CLASSIFICATIONS AND MECHANISMS OF DRUG REACTIONS:

1. NON-IMMUNOLOGICAL

 Predictable
• Overdosage ---- can lead to clinical manifestations that are exaggeration of pharmacologic effects
of the drug. Eg. coumarin toxicity leads to mucosal bleeding
• Side effects ---- they are unwanted or toxic effects that are not separable from the desired
pharmacologic action of drugs eg. drowsiness caused by antihistaminics.
• Cumulative toxicity --- results from prolonged exposure to the drug with gradual accumulation of
the drug or its metabolites in the skin or mucous membranes ------- eg. cutaneous
hyperpigmentation from minocyclin therapy.
• Delayed toxicity --- eg. keratoses and skin tumours that appear after many years of arsenic
exposure.
• Facultative effects --- these are consequences of drug induced alterations in skin and mucosal flora.
Eg. broad spectrum antibiotics, steroids and immunosuppresives can lead to multiplication of
candida albicans and its transition from saprophytic to pathogenic states.
• Drug interactions ---- these may result either from alteration of the absorption, distribution,
metabolism or excretion of one drug by the other or from combination of these effects. They may
be synergistic, antagostic or inconsequential. Eg. tetracycline with isotretinoin causes psuedotumor
cerebri.
• Metabolic alterations ------- medications can induce metabolic changes which result in cutaneous
pathology. For eg. isotretinoin induced changes in lipid metabolism may cause eruptive xanthomas.
• Teratogenicity --- THALIDOMIDE, RETINOIDS and CYTOTOXIC DRUGS ARE PROVEN TERATOGENS.
• Effects on spermatogenesis ---------- most chemotherapeutic agents potentially damage sperms;
conception should be avoided after Griseofulvin for 3 months. A number of drugs cause
oligospermia ------- oestrogens, cyproterone acetate, cytotoxic drugs, colchicines, ketoconazole,
sulfasalazine.
• Non immunological activation of effector pathways ---- mechanisms include -------
(a) pharmacologic destabilization of mast cells causing direct mediator release resulting in
urticaria/angioedema ----------- opiates
(b) direct activation of complement pathways ---------- radiocontrast induced urticaria
(c) alteration of arachidonic acid metabolism --------- aspirin and other NSAIDS.
• Exacerbation of disease ---- psoriasis is exacerbated by beta blockers
• Drug induced chromosomal damage---- substances capable of inducing chromosomal damage are
called clastogens ------- amtimitotics and abtibiotics can cause this.

 Unpredictable
• Intolerance ---- The characteristic effects of the drug are produced to an exaggerated extent by an
abnormally small dose. This may be due to genetic variation in the rate of drug metabolism.
Alternatively it may be due to delayed metabolism or excretion due to impaired hepatic or renal
function.
• Idiosyncracy ----- IT IS AN UNCHARACTERISTIC RESPONSE NOT PREDICTABLE FROM ANIMAL
EXPERIMENTS AND NOT IMMUNOLOGICALLY MEDIATED. CAUSE IS OFTEN UNKNOWN. GENETIC
VARIATIONS IN METABOLIC PATHWAYS MAY BE RESPONSIBLE. SUCH GENETIC ABNORMALITIES
INCLUDE GLUCOSE-6-PHOSPHATASE DEHYDROGENASE DEFICIENCY, HEREDITARY
METHAEMOGLOBINEMIA, PORPHYRIA, MALIGNANT HYPERTHERMIA OF ANAESTHESIA.

