Mechanism of Adverse Drug Reactions

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Mechanism of Adverse Drug Reactions

• Type A ???????(Pharmacological)
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• Type B ???????(idiosyncratic or allergic)
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• ???????????(dose-response relationship)
• ???????,???????????
• ?????,???????? (Desensitization)

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• Allergic or pseudoallergic ?
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• Type I IgE dependent (Anaphylaxis)
• ????????????
• Type II Cytotoxic (Biological)
• ???Pemphigus, Thromobocytopenic petechia,
• Type III Immune-complex (Chemical, Connective )
• ???Vasculitis, ???serum sickness,
• Type IV Cell mediated , Delayed type
• Granulomatous, Eczematous
• ???-????????????? (SIS-TEN)
• Th1-INF?-Mono, Th2-IL-5-Eosin, IL-8 PMN, CD4/8

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Mechanism of Frug Hypersensitivity
Annals of Internal Medicine 2003, 139(8) 684
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??ADR????????????

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• ??(exanthema)?????
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• ?????,????? (SJS/TEN)
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Severe Cutaneous ADR
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• ????????(AGEP)
• ???(??????????)
• ???(??????)
• ???????????????(DRESS)
• SJS-TEN(???????)
• ?????? SJS? TEN

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?????Anaphylaxis

• ???Urticaria
• ??????Angioedema ? Anaphylaxis??
• ADR??? Anaphylaxis 30
• Urticaria 10 ?????
• ????????????
• Mortality5
• ??????ß-lactam Penicillins, Cephalosporins,
  NSAID, contrast media, monoclonal Aby

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?????Exanthematous Drug Eruption

• ???????????
• From trunk to extremities
• Maculopapules or urticaria
• may confluent
• Purpura at ankle, feet, waist
• Mucosa is spared
• ??????????
• ADR??? Child 10-20, Adult 50-70
• ???????4(7)-14days

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?????Exanthematous Drug Eruption

• Type IV, or ????
• direct binding to MHC-2 in KC(sulfa)
• AminoPC in Infectious mononucleosis
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• ???????,??,Nikolskys sign, ????
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• D Dx
• Viral exanthema, Toxic shock syndrome, GVHD,
  Kawasakis, Stills

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?????Exanthematous Drug Eruption
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Perifollicular papules with central pustules
Exanthematous Rash with Purpura Vasculitis
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?????Exanthematous Drug Eruption

• Mortality????????0
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• Hypereosinophilia DRESS
• Palpable purpura, arthritis Vasculitis
• Facial edema DRESS, Erythroderma
• Mucosa involvement TEN, SJS
• Painful skin TEN

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??? Vasculitis

• Palpable purpura
• ???????,????
• ?????????? (Type III reaction)
• Dermato-arthritis syndrome
• r/o bacteremia/sepsis first
• ????????
• ADR??? lt 10
• ???????7-21days,
• challenge lt 3days

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Leukocytoclastic Vasculitis

• ??????
• Palpable purpura
• ?????????
• ?????
• Check
• CBC, WBC/DC
• LFT
• RFT
• C3, C4

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??? Vasculitis

• Mortality???
• ??????
• Penicillins,
• NSAID(oral, topical)
• Sulfonamide,
• Cephalosporins,
• Anticonvulsant,
• Allopurinol,
• Thiazide,
• Bio products (G,M-CSF, biologics, etc.)

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DRESS Drug Rashes with Eosinophilia and
Systemic Symptoms
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DRESS Hypersensitivity Syndrome???????????????

• ???????????????
• Drug Rash (Reaction) with Eosinophilia and
  Systemic Symptoms
• ?????????,???HHV-6,7
• Immune , IL-5Th2eosinophils
• ADR??? 70-90
• ???????15-40days
• ??????????
• Mortality5-10

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DRESS Hypersensitivity Syndrome

• Febrile (85) mobilliform rash(75)
• ???? ???follicular accentuation,????????????
• ????????????????
• Systemic involvement
• Hepatitis, myocarditis, interstitial pneumonitis,
  nephritis, thyroiditis etc.
• Lymphadenopathy
• Rx of Corticosteroids first choice
• May relapse during tapering

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DRESS Hypersensitivity Syndrome???????????????

