8/14/2019 Classifications and Mechanisms of Drug Reactions

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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. cutaneoushyperpigmentation 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 ofcandida 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 maybe synergistic, antagostic or inconsequential. Eg. tetracycline with isotretinoin causes psuedotumorcerebri.

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 causeoligospermia ------- 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 inurticaria/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 renalfunction.

Idiosyncracy ----- IT IS AN UNCHARACTERISTIC RESPONSE NOT PREDICTABLE FROM ANIMAL

EXPERIMENTS AND NOT IMMUNOLOGICALLY MEDIATED. CAUSE IS OFTEN UNKNOWN. GENETICVARIATIONS IN METABOLIC PATHWAYS MAY BE RESPONSIBLE. SUCH GENETIC ABNORMALITIESINCLUDE GLUCOSE-6-PHOSPHATASE DEHYDROGENASE DEFICIENCY, HEREDITARYMETHAEMOGLOBINEMIA, PORPHYRIA, MALIGNANT HYPERTHERMIA OF ANAESTHESIA.

2. IMMUNOLOGICAL: Allergic hypersensitivity reactions are caused by immunological sensitization toa drug as a result of previous exposure to that drug or to a chemically related cross reactingsubstance. Only 6-10% of ADRs are immunologically mediated. Macromolecular drugs such asprotein or peptide hormones, insulin or dextran are antigenic in their own right. In contrast, mostdrugs are small organic molecules with a molecular mass of less than 1 kDa; conjugation of freedrug 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 ---------------

8/14/2019 Classifications and Mechanisms of Drug Reactions

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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 slowacetylators 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 celldegranulation resulting in clinical manifestations of variable severity from pruritus to urticaria tofrank anaphylaxis. PENICILLINS ARE THE MOST COMMON DRUGS TO ELICIT THIS TYPE OFREACTION.

Cytotoxic drug induced reactions(Type II hypersensitivity)--- Drugs can induce cytotoxicityby various mechanisms--

(A) A drug may act as hapten by binding to tissue proteins thereby forming an antigen susceptible toantibody or lymphocyte mediated immune response

(B) A drug may also bind to cells and form drug-antibody complex on the cellular surface leading tocytolysis

(C) Drug may induce antibody formation to specific antigens causing indirect cytotoxicityEg. 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 C3aand C5a which trigger the release of mediators from mast cells and basophils directlyresulting in urticaria or anaphylaxis.

(b) Serum sickness ------- reactions are caused by formation of drug antibody conjugates thatenter the circulation and cause serum sickness. A drug has to be present in circulation longenough for antibody largely of IgG or IgM class to be synthesized and to form thecomplexes. Therefore they develop after 6 days of more of drug administration. It ischaracterized by fever, arthralgias, lymphadenopathy and an morbilliform or urticarialeruption. Previously reported with the use of large doses of heterologous antibody as withhorse antiserum for treatment of diphtheria, it has now been reported with the use ofantilymphocyte globulin therapy.

(c) Vasculitis -------- DRUG INDUCED IMMUNE COMPLEXES PLAY A PART IN THE PATHOGENESISOF CUTANEOUS NECROTIZING VASCULITIS. Deposition of immune complexes on vascularendothelium results in activation of the complement cascade with generation ofanaphylotoxins C3a and C5a ---- neutrophils come to the site ------ release lysosomalenzymes ---------- inflammation. Vasoactive amines are released from mast cells andbasophils that increase vascular permeability. Immune complex interaction with the plateletFc receptor causes their aggregation --------- microthrombi formation. All these lead toleucocytoclastic vasculitis

(d) Arthus phenomenon -------- it is a localized form of immune complex vasculitis. Intradermaland subcutaneous injection of antigen such as vaccine into a sensitized individual withcirculating antibodies usually of IgG1 class leads to local immune complex formation and acascade 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 whichantigen is presented thereby stimulating production and release of lymphokines ---- like in allergiccontact dermatitis as with penicillin. Nevertheless, it is thought that a number of ACDRs includingsome 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