Classification and mechanisms of drug reaction
1-non-immunological mechanisms,
2-immunological
•directed against the drug itself
•a reactive metabolite or some contaminant of the drug
• Non-immunological drug reactions
Overdosage
The manifestations are a predictable exaggeration of the
desired pharmacological actions of the drug, and are
directly related to the total amount of drug in the body.
Overdosage may be absolute, as a result of a prescribing
or dispensing error or due to deliberate excess intake by
the patient. It may also occur despite standard dosage due
to varying individual rates of absorption, metabolism
or excretion
An inappropriately large dose may be given to an infant
or very old person or to one with renal impairment. Drug
interaction may also cause drug overdosage
.
• Side effects
These include unwanted or toxic effects, which are not
separable from the desired pharmacological action of the
drug.
Examples are the drowsiness induced by antihistamines;
and the anagen alopecia caused by cytotoxic drugs.
• Cumulative toxicity
Prolonged exposure may lead to cumulative toxicity.
Accumulation of drugs in the skin may lead to colour
disturbance, as a result of either deposition within phagocytic
cells or mucous membranes (e.g. prolonged administration
of gold, silver, bismuth or mercury) or binding of
the drug or a metabolite to a skin component (e.g. highdose
chlorpromazine therapy).
• Delayed toxicity
Examples are the keratoses and skin tumours that appear
many years after inorganic arsenic
,
the delayed hepatotoxicity
associated with methotrexate therapy.
• Facultative effects
Antibiotics that
destroy Gram-positive bacteria may allow the multiplication
of resistant Gram-negative species.
Broad-spectrum
antibiotics, corticosteroids and immunosuppressive drugs
may promote multiplication of Candida albicans
Corticosteroids promote the spread of tinea and erythrasma.
Antibiotics such as clindamycin and tetracycline
may be associated with pseudomembranous enterocolitis
• Drug interactions
Interactions between two or more drugs administered
simultaneously may occur before entry into the body (in
an intravenous drip), in the intestine, in the blood and/or
at tissue receptor sites;
interaction may also occur indirectly as a result
of acceleration or slowing in the rate of
drug metabolism or excretion.
Intestinal drug interactions.Examples include inhibition of
griseofulvin absorption by phenobarbital ,inhibition of
tetracycline absorption by antiacids and decreased
absorption of the oral contraceptive by tetracycline
Displacement from carrier or receptor sites.
Many acidic drugs such as salicylates, coumarins, sulphonamides
and phenylbutazone are bound to plasma albumin
, and compete for binding sites.
sulphonamide may displace tolbutamide from albumin
leading to hypoglycaemia
phenylbutazone may displace warfarin from
albumin, causing bleeding and ecchymoses
Ciprofloxacin increases plasma levels of theophylline
• Enzyme stimulation or inhibition
Antibiotics, if administered over a period of time
(e.g. rifampicin for tuberculosis), can
be enzyme inducers.
Barbiturates stimulate metabolism of griseofulvin,
phenytoin and coumarin anticoagulants,
griseofulvin induces increased metabolism of coumarins
Similarly, rifampicin, phenytoin and carbamazepine
increase the metabolism of ciclosporin
.
Drugs causing enzyme inhibition include chloramphenicol, cimetidine,
monoamine oxidase inhibitors, pethidine and morphine.
Ketoconazole may potentiate oral anticoagulants
erythromycin may potentiate carbamazepine
• Altered drug excretion
aspirin-induced reduction in renal clearance
of methotrexate
probenecid-induced reduction in the renal excretion of
penicillin,
• Metabolic changes
Drugs may induce cutaneous changes by their effects on nutritional
or metabolic status. Thus, drugs such as phenytoin that interfere
with folate absorption or metabolism increase the risk of
aphthous stomatitis, and isotretinoin may cause
xanthomas by elevation of very low-density
lipoproteins
• Teratogenicity and other effects on the fetus
The fetus is particularly at risk from druginduced
developmental malformations during the period
of organogenesis, which lasts from about the third to
the tenth week of gestation.
Thalidomide, retinoids and
cytotoxic drugs are proven teratogens
.
High-dose corticosteroids have been linked to cleft palate.
• Effects on spermatogenesis
A number of drugs cause oligospermia , which may come to light
only as a result of infertility investigations; oestrogens, androgens
, cyproterone acetate, cytotoxic drugs, including methotrexate
given for psoriasis colchicine , most monoamine
, oxidase inhibitors, ketoconazole and sulfasalazine
conception should also be avoided after griseofulvin for 3 months
.
Sex hormones, psychotropic drugs, benzodiazepines,
tetracycline, rifampicin, penicillamine and the folate
antagonist pyrimethamine are possibly teratogenic
and should be avoided in the first
trimester of pregnancy.
Chlorpheniramine appears safe to use
chloroquine has caused a neonatal chorioretinitis.
