•  Not all adverse drug reactions are drug allergies

• Allergic Drug Reactions: characteristics

  • Skin eruptions

  • Anaphylactoid reactions

  • Fever

  • Edema

Immune-mediated Drug reactions: Different mechanisms: Four types

• Type I: IgE-mediated

  • Acute,allergic reactions to: insect stings, pollen, drugs

  • IgE: fixed to blood basophils, tissue mast cells

  • causes: anaphylaxis, angioedema, urticaria

• Type II: Complement-dependent

  • IgG or IgM antibody-mediated

  • Antibody affixed to circulating blood cell:complement-dependent lysis occurs

• Type III: - Serum Sickness:

  • Involves IgG immune complexes; multisystem complement-dependent vasculitis

• Type IV: cell-mediated allergy

  • e.g. Mechanism for allergic contact dermatitis (topical drug application)

 Immediate (Type I) Drug Allergy: Mechanisms

• Similar to humoral antibody responses to foreign antigens

• Responding antibody-forming precursors cells that produce antibodies are of the IgE class

• IgE class-specific antibody responses depend on helper T cells (TH2):

  • Which secrete IL-4

  • And promote B-cell differentiation to IgE-forming cells

  • Suppressor T cells secrete IFNg which blocks B-cell differentiation to IgE production and inhibits the IgE response (TH1)

    • : suppressors for humoral responses; helpers for cellular responses

  • Nonallergic individuals: IgE globulin: lowest of any immunoglobulin

    • Allergic individuals:IgE levels increase 10 full or more

  •  IgE antibodies:

    • Fix to blood basophils

    • Fixed to tissue mast cells

    • Skin-sensitizing/reaginic antibodies

•  IgE antibody attaches to high-affinity Fc receptorson blood basophils or tissue mast cells, the prerequisites for acute allergic reactions.

  • Important Sites for mast cell distribution/IgE sensitization:

    •  Lung

    •  Scan

    •  Gastrointestinal tract

• Acute allergic reaction sequence:

  •  Drug reintroduction IgE antibodies (attached to Fc receptors on sensitized basophilic lymphocyte and mast cell surfaces) bind antigenic drug form

  •  Mediator release from granules when IgE molecules in two adjacent Fc_eR are bridged by binding specific antigen

  • Mediators release:

    • Include histamine, leukotrienes

    • dDecrease cAMP within the mast cell

    • Mediator release inhibition: involve cAMP systems

    • Vasoactive substances generated during histamine release: kinins

    • Mediators immediate skin/smooth muscle responsestissue injury, and inflammatory responses (mediator-induced reactions may be highly detrimental -- laryngospasm, hypotension, bronchospasm

•   Drug treatment

  • Following drug sensitivity testing and verification of Immediate Drug Allergy--scratch test: Treatment options:

    • Prednisone:

      • Immunosuppressive

      • Blocks proliferation of IgE-producingspace for clones

      • Inhibits IL-4 helper T cell production in the IgE response

    • Reduction of mediator release from basophils and mast cells: (bronchodilation)

      •  Isoproterenol

      •  Epinephrine

      •  Theophylline

    • Antihistamines: histamine-receptor competitive inhibitor

      •  Reduces bronchoconstriction (histamine response)

      •  Reduces capillary permeability (histamine response)

    • Corticosteroids:

      •  Decrease tissue injury

      •  Decrease edema in inflamed tissue

      •  Restore responsiveness to catecholamines and cells which may have become refractory to beta-receptor activation

    • Cromolyn mediates inhibition of anaphylaxis mediators (released after antibody-antigen interaction)

    • Ketotifen an antihistaminic;

      •  Effects eosinophils: prevents allergic reactions

• Drug Desensitization:

  • Desensitization through very gradual dose increases (over hours/days) may be possible even in the presence of known allergies (e.g., penicillin)

  • Acute anaphylactic shock may occur during desensitization; Management of anaphylatic shock may be required.

  • Mechanism of desensitization: not completely determined