1.c.1 adverse drug reaction

Pharmacy Practice
(BP703TT)
Adverse Drug Reaction
By:
Dr. C. J. Tank

Adverse Drug Reactions
 When a drug is administered to a patient, two types of effects
can be produced, i.e. Desired and Undesired effects.
 The desired effects are clinically useful, whereas undesired drug
effects are harmful to the patient and are commonly referred as
adverse drug reactions (ADR).
 ADR is noxious (injurious) and unintended response of a drugs.
As adverse drug reactions are unexpected reactions, they are
different from side effects that are expected reactions of drugs.

Adverse Drug Reactions
 ADRs may develop promptly or only after prolonged
medication or even after stoppage of administration
of the drug. They are more commonly with multiple
drug therapy and in the elderly.

Classifications of Adverse Drug Reaction
 Adverse drug reactions are due to following reasons,
accordingly they are classified :
1. Excessive Pharmacological effects
2. Secondary Pharmacological effects
3. Idiosyncrasy
4. Allergic reactions
5. Genetic make up of the patients
6. Sudden drug withdrawal
7. Drug interactions

Excessive Pharmacological effects
 It appears due to over dosage of a drug.
 This is particularly troublesome with cardioactive,
hypotensive, hypoglycemia and central nervous system
depressive agents.
 e.g. Hypotensive agent used in hypertension in excess dose
causes profound hypotension.
 For example, anti-diabetic drugs are beneficial in diabetes
mellitus but sometimes hypoglycemia is developed due to
excessive pharmacological effect and so regarded as adverse
drug effect.

Excessive Pharmacological effects
 Adverse reaction due to excess pharmacological effects may also appear at
usual therapeutic dose in certain conditions. These include:
 Patients with kidney disease particularly those who have lost more than
70% kidney function.
 Hypoalbuminemia which may be due to failure of albumin production as
in liver disease or albumin loss as in nephrotic syndrome.
 Patients at the extremes of the age range, i.e. infants and neonates.
 Adverse reaction in these conditions can be minimized by dose
adjustment after knowing the pharmacokinetic behavior of an
administered drug.

Secondary Pharmacological Effects
 Drugs have several pharmacological actions at usual therapeutic dose but it
is prescribed solely for one of these beneficial actions.
 For example, Antihistamines are prescribed for their Antiallergic skin
reactions or for their antinausea effects, but they also produce drowsiness
due to central nervous system depression (secondary pharmacological
effects).
 This action may be of little importance for patients lying on bed but it may
have disastrous consequences if a patient is motor driver. This effect may
be greatly exacerbated if the patient is also taking hypnotics, tranquilizer,
cough suppressant as medicines or is consuming alcohol.

Idiosyncrasy
 The term, idiosyncrasy is used for unusual, unexpected
drug effect which cannot be readily explained or
predicted.
 It also includes drug induced fetal abnormalities such as
phocomelia developing in offspring of mother exposed to
thalidomide. Thalidomide develops as potential
teratogenicity if given to mothers during initial period of
gestation when the limb buds are formed.
 Structural changes at molecular level occur in the fetal
skeletal and neurological tissue but the nature of these
changes are known for the development of fetal
abnormalities-phocomelia.

Idiosyncrasy
Drug induced cancer is an idiosyncratic reaction.
 Vaginal adenocarcinoma in girls with prolonged use of
stilbesterol.
 Tumors in kidney pelvis with prolonged use of stilbesterol.
 Uterine cancer in patients with prolonged use of oestrogens.
 Lymphoid tumors in patients receiving long term
immunosuppressive therapy with azathioprine,
cyclophosphamide and other similar agent.

Allergic Drug Reactions
 Allergic drug reactions account for 5 to 10% of all adverse
drug reactions.
 Any drug has the potential to cause an allergic reaction.
Symptoms of adverse drug reactions include cough, nausea,
vomiting, diarrhea, and headaches. Skin reactions (i.e. rashes,
itching) are the most common form of allergic drug reaction.
 Allergic drug reactions range from very mild reactions to
anaphylaxis and death may occur rarely after exposure to
wide variety of drugs.

 Allergy symptoms are the result of a chain reaction that starts in the
immune system. Your immune system controls how your body defends
itself.
 For instance, if you have an allergy to a particular medication, your
immune system identifies that drug as an invader or allergen. Your
immune system may react to medications in several ways.
 One type of immune reaction is due to production of antibodies called
Immunoglobulin E (IgE) specific to the drug. These antibodies travel to
cells that release chemicals, triggering an immediate allergic reaction. This
reaction causes symptoms in the nose, lungs, throat, sinuses, ears, lining
of the stomach or on the skin and usually occurs within minutes to a few
hours of taking the drug.

