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Topic 19. Drug allergyAlmost any drug can cause a cutaneous reaction, and many infla. skin conditions can be caused orexacerbated 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 aspirin2) 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

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Drug reactions

1) Immediate type 30 min IgE mediated2) Late type 3-8 hours IgE mediated late phase reaction (IL5,eo-s), Arthrus reaction, IC reaction3) 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

Type II Ab mediated cytotoxicity Thrombocytopenic purpuraType III IC mediated reaction Leukocytoclastic vasculitis

Serum sicknessType IV delayed type HS (cell mediated) Allergic contact dermatitis

Some exanthems Photoallergic reactions

Multiple drug allergy syndromes

Specific disease background1. Sulfonamide - AIDS2. Penicillin - abnormal lymphocytes

(+) family history1. Penicillin allergy: 10x more likely to develop allergy to

other antibiotics

Atopy genetic predisposition toward the development ofimmediate hypersensitivity reactions

High immunogenicity to drug - hapten complexPseudo-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)

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SCORTEN - 7 point

SCORTEN Scale is a severity-of-illness scale with which the severity of certain bullous conditions can besystematically determined.

The term "SCORTEN" stands forSCORe ofToxic Epidermal Necrosis

It was originally developed forToxic Epidermal Necrolysisbut can be used with burn victims, sufferers

of SJS, cutaneous drug reactions, or exfoliative wounds these conditions have in common that theycompromise 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. Age > 40 years2. Malignant tumour in history3. BSA (body surface area) necrolysis > 10%4. Pulse > 120/min5. serum BUN > 10mmol/L6. HCO3 < 20mmol/L7. Glucose > 14mmol/L

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

Urticaria salicylates (most common) histamine releasers Antibiotics

Allergic vasculitis Sulphonamides Phenylbutazone phenytoin oral contraceptives are among the possible causes

Erythema multiforme Sulphonamides Barbiturates Phenylbutazone.

Purpura Thiazides Sulphonamides Phenylbutazone Barbiturates Quinine

Bullous eruptions Bullae may also develop at pressure sites in drug induced comaEczema Penicillin

Sulphonamides Phenothiazines Local anaesthetics

SCORTEN of 5 or more > 90% mortality

http://en.wikipedia.org/wiki/Bulloushttp://en.wikipedia.org/wiki/Toxic_Epidermal_Necrolysishttp://en.wikipedia.org/wiki/Mortality_ratehttp://en.wikipedia.org/wiki/Mortality_ratehttp://en.wikipedia.org/wiki/Toxic_Epidermal_Necrolysishttp://en.wikipedia.org/wiki/Bullous