of the drug which may result in toxicity.
5. Anti-infective or cytotoxic action
6. Modification of the immune status.
Therapeutic Drug Monitoring
The response to a drug depends on the plasma Stimulation
concentration attained in the patient. In some
Stimulation is the increase in activity of the
situations it may be necessary to monitor treatment
specialized cells, e.g. adrenaline stimulates the
by measuring plasma drug concentrations. Such
heart.
situations are:
1. While using drugs with low safety margin—
Depression
to avoid therapeutic failure, e.g. digoxin,
theophylline, lithium. Depression is the decrease in activity of the
2. To reduce the risk of toxicity, e.g. amino- specialized cells, e.g. quinidine depresses the
glycosides. heart; barbiturates depress the central nervous
3. To treat poisoning. system. Some drugs may stimulate one system and
depress another, e.g. morphine depresses the CNS
METHODS OF PROLONGING DRUG ACTION but stimulates the vagus.
(TABLE 1.4)
In several situations it may be desirable to use Irritation
long-acting drugs. But when such drugs are not This can occur on all types of tissues in the body
available, the duration of action of the available and may result in inflammation, corrosion and
drugs may be prolonged. necrosis of cells.
The duration of action of drugs can be
prolonged by interfering with the pharmaco-
Replacement
kinetic processes, i.e. by
1. Slowing absorption. Drugs may be used for replacement when there is
2. Using a more plasma protein bound derivative. deficiency of natural substances like hormones,
3. Inhibiting metabolism. metabolites or nutrients, e.g. insulin in diabetes
4. Delaying excretion. mellitus, iron in anemia, vitamin C in scurvy.
 General Pharmacology 19

TABLE 1.4: Methods of prolonging duration of action of drugs

Processes Methods Examples
ABSORPTION
Oral Sustained release preparation,
coating with resins, etc. Iron, deriphylline
Parenteral 1. Reducing solubility Procaine + Penicillin
— Oily suspension Depot progestins
2. Altering particle size Insulin zinc suspension as large crystals
that are slowly absorbed
3. Pellet implantation DOCA
— Sialistic capsules Testosterone
4. Reduction in vascularity Adrenaline +
of the absorbing surface lignocaine (vasoconstrictor)
5. Combining with protein Protamine + zinc + insulin
6. Chemical alteration
— Esterification Estrogen
Testosterone
Dermal Transdermal adhesive patches, Scopolamine
Ointments Nitroglycerine
Ocuserts (Transmucosal)—used in eye Pilocarpine
DISTRIBUTION Choosing more protein bound Sulfonamides-like
member of the group sulfamethoxypyridazine
METABOLISM Inhibiting the metabolizing Physostigmine prolongs the action
enzyme cholinesterase of acetylcholine
By inhibiting enzyme peptidase Cilastatin—prolongs action of imipenem
in renal tubular cells
EXCRETION Competition for same Probenecid prolongs the action of
transport system penicillin and ampicillin
— for renal tubular secretion

Anti-infective and Cytotoxic Action ion channels. Drugs may act on the cell membrane,
inside or outside the cell to produce their effect.
Drugs may act by specifically destroying infective
Drugs may act by one or more complex mecha-
organisms, e.g. penicillins, or by cytotoxic effect
nisms of action. Some of them are yet to be
on cancer cells, e.g. anticancer drugs.
understood. But the fundamental mechanisms of
drug action may be:
Modification of Immune Status
Vaccines and sera act by improving our immunity Through Receptors
while immunosuppressants act by depressing Drugs may act by interacting with specific
immunity, e.g. glucocorticoids. receptors in the body (see below).