Tetracyclines are deposited in developing bones and
cause discoloration and enamel hypoplasia of teeth
• Exacerbation of disease
lithium exacerbation of acne and psoriasis,
b-blocker induction of a psoriasiform dermatitis
corticosteroid withdrawal resulting in exacerbation of psoriasis
cimetidine, penicillin or sulphonamide exacerbationof lupus erythematosus (LE)
vasodilator exacerbation of rosacea.
• Idiosyncrasy
This describes an uncharacteristic response, not predictable
, and not mediated by animmunological mechanism
The cause is often unknown, but genetic variation in
metabolic pathways may be involved.
Such genetic abnormalities include glucose-6- phosphate dehydrogenase
deficiency, hereditary methaemoglobinaemia, porphyria, glucocorticoid
glaucoma and malignant hyperthermia of anaesthesia,
all of whichare characterized by unusual pharmacological responses to various drugs.
• Miscellaneous
Jarisch-Herxheimer reaction
The reaction has been attributed to sudden release of pharmacologically
and/or immunologically active substances from killed
microorganisms or damaged tissues.
This is the focal exacerbation of lesions of infective origin
when potent antimicrobial therapy is initiated,
classically observed in the treatment of early syphilis with penicillin;
penicillin or minocycline for erythema chronicum migrans
due to Borrelia burgdorferi infection
• Immunological drug reactions
1--IgE-dependent (type I) drug reactions: urticaria and
Anaphylaxis
cross-linkage by polyvalent drug-protein conjugates of two
or more specific IgE molecules, fixed to sensitized
tissue mast cells or circulating basophil
leukocytes, triggers the cell to release a variety of chemical mediators
including;
histamine, prostaglandin D2., Interleukin-5, Peptides, leukotriene C4
Such cytokines in turn have effects on a variety of target tissues
including skin, respiratory, gastrointestinal and/or
cardiovascular systems.
Dilatation and increased permeability of small blood vessels
with resultant oedema and hypotension, contraction of
bronchiolar smooth muscle and excessive
mucus secretion,
Clinically, this may produce pruritus, urticaria, bronchospasm
and laryngeal oedema, and in severe cases anaphylactic
shock with hypotension andpossible death.
Immediate reactions occur within minutesof drug administration
Penicillins are the commonest cause of IgE-dependent drug eruptions
.
• 2--Antibody-mediated (type II) drug reactions
Binding of antibody to cells may lead to cell damage
following complement-mediated cytolysis.
The classical example of immune complex formation between a drug
(as hapten) bound to the surface of a cell (in this case, platelets) and
IgG-class antibody,
A number of drugs, including penicillin, quinine and sulphonamides,
may rarely producea haemolytic anaemia via this mechanism
Methyldopa
very occasionally induces a haemolytic anaemia mediated
by autoantibodies directed against red cell antigens
• 3---Immune complex-dependent
(type III) drug reactions
Urticaria and anaphylaxis. Immune complexes may activate the complement
cascade, with resultant formation of anaphylaToxins
Serum sickness. Serum sickness-like reactions and other
immune complex-mediated conditions necessitate a drug
antigen to persist in the circulation for long enough for
antibody, largely of IgG or IgM class, to be synthesized
and to combine with it to form circulating antibody antigen
immune complexes.
They therefore develop about 6 days or more after drug administration.
It has been reportedmore recently with antilymphocyte globulin therapy
Vasculitis . Drug-induced immune complexes play a part in
the pathogenesis of cutaneous necrotizing vasculitis.
Deposition of immune complexes on vascular endothelium
results in activation of the complement cascade,
Hydralazine
Arthus reaction.The Arthus reaction is a localized form of immune complex vasculitis.
Intradermal or subcutaneous injection of antigen such as a vaccine into
a sensitized individual with circulating precipitating antibodies
, usually of IgG1 dass, leads to local immune complex formation
and the cascade of events described above.
Clinically, there is erythema and oedema, hacmorrhage and occasionally
necrosis at the injection site, which reaches a peak at4-10 h,and
then gradually wanes.
• 4--Cell-Inediated (type IV) reactions
fixed drug reactions, lichenoid reactions, LE-likc reactions and erythema multifonne,
Stevens-Johnson syndrome and TEN, involve T-Iymphocyte responses to altered self.
Viruses incriminated, especially in the drug hypersensitivity syndrome, indude human herpesvirus
6, Epstein-Barr virus, cytomegalovirus and hepatitis C virus
Patients with acute drugallergy to carbamazepine, phenytoin, sulfamethoxazole,
allopurinol or paracetamol had activated drug-specific CD4+or CD8+T
cells in the circulation
Lichenoid drug eruptions. The mechanisms underlying
lichenoid drug eruptions are essentially unknown, but
they may develop as a result of autoreactive cytotoxic
T-cell clones directed against a drug-dass II MHC antigen
complex, such that keratinocytes and Langerhans' cells
are viewed by the immune system as 'non-self'.