Immunologic Reactions to Drugs and Drug Allergy

• Not all adverse drug reactions are drug allergies:

  • Examples of drugs that cause true allergic reactions:

    • Iodides

    • Phenytoin

    • Penicillin

    • Sulfonamides

• Allergic Drug Reactions: characteristics

  • Skin eruptions

  • Anaphylactoid reactions

  • Fever

  • Edema

  • eosinophilia

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

    • Decrease cAMP within the mast cell

    • Mediator release inhibition: involve cAMP systems

    • Vasoactive substances generated during histamine release: kinins

    • Mediators → immediate skin/smooth muscle responses→tissue 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:  inhibition of anaphylaxis mediators (released after antibody-antigen interaction)

    • Ketotifen: 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

Haynes, B. F., Fauci, A.S. Disorders of the Immune System, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1753-1776.

Carpenter, C. B. The Major Histocompatibility Gene Complex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1777-1782.

Cooper,M.D, and Lawton III, A. R. Primary Immune Deficiency Diseases, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1783-1791

 

 

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