•  Not all adverse drug reactions are drug allergies

return to menu I--return to menu II

• Allergic Drug Reactions: characteristics
  • skin eruptions
  • anaphylactoid reactions
  • fever
  • edema
  • eosinophilia

return to menu I--return to menu II

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)

return to menu I--return to menu II

 Immediate (Type I) Drug Allergy: Mechanisms

• similar to humoral antibody responses to foreign antigens

return to menu I--return to menu II

•  Drug = Hapten
  • 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

  return to menu I--return to menu II

  •  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

  return to menu I--return to menu II

  • 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 responsestissue injury, and inflammatory responses (mediator-induced reactions may be highly detrimental -- laryngospasm, hypotension, bronchospasm

return to menu I--return to menu II

•   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

return to menu I--return to menu II

• 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

return to menu I--return to menu II