MECHANISMS OF DRUG ACTION Through Enzymes and Pumps

Most drugs produce their effects by binding to Drugs may act by inhibition of various enzymes,
specific target proteins like receptors, enzymes and thus altering the enzyme-mediated reactions, e.g.
 20 Pharmacology for Physiotherapy

allopurinol inhibits the enzyme xanthine oxidase; Agonist: An agonist is a substance that binds to
acetazolamide inhibits carbonic anhydrase. the receptor and produces a response. It has
Membrane pumps like H+ K+ ATPase, Na+ K+ affinity and intrinsic activity.
ATPase may be inhibited by drugs, e.g.
Antagonist: An antagonist is a substance that
omeprazole, digoxin.
binds to the receptor and prevents the action of
agonist on the receptor. It has affinity but no
Through Ion Channels
intrinsic activity.
Drugs may interfere with the movement of ions
Partial agonist binds to the receptor but has low
across specific channels, e.g. calcium channel
intrinsic activity.
blockers, potassium channel openers.
Ligand is a molecule which binds selectively to a
Physical Action specific receptor.
The action of a drug could result from its physical Last three decades have seen an explosion in
properties like: our knowledge of the receptors. Various receptors
Adsorption – Activated charcoal in poisoning have been identified, isolated and extensively
Mass of the drug – Bulk laxatives like psyllium, bran studied.
Osmotic property – Osmotic diuretics—Mannitol
Site: The receptors may be present in the cell
– Osmotic purgatives—Magne-
membrane, in the cytoplasm or on the nucleus.
sium sulphate
Radioactivity – 131I Nature of receptors: Receptors are proteins.
Radio-opacity – Barium sulphate contrast media.
Synthesis and life-span: Receptor proteins are
Chemical Interaction synthesized by the cells. They have a definite life
Drugs may act by chemical reaction. span after which the receptors are degraded by
Antacids – neutralise gastric acids the cell and new receptors are synthesized.
Oxidising agents – like potassium permanganate -
germicidal Functions of Receptors
Chelating agents – bind heavy metals making them The two functions of receptors are:
nontoxic. 1. Recognition and binding of the ligand
2. Propagation of the message.
Altering Metabolic Processes
For the above function, the receptor has two
Drugs like antimicrobials alter the metabolic sites (domains):
pathway in the microorganisms resulting in i. A ligand binding site—the site to bind the drug
destruction of the microorganism, e.g. molecule
sulfonamides interfere with bacterial folic acid ii. An effector site—which undergoes a change
synthesis. to propagate the message.
Drug-receptor interaction has been considered
Receptor to be similar to ‘lock and key’ relationship where
A receptor is a site on the cell with which an the drug specifically fits into the particular
agonist binds to bring about a change, e.g. receptor (lock) like a key. Interaction of the agonist
histamine receptor, α and β adrenergic receptors. with the receptor brings about changes in the
receptor which in turn conveys the signal to the
Affinity is the ability of a drug to bind to a receptor.
effector system. The final response is brought
Intrinsic activity or efficacy is the ability of a drug about by the effector system through second
to produce a response after binding to the receptor. messengers. The agonist itself is the first
 General Pharmacology 21

