CUTANEOUS DRUG REACTIONSDr. Frances Rose Palabrica

INTRODUCTION: Adverse cutaneous reactions to drugs can arise as a result of immunologic or non immunologic mechanisms. Immunologic True for most drug reactions Gell and Coombs classification:Type I: immediate type hypersensitivity rxnsType II: cytotoxic reactionsType III: immune complex reactionsType IV: delayed type hypersensitivity rxns

Type I: Immediate type IgE mediated Reactions occur within minutes of exposure to the drug Symptoms: Urticaria Laryngeal edema Wheezing Cardiorespiratory collapse Wide variety of drugs, biological and drug formulation agents Antibiotics: most important cause Insulin Enzymes (asparginase) Heterologous antisera (equine antitoxins, antilymphocyte globulin) Murine monoclonal antibodies Protamine Heparin

Type II: Cytotoxic Reactions Involve IgG or IgM antibodies that recognize drug antigen on cell membrane In the presence of complement, the Ab-coated cell is either cleared by monocyte-macrophage system or destroyed. Acquired haemolytic anemia (a-methyldopa and penicillin) Thrombocytopenia (quinidine) Very serious and life threatening

Type III: Immune Complex Reactions Mediated by immune complexes formed in slight antigen excess Immune complex is deposited in blood vessel walls and causes injury by activating the complement cascade (e.g. serum sickness Penicillin, sulphonamide, thiouracils and phenytoin associated with serum sickness-like symptoms Signs and symptoms appear 1-3 weeks after starting use of an offending drug and begin to subside when the drug and /or its metabolites are completely eliminated from the body Fever Rash Urticaria Lymphadenopathy Arthralgias Type IV: Delayed type or cell mediated reactions Mediated by cellular immune mechanisms Classic reaction: allergic contact dermatitis Responsible for delayed cutaneous eruptions (e.g. maculopapular rash due to antbiotic like amoxicillin and sulphonamides) May also be systemic and involve lymphoid organs and other tissues throughout the body Cutaneous manifestations are the most common presentation for drug allergic reactions Characterization of cutaneous lesions is important in regard to determining the cause, further diagnostic tests and management decisions

EXANTHEMATOUS ERUPTIONS Most common manifestation of drug allergy is a generalized exanthema (maculopapular eruptions) Lesions are pruritic Often begins as macules that can evolve into papules and eventually may coalesce into plaques Typically involve the trunk and spread outward to the limbs in a bilateral symmetric manner Many drug-induced exanthems are manifestations of delayed-type hypersensitivity Development of exanthema evolves after several days of taking the offending drug Do not evolve into anaphylactic reactions because they are not IgE-mediated Scaling may occur with resolution Frequent drug implicated: Allopurinol Aminopenicillins Cephalosporins Anti epileptic agents Antibacterial sulphonamides

FIXED DRUG ERUPTIONS Eruptions recur at the same skin or mucosal site on reintroduction of the causative drug Round or oval, sharply demarcated, red to livid, slightly elevated plaques, ranging from a few mm to several cm in diameter May also present as vesicles; mucosal lesions are usually bullous Predilection for the lips, hands, and genitalia (esp in men) Common meds implicated: Tetracycline NSAIDs Carbamazepine

URTICARIA AND ANGIOEDEMA Most common manifestation of IgE-mediated drug allergy Important to recognize that non-IgE mediated drug allergic reactions can manifest with urticaria and angioedema as well Serum sickness: urticaria is one of its most common manifestation Angioedema due to ACE inhibitors: bradykinin-mediated

PUSTULAR ERUPTIONSCommon drugs implicated: Glucocorticoids Androgens Lithium Phenytoin Isoniazid Sirolimus

ACUTE GENERALIZED ECZEMATOUS PUSTULOSIS (AGEP) Rare type of drug eruption Begins with erythema or edema in the intertriginous areas or face development of fine nonfollicular sterile pustules Fever, neutrophilia and eosinophilia ( of cases) may be present Drugs: antibiotics and calcium channel blockers T cell mediated drug reactionsBLISTERING ERUPTIONS Erythema multiforme minor Cell mediated hypersensitivity reactions associated with viruses, other infectious agents and drugs Polymorphic maculopapular lesion that spreads peripherally and clears centrally to form an annular pattern know as a target lesion3 zones Erythematous central papule that may blister Edematous middle ring Erythematous outer ringMay progress to the development of blisters and progressive involvement of the mucous membraneserythema multiforme majorSTEVEN-JOHNSON SYNDROME (SJS) AND TOXIC EPIDERNAL NECROLYSIS (TEN)Characterized by blisters and epidermal detachment resulting from the epidermal necrosis in the absence of substantial dermal inflammationDrugs with high relative risk of developing SJS/TEN Sulphonamides Cephalosporins Imidazole agents Oxicam derivativesDrugs with moderate risk Quinolones Carbamazepine Phenytoin Valproic acid GlucocorticoidsSJS Epidermal detachment 1 mucosal surface Associated with high temperature and severe constitutional symptoms Ocular involvement may be particularly serious Liver, kidney and lungs may involved singly or in combination Treatment: discontinuation of drug; use of steroid is controversial If treatment is started too late (3-4 days after the onset), it is possible that TEN could supervene, in which case systemic steroids are contraindicated

TEN Epidermal detachment 30% or more 10-30% detachment:overlap between SJS & TEN Almost always drug induced Widespread areas of confluent erythema followed by epidermal necrosis and etachment with severe mucosal involvement Significant loss of skin equivalent to a 3rd degree burn Glucocorticoids are contraindicated Must be managed in a burn unit Significant risk of infection; mortality rates as high as 50% have been reported Should be distinguished from Staph scalded syndrome

DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS) Drug induced multiorgan inflammatory response that may be life threatening Phenytoin hypersensitivity syndrome, drug hypersensitivity syndrome, drug induced hypersensitivity syndrome, drug induced delayed multiorgan hypersensitivity syndrome Characteristic features Cutaneous eruptions (exanthems, erythema multiforme purpura) Fever Eosinophilia Hepatic dysfunction Renal dysfunction Lymphadenopathy

Implicated medications: Anti convulsants Sulphonamides Allopurinol Minocycline Dapson Sulfasalazine Abacavir Nevirapine Hydroxychloroquine

Reactions develop later, usually 2-8 wks after the therapy is started Symptoms may worsen after the drug is discontinued May persist for weeks or months after drug is discontinued

Management: Withdrawal of the offending drug/s 1:1000 epinephrine, 0.3-0.5ml IM anterolateral thigh for anaphylactic reactions (IgE-mediated) Glucocorticosteroids Immune complex reactions, drug induced hematologic diseases, early stages of SJS and contact sensitivities Oral anti histamines

Drug desensitization Induction of drug tolerance Modifies a patients response to a drug to temporarily allow treatment with it safely Indicated only in situations where an alternate medication cannot be used Contraindicated for patients who had SJS/TEN, except when benefit of treatment of a life threatening reaction