DRUG-INDUCED HYPERSENSITVITY REACTIONS

Hypersensitivity or "allergic" reactions to drugs do not appear to have a high incidence in veterinary medicine (perhaps <10% of all drug-related ad­verse effects). Nevertheless immune-mediated responses due to the antigenic properties of some drugs can lead to serious and even fatal consequences. Hypersensitivity in animals has been associated most frequently with penicillins and cephalosporins but tetracyclines, chloramphenicol, sulfonamides, macrolides, lincosamides, nitrofurans, isoniazid, levamisole, corticosteroids, protein hormones, iodinated contrast media for use in radiography, and several other drugs may precipitate various forms and degrees of immune-based reac­tions. In addition, several carriers and solubilizers are also capable of bringing about the sudden release or activation of autacoids such as histamine, serotonin, kinins, prostaglandins, leukotrienes, and platelet-activating factor, leading to clinical signs associated with type I hypersensitivity. Examples of such sub­stances capable of releasing autacoids include polysorbate 80 (surfactant used as an emulsifier and dispersing agent), carboxymethylcellulose (used as a car­rier to prepare suspensions), certain diamidines (antiprotozoal agents), mor­phine, and tubocurarine.

Generally, hypersensitivity reactions cannot be anticipated unless the ani­mal has a history of being sensitive to some drug or perhaps of atopy. Unlike type A adverse drug reactions, allergic responses are not usually dose related and severe manifestations can occur following exposure to very limited amounts of an antigenic drug.

Because most drug molecules are relatively small they do not usually elicit an immune response of their own accord; to become immunogenic, they or their metabolites must form covalent bonds with macromolecules such as en­dogenous proteins, and to a lesser extent with polysaccharides or polynucleotides. This covalent binding of drugs (thus acting as haptens) to appropriate endogenous macromolecules is the exception rather than the rule, but does occur to a significant degree with some classes of drugs. An additional dimen­sion in the occurrence of hypersensitivity reactions following the repeated ad­ministration of a drug preparation, is that in several microbiological products either contaminant proteins or polymeric complexes are present that can act as primary antigens. This particular problem has been encountered with penicil­lins, cephalosporins, polymyxin, amphotericin B, and several other antibiotic preparations. Cross-reactivity must also always be considered in a patient with a history of allergic drug reactions. In this instance, administration of closely related drugs may precipitate signs of hypersensitivity. Cross-reactivity may be encountered with the penicillins, cephalosporins, and sulfonamides. Because a sulfamyl group is common to all of them, cross-reactivity also occurs between sulfonamides, furosemide, thiazide diuretics, and the sulfonyl-urea group of oral hypoglycemic drugs.

Immunologic Mechanisms: Drug reactions mediated by immune mechanisms may be associated with any 1 of the 4 basic types of hypersensitivity.

Type I Reactions (Anaphytaxis): Initiated by antigen reaction with basophils and mast cells previously sensitized by IgE antibody, leading to the sud­den release of pharmacologically active substances (vasoactive amines, kinins, prostaglandins, leukotrienes, platelet-activating factor, and various chemotactic factors). General and local anaphylactic reactions due to drugs may occur.

Type II Reactions (Antibody-Mediated Cytotoxicity or Cell-Stimulating): Initiated by IgG, IgM or IgA antibodies reacting to antigenic substances on the surface of body cells (either a normal component or a foreign hapten) or asso­ciated structures such as myoneural receptors, intracellular cement substance, etc. Complement also participates in this reaction as do certain kinds of mono-nuclear cells. Many types of body cells can be damaged but blood cells seem to be especially susceptible to immune-mediated lysis and phagocytosis. Stimula­tion of secretor organs (e.g., thyroid) or neutralization of biologically active molecules (e.g., insulin) may lead to specific deficiency states. The types of allergic drug manifestations related to type II reactions (autoimmune responses) in­clude hemolytic anemia, leukopenia, thrombocytopenia, glomerular nephritis, and resistance to insulin replacement therapy. Transfusion reactions are also a form of type II hypersensitivity.

Type III Reactions (Immune-Complex Damage): Initiated when antigen reacts with precipitating antibody, forming complexes of various sizes that may then localize in tissues, usually small blood vessel walls, causing damage (vasculitis) and/or interference with the function of the tissue membranes involved. The prerequisites for this type of reaction are a continuous source of circulating antigen and the continuous production of specific antibody (IgM or IgG, though IgE may also play a role). The best example of a drug-induced type III reaction is serum sickness, which involve IgG and is a multi system dependent vasculitis. Drugs acting as haptens and capable of producing serum sickness include penicillins, lincomycin,  erythromycin, sulphonamides, tri methoprirn-sulphonamide combinations and certain hormones.

Type IV Reactions (Cell-Mediated Immune Reaction or Delayed Hypersenstivity): Initiated by the action of active, sensitized lymphocytes (T-cells) responding specifically to an allergen by the release of lymphokines and/or the development of cytotoxicity without antibodies being involved. Activated macrophages (due to lymphokine release) also become cytotoxic.  Cell-mediated hy­persensitivity is the mechanism involved in allergic contact dermatitis, which may result from topically applied or locally-injected drugs.