messenger. The entire process involves a chain of response curve (DRC). Initially the extent of
events triggered by drug receptor interaction. response increases with increase in dose till the
maximum response is reached. After the
Receptor Families maximum effect has been obtained, further
increase in doses does not increase the response.
Four families (types) of cell surface receptors are
If the dose is plotted on a logarithmic scale, the
identified. The receptor families are:
curve becomes sigmoid or ‘S’ shaped (Fig. 1.7).
1. Ion channels
2. G-protein coupled receptors
Drug Potency and Maximal Efficacy
3. Enzymatic receptors
4. Nuclear receptors (receptors that regulate gene The amount of drug required to produce a
transcription). response indicates the potency. For example,
1 mg of bumetanide produces the same diuresis
Receptor Regulation as 50 mg of frusemide. Thus, bumetanide is more
potent than frusemide. In Figure 1.8, drugs A and
The number of receptors (density) and their
B are more potent than drugs C and D, drug A
sensitivity can be altered in many situations.
being the most potent and drug D—the least
Denervation or prolonged deprivation of the
potent. Hence higher doses of drugs C and D are
agonist or constant action of the antagonist all
to be administered as compared to drugs A and B.
result in an increase in the number and sensitivity
Generally potency is of little clinical significance
of the receptors. This phenomenon is called ‘up
unless very large doses of the drug needs to be
regulation.’
given due to low potency.
Prolonged use of a β adrenergic antagonist like
propranolol results in up regulation of β Maximal efficacy: Efficacy indicates the
adrenergic receptors. maximum response that can be produced by a
On the other hand, continued stimulation of drug, e.g. frusemide produces powerful diuresis,
the receptors causes desensitization and a not produced by any dose of amiloride. In Figure
decrease in the number of receptors—known as 1.8, drugs B and C are more efficacious than drugs
‘down regulation’ of the receptors. A and D. Drug A is more potent but less efficacious
than drugs B and C. Such differences in efficacy
Clinical importance of receptor regulation: After
are of great clinical importance.
prolonged administration, a receptor antagonist
should always be tapered. For example, if propra- Therapeutic index: The dose response curves
nolol—a β adrenoceptor blocker is suddenly for different actions of a drug could be different.
withdrawn after long-term use, it precipitates Thus salbutamol may have one DRC for
angina due to upregulation of β receptors. bronchodilation and another for tachycardia. The
Constant use of β adrenergic agonists in distance between beneficial effect DRC and
bronchial asthma results in reduced therapeutic unwanted effect DRC indicates the safety margin
response due to down regulation of β2 receptors. of the drug (Fig. 1.9).

Dose Response Relationship Median lethal dose (LD50) is the dose which is
lethal to 50 percent of animals of the test
The response to different doses of a drug can be population.
plotted on a graph to obtain the Dose Response
Curve. Median effective dose (ED50) is the dose that
The clinical response to the increasing dose of produces a desired effect in 50 percent of the test
the drug is defined by the shape of the dose population.
 22 Pharmacology for Physiotherapy

Fig. 1.9: The distance between curves A and B

indicates safety margin of the drug. The greater the
Fig. 1.7: Log dose response curve distance, more selective is the drug

Therapeutic index (TI) is the ratio of the • TI varies from species to species
median lethal dose to the median effective dose. • For a drug to be considered reasonably safe,
it’s TI must be > 1
LD50
Therapeutic index = ___________ • Penicillin has a high TI while lithium and
ED50 digoxin have low TI.
It gives an idea about the safety of the drug.
• The higher the therapeutic index, the safer Drug Synergism and Antagonism
is the drug When two or more drugs are given concurrently
the effect may be additive, synergistic or
antagonistic.

Additive Effect
The effect of two or more drugs get added up and
the total effect is equal to the sum of their
individual actions.
Examples are ephedrine with theophylline in
bronchial asthma; nitrous oxide and ether as
general anesthetics.

Synergism
When the action of one drug is enhanced or
facilitated by another drug, the combination is
Fig. 1.8: Dose response curves of four drugs showing synergistic. In Greek, ergon = work; syn = with.
different potencies and maximal efficacies. Drug A is Here, the total effect of the combination is greater
more potent but less efficacious than B and C. Drug D than the sum of their independent effects. It is often
is less potent and less efficacious than drugs B and C called ‘potentiation’ or ‘supra-additive’ effect.
 General Pharmacology 23

Examples are — acetylcholine + physostigmine

levodopa + carbidopa.

