allergic and pseudoallergic drug reactions

1. Allergic and Pseudoallergic Drug Reactions Pharmacotherapy II and Treatment in common diseases Usasiri Srisakul 7 Nov 2003

3. Allergic and PseudoallergicDrug reactions 5-10% of all adverse drug reactions Allergic drug reaction : an adverse effect involving immunologic mechanisms Allergic-like or Pseudoallergic reactions : Adverse effects not proven to be immune mediated, but resembling allergic reaction in their clinical presentation

4. Clinical manifestations Anaphylaxis : acute, life-threatening, multiple organ systems Skin: pruritus, urticaria, erythema and angioedema GI: nausea, abd. Pain, vomiting and diarrhea Respi: SOB, bronchospasm CVS: hypotension, tachycardia and dysrhythmias

5. Begin within 30 mins � 2 hrs after exposure Fatal anaphylaxis risk in first few hours : asphyxia due to laryngeal edema or CVS collapse After recovery: May recurrent 6-8 hours (late phase reactions) after antigen exposure

6. Clinical manifestation 2. Serum Sickness Condition of Ag excess ? circulating immune complex from heterologous antiserum ex. equine serum antitoxins Occurs in 7-14 days : fever, malaise and lymphadenopathy most common, may skin eryption Drugs: sulfonamides, penicillins and cecholosporins(cefaclor) SLE reactions from drugs ex. Hydralazine, isoniazid and phenytoin

7. 3. Drug Fever Inflammatory process of drug reaction : methyldopa, procainamide, phenytoin, barniturates quinidine and antibiotics Drugs may affect the CNS to alter temp. regulation or release pyrogens (IL-1, TNF) from WBC Fever resulting from massive tumor destruction due to chemotherapy Temporal relationship between fever and drugs

8. 4. Drug-induced Autoimmunity SLE induced by procainamide, hydralazine or isoniazid : arthralgias, myalgias and polyarthritis�may multiple organs occur Reactions develop several months Resolve after discontinued Others belived to involve autoimmune mechanisms

9. Hemolytic anemia: methyldopa Interstitial nephritis: methicillin: fever, rash, eosinophillia, proteinuria, hematuria Hepatitis: phenytoin,sulfonamides, isoniazid: hepatocellular necrosis or cholestatic hepatitis

10. Clinical manifestation 5. Vasculitis : inflammation and necrosis of blood vessels Skin and multiple organ involve : liver, kidney, joints, CNS Cutaneous vasculitis in lower extremities: purpuric lesion, papules, nodules, ulceration, vesiculobullous lesion Allopurinol, beta-lactam antibiotics, sulfonamides, thaizide diuretics and phenytoin

11. 6. Dermatologic reactions Cutaneous lesions are the most common Mild and resolve but some progress to serious or life threatening reactions: toxic epidermal necrosis (TEN) and Stevens-Johnson syndrome Antibiotics are the most frequency Clinical manifestation

12. Toxic Epidermal Necrosis (TEN)

13. Steven-Johnson Syndrome

14. Angioedema

15. 7. Respiratory reactions Upper and lower tract reactions: rhinitis, asthma Direct injury from systemic reaction ex.anaphylaxis Asthma: aspirin, other NSAIDs, sulfites as preservative in food and medications Chronic fibrotic pulmonary reactions Anti-neoplastics: bleomycin Clinical manifestation

16. 8. Hematologic reactions Eosinophillia is a common in drug hypersensitivity Hemolytic anemia Thrombocxytopenia, granulocytopenia and agranulocytosis Clinical manifestation

17. Mechanism of Allergic Drug Reactions Immunologic review Humeral Immunity: B-cell Cell-mediated Immunity: T cell Inflammation Mediators Allergic reaction mediators Hypersensitivity types

18. ?????????????? (Hypersensitivity)

19. ?????????????????????????????????????????????????????????????????????????? ???????????????????????????????????????????????? lymphocytes

20. Type I Hypersensitivity

21. �B cell ? IgE ? cover mast cell ???? Fc ??? IgE ???????????????? Fab ?????????????????????????? mast cell degranulation? proinflammatory mediators

22. H1 receptors ? vascular permeability, vasodilatation, urticaria, brochospasm, coughing ??? increase gut permeability

23. ???????????????????????????????????????????????????????? (urticaria) ???????????????????????????? ?????????? ???????? (shortness of breath) ????????????? (Tachycardia) ?????????? (hypotension)

24. ??????????????????????? ?????? 1.�antihistamines 2.�bronchodilators ? theophyllines , ?-adrenergics 3.�cromolyn sodium ?stabilized ????????? mast cell 4. anticholinergics

25. Type II Hypersensitivitycytotoxic ???? cytolytic hypersensitivity

26. IgG ??? IgM ->Fab ?????????????????????????? antigen-antibody complex? Fc ????????? complement ???? ????????????????????? ?classic pathway, cell injury

27. Type III Hypersensitivity

28. ?????? serum sickness, glomerulonephritis, SLE, arthritis (?????????) ??? vasculitis (???????????????)

29. Type IV Hypersensitivity delayed hypersensitivity

30. ?????? cutaneous basophil hypersensitivity (Jones-Mote), contact hypersensitivity, tuberculin-type hypersensitivity, granulomatous hypersensitivity ??? transplant rejection

31. Anaphylactoid reaction Number of substances can produce and anaphylactoid reaction(anaphylaxis-like) Release inflammatory mediators by pharmacologic effect but not through IgE call �pseudoallergic reaction� Drugs: opiates, iodinated radiocontrast agents, vancomycin, amphotericin

32. Factors related to the occurrence or severity of allergic drug reaction Dose of allergen Duration of exposure Route of exposure: more sensitize in topical route, safe in oral route, parenteral route is most hazardous Sensitivity of the individual: genetics, metabolism Pt. Who has history of allergic rhinitis, asthma, and/or atopic dermatitis, esp. drug allergy Age: less in children Diseases predispose to drug reaction ex. Rash after penicillin administration in infectious pt. Reaction after bactrim in AIDS pt.

