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Drug Reactions

Drug Reactions

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Drug Reactions

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  1. Drug Reactions Christian Millett, MD

  2. Overview • The skin is one of the most common targets for adverse drug reactions • Exanthematous eruptions and urticaria are the two most common forms of cutaneous drug reactions • The most commonly offending drugs are: penicillins, sulfonamides, and NSAIDs

  3. Pathogenesis • Common cutaneous drug eruptions are hypersensitivity reactions with an underlying immunologic mechanism • Type I (IgE-dependent) • Urticaria, Angioedema • Type II (Cytotoxic) • Petechiae (2o to drug-induced thrombocytopenia) • Type III (Immune complex) • Vasculitis, Serum sickness • Type IV (Delayed cell-mediated) • Exanthematous, Fixed, Lichenoid, SJS/TEN

  4. Pathogenesis • Idiosyncratic: • AGEP (acute generalized exanthematous pustulosis) • DRESS (drug reaction with eosinophilia and systemic symptoms) • SJS/TEN • May involve a combination of immunologic interactions and genetic predisposition

  5. Diagnosis • Most immunologically mediated drug reactions occur within 7-21 days after initiation of a new medication • Clinical characteristics • Type of primary lesion • Number and distribution of lesions • Mucous membrane involvement • Systemic signs and symptoms • Chronological factors • Drugs and dates of administration • Date of eruption • Time between drug introduction and rash • Response to removal of suspected agent

  6. Clinical Features

  7. Exanthematous • Morbilliform • Polymorphous (i.e. “maculopapular”) • 7-14 days after starting a new medication • Can be earlier in cases of rechallenge • Symmetic distribution of confluent erythematous macules • Can be slightly palpable • Begins on the trunk and upper extremities • Mucous membranes are usually spared • Can be accompanied by pruritus and low-grade fever

  8. Exanthematous • Rash disappears spontaneously after 1 to 2 weeks without sequelae • Ddx: viral exanthems • Tx: supportive • Topical steroids • Discontinue the offending agent or “treat through” • Common meds: penicillins, sulfonamides, cephalosporins, anticonvulsants

  9. Exanthematous

  10. Urticaria and Angioedema • IgE-mediated immediate hypersensitivity reaction • Antigen binds to IgE on the surface of mast cells • Induces degranulation and histamine release

  11. Urticaria • Transient erythematous, edematous papules and plaques • Associated with pruritus • Lesions can occur anywhere on the body (including palms and soles) • Individual lesions never last >24 hours • Except in the case of urticarial vasculitis

  12. Urticaria • Most common agents: penicillins, cephalosporins, sulfonamides, tetracyclines • Tx: • Withdrawal of causative agent • H1 antihistamines

  13. Urticaria

  14. Angioedema • Edema of the deep dermis, subcutis, and submucosal tissues • Presents as swelling • Usually involves the face • Can occur anywhere from 1 day to several years after starting the drug • Most commonly due to ACE inhibitors • Can also be caused by penicillins, NSAIDs, and radiographic contrast media

  15. Phototoxicity • Direct interaction of UV rays with the drug in the skin • Leads to generation of reaction oxygen species • Limited to sun-exposed areas • Appears as exaggerated sunburn • Most commonly due to tetracyclines, NSAIDs, and fluoroquinolones

  16. Phototoxicity

  17. Photoallergy • Result of cell-mediated hypersensitivity to an allergen activated or produced by the effect of light on a drug in the skin • Leads to generation of reaction oxygen species • Limited to sun-exposed areas • Lesions can resemble lichen planus • Most commonly due to thiazides and sulfonamides

  18. Photoallergy

  19. Vasculitis • Typically involves small vessels • Deposition of immune complexes in postcapillary venules • Results in activation of the complement cascade • Presents as palpable purpura • Primarily on the lower extremities • Most patients only have cutaneous disease but the possibility of systemic involvement must be considered

  20. Vasculitis • Occurs 7-21 days after drug administration • 1-3 days following rechallenge • Tx: • Withdrawal of the offending agent • Systemic steroids (if systemic involvement) • Most common agents: penicillins, NSAIDs, sulfonamides, cephalosporins

  21. Vasculitis

  22. AGEP • Acute generalized exanthematous pustulosis • Presents as numerous small, sterile pustules arising within large areas of erythema • Lesions begin on face or in intertriginous zones • Accompanied by high fever • Eruption begins <2 days after drug administration • Ddx: pustular psoriasis

