Adverse Drug Reactions 161
11ome cases. Old persons and young children are more susceptible
Adverse Drug
.Reactions 7
CHAPTER
Drugs are prescribed with a specific intention and a physician
would expect a drug to act effectively and selectively without
any undesirable phenomenon in the organism. Thus when a
physician prescribes a drug for cardiac dysfunction he would very
much like to select a drug which acts only on heart, and on no
other physiological system. A drug with such an ideal selectivity,
however, exists only in our imagination as there is no drug which
does not exert some action on the system other than one on which
its clinical use is based. To a certain extent such side effects are
tolerated but they become problematic when the side effects are
also as potent as therapeutic effect and particularly when they
cause distress to the patient and treating physician. All such
side effects of drugs are generally classified as Adverse Drug
Reaction.
WHO defines an adverse drug reaction as "any no ·ious and
unintended effects of drug which occur at doses norrr.c1lly used
in n,r.n for the prophylaxis, diagnosis or therapy of disease or
for the modification of physiological functions".
SIGNIFICANCE OF ADVERSE DhTJG REACTIONS
Some physicians have a tendency to overprescribe a patient
with potent drugs. Self-medication by patients lead to misuse of
drugs causing adverse drug reactions. Sometimes physicians fail
to set the therapeutic end point for drugs like corticosteroids,
diuretics, etc. Continued use of such drugs invariably gives rise to
their adverse drug reactions. Several factors such as environment,
diet, physical and psychic condition of the patient etc. could be held
responsible for the onset of such actions. Difference in bio-
availability from various manufacturers of oxytetracycline,
theophyl!ine, chloramphenicol, etc., have resu 1..ed in toxicity in
160
lo adverse drug reactions because of their difference in metabolism
and excretion pattern.
How to Avoid Adverse Effects
Some scientists believe that a new delivery system that bypass
both the liver and the gastro-intestinal tract and approach target
organs directly by more natural means may medicate patients
more effectively and avoid many side reactions. Adverse drug reac-
tions can be minimised by :
1. Decreasing rate of parenterals administration.
2. Decreasing frequency of administration by use of prolonged
action formulation.
3. Buffering to the optimum pH before injecting or applying
the medication.
4. Adjusting tonicity to suit body fluids.
5. Achieving appropriate rates of dissolution and absorption
of oral formulations.
6. Administering minimum effective dose for the shortest pos-
sible time.
7. Monitoring closely the blood levels of toxic drugs particularly
those which are hepatotoxic or nephrotoxic.
DRUG INDUCED DISEASES
Drugs may induce diseases due to following factors :
1. Overdose;
2. Drug-interactions;
3. Secondary effects;
4. Idiosyncracy;
5. Hypersensitivity.
1. Overdose
Many factors affect the plasma concentration of drug like
absorption, distribution, pro~ain and tissue binding, metabolism
and excretion. All these factors can change normal dose into a
subtherapeutic dose or overdoses. e.g. Diphenyl hydantoin . The
dose is 4-5 mg/kg body weight. It is reported that this dosage
gives 4-7 folds blooj levels of the drug. There are several reasons
for it. Diphenyl hydantuin is metabolised in liver, where it
162 Hospital and Clinical Pharma<"¥
undergoes parahydroxylation. Some people have been found to
lack the hydroxylating en'zymes. Due to this Diphenyl hydantoin
gets deposited and then it leads to toxicity at normal doses. Liver
diseases can interfere with metabolism of diphenyl hydantoin.
Similarly drugs like isoniazid, aminosalicylic acid and
disulfiram inhibit the metabolism of diphenyl hydantoin.