33. Drugs commonly causing allergic or allergic-like reaction Beta-lactam antibiotics Penicillin: 0.7-8% : urticaria, pruritus, angioedema. 10% fetal. All four types hypersensitivites Wide variety of idiopathic reactions: maculopapular eruption, Stevens-Johnson syndrome, exfoliative dermatitis Rash increase 69-100% in Epstein-Barr virus infection, cytomegalovirus, lymphocytic leukemia

34. Mechanism: penicilloyl-protein conjugate ? �antigenic determinant� Cross-reactivity to other beta-lactam antibiotics: cephalosporins Weakly cross-reactivity to monobactam and aztreonam Cross-reactivity to carbapenems, imipenem? should not be administered to pt with positive penicillin skin test Drugs commonly causing allergic or allergic-like reaction

35. 2. Radiocontrast media Frequency case allergic-like reactions Commonly 5-10%: urticaria, dyspnea,angioedema, bronchospasm, fetal (0.01%) May cause dose-dependent toxic reactions to CVS and renal function Mechanism unclear: not IgE mediated Drugs commonly causing allergic or allergic-like reaction

36. Direct activation of complement system, relase inflammatory mediators Low-osmolar agents and nonionic less frequency of reactions than high-osmolar or conventional agents Risk in pt with history Skin test and oral testing is not useful Drugs commonly causing allergic or allergic-like reaction

37. Pretreatment: Prednisolone 5o mg orally 13, 7, 1 hrs before Diphenhydramine 50 mg orally and 25 mg IM 1 hr before Ephedrine 25 mg orally 1 hr before (omitted angina, dysrhythymia or hypertension) Drugs commonly causing allergic or allergic-like reaction

38. 3. Insulin A protein : a complete antigen from beef, pork or human(recombinant) origin Variety reactions: insulin, other substances ex.protamine Pts have anti-insulin antibodies after 2-3 months of therapy Drugs commonly causing allergic or allergic-like reaction

39. Local reactions: most common: wheal, flare at he injection site after 8-12 hrs. ? mild do not require treatment and resolve with continued therapy ? if not tolerate: give different insulin source(higher purity) Rare systemic reactions: urticaria, anaphylaxis. IgE mediated Skin test for least systemic reactions Insulin desensitization in some pts Drugs commonly causing allergic or allergic-like reaction

40. 4. Aspirin and NSAIDs 2 types: 1% urticaria/angioedema or 0.5% rhinosinusitis/asthma Rhinosinusitis/asthma Middle-age pts Ketorolac cause severe, life-threatening bronchospasm Drugs commonly causing allergic or allergic-like reaction

41. Suspected mechanism: COX blockade, facilitate others metabolites ex.leukotrienes or direct stimulate mast cells Asthma pts: should be challenged with great caution (resuscitation equipment in hand) Pt known aspirin sensitive ? Major prevention NSAIDs associated with pulmonary infiltrates and eosinophilia (PIE) syndrome: fever, cough, dyspnea and eosinophilia in 2-6 weeks after treatment Report more frequency for Naproxen Resolve rapidly after discontinuation Drugs commonly causing allergic or allergic-like reaction

42. 5. Sulfonamides Common cause of allergic reactions Number of drug classes: antimicrobials, diuretics, oral hypoglycemics and carbonic anhydrase inhibitors Typically case delayed cutaneous reactions beginning with fever and followed by rash Other systemic reactions are rare but fatal: GI, hepatic, renal, hematologic complication Mechanism: immune mediated and reactive metabolites(hydroxylamines) Drugs commonly causing allergic or allergic-like reaction

43. TMX/sulfa for treatment of PCP in AIDS Much more frequently in pts without AIDS Cutaneous eruptions 69% Less than 14 days of treatment Drugs commonly causing allergic or allergic-like reaction

44. Detection and Management of Allergic and Pseudoallergic Drug Reactions Detection Pts at high risk: history, specific tests Skin tests drug-specific IgE Predict high risk of immediate hypersensitivity Not predict the risk of delayed or dermatologic reactions Pts with history of penicillin allergy are recognized 4-6 fold greater risk of subsequent reactions Pts with negative history of penicillin NOT eliminate risk: may cause serious and even fetal reactions

45. Treatment of Anaphylaxis Minimize the risk of death and serious morbidity Restore respiratory and CVS (Protocol Table82.4) Epinephrine, IV fluids, ET tubation Hypotension: vasopressor, NE, dopoamine

46. Other agents may be required Corticosteroids(hydrocortisone sodium succinate) ? prevent late-phase reaction Aminophylline for treat bronchospasm H1 blocker: diphenhydramine ? reduce symptoms associated with anaphylaxis H2 blocker: cimetidine ? treatment of refractory hypotension Treatment of Anaphylaxis

47. Desensitization: no alternative drugs or necessary to treat with penicillin Reduce risk of anaphylaxis but NOT others types ex. Exfoliative dermatitis or Steven-Johnson syndrome Performed with resuscitation setting available Premedication is controversial because mask sign of reactions Protocol for oral and IV penicillin desensitization (Table 82.5 and 82.6) Treatment of Anaphylaxis