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Drug Allergy

The immune system normally functions to inactivate and remove high-molecular

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weight “foreign” matter taken up by the organism. Immune responses can, however,
occur without appropriate cause or with exaggerated intensity and may harm the
organism; for instance, when allergic reactions are caused by drugs (active ingredient
or pharmaceutical excipients). Only a few drugs, e. g., (heterologous) proteins, have a
molecular weight large enough to act as effective antigens or immunogens, capable by
themselves of initiating an immune response. Most drugs or their metabolites (socalled
haptens) must first be converted to an antigen by linkage to a body protein. In the case
of penicillin G, a cleavage product (penicilloyl residue) probably undergoes covalent
binding to protein.

During initial contact with the drug, the immune system is sensitized: antigen-specific
lymphocytes of the T-type and B-type (antibody formation) proliferate in lymphatic
tissue and some of them remain as so-called memory cells. Usually, these processes
remain clinically silent.

During the second contact, antibodies are already present andmemory cells proliferate
rapidly. A detectable immune response—the allergic reaction—occurs. This can be of
severe intensity, even at a low dose of the antigen.

Four types of reactions can be distinguished:

Type 1, anaphylactic reaction.

Drug-specific antibodies of the IgE type combine via their Fc moiety with receptors on
the surface of mast cells. Binding of the drug provides the stimulus for the release of
histamine and other mediators. In the most severe form, a life-threatening anaphylactic
shock develops, accompanied by hypotension, bronchospasm (asthma attack), laryngeal
edema, urticaria, stimulation of gut musculature, and spontaneous bowel movements.

Type 2, cytotoxic reaction.

Drug–antibody (IgG) complexes adhere to the surface of blood cells, where either
circulating drug molecules or complexes already formed in blood accumulate. These
complexes mediate the activation of complement, a family of proteins that circulate
in the blood in an inactive form, but can be activated in a cascade like succession
by an appropriate stimulus. “Activated complement,” normally directed against
microorganisms, can destroy the cell membranes and thereby cause cell death; it also
promotes phagocytosis, attracts neutrophil granulocytes (chemotaxis), and stimulates
other inflammatory responses. Activation of complement on blood cells results in their
destruction, evidenced by hemolytic anemia, agranulocytosis, and thrombocytopenia.

Type 3, immune-complex vasculitis

(serum sickness, Arthus reaction). Drug–antibody complexes precipitate on vascular
walls, complement is activated, and an inflammatory reaction is triggered. Attracted
neutrophils, in a futile attempt to phagocytose the complexes, liberate lysosomal enzymes
that damage the vascular walls (inflammation, vasculitis). Symptoms may include fever,

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exanthema, swelling of lymph nodes, arthritis, nephritis, and neuropathy.

Type 4, contact dermatitis.

A cutaneously applied drug is bound to the surface of T-lymphocytes directed

specifically against it. The lymphocytes release signal molecules (lymphokines) into their
vicinity that activate macrophages and provoke an inflammatory reaction. Remarkably,
virtually no drug group is completely free of allergic side effects. However, some
chemical structures are prone to cause allergic reactions.

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