A,nother factor which influences the patient response is renal
function, e.g., we normally see congestive heart failure, patients
maintai~d on 0.25-0.5 mg of digoxin daily. Yet, patient with
impaired renal function or one with hypokalemia may exhibit
digitalis toxicity at this dosage. A patient with normal renal
function loses by various routes about 35% of digoxin in body
every day. The maintenance dose is meant to replace that loss.
In anuric patients only 14% of the digoxin in the body is lost per
day. Therefore if normal dose of 0.25-0.5 mg is continued in the
presence of this anuria (scanty urine), drug accumulation and
inevitable digitalis toxicity will result in increase in cardiac
sensitivity to digoxin associated with hypokalemia.
Administration of thiazide diuretics, furosemide, results in
large loads of sodium to be presented to the renal tubules for
excretion. Increased sodium-potassium exchange results, in
marked increase in the potassium excretion. Hence for digitalis
therapy, the diuretic use has to be taken in account for desired
responses.
Overdoses of aspirin may cause--gastrointestinal pain or even
bleeding. So a pharmacist should recommend his patients with
gastro-intestinal intolerance to aspirin that the tablets be
crushed and suspended in about 15 ml of water and this mixture
added to a full dose of non-aluminium liquid antacid.
2. Drug interactions
This is a new awareness on the part of pharmacist who are
recognising the impact of drug interactions on patient response
and drug therapy. The pharmacist should have a basic
understanding of the drug interactions and also have an up-to-
date knowledge to become a guide to the patients and hence
avoid any Pntoward drug induced diseases which could occur due
to such interactions.
3. Secondary effects
No drug has a single pharmacological effect. Any effects
163
Adverse Drug Reactions
which are associated with a drug besides the desired effects are
called as secondary effects.
Examples:
1. Sedation accompanying antihistaminic effect.
2. Loss of potassium or extracellular fluid concentration follo-
wing thiazide diuretic therapy in treating hypertension.
3. Marked CNS depression following reserpine.
4. Therapeutic dose of salicylates are as potent as some of
the sulfonylureas in lowering blood glucose levels t.n both
diabetic and non-diabetic patients.
5. Long term diphenylhydantoin therapy leads to folic acid
deficiency leading to megaloblastic anaemia (RBC
formation gets disturbed). Hence folic acid should be
administered 0.5-5 mg daily while on diphenylhydantoin
therapy.
4. Idiosyncracy
Idiosyncracy is the term used to describe abnormal drug
response. It covers unusual bizzare or unexpected drug responses
which cannot be explained or predicted in incfyiidual recipients.
Characteristics of idiosyncracy are as follows :
1. It occurs in genetically abnormal subjects.
2. It arises only for few drugs.
3. Prior drugs exposure is necessary.
4. Its response is dose dependent.
5. Its mechanism is explaint,;d by drug receptor interaction.
It is the usual drug reaction that cannot be explained by the
inherent properties of the drug themselves but instead by some
altered characteristics within the patient taking the drug. This
alteration may be permanent or temporary.
Many drugs have been shown to induce haemolytic anaemia
in certain patients. Some of these patients have been found to
have a deficiency of erythrocyte glucose-6 phosphate dehydro-
genase. It is responsible for converting glucose-6 phosphate to 6-
phosphogluconate in the first step of the pentose phosphate
pathway. The reaction is coupled with the reduction of
nicotinamide adenine dinucleotide phosphate (NADP) to reduced
form (NADPH). In the red cells NADPH maintains glutathione
 Adverse Drug Reactions 165

