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Drug Reactions

Drug Reactions. Christian Millett, MD. 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.

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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

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