  23. AGEP • Caused by: • Penicillins • Cephalosporins • Macrolides • Calcium channel blockers • Antimalarials

  24. Fixed drug eruption • Presents as one or a few round, sharply demarcated, erythematous to dusky plaques • Common locations: face, hands/feet, genitalia • Resolves with postinflammatory hyperpigmentation • Upon rechallenge, lesions recur at the same sites

  25. Fixed drug eruption • Caused by: sulfonamides, NSAIDs, tetracyclines

  26. Drug-induced diseases • Sweet’s syndrome • G-CSF, all-trans-retinoic acid • Neutrophilic eccrine hidradenitis • cytarabine • Bullous pemphigoid • furosemide • Pemphigus • penicillamine, captopril

  27. Drug-induced diseases • Psoriasis • NSAIDs, antimalarials, ACE inhibitors, beta blockers, lithium • Acne • corticosteroids, androgens, lithium, oral contraceptives, EGFR inhibitors

  28. Drug-induced lupus • Systemic LE (SLE) • symptoms usually develop >1 year after medication is begun • associated with antihistone antibodies • caused most commonly by procainamide and hydralazine (also minocycline) • Subacute cutaneous LE (SCLE) • lesions usually occur on upper trunk and extensor arms • associated with anti-Ro and anti-La antibodies • caused most commonly by HCTZ and calcium channel blockers (also TNF-a blockers)

  29. Drug-induced findings • Mucosal ulceration • methotrextate, doxorubicin, 5-FU • Hair loss • Telogen effluvium (anticoagulants, beta blockers, lithium) • Anagen effluvium (chemotherapeutics) • Hyperpigmentation • minocycline, antimalarials, amiodarone, bleomycin

  30. Drug-induced findings • Injection site reactions

  31. Drug-induced findings • Coumadin necrosis • Lesions begin 2-5 days after therapy is begun • Coincide with the early drop in protein C function • Erythematous plaques => hemorrhagic bullae and necrotic ulcers • Most common sites: breasts, thighs, buttocks • Tx: discontinue coumadin, vit K, start heparin • Heparin-induced thrombocytopenia (HIT) • Due to antibodies that bind to complexes of heparin and platelet factor 4 => platelet aggregation and consumption • Cutaneous necrosis is seen as a result of thrombosis • Tx: discontinue heparin, start argatroban

  32. Drug-induced findings • Heparin-induced thrombocytopenia (HIT)

  33. DRESS • Drug reaction with eosinophilia and systemic symptoms • Underlying mechanism may be alteration in metabolism of particular drugs • Most common agents are anticonvulsants and sulfonamides • Occurs 2-6 weeks after drug is begun

  34. DRESS • Usually presents as a morbilliform eruption • Edema of the face is a frequent finding • Lymphadenopathy is often present • Prominent eosinophilia is common • Tx: • Withdrawal of the offending agent • Oral corticosteroids

  35. SJS/TEN • Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare, life-threatening mucocutaneous diseases • Almost always drug-related • Extensive erythema and exfoliation • Due to keratinocyte cell death via apoptosis (induced by Fas-FasL interaction) => separation of skin at the dermo-epidermal junction (DEJ) • High fever and skin pain

  36. SJS/TEN • Onset between 7-21 days after initiation of drug therapy • Can be <2 days when patients re-exposed to the drug • Immunocompromised patients at greater risk • Mortality rate: 1-5% for SJS; 25-30% for TEN

  37. SJS/TEN • Most frequently implicated drugs: antibiotics, NSAIDs, anticonvulsants • Classified based on body surface area (BSA) • SJS: <10% of BSA • SJS-TEN overlap: 10-30% of BSA • TEN: >30% of BSA

  38. SJS/TEN

  39. SJS/TEN • Clinical features: • Initial symptoms can be: fever, eye pain, dysphagia • Can precede skin findings by 1-3 days • Skin lesions appear first on trunk => face, extremities • Erythematous to dusky red macules => patches • As epidermis detaches from dermis, blisters form • Positive Nikolsky sign • Skin is very painful

  40. SJS/TEN

  41. SJS/TEN

  42. SJS/TEN • Erythema and erosions of the buccal, ocular, and genital mucosa

  43. SJS/TEN

  44. SJS/TEN • Treatment: • Immediate discontinuation of the causative drug • Supportive care • Systemic corticosteroids vs. IVIG

  45. Take Home Points • Morbilliform eruptions and urticaria are the two most common forms of cutaneous drug reactions • The most commonly implicated drugs are: penicillins, sulfonamides, and NSAIDs • Most drug reactions occur within 7-21 days after initiation of the medication • Mucosal involvement and a positive Nikolsky sign are necessary for a diagnosis of SJS/TEN