Drug Interactions

Allergic reactions to drugs are the resultant of the interaction of drug or metabolite (or a nondrug element in the formulation) with patient and disease, and subsequent re-exposure.

Lack of previous exposure is not the same as lack of history of previous exposure, and 'first dose reactions' are among the most dramatic. Exposure is not necessarily medical, e.g. penicillins may occur in dairy products following treatment of mastitis in cows (despite laws to prevent this), and penicillin antibodies are commonly present in those who deny ever having received the drug. Immune responses to drugs may be harmful (allergy) or harmless; the fact that antibodies are produced does not mean a patient will necessarily respond to re-exposure with clinical manifestations; most of the UK population has antibodies to penicillins but, fortunately, comparatively few react clinically to penicillin administration.

Whilst macromolecules (proteins, peptides, dex-tran polysaccharides) can act as complete antigens, most drugs are simple chemicals (mol. wt less than 1000) and act as incomplete antigens or haptens, which become complete antigens in combination with a body protein.

The chief target organs of drug allergy are the skin, respiratory tract, gastrointestinal tract, blood and blood vessels.

Allergic reactions in general may be classified according to four types of hypersensitivity, and drugs can elicit reactions of all types, namely:

Type I reactions: immediate or anaphylactic type.

The drug causes formation of tissue-sensitising IgE antibodies that are fixed to mast cells or leucocytes; on subsequent administration the allergen (conjugate of drug or metabolite with tissue protein) reacts with these antibodies, activating but not damaging the cell to which they are fixed and causing release of pharmacologically active substances, e.g. histamine, leukotrienes, prostaglandins, platelet activating factor, and causing effects such as urticaria, anaphylactic shock and asthma. Allergy develops within minutes and lasts 1-2 hours.

Type II reactions: antibody-dependent cytotoxic type. The drug or metabolite combines with a protein in the body so that the body no longer recognises the protein as self, treats it as a foreign protein and forms antibodies (IgG, IgM) that combine with the antigen and activate complement which damages cells, e.g. penicillin- or methyldopa-induced haemolytic anaemia.

Type III reactions: immune complex-mediated type. Antigen and antibody form large complexes and activate complement. Small blood vessels are damaged or blocked. Leucocytes attracted to the site of reaction engulf the immune complexes and release pharmacologically active substances (including lysosomal enzymes), starting an inflammatory process. These reactions include serum sickness, glomerulonephritis, vasculitis and pulmonary disease.

Type IV reactions: lymphocyte-mediated type.

Antigen-specific receptors develop on T-lympho-cytes. Subsequent administration leads to a local or tissue allergic reaction, e.g. contact dermatitis.

Cross-allergy within a group of drugs is usual, e.g. the penicillins. When allergy to a particular drug is established, a substitute should be selected from a chemically different group. Patients with allergic diseases, e.g. eczema, are more likely to develop allergy to drugs.

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