• ?????????
• phenytoin (arene oxide) 11000
• sulfonamide (hydoxylamine?) 110,000
• ??????
• Aromatic Anticonvulsant( phenytoin,
  carbamazepine, phenobarbital)
• Allopurinol (in renal dysfunction)
• Lamotrigine (esp. with Valproate)
• Sulfonamide, dapsone
• Minocycline, gold salt

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????????Acute Generalized Exanthematous
Pustulosis (AGEP)

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????????(AGEP) Acute Generalized Exanthematous
Pustulosis

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• ????1-2?
• Mortality1-2

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AGEP / EMto Pseudoephedrine
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????????(AGEP)

• ??????recall reaction
• Patch test ????80
• Neutrophilia, IL-3, 8, G-CSF from T cells
• ADR??? 70-90???????
• lt??,??????
• ??????
• ß-lactame (PC, aminoPC, Cephalosporins)
• Macrolides,
• Calcium channel blockers (esp. diltiazem)
• Sulfasalazine-COX 2 Inh

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Erythroderma in Anticonvulsant Hypersensitivity
Syndrome
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???(??????) Exfoliative dermatitis, Erythroderma

• ?????,??flexural??,???
• 2-6???????(gt90)
• ????
• Scalinglamellar, crusty?branny
• Hyper-/hypo-thermia, Tachycardia, CHF
• lymphadenopathyy, hepatomegaly
• Eosinophilia and lymphopenia
• ADR??? 19 (5.5-42)?????
• ???????wks to mons (epoprostenol)
• ???2-6wks??
• Mortality?

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???(??????)

• ??????
• Allopurinol,
• Ampicillin/Amoxicillin/Penicillins,
• (14 floxacillin)
• carbamazepine (ox-), phenobabital, phenytoin
• dapsone, sulfasalazine, sulfonamide,
  clofazimine,
• omeprazole, phenothiazines, vancomycine,
  captopril, nefedipine, isoniazide, ethambutol
  (HIV)

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Erythema Multiforme, SJS/TEN

• Continuous spectrum or Different entity?
• ?????Erythema Multiforme
• ???-?????(SJS)
• Stevens-Johnson Syndrome
• ???????TEN
• Toxic Epidermal Necrolysis
• Target erythema, Blisters, Tender skin, Epidermal
  detachment, Exfoliation,
• Multiple Mucosal involvement

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EM?SJS(10)?SJS/TEN?TEN(30)
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Stevens-Johnson Syndrome Toxic Epidermal
Necrolysis

• Category
• Incidence per mil-yr
• Drug related ratio
• Mortality
• Primary eruptions (major feature)
• Isolate vs Confluence
• Detachment ( BSA)
• Interface vs Necrosis
• Systemic symptoms

• TEN
• 0.4-1.2
• 80-95
• 25-50
• Red edema denuded
• Confluence
• gt 30
• I lt Necrosis
• Always

SJS 1.2-6 50 5 Target dusky red Isolated ? lt
10 Interface gt N usually
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Toxic Epidermal Necrolysis
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Stevens-Johnson Syndrome Toxic Epidermal
Necrolysis

• Prodromal URI-like
• 1-14 days before in SJS, 1-3 days in TEN
• Systemic hepatitis
• ADR ???70-90
• ???????14-56??????weeks,
• TEN 7-21days, Re-exposure lt2 days)
• Valproate, Aromatic anticonvulsants first 2 Ms
• Treatmentwithdraw culpit drug, Skin care
• Steroid, IVIG (anti sFasL)
• About 3 weeks for heal

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Stevens-Johnson Syndrome Toxic Epidermal
Necrolysis

• ??????
• Allopurinol,
• Ampicillin/Amoxicillin/Penicillins,
• Aromatic anticonvulsants
• Barbiturates, carbamazepine (ox-), phenytoin
• Lamotrigine, Valproic acid
• Phenylbutazone, Piroxicam
• Sulfa, sulfasalazine, Baktar

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SCORTEN SEVERITY OF ILLNESS SCORE
CSORTEN parameter Individual score SCORTEN Sum of score Predicted Mortality
Age gt 40 years Yes 1, No 0 0-1 3.2
Malignancy Yes 1, No 0 2 12.1
Tachycardia ( gt 120/min ) Yes 1, No 0 3 35.8
10BSA Initial skin detachment Yes 1, No 0 4 58.3
Serum Urea gt 10mmol/l (60) Yes 1, No 0 5 90
Serum glucose gt 14 mmol/l(250) Yes 1, No 0
Bicarbonate lt 20 mmol/l Yes 1, No 0
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