164 Hospital and Clinical Pharmacy as anaphylactic shock.

In allergy drug combines with protein and acts as an antigen.
in the reduced form. Drugs such as ;mtimalarials, analgesics and This antigen causes formation of antibodies. When such person
antipyretics, sulfonamides increase the rate of oxidation of again comes in contact with antigen, antigen-antibody reaction
glutathione, thereby increasing the demand for red cell NADPH. will occur. This reaction makes mast cells to release histamine
Patients with· a G-6 PD deficiency are unable to provide adequate which cause manifestations with symptoms of allergy.
amount of NADPH, oxidised glutathione accumulates and the
integrity of red cell membrane is altered re;ulting in haemolysis. Examples of drugs which induce various diseases
1. Carcinogenic
G-6-Pd
Gulucose 6 phosphate - - - - - - . 6 Phosphogluconate +H2 -Androgens
Glucose-6
Phosphate -Estrogens
dehydrogenase
j -Oral contraceptives
2. Hepatotoxic
NADP------➔ NADPH -Causing hepatic changes, excretory, metabolic function
• NADPH keeps glutathione in reduced form.•
-Amphetamine
• Certain drugs like antimalarials or antipyretics can oxidize glutathione.
-Chloramphenicol
in presence of
-PAS
Haemoglobin - - - - - - - - - - Denatured Haemoglobin
Oxidized glutathione 3. Nephrotoxic

l -Corticosteroids
(formed due to absence
of NADPH or G-6 PD)
-Aldosterone
-Salicylates '
Haemolytic - Decrease- Destroyed- Erythrocyte
anaemia in RSC in spleen shrinkage -Furosemide
4. Diabetogenic
5. Hypersensitivity -Ascorbic acid derivative
One of the. well known examples under this category is -Nicotinic acid
penicillin hypersensitivity. The penicillin in the body is -Furosemide
metabolised to penicillanic acid and this reacts with lysine group
of tissue protein to form penicilloyl protein conjugates. 5. Dermatological toxicity
Approximately 95% of all penicillins that react with proteins -PAS
follows this path of degradation. -Lasix
Anl:!,phylaxis rarely occurs with natural penicillin G given -Nitrofurantoin
intravenously. It is an allergic reaction which occurs after second 'Phototoxic' reactions are most common toxic reaction of drug
or subsequent exposure of drug causing allergy. Anaphylaxis may , towards skin. It occurs due to reaction of a drug or its metabolite
be generalised or localised. with ultraviolet rays. It is a dose related effect occurring after
In localised anaphylaxis to gut there is abdominal pain and first exposure of drug with skin. It does not show cross
asthma to bronchi. Generalised anaphylaxis is characterised by sensitivity. Tetracycline, and nifedipine are phototoxic drugs.
bronchospasm, circulatory collapse with hypotension and
sometimes skin rash. Severe form of anaphylaxis is referred to
 167
166 Hospital and Clinical Pharmacy Aduerse Drug Reactions

Light acts on drug and skin proteins and forms an antigen 2. A single teratogen may produce a variety of abnormalities.
which leads to photo-allergic reactions. Photo allergy is dose 3. A variety of teratogens may produce similar abnormalities.
independent and needs previous exposure to the drug. It is 4. Teratogenic abnormalities may be indistinguishable from
characterised by papulae, eczematous eruption. PABA, estrogens, hereditary malformation.
coaltar are few examples of phototoxic subt:tances. 5. A drug may have inoccuous effects in an adults but can be
Steven Johnson syndrome : It is a toxic reaction induced by very damaging to a foetus.
some drugs. It is characterised by papulae, vesicles on skin and Teratogenic effects are based on following principles :
mucous membrane and haemorrhage of skin e.g.:
-penicillin 1. Specificity
-phenytoin 2. Timing of exposure
-meprobamate 3. Genotype of mother and foetus
4. Simultaneous drug exposure.
6. GIT toxicity Depending on the stage of development a teratogen may show
Constipation different adverse effect or even no effect. When thalidomide was
-Haematinics taken after 21-22 days of gestation; following effects are observed :
-Tricyclic antidepressants -Absence of external ears.
Diarrhoea -Paralysis of cranial nerves.
-Antibiotics After about 24-27 days, the phocomelia effect was maximum
(shortening or complete absence of the limbs), and a day or two
-Digoxin
later defects of legs occurred. This sensitive period terminates
-Neomycin
after 34-36 day of gestation.
Pancreatitis
Teratogens in First Trimester
-Cimetidine -Steroids, salicylates, phenylbutazone, amphetamine,
-Methyldopa LSD, antihistamines.
TERATOGENECITY Teratogens throughout pregnancy
Any drug of a chemical substance which produces deviations or -Chloramphenicol (grey baby syndrome)
aonormalities in the development of embryo is called a teratogen.
-Quinine (deafness)
Foetus is more sensitive to drugs than mother since foetal
-Antidiabetics (tolbutamide)
hepatic enzymes function is minimum and rapidly growing foetal
tissues are more susceptible to the effect. During gestation there -Insulin
is increase in plasma proteins which binds drugs poorly resulting Teratogens prior to delivery
in more free drug. -Reserpine, CNS depressants like tranquillizers,
Drugs are teratogenic only at specific times during embryo- salicylates.
genesis. Thalidomide serves as an excellent example to explain the
pattern of pathogenesis of anomalies. Following important points Drugs excreted in milk
may be noted for teratogenesis : -Large doses of reserpine (cause nasal stiffness).
1. A teratogen may exert the effect on a developmental struc- -Tetracycline (Bone growth is affected)
ture upto the time of its critical differentiation. -Antihistamine.
168 Hospital and Clinical Pharmacv

