Efi.

Gelerstein 2011

Topic 19. Drug allergy Almost any drug can cause a cutaneous reaction, and many infla. skin conditions can be caused or exacerbated by drugs. A drug reaction can reasonably be included in the DD of most skin diseases. Adverse drug reactions 1) Intolerance pharmacologically predictable, individual susceptibility -pharmacogenetics, e.g. tinnitus due to small amount of aspirin 2) Idiosyncratic genetic defect (G6PD def.) 3) Cumulative effect (amiodaron hyperpigmentation) 4) Drug-specific reactions Drug allergy: pseudo-allergic reaction True allergic reaction Specificity, immune memory Immune-mediated drug allergy 1) Hapten model Drug binds covalently to proteins APC processing peptide presentation endogen: MHC-I (8-10 amino acid), exogen MHCII (13-23 amino acid) 2) Direct recognition model Drug binds directly to peptides Processing not required Fixed APC binds SMX and presents it to T cells Drugs as antigens High MW Complete Ag (insulin, hormones, enzymes, protamine, antise., recombinant proteins) Small MW Functionally complete Ag (Succinylcholine, ammonium) Haptens Small MW, incomplete Ag binds covalently to a larger molecule: multivalent hapten carrier complex = complete antigen Drug induced hypersensitivity reactions Autoimmune diseases (pemphigoid, SLE, lichen, hemolytic anemia) IgE mediated anaphylaxis, urticaria Immune complex vasculitis, fever, serum sickness Contact dermatitis Morbilliform exanthematous reaction, maculopapular reaction Fix drug eruption, erythema multiforme, Steven Johnson sy, Lyell sy. (toxic epidermal necrolysis, TEN) Stevens Johnsons syndrome: Severe variant of erythema multiforme associated with fever and mucous mem. lesions. The oral mucosa, lips and bulbar conjunctivae are most commonly affected Rapidly spreading macules leads to epidermal blistering, necrosis. Triggered by: Sulfa drugs, antiepileptic, antibiotics.

T cell role T memory, B memory - B activation needs T cell help Drug specific Th2 cells - in urticaria, anaphylaxis Drug specific Th1 cells - CD8+ cytotoxic T cells, effector function, toxic for keratinocytes, B cells in contact dermatitis, morbilliform exanthema, bullous reactions

Efi. Gelerstein 2011

Drug reactions 1) Immediate type 30 min IgE mediated 2) Late type 3-8 hours IgE mediated late phase reaction (IL5,eo-s), Arthrus reaction, IC reaction 3) Delayed type 24-48 hours contact HS, morbilliform reactions, bullous reactions (EM, SJS, TEN) Coombs-Gell classification This classification divides drug allergies into 4 pathophysiological types: Type I anaphylaxis (IgE) Urticaria Angioedema Anaphylaxis Thrombocytopenic purpura Leukocytoclastic vasculitis Serum sickness Allergic contact dermatitis Some exanthems Photoallergic reactions

Type II Type III Type IV

Ab mediated cytotoxicity IC mediated reaction delayed type HS (cell mediated)

Multiple drug allergy syndromes Specific disease background 1. Sulfonamide - AIDS 2. Penicillin - abnormal lymphocytes (+) family history 1. Penicillin allergy: 10x more likely to develop allergy to other antibiotics Atopy genetic predisposition toward the development of immediate hypersensitivity reactions High immunogenicity to drug - hapten complex Pseudo-allergic reactions Contrast materials shock Aspirin asthma Opiate urticaria Protamine pulmonary hypertension NSAID urticaria Primaquine (malaria) haemolytic anemia G6PD deficiency Local anesthetics syncope Vancomycin flushing INH hepatitis Diagnosis of drug allergy Case history Histology, immunehistology Stop the drug, treat the symptoms Lymphocyte transformation test, measure spec IgE, basophile degranulation test Provocation (skin tests, oral challenge)

Efi. Gelerstein 2011

SCORTEN - 7 point SCORTEN Scale is a severity-of-illness scale with which the severity of certain bullous conditions can be systematically determined. The term "SCORTEN" stands for SCORe of Toxic Epidermal Necrosis It was originally developed for Toxic Epidermal Necrolysis but can be used with burn victims, sufferers of SJS, cutaneous drug reactions, or exfoliative wounds these conditions have in common that they compromise the integrity of the skin and/or mucous mem. In the SCORTEN Scale 7 independent risk factors for high mortality are systematically scored, so as to determine the mortality rate for that particular patient. 1. 2. 3. 4. 5. 6. 7. Age > 40 years Malignant tumour in history BSA (body surface area) necrolysis > 10% Pulse > 120/min serum BUN > 10mmol/L HCO3 < 20mmol/L Glucose > 14mmol/L

SCORTEN of 5 or more > 90% mortality

Some common reaction patterns and drugs which can cause them: Toxic (reactive) erythema Antibiotics (esp. Ampicillin) sulphonamides and related compounds (diuretics and hypoglycaemics) Barbiturates phenylbutazone salicylates (most common) histamine releasers Antibiotics Sulphonamides Phenylbutazone phenytoin oral contraceptives are among the possible causes Sulphonamides Barbiturates Phenylbutazone. Thiazides Sulphonamides Phenylbutazone Barbiturates Quinine Bullae may also develop at pressure sites in drug induced coma Penicillin Sulphonamides Phenothiazines Local anaesthetics

Urticaria

Allergic vasculitis

Erythema multiforme

Purpura

Bullous eruptions Eczema