Med - Adr 3rd Yr 08 Copy

Adverse Drug Reaction JMAbong

Adverse Reaction to Drugs • Predictable overdosage side effects secondary effects drug-drug interaction

• Unpredictable idiosyncratic pseudoallergic drug hypersensitivity type 1 reaction type 2 reaction type 3 reaction type 4 reaction

CLINICAL MANIFESTATIONS OF DRUG ALLERGY Multisystemic Manifestation • • • •

anaphylaxis serum sickness like reactions drug fever drug-induced autoimmunity reactions simulating systemic lupus erythematosus and others • vasculitis

Reactions Predominantly Involving One Organ System • • • • • • •

Dermatologic manifestations Respiratory or pulmonary manifestations Hematologic manifestations Renal manifestations Reactions involving lymphoid cells Cardiac manifestations Neurologic manifestations

Drug Hypersensitivity IgE Mediated Reactions •Clinical presentation: urticaria/angioedema/anaphylaxis •Caused by many drugs and biologicals •Most often due to beta lactam antibiotics •Less common with many non-beta lactam antibiotics

Drug Hypersensitivity Ig Mediated Cytotoxic Reactions •IgG or IgM antibodies and complement interact with allergen associated with cell membranes •Most often involves blood elements • Serious and life-threatening •Tend to occur after large doses •Immunohemolytic anemia(e.g. penicillin) •Immune thrombocytopenia (e.g. quinidine) •Immune neutropenia (e.g. thiouracils)

Drug Hypersensitivity Immune Complex Reactions •Complex formation can result in complement activation, leading to : vascular permeability changes mast cell activation inflammatory mediators and chemotactic agents neutrophil influx •Symptoms occur 1-3 weeks after last dose

Drug Hypersensitivity Cell- Mediated Reactions •Allergic Contact Dermatitis •Photoallergic Dermatitis •Late cutaneous morbilliform and bullous reactions

Classification Immune Complex Reaction Complex formation can result in Complement activation, leading to vascular permeability changes mast cell activation inflammatory mediators and chemotactic agents neutrophil influx

Classification Immune complex reactions Can cause drug induced lupus syndromes Examples: Hydralazine Procainamide Isoniazid Phenytoin

Classification Immune complex reactions Circulating immune complex cause serum sickness reactions Symptoms of serum sickness; Fever Skin lesions Lymphadenopathy Arthralgias Nephritis hepatitis

Classification T cell mediated Reactions Mediated by lymphocytes Require memory T cells specific for drug allergen Allergic contact dermatitis is classic clinical manifestation

Other Reactions Delayed Dermatologic Reactions Clinical manifestations: Maculopapular, morbilliform or erythematous Exfoliative dermatitis Photosensitive reactions Eczema

Other Reactions Delayed Dermatologic Reactions Example of causative agents: Nitrofurantoin Sulfasalazine

Classification of EM,SJS and TEN (Patterson 2002) Skin lesions

Extent of skin detachment

Bullous EM

Typical target or raised atypical target

<10%

SJS

Erythematous or purpuric macules or flat atypical target

<10%

Overlap SJS/TENS

purpuric macules or flat atypical target

10%-30%

TEN with spots

purpuric macules or flat atypical target

>30%

Features • EM: – Classic von Hebra type of EM is a symmetric eruption with predilection for extremities – Characteristic primary lesion is the three zone target lesions – Mucosal lesion limited to oral mucosa and not severe – Often associated with HSV(1-3 weeks) • Maybe recurrent

– Causes: HSV, drugs or none

SJS • Diffuse ,severe, mucocutaneous eruption involving two or more mucosal surfaces with or without visceral involvement • Majority are due to drug exposure usually starts 7-21 days after initiation of drug. • Other causes: Mycoplasma pneumoniae

TEN • Term introduced by Lyell in 1956 • Extensive loss of epidermis due to necrosis • Clinical entity with single or multiple pathogenic pathways • Death may be due to multiorgan failure or septic shock

Pathogenetic pathway

• First step in pathogenesis is involvement of Fas-Fas ligand apoptosis

TEN • Most severe adverse drug reaction • Possible relationship with medications can be established in 90% of patients • Mortality rate is 30% usually sepsis • Pathogenesis: – Cell mediated responses , CD8 cells – apoptosis of keratinocytes due to Fas Fas ligand interaction

TEN • Adulthood • Erythema, plaques, papules, blisters, macules, target lesion • Area of skin detachment >30% • Mucosal involvement • Mortality rate <5%

SJS • Any age • Erythema, plaques, papules, blisters, macules, target lesion • Area of skin detachment <10% • Mucosal involvement at least two sites • Mortality rate 30%

Treatment • Mainly supportive as in burn patients • Withdrawal of potentially responsible drugs • Aggressive Fluid replacement • Prevention of wound desiccation and super infection with topical antimicrobials

Treatment • Nutritional support • Ophthalmologic care is critical • Agents to halt progression such as: – High dose corticosteroids – not presently recommended – Plasmapheresis, cylcosporine, cycloposphamide – Intravenous immunoglobulin

Diagnosing Drug Allergy Factors to consider time of onset of rxn after starting drug time of resolution after dc drug type of rash other system involvement concurrent drug use hx of other drug reactions family hx of drug allergy presence of chronic diseases hx of atopy

Diagnostic Testing Skin testing Detects IgE antibody Preferable to in vitro for specific IgE (more sensitive and specific) Limited number of agents can be reliable skin tested: Penicillin Insulin Heterologous antisera Streptokisnase Chymopapain

Diagnostic Testing Skin Testing A positive test result: Suggest a diagnosis May predict which persons are at greater risk of future reactions

Management Treatment of Severe Immediate or Accelerated Rxn Epineprhine(if rxn severity dictates) Discontinue drug Antihistamine for urticaria, angioedema and pruritus Nonsedating preferred Oral corticosteroids may be considered

Management Treatment of late reactions Discontinue all nonessential suspect drug For mild mp rashes, antihistamines For more severe rashes, short course cs may be given Short course cs in combination with antihistamines in: Serum sickness like reaction Exfoliative dermatitis More severe maculopapular rashes