Antagonism
One drug opposing or inhibiting the action of
another is antagonism. Based on the mechanisms,
antagonism can be:
• Chemical antagonism
• Physiological antagonism
• Antagonism at the receptor level
— Reversible (Competitive)
— Irreversible
• Non-competitive antagonism. Fig. 1.10: Dose response curves of an agonist: (A) in
the absence of competitive antagonist; (B) in the
Chemical antagonism: Two substances interact presence of increasing doses of a competitive
chemically to result in inactivation of the effect, antagonist
e.g. chelating agents inactivate heavy metals like
lead and mercury to form inactive complexes;
Irreversible antagonism: The antagonist binds
antacids like aluminium hydroxide neutralize
firmly by covalent bonds to the receptor. Thus it
gastric acid.
blocks the action of the agonist and the blockade
Physiological antagonism: Two drugs act at cannot be overcome by increasing the dose of the
different sites to produce opposing effects. For agonist and hence it is irreversible antagonism,
example, histamine acts on H2 receptors to e.g. adrenaline and phenoxybenzamine at alpha
produce bronchospasm and hypotension while adrenergic receptors (Fig. 1.11).
adrenaline reverses these effects by acting on
adrenergic receptors.
Insulin and glucagon have opposite effects on
the blood sugar level.
Antagonism at the receptor level: The antagonist
inhibits the binding of the agonist to the receptor.
Such antagonism may be reversible or irreversible.
Reversible or competitive antagonism: The
agonist and antagonist compete for the same
receptor. By increasing the concentration of the
agonist, the antagonism can be overcome. It is thus
reversible antagonism. Acetylcholine and atropine
compete for the muscarinic receptors. The
antagonism can be overcome by increasing the
concentration of acetylcholine at the receptor. Fig. 1.11: Dose response curves of an agonist:
d-tubocurarine and acetylcholine compete for the (A) in the absence of antagonist. (B1), (B2) and (B3) in
nicotinic receptors at the neuromuscular junction the presence of increasing doses of an irreversible
(Fig. 1.10). antagonist
 24 Pharmacology for Physiotherapy

Noncompetitive antagonism: The antagonist In the elderly, the capacity of the liver and
blocks at the level of receptor-effector linkage. For kidney to handle the drug is reduced and are
example, verapamil blocks the cardiac calcium more susceptible to adverse effects. Hence
channels and inhibits the entry of Ca++ during lower doses are recommended, e.g. elderly are
depolarization. It thereby antagonises the effect at a higher risk of ototoxicity and
of cardiac stimulants like isoprenaline and nephrotoxicity by streptomycin.
adrenaline.
3. Sex: The hormonal effects and smaller body
FACTORS THAT MODIFY size may influence drug response in women.
THE EFFECTS OF DRUGS Special care is necessary while prescribing for
pregnant and lactating women and during
The same dose of a drug can produce different menstruation.
degrees of response in different patients and even
in the same patient under different situations. 4. Species and race: Response to drugs may
Various factors modify the response to a drug. vary with species and race. For example,
They are: rabbits are resistant to atropine. Then it
becomes difficult to extrapolate the results of
1. Body weight: The recommended dose is
animal experiments. Blacks need higher doses
calculated for medium built persons. For the
of atropine to produce mydriasis.
obese and underweight persons, the dose has
to be calculated individually. Though body 5. Diet and environment: Food interferes with
surface area is a better parameter for more the absorption of many drugs. For example,
accurate calculation of the dose, it is incon- tetracyclines form complexes with calcium
venient and hence not generally used. present in the food and are poorly absorbed.
Formula: Polycyclic hydrocarbons present in
cigarette smoke may induce microsomal
Body weight (kg)
Dose = _________________________ × average adult dose enzymes resulting in enhanced metabolism of
70 some drugs.
2. Age: The pharmacokinetics of many drugs
6. Route of administration: Occasionally route
change with age resulting in altered response
of administration may modify the pharmaco-
in extremes of age. In the newborn, the liver
dynamic response, e.g. magnesium sulfate
and kidneys are not fully mature to handle the
given orally is a purgative. But given IV it
drugs, e.g. chloramphenicol can produce grey
causes CNS depression and has anti-
baby syndrome. The blood-brain barrier is not
convulsant effects. Applied topically (poultice),
well-formed and drugs can easily reach the
it reduces local edema. Hypertonic magne-
brain. The gastric acidity is low, intestinal
sium sulfate retention enema reduces
motility is slow, skin is delicate and permeable
intracranial tension.
to drugs applied topically. Hence calculation
of the appropriate dose, depending on body 7. Genetic factors: Variations in an individual’s
weight is important to avoid toxicity. Also response to drugs could be genetically
pharmacodynamic differences could exist, e.g. mediated. Pharmacogenetics is concerned
barbiturates which produce sedation in adults with the genetically mediated variations in
may produce excitation in children. drug responses. The differences in response is
Formula for calculation of dose for children most commonly due to variations in the
Young’s formula amount of drug metabolizing enzymes since
Age (years) the production of these enzymes are
Child’s dose = __________________ × Adult dose
Age + 12 genetically controlled.
 General Pharmacology 25