 The most common immune response to a drug is due to the expansion of
T cells, a type of white blood cell that recognize the drug as foreign.
 These T cells orchestrate a delayed immune response that most often
affects the skin, causing itchy rashes, and occurs days to weeks after
exposure to the drug.
 Most allergic reactions occur within hours to two weeks after taking the
medication and most people react to medications to which they have
been exposed in the past. This process is called "sensitization”
 Such individual when re-exposed to the same drug, antigen reacts with
the antibodies and liberates the mediators of allergic reaction from mast
cells, e.g. kinins, histamine, serotonins and prostaglandins.

 Symptoms of an allergic reaction become apparent which are
characteristic of the mediator and not the drug. Some example of allergic
reactions and their initiating drugs are shown in Table.
Allergic Response Allergic drug reaction
Anaphylaxis Penicillins
Haemolytic anaemia
(Red Blood Cell destruction)
Penicillin, Sulphonamide, Guinidine
Leucopenia
(White blood cell destruction)
Sulphonaides, phyenylbutazone
Skin rashes Sulpha drugs, Penicillin, Barbiturates
Hepatitis Phenothiazine, Methyl dopa
Nephritis Methicillin, Oxacillin, Rifampicin
Vasculitis Sulpha Drugs
Lupus syndrome Procainamide, hydrazine, isoniazid

Genetically Determined Toxicity
 Patients of selected genetic makeup are at substantially great then average risk for
some specific drug toxicities.
 For example glucose-6-phosphate dehydrogenase (G6PD) is involved in
degradation of glucose for producing energy.
 G6PD deficiency is a condition in which red blood cells break down when the body
is exposed to certain drugs or the stress of infection. It is hereditary, which means
it is passed down in families. G6PD deficiency occurs when a person is missing or
does not have enough of an enzyme called G6PD. This enzyme helps red blood
cells work properly.
 Too little G6PD leads to the destruction of red blood cells.
 Certain population in Africa and South East Asia are deficient in glucose-6-
phosphate dehydrogenase and therefore, there are substantial risks of developing
haemolytic disease after the use of antimalarial drug - Primaquine,
Sulphonamides, Guanidine and Nitrofurantoin.

Genetically Determined Toxicity
 Similarly there is other genetically determined toxicity. These include:
 Patients with porphyria are susceptible to CNS depressive agents like
barbiturates.
 Individual with pseudocholinestrase deficiency is highly susceptible to
succinylcholine. They may develop paralysis and often apnoea.
 Many drugs are detoxified in liver by acetylation. The ability of acetylation
of many drugs in liver is variable between individuals. Slow acetylators
have greater risk of toxicity for some drugs like isoniazide, procainamide,
hydrallazine, phenelzine and dapsone.

Toxicity Following Drug Withdrawal
 Tolerance occurs after prolong use of variety of drugs of narcotic
analgesics, hypnotics, ethyl alcohol, some hypotensive agents (Clonidine)
and corticosteroid drugs. Sudden withdrawal of such drugs shows severe
adverse effects.
 In patients habituated to central nervous depressants such as ethyl
alcohol, barbiturates and some benzodiazepines, withdrawal of the usual
dose may produce marked agitation, tachycardia, confusion, delirium and
convulsions.
 Clonidine is used in hypertension but its sudden withdrawal may cause
severe hypertension.

Toxicity Following Drug Withdrawal
 Long term of corticosteroid therapy is less common because it may cause
atrophy of recipient’s adrenal glands.
 Therefore, sudden withdrawal can precipitate an acute adrenal crisis
(Addison’s disease) in which the patients become profoundly weak,
hypotensive and are collapsed.
 Such circumstances, can be avoided by gradual removal of corticosteroid
over a period of weeks depending upon length of time they have been
consumed.

Drug Interaction
 Whenever two or more drugs are being taken, there is a chance that there
will be an interaction among the drugs. The interaction may increase or
decrease the effectiveness of the drugs or the side effects of the drugs.
 The likelihood of drug interactions increases as the number of drugs being
taken increases. Therefore, people who take several drugs are at the
greatest risk for interactions.
 A drug interaction is a reaction between two (or more) drugs or between a
drug and a food, beverage, or supplement.
 Taking a drug while having certain medical conditions can also cause a
drug interaction. For example, taking a nasal decongestant if you have high
blood pressure may cause an unwanted reaction.

Summary
 Classifications of Adverse Drug Reaction
– 1. Excessive Pharmacological effects
– 2. Secondary Pharmacological effects
– 3. Idiosyncrasy
– 4. Allergic reactions
– 5. Genetic make up of the patients
– 6. Sudden drug withdrawal
– 7. Drug interactions

1.c.1 adverse drug reaction

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