17.4: Drug Toxicity: Allergic Reactions

Drug-related allergies are immune-mediated responses triggered by the administration of pharmacological agents. These hypersensitivity reactions are classified based on the immune mechanisms involved. The four primary types—Type I, II, III, and IV—are mediated by different immunological pathways and exhibit distinct clinical manifestations.

Type I Hypersensitivity/ IgE-Mediated Reactions: Immunoglobulin E (IgE) immediately mediates Type I hypersensitivity reactions. Upon initial exposure to a drug, IgE antibodies bind to mast cells and basophils, sensitizing these cells. Subsequent drug exposure leads to cross-linking of IgE, triggering mast cell degranulation and histamine release. This cascade results in vasodilation, increased vascular permeability, edema, and inflammation. Clinically, Type I hypersensitivity presents as urticaria, angioedema, and, in severe cases, anaphylaxis—a potentially fatal reaction characterized by bronchospasm, hypotension, and cardiovascular collapse.

Type II Hypersensitivity/Cytotoxic Reactions: Type II reactions involve immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies targeting drug-bound cell surface antigens. This interaction activates the complement cascade, leading to cell lysis and destruction. Such reactions manifest as hemolytic anemia, thrombocytopenic purpura, and granulocytopenia. Drug-induced hemolytic anemia, for example, results from red blood cell destruction, leading to pallor, jaundice, and fatigue. The severity of these reactions depends on the extent of cell destruction and immune activation.

Type III Hypersensitivity/ Immune Complex Reactions: Type III reactions occur when drug-antibody immune complexes deposit in tissues, particularly in blood vessels, joints, and kidneys. These immune complexes activate complement proteins and recruit inflammatory mediators, leading to widespread inflammation. Clinically, this reaction manifests as serum sickness, which is characterized by fever, rash, arthralgia, and lymphadenopathy. The delayed onset, typically occurring 1–3 weeks after drug exposure, distinguishes Type III hypersensitivity from other allergic reactions.

Type IV Hypersensitivity/ Delayed T-Cell-Mediated Reactions: Unlike antibody-mediated reactions, Type IV hypersensitivity involves T cells. Small drug molecules, known as haptens, bind to carrier proteins, forming immunogenic complexes that stimulate T-cell activation. Sensitized T cells release cytokines upon re-exposure to the drug, leading to immune cell recruitment and tissue damage. This reaction typically presents as contact dermatitis, maculopapular eruptions, or severe conditions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The delayed onset, often occurring 48–72 hours post-exposure, is characteristic of this hypersensitivity type.

Understanding the mechanisms of drug-related allergies is crucial for accurate diagnosis, prevention, and management. Identifying specific hypersensitivity reactions allows for appropriate therapeutic interventions, including avoiding the offending drug, administering corticosteroids, antihistamines, or epinephrine in severe cases, and potential desensitization protocols when necessary.

Drug-related allergies are immune-mediated and classified into antibody-mediated Types I, II, and III, and the cell-mediated Type IV.

Type I, or IgE-mediated reactions, cause anaphylaxis. Allergen exposure triggers crosslinking of IgE bound to mast cells and basophils. This releases histamine, causing vasodilation, edema, and inflammation.

Type II, or cytotoxic reactions, involve IgG and IgM antibodies targeting cell-surface antigens. This activates the complement system, causing cell destruction and conditions like hemolytic anemia, thrombocytopenic purpura, and granulocytopenia.

Type III, or immune complex reactions, happen when IgG forms antigen–antibody complexes that deposit in tissues and trigger inflammation. This causes serum sickness, characterized by skin eruptions, arthralgia, and fever.

Type IV, or delayed hypersensitivity reactions, are T-cell-mediated. Small molecules, or haptens, bind to carrier proteins, forming immunogenic complexes.

On re-exposure, sensitized T-cells release cytokines, recruiting immune cells and causing mild to severe inflammatory conditions.