Examples of liver and kidneys. These may result in

a. Acetylation of drugs: The rate of drug cumulation and toxicity of drugs like
acetylation differs among individuals who propranolol and lignocaine.
may be fast or slow acetylators, e.g. INH, • Renal dysfunction: Drugs mainly excreted
sulfonamides and hydralazine are through kidneys are likely to accumulate
acetylated. Slow acetylators treated with and cause toxicity, e.g. Streptomycin,
hydralazine are more likely to develop amphotericin B—Dose of such drugs need
lupus erythematosus. to be reduced.
b. Atypical pseudocholinesterase: Succinyl- 10. Repeated dosing can result in
choline is metabolized by pseudo- • Cumulation
cholinesterase. Some people inherit • Tolerance
atypical pseudocholinesterase and they • Tachyphylaxis.
develop a prolonged apnea due to
Cumulation: Drugs like digoxin which are slowly
succinylcholine.
eliminated may cumulate resulting in toxicity.
c. G6PD deficiency: Primaquine, sulphones
and quinolones can cause hemolysis in Tolerance: Tolerance is the requirement of higher
such people. doses of a drug to produce a given response.
d. Malignant hyperthermia: Halothane and Tolerance may be natural or acquired.
succinylcholine can trigger malignant Natural tolerance: The species/race shows less
hyperthermia in some genetically sensitivity to the drug, e.g. rabbits show tolerance
predisposed individuals. to atropine; Black race are tolerant to mydriatics.
Acquired tolerance: develops on repeated
8. Dose: It is fascinating that the response to a
administration of a drug. The patient who was
drug may be modified by the dose adminis-
initially responsive becomes tolerant, e.g. barbitu-
tered. Generally as the dose is increased, the
rates, opioids, nitrites produce tolerance.
magnitude of the response also increases
Tolerance may develop to some actions of the
proportionately till the ‘maximum’ is reached.
drug and not to others, e.g. morphine—tolerance
Further increases in doses may with some
develops to analgesic and euphoric effects of
drugs produce effects opposite to their lower- morphine but not to its constipating and miotic
dose effect, e.g. (i) in myasthenia gravis, effects.
neostigmine enhances muscle power in Barbiturates—tolerance develops to sedative
therapeutic doses, but in high doses it causes but not antiepileptic effects of barbiturates.
muscle paralysis, (ii) physiological doses of
vitamin D promotes calcification while Mechanisms: The mechanisms of development
hypervitaminosis D leads to decalcification. of tolerance could be:
9. Diseases: Presence of certain diseases can Pharmacokinetic: Changes in absorption,
influence drug responses, e.g. distribution, metabolism and excretion of drugs
• Malabsorption: Drugs are poorly absorbed. may result in reduced concentration of the drug
• Liver diseases: Rate of drug metabolism is at the site of action and is also known as
reduced due to dysfunction of hepatocytes. dispositional tolerance, e.g. barbiturates induce
Also protein binding is reduced due to low microsomal enzymes and enhance their own
serum albumin. metabolism.
• Cardiac diseases: In CCF, there is edema of Pharmacodynamic: Changes in the target tissue,
the gut mucosa and decreased perfusion may make it less responsive to the drug. It is also
 26 Pharmacology for Physiotherapy

