Drug Induced Skin RXN

Describe the pathophysiology and epidemiology of drug-induced skin reactions

• Epidemiology

  • Adverse cutaneous rxn to drugs are more prevalent in women over men:

    • Women tend to have a higher percentage of body fat and lower body water content than men, which can impact the distribution of certain medications, potentially leading to increased drug accumulation and toxicity. 

    • Estrogen, fluctuations in hormone levels (during menstruation, pregnancy, or menopause) can impact how drugs are processed and eliminated, potentially increasing the risk of adverse effects. 

  • Pathophysiology

    • Non-immunologically mediated reactions: accumulation and direct release of mast cell mediators, intolerance, Jarisch-Herxheimer phenomenon, overdosage, or phototoxic dermatitis

    • Direct release of mast cell mediators is a dose-dependent phenomenon that does not involve antibodies

    • Jarisch-Herxheimer phenomenon: result from bacterial endotoxins and microbial antigens that are liberated by the destruction of microorganisms

      • Treatment should not stop due to reaction b/c symptoms will resolve with continued therapy

Discuss the types of drug-induced skin reactions

Classifications	Details
Type A Rxns	Associated with administration of therapeutic dosages of drug (exception: drug overdose) Predictable and avoidable Responsible for most adverse drug events Overdose Cytotoxic rxn Drug-drug Drug-food Drug-disease
Type B Rxns	Generally independent of the dose Rarely predictable or avoidable Among most serious and potentially life threatening 4 types of immunologically mediated rxn: Type I (immediate): IgE-mediated release of antibodies against antigen → mast cell degranulation and release of histamine, other inflammatory mediators Type II (cytotoxic): engaged IgG and IgM → t complement system activation and cell dmg/lysis Type III (immune-complex): IgG, sometimes IgA, build-up of immune complexes results in complement system activation → polymorphonuclear leukocytes (PMNs, contain neutrophils, eosinophils, basophils) and chemotaxis → tissue dmg  Type IV (delated): T-cell medicated,  T cells or macrophages are activated as result of cytokine release → tissue dmg

List drug classes and drugs that are associated with severe cutaneous adverse reactions (SCARs):

• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms, and erythema multiforme

Acute types	Common Causative Agents
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) SJS: <10% BSA with skin detachment SJS-TEN overlap: 10-30% BSA with skin detachment TEN: >30% BSA Acute Onset: 1-3wks after starting offending medication Purpura (purpuric macules) and erhythema Treatment of SJS and TEN: Broad spectrum antibiotics, vanco for infections Adults: IV immunoglobulin 2-3g/kg for severe disease Peds: IVIG 0.05-0.1g/kg/day Treatment of TEN in the burn unit	Allopurinol (HLA-B*5801), sulfonamides, anticonvulsants (carbamazepine: HLA-B*1502)
Drug reaction with eosinophilia and systemic symptoms (DRESS) Classic Triad: fever, exanthem, internal organ involvement with possible pharyngitis and lymphadenopathy Onset: 2-8 weeks after drug initiation, may develop 3 months or later into therapy	Allopurinol, sulfonamides, anticonvulsants, vancomycin, dapsone, minocycline
Erythema multiforme Type IV rxn Often secondary to antibiotic Starts on trunk as pruritic red macules, papules, extends to extremities  Onset: 1-3 weeks after drug initiation	PCNs (penicillins), cephalosporins, sulfonamides, anticonvulsants, allopurinol

Chronic types	Common Causative Agents
Drug-induced lupus Cutaneous symptoms more commonly associated with hydralazine, procainamide Onset is slow and graduate	Hydralaine, procainamide
Drug-induced acne Eruptions may occur 1-3 weeks after causative medication is started Topical acne treatments can be used to manage symptoms if the offending drug cannot be discontinued or replaced	Lithium (dose-related)

Identify the pharmacogenetics of drugs associated with hypersensitivity and SCARs

• HLA (human leukocyte antigen)

  • HLA Class I: HLA-A, HLA-B, HLA-C

  • Many different alleles, associated with:

    • T-cell mediated immune responses to infectious pathogens

    • Drug-induced hypersensitivity rxn

Gene	Drug
HLA-B	Abacavir (Ziagen): HLA-B*5701 HLA-B*5701 screening Nucleoside reverse transcriptase inhibitor against HIV-1 infection Available in antiretroviral coformulated tablets: Epzicom, Trizivir, Triumeq Hypersensitivity RXN: 5-8% Symptoms: fever, malaise, skin rash, GI, eosinophilia within first 6 wk of treatment
	Allopurinol (Zyloprime) Responsible for 5% of hypersensitivity syndrome or severe cutaneous adverse rxn (SCARs) HLA-B*5801: Asian subpopulations FDA-approved drug label doesn’t discuss screening for it but still should CPIC recommends that it should not be prescribed to pt who test positive for HLA-B*5801 Initial low dose (100 mg qd, then titrate slowly up to max 800mg) Manifestations: Maculopapular exanthema (mild) Hypersensitivity rxn SJS or TEN
	Carbamazepine (Tegretol) High incidence of SCARs within 3 months of therapy Carriers of HLA-B*1502 are high risk of SJS/TEN with CBZ in asians HLA-B*1502 does not affect clinical efficacy or dosing or CBZ
CYP2D6	Tamoxifen (Novaldex) Fluoxetine (Prozac) Atomoxetine (Strattera)
VKORC1 A/A and A/B haplotypes CYP2C9*2 and *3 alleles	Warfarin (Coumadin)

• Treatment and Management

  • Immediate DC of causative agent 

  • Monitor signs of impending cardiovascular collapse

  • DO NOT RECHALLENGE with drugs causing urticaria, bullae, angioedema, DRESS, anaphylaxis, or erythema multiforme or rxns