- Heavy metals like, mercury, lead and arsenicals.

Different approaches for detection of adverse reaction

8
- Cohort study.
- Spontaneous reports of suspected adverse drug reactioni;
- Revie.w of vital statistics.
Drug in Clinical
- Case-control studies.
Cohort study
Toxicity CHAPTER
It is an approach used for detection of adverse drur -~
reactions. This is used when group of drug receivers are followed Poisons are the substances administered either by mouth,
to evaluate outcomes after drug exposure. It is used when injection, inhalation or through skin/mucous membrane. They
detection of events occur with frequency more than 1 in 500 produce harmful, dangerous or fatal symptoms in animals and
exposed. It involves short-term and long-term clinical trials and human beings. ·
post marketing surveillance of established and new drugs. Poisoning could be accidental, occupational, suicidal or
ROLE OF PHARMACIST IN MONITORING ADVERSE criminal. Generally self-medication is an important cause of
DRUG REACTIONS drug poisoning and is particularly seen with OTC drugs. Acute
Taking into consideration intensity and seriousness of the poisoning is generally observed with over-use of drugs or
reaction, pharmacist can advice if immediate discontinuation insecticides and hence emergency treatment of acute poisoning
of therapy is required. Pharmacist must weigh the known ri5k/ is symptomatic.
benefit ratio of the continued administration of drug against
the availability of other drugs or no drug therapy. CLASSIFICATION OF POISONS
Pharmacist is involved in following steps of monitoring of Poisons are classified into three main categories :
adverse drug reactions :
l. Literature review; 1. Corrosives :
2. Patient history; Strong acids (H2SO4 , HNO3, HCl)
Strong alkalies (caustic soda, caustic potash)
3. Drug level studies;
4. Therapeutic decision-making. 2. Irritants :
Pharmacist with better knowledge of the pharmacological (a) Inorganic :
action, adverse reactions and the pathophysiology of diseases Non-metallic like P, Cl, Br, I
can make the therapy to be safer. Metallic-heavy metal (As, Sb, Pb etc.)
REVISION EXERCISE
(b) Organic :
Short Answer Questions : Herbal-castor seeds, croton oil etc.
l. Explain significance of adverse drug reaction. Animal-snake venoms, cantharides.
2. Write various measures which can be taken to avoid
(c) Mechanical : Diamond dust, glass powder.
adverse effects.
Long Answer Questions : 3. Neurotics :
l. Discuss in detail drug induced diseases. (a) Cerebral:
2. What is teratogenecity? Discuss in detail teratogens (i) Sleep causing (Narcotics) opium and its deri-
in first trimester and throughout the pregnancy. 169
Very Short Answer Questions :
1. Define Adverse drug reactions.
2. What is hypersensitinity?
nn