called functional tolerance. It could be due to down In fact all forms of treatment including
regulation of receptors as in opioids or due to physiotherapy and surgery have placebo effect.
compensatory mechanisms of the body, e.g. Substances used as placebo include lactose,
blunting of response to some antihypertensives some vitamins, minerals and distilled water
due to salt and water retention. injections.
Cross tolerance is the development of tolerance 12. Presence of other drugs: When two or more
to pharmacologically related drugs, i.e. to drugs drugs are used together, one of them can alter
belonging to a particular group. Thus chronic the response of the other resulting in drug
alcoholics also show tolerance to barbiturates and interactions (see Drug Interactions page 28).
general anesthetics.
ADVERSE DRUG REACTIONS
Tachyphylaxis is the rapid development of
tolerance. When some drugs are administered All drugs can produce unwanted effects. WHO
repeatedly at short intervals, tolerance develops has defined an adverse drug reaction as “any
rapidly and is known as tachyphylaxis or acute response to a drug that is noxious and unintended
tolerance, e.g. ephedrine, amphetamine, tyramine and that occurs at doses used in man for
and 5-hydroxytryptamine. This is thought to be prophylaxis, diagnosis or therapy.”
due to depletion of noradrenaline stores as the All drugs can cause adverse effects. Some
above drugs act by displacing noradrenaline from patients are more likely to develop adverse effects
the sympathetic nerve endings. Other mechanisms to drugs.
involved may be slow dissociation of the drug
from the receptor thereby blocking the receptor. 1. Side Effects
Thus ephedrine given repeatedly in bronchial Side effects are unwanted effects of a drug that are
asthma may not give the desired response. extension of pharmacological effects and are seen
with the therapeutic dose of the drug. They are
11. Psychological factor: The doctor patient predictable, common and can occur in all people,
relationship influences the response to a drug e.g. hypoglycemia due to insulin; hypokalemia
often to a large extent by acting on the patient’s following frusemide.
psychology. The patients confidence in the
doctor may itself be sufficient to relieve a 2. Toxic Effects
suffering, particularly the psychosomatic
Toxic effects are seen with higher doses of the drug
disorders. This can be substantiated by the fact
and can be serious, e.g. morphine causes
that large number of patients respond to
respiratory depression in overdosage.
placebo. Placebo is the inert dosage form with
no specific biological activity but only 3. Intolerance
resembles the actual preparation in
Drug intolerance is the inability of a person to
appearance. Placebo = ‘I shall be pleasing’ (in
tolerate a drug and is unpredictable. Patients show
Latin).
exaggerated response to even small doses of the
Placebo medicines are used in:
drug, e.g. vestibular dysfunction after a single dose
1. Clinical trials as a control
of streptomycin seen in some patients. Intolerance
2. To benefit or please a patient psycho-
could also be qualitative, e.g. idiosyncrasy and
logically when he does not actually require
allergic reactions.
an active drug as in mild psychosomatic
disorders and in chronic incurable Idiosyncrasy is a genetically determined abnormal
diseases. reaction to a drug, e.g. primaquine and
 General Pharmacology 27

sulfonamides induce hemolysis in patients with antibody complexes activate the complement
G6PD deficiency; some patients show excitement system resulting in cytolysis causing thrombo-
with barbiturates. In addition, some responses like cytopenia, agranulocytosis and aplastic anemia.
chloramphenicol-induced agranulocytosis,
where no definite genetic background is known, Type III (Arthus) reactions: The antigen binds to
are also included under idiosyncrasy. In some circulating antibodies and the complexes are
cases the person may be highly sensitive even to deposited on the vessel wall where it initiates the
low doses of a drug or highly insensitive even to inflammatory response resulting in vasculitis.
high doses of the drug. Rashes, fever, arthralgia, lymphadenopathy,
serum sickness and Steven-Johnson’s syndrome
Allergic reactions to drugs are immunologically- are some of the manifestations of arthus type
mediated reactions which are not related to the reaction.
therapeutic effects of the drug. The drug or its
metabolite acts as an antigen to induce antibody Type IV (Delayed hypersensitivity) reactions
formation. Subsequent exposure to the drug may are mediated by T-lymphocytes and macro-
result in allergic reactions. The manifestations of phages. The antigen reacts with receptors on
allergy are seen mainly on the target organs viz. T-lymphocytes which produce lymphokines
skin, respiratory tract, gastrointestinal tract, blood leading to a local allergic reaction, e.g. contact
and blood vessels. dermatitis.