Clinical Manifestation of Drug-Induced Hypersentivity - Anaphytaxis: Anaphylaxis is an acute, systemic, life-threatening reaction characterized in many species by hypotension, bronchospasm, angioedema, urticaria, erythema, pruritis, pharyngeal and/or laryngeal edema, cardiac dysrhythmias, vomiting, colic and hyperperistalsis. Many of these clinical signs may be present or only a single sign may be evident in a particular case. Anaphylaxis most commonly follows the parenteral administration of drugs but may also occur after inhala­tion or oral exposure. Clinical signs usually develop within seconds to minutes after injection and are at their peak in 10-30 minutes, but the onset may be delayed for an hour or more after administration of a relatively insoluble, re­pository dosage form such as benzathine penicillin. If the reaction is not fatal, the manifestations will subside over a period of hours. Death generally is attributable to cardiac arrest, shock or asphyxia.

Treatment of drug-induced anaphylactic reactions should proceed as fol­lows: epinephrine or other β-adrenoceptor agonists; theophylline or other phosphodiesterase inhibitors; a glucocorticoid that will modify the effects of the released mediators on target tissues; sodium chromoglycate, which inhibits the degranulation of mast cells. Antihistaminic agents (H₁ blockers) are not particularly useful once histamine release has occurred. They will, however, limit the adverse effects of histamine if administered on a prophylactic basis.

Serum Sickness: Serum sickness is a systemic reaction that occurs in re­sponse to certain drugs and manifest by lymphadenopathy, neuropathy, vasculitis, nephritis, arthritis, urticaria, and fever. Generally, the onset of serum sickness in response to a drug is delayed until 10-20 days after the inception of therapy. An accelerated form of the reaction (onset in 2-3 days) may occur in individuals that have been previously sensitized to the drug. Clinical signs often persist for several days after withdrawal of the drug.

Drugs that have been incriminated most frequently in the production of serum sickness include the sulfonamides, penicillins, streptomycin, lincomycin, erythromycin, para-aminosalicylic acid, and certain anticonvulsants and hor­mones. Immediate withdrawal of the drug is necessary to reduce the severity of this form of type III reaction, though corticosteroids are also useful in attenuat­ing severe serum sickness reactions.

Hematologic Manifestations: Hemolytic anemia, thrombocytopenia and agranulocytosis are occasional manifestations of immune-mediated adverse drug reactions. Several mechanisms and type 1 of hypersensitivity reactions may be involved. Anemia may be due to frank hemolysis or to a shortened RBC life span because of antigen-antibody reactions involving the membrane. Auto­immune hemolytic anemia is a special type of this case. Drugs that may pro­duce immune-mediated hemolytic anemia in man include penicillin, n-methyldopa, dipyrone, quinine, quinidine, p-aminosalicylic acid, phenacetin, and rifampin. Estrogens are of particular significance in the dog.

Immune-mediated thrombocytopenia may result from mechanisms similar to those associated with RBC hemolysis. The drugs incriminated include sulfon­amides, isoniazid, rifampin, estrogens, and phenylbutazone.

Agranulocytosis, a potentially fatal allergic drug reaction, is more common in man than in other animals. The contribution of immune-mediated reactions to drug-induced agranulocytosis remains obscure but antileukocyte antibodies have been demonstrated in several instances. The immunologic effects may be on the stem cells in the bone marrow. Drugs most frequently associated with agranulocytosis in man are phenylbutazone, oxyphenbutazone, amidopyrine, sulfonamides, cephalothin, semisynthetic penicillins, chloramphenicol, p-aminosalicylic acid, phenothiazines, gold compounds, anticonvulsants, propylthiouracil, indomethacin, dipyrone, tolbutamide, barbiturates, antihistaminics and arsenicals.

Autoimmune Reactions: Besides hemolytic anemia and thrombocytopenia, drugs have been incriminated in the development of systemic lupus erythematosus, polymyositis, hepatitis, tubular nephropathy, and inhibition of coagula­tion factor VIII. Drug-induced systemic lupus erythematosus has been observed in patients treated with isoniazid, griseofulvin, and tetracycline. Auto­immune reactions to drugs usually subside within several months after the offending drug is withdrawn. Immunosuppressive therapy is warranted only when the autoimmune response is unusually severe.

Cutaneous Manifestations: Contact dermatitis, initiated by local exposure to a drug that acts as hapten, is a hypersensitivity reaction (type IV) that may be encountered in animals. The extent and seveority of the lesion that develops will depend on the area of application, its degree of penetration and several other factors. Delayed hypersensitivity reactions develop at an injec­tion site. Other cutaneous manifestations may result from immune-mediated responses to drugs. Examples include urticaria and angioedema (type 1), cuta­neous lesions of systemic lupus erythematosus (type III) and petechiae or purpura caused by thrombocytopenia or vasculitis (types II and III). Cutaneous drug eruptions may be expressed in a wide variety of pathological lesions. Drugs that have been reported to cause skin eruptions include tetracaine, chloramphenicol, penicillin G, ampicillin, tetracycline, gentamicin, streptomycin, neomycin, thiabendazole, 5-fluorocytosine, phenytoin, quinidine, thiacetarsamide, prednisolone, acepromazine, estrogens, thyroid extract, benzoyl peroxide and sulfonamides.

Diagnosis: If the need for diagnosis justifies the inherent risk to the animal, a clinical diagnosis of drug-induced hypersensitivity may be based on the follow­ing criteria: the reaction should 1) be elicited by a small amount of the drug; 2) not resemble the normal pharmacological action of the drug; 3) occur only after a lapse of an induction period of 5-7 days following initial exposure to the drug; 4) include clinical signs considered characteristic of hypersensitivity; and 5) occur promptly following re-exposure to the drug.