2. IMMUNOLOGICAL: Allergic hypersensitivity reactions are caused by immunological sensitization to

a drug as a result of previous exposure to that drug or to a chemically related cross reacting
substance. Only 6-10% of ADRs are immunologically mediated. Macromolecular drugs such as
protein or peptide hormones, insulin or dextran are antigenic in their own right. In contrast, most
drugs are small organic molecules with a molecular mass of less than 1 kDa; conjugation of free
drug as a hapten with a macromolecular carrier is then required to initiate immune response.
Fortunately only few drugs have the capacity to covalently with tissue proteins.
Factors concerned in the development of hypersensitivity are ---------------
 • ROUTE OF ADMINISTRATION may affect its immunogenicity. Topical drug exposure is more likely to
result in sensitization than oral administration and favours development of contact dermatitis.
Anaphylaxis is more likely associated with IV drug administration.
• ANTIGENIC LOAD IN TERMS OF DEGREE OF DRUG EXPOSURE AND INDIVIDUAL GENETIC VARIATION
IN DRUG ABSORPTION AND METABOLISM ---- Hydralazine induced LE occurs more in slow
acetylators and 10 times commoner in HLA-DR4.
• ALLERGIC DRUG REACTIONS ARE LESS COMMON IN CHILDHOOD AND AGED because of impaired
immunological responsiveness
• IMMUNOSUPRESSION may increase the risk by inhibiting the regulatory function of suppressor T
cells.

 IgE dependant drug reactions(Type I hypersensitivity) ---- involve IgE mediated mast cell
degranulation resulting in clinical manifestations of variable severity from pruritus to urticaria to
frank anaphylaxis. PENICILLINS ARE THE MOST COMMON DRUGS TO ELICIT THIS TYPE OF
REACTION.
 Cytotoxic drug induced reactions(Type II hypersensitivity)--- Drugs can induce cytotoxicity
by various mechanisms--
(A) A drug may act as hapten by binding to tissue proteins thereby forming an antigen susceptible to
antibody or lymphocyte mediated immune response
(B) A drug may also bind to cells and form drug-antibody complex on the cellular surface leading to
cytolysis
(C) Drug may induce antibody formation to specific antigens causing indirect cytotoxicity
Eg. penicillin induced hemolysis and quinine induced cocktail
purpura.
 Immune complex dependant drug reactions (Type III hypersensitivity) -----
(a) Urticaria and anaphylaxis ------- Immune complexes may activate the complement cascade
with resultant formation of anaphylatoxins such as complement protein fragments like C3a
and C5a which trigger the release of mediators from mast cells and basophils directly
resulting in urticaria or anaphylaxis.
(b) Serum sickness ------- reactions are caused by formation of drug antibody conjugates that
enter the circulation and cause serum sickness. A drug has to be present in circulation long
enough for antibody largely of IgG or IgM class to be synthesized and to form the
complexes. Therefore they develop after 6 days of more of drug administration. It is
characterized by fever, arthralgias, lymphadenopathy and an morbilliform or urticarial
eruption. Previously reported with the use of large doses of heterologous antibody as with
horse antiserum for treatment of diphtheria, it has now been reported with the use of
antilymphocyte globulin therapy.
(c) 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 with generation of
anaphylotoxins C3a and C5a ---- neutrophils come to the site ------ release lysosomal
enzymes ---------- inflammation. Vasoactive amines are released from mast cells and
basophils that increase vascular permeability. Immune complex interaction with the platelet
Fc receptor causes their aggregation --------- microthrombi formation. All these lead to
leucocytoclastic vasculitis
(d) Arthus phenomenon -------- it is a localized form of immune complex vasculitis. Intradermal
and subcutaneous injection of antigen such as vaccine into a sensitized individual with
circulating antibodies usually of IgG1 class leads to local immune complex formation and a
cascade of events described above. CLINICALLY THERE IS ERYTHEMA AND OEDEMA,
HEMORRHAGE AND OCCASIONALLY NECROSIS AT THE INJECTION SITE WHICH REACHES A
PEAK AT 4-10 HOURS AND THEN GRADUALLY WANES.

 CMI (Type IV hypersensitivity)--- these reactions are mediated by T lymphocytes to which

antigen is presented thereby stimulating production and release of lymphokines ---- like in allergic
contact dermatitis as with penicillin. Nevertheless, it is thought that a number of ACDRs including
some morbilliform and bullous ACDRs, FDE, lichenoid reactions, LE like reactions and EM-SJS and
TEN involve T lymphocyte response to altered self.

3. MISCELLENEOUS

 Jarisch-Herxheimer reactions
 Infectious mononucleosis ampicillin reaction