Types of Allergic Reactions 4. Iatrogenic Diseases (Physician Induced)

and their Mechanisms These are drug induced diseases. Even after the
drug is withdrawn toxic effects can persist, e.g.
Drugs can induce both types of allergic reactions
isoniazid induced hepatitis; chloroquine induced
viz humoral and cell-mediated immunity.
retinopathy.
Mechanism involved in type I, II and III are
humoral while type IV is by cell-mediated
5. Drug Dependence
immunity.
Drugs that influence the behavior and mood are
Type I (Anaphylactic) reaction: Certain drugs
often misused to obtain their pleasurable effects.
induce the synthesis of IgE antibodies which are
Repeated use of such drugs result in dependence.
fixed to the mast cells. On subsequent exposure,
Several words like drug abuse, addiction and
the antigen-antibody complexes cause
dependence are used confusingly. Drug
degranulation of mast cells releasing the
dependence is a state of compulsive use of drugs
mediators of inflammation like histamine,
in spite of the knowledge of risks associated with
leukotrienes, prostaglandins and platelet-
its use. It is also referred to as drug addiction.
activating factor. These are responsible for the
Dependence could be ‘psychologic’ or ‘physical’
characteristic signs and symptoms of anaphylaxis
dependence. Psychologic dependence is
like bronchospasm, laryngeal edema and
compulsive drug-seeking behavior to obtain its
hypotension which could be fatal. Allergy
pleasurable effects, e.g. cigarette smoking.
develops within minutes and is called immediate
Physical dependence is said to be present
hypersensitivity reaction, e.g. penicillins. Skin
when withdrawal of the drug produces adverse
tests may predict this type of reactions.
symptoms. The body undergoes physiological
Type II (Cytolytic) reactions: The drug binds to a changes to adapt itself to the continued presence
protein and together they act as antigen and of the drug in the body. Stopping the drug results
induce the formation of antibodies. The antigen in ‘withdrawal syndrome.’ The symptoms of
 28 Pharmacology for Physiotherapy

withdrawal syndrome are disturbing and the 8. Other Adverse Drug Reactions
person then craves for the drug, e.g. alcohol, Drugs can also damage various organ systems.
opioids and barbiturates.
Mild degree of physical dependence is seen in Organ system affected Examples
people who drink too much of coffee.
1. Hepatotoxicity Isoniazid, pyrazinamide,
paracetamol,
6. Teratogenicity chlorpromazine,
Teratogenicity is the ability of a drug to cause fetal 6-Mercaptopurine,
abnormalities when administered to the pregnant halothane, ethanol,
phenylbutazone
lady. Teratos in Greek means monster. The seda-
tive-thalidomide taken during early pregnancy for 2. Nephrotoxicity Analgesics,
aminoglycosides,
relief from morning sickness resulted in thousands
cyclosporine, cisplatin,
of babies being born with phocomelia (seal limbs).
cephelexin, penicillamine,
This thalidomide disaster (1958-61) opened the gold salts
eyes of various nations and made it mandatory to
3. Ototoxicity Aminoglycosides,
impose strict teratogenicity tests before a new drug frusemide
is approved for use.
4. Ocular toxicity Chloroquine, ethambutol
Depending on the stage of pregnancy during
5. Gastrointestinal Opioids, broad spectrum
which the teratogen is administered, it can
systems antibiotics
produce various abnormalities.
6. Cardiovascular Digoxin, doxorubicin
i. Conception — Usually resistant to
system
to 16 days teratogenic effects.
7. Respiratory system Aspirin, bleomycin,
If affected, abortion occurs.
busulfan, amiodarone,
ii. Period of — Most vulnerable period; methotrexate
organogenesis major physical
8. Musculoskeletal Corticosteroids, heparin
(17 to 55 days abnormalities occur. system
of gestation)
9. Behavioral toxicity Corticosteroids, reserpine
iii. Fetal period — Period of growth and
10. Neurological INH, haloperidol,
—56 days development—hence
system ethambutol, quinine,
onwards developmental and func- doxorubicin vincristine
tional abnormalities
11. Dermatological Doxycycline,
result. toxicity sulfonamides
Therefore, in general drugs should be avoided
12. Electrolyte Diuretics,
during pregnancy especially in the first trimester. disturbances mineralocorticoids
The type of malformation also depends on the
13. Hematological Chloramphenicol,
drug, e.g. thalidomide causes phocomelia; tetra- toxicity sulfonamides
cyclines cause deformed teeth; sodium valproate
14. Endocrine disorders Methyldopa, oral
causes spina bifida. contraceptives

7. Carcinogenicity and Mutagenicity

DRUG INTERACTIONS
Some drugs can cause cancers and genetic
abnormalities. For example anticancer drugs can Definition: Drug interaction is the alteration in
themselves be carcinogenic; other examples are the duration or magnitude of the pharmacological
radioactive isotopes and some hormones. effects of one drug by another drug.
 General Pharmacology 29

When two or more drugs are given con- carbamazepine and rifampicin are enzyme
currently, the response may be greater or lesser inducers while chloramphenicol and cimetidine
than the sum of their individual effects. Such are some enzyme inhibitors.
responses may be beneficial or harmful. For
example a combination of drugs is used in Excretion: When drugs compete for the same renal
hypertension—hydralazine + propranolol for tubular transport system, they prolong each others
their beneficial interaction. But unwanted drug duration of action, e.g. penicillin and probenecid.
interactions may result in severe toxicity. Such 2. Pharmacodynamic mechanisms: Drugs acting
interactions can be avoided by adequate on the same receptors or physiological systems
knowledge of their mechanisms and by judicious result in additive, synergistic or antagonistic
use of drugs. effects. Many clinically important drug interac-
tions have this basis. Atropine opposes the effects
Site: Drug interaction can occur:
of physostigmine; naloxone antagonises
i. In vitro in the syringe before administration—
morphine; antihypertensive effects of β blockers
mixing of drugs in syringes can cause
are reduced by ephedrine or other vasoconstrictors
chemical or physical interactions—such
in cold remedies.
drug combinations are incompatible in
solution, e.g. penicillin and gentamicin
should never be mixed in the same syringe. GENE THERAPY
ii. In vivo, i.e. in the body after administration.
Gene therapy is the replacement of defective gene
Pharmacological basis of drug interactions: by the insertion of a normal, functional gene. Gene
The two major mechanisms of drug interactions transfer may be done to replace a missing or
include pharmacokinetic and pharmacodynamic defective gene or provide extra-copies of a
mechanisms. normally expressed gene. Gene therapy is aimed
at genetically correcting the defect in the affected
1. Pharmacokinetic mechanisms: Alteration in part of the body. Unlike all other drugs which
the extent or duration of response may be only alter the rate of normal cell functions, gene
produced by influencing absorption, distribution, therapy can confer new functions to the cell.
metabolism or excretion of one drug by another. Gene transfer requires the use of vectors to
deliver the DNA material, such as:
Absorption of drugs from the gut may be affected
i. Viral vectors like retroviral vectors and
by:
adenoviral vectors.
i. Binding—Tetracyclines chelate iron and
ii. Liposomes.
antacids resulting in reduced absorption
ii. Altering gastric pH Therapeutic applications of gene therapy: Gene
iii. Altering GI motility. therapy is at present a developing area. Though
originally it was seen as a remedy for inherited
Distribution: Competition for plasma protein or
single gene defects, gene therapy has now found
tissue binding results in displacement inter-
to be useful in several acquired disorders. The
actions, e.g. warfarin is displaced by
principle applications are in the treatment of
phenylbutazone from protein binding sites.
cancer, cardiovascular diseases, atherosclerosis,
Metabolism: Enzyme induction and inhibition of immunodeficiency disorders—particularly AIDS;
metabolism can both result in drug interactions anemia, Alzheimer’s disease and many infectious
(see page 14), e.g. phenytoin, phenobarbitone, diseases.