Professor Ihab Younis, M.D .

1. Professor Ihab Younis, M.D.

2. Etiology • It occurs in approximately 2-5% of inpatients and in greater than 1% of outpatients • Most estimates of the incidence of drug eruptions are inaccurate, because many mild and transitory eruptions are not recorded, and because skin disorders are sometimes falsely attributed to drugs • Elderly patients have an increased prevalence of adverse drug reactions • It may be divided into immunologically and nonimmunologically mediated reactions

3. A - Immunologically mediated reactions The 4 types of hypersensitivity occur:

4. Type I (IgE-Dependant) • The drug or protein conjugates with two or more specific IgE molecules, then gets fixed to sensitized mast cells or circulating basophil. This triggers the cell to release a variety of chemical mediators e.g.histamine and cytokines

5. Clinically, this may produce pruritus, urticaria, bronchospasm, laryngeal edema and in severe cases anaphylactic shock with hypotension and possible death • Immediate reactions occur within minutes of drug administration; accelerated reactions may occur within hours or days, and are generally urticarial but may involve laryngeal oedema • Penicillins are the commonest cause of IgE-dependent drug eruptions

6. Type II (Antibody Mediated) • An immune complex is formed from: The drug + a cell + Ig G antibodies with subsequent complement fixation • Example:thrombo- cytopenic purpura that may result from antibodies to quinidine

7. Type III (Immune Complex Reaction) • Soluble immune complexes are formed from Ig G class antibodies & a soluble antigen (not attached to the organ involved) • Example:Vasculitis induced by antibiotics results from deposition of immune complexes on vascular endothelium resulting in activation of the complement cascade

8. Type IV (Delayed or cell-mediated) • First,sensitization to the drug occurs when Langerhans' cells take up and process antigen, and migrate to regional lymph nodes, where they activate T cells with the consequent production of memory T cells, which end up in the dermis. On consequent exposure to the drug T cells & keratinocytes release cytokines causing inflammation • Example:Contact dermatitis to neomycin

9. B- Nonimmunologically- mediated reactions 1-Accumulation: e.g. argyria (blue-gray discoloration of skin and nails) observed with use of silver nitrate nasal sprays 2-Side effects: unwanted or toxic effects, which are not separable from the desired pharmacological action of the drug e.g. the drowsiness induced by antihistamines

10. 3-Direct release : The direct release of mast cell mediators is a dose-dependent phenomenon that does not involve antibodies. For example, aspirin and other NSAIDs cause a shift in leukotriene production, which triggers the release of histamine and other mast-cell mediators 4-Idiosyncrasy: a response, not predictable from animal experiments, and its cause is often unknown, but genetic variation in metabolic pathways may be involved e.g. dapsone induced hemolysis due to glucose-6-phosphate dehydrogenase deficiency

11. 5-Intolerance:The characteristic effects of the drug are produced to an exaggerated extent by an abnormally small dose. This may simply represent an extreme within normal biological variation or may occur in patients with altered metabolism. For example, individuals who are slow acetylators of the enzyme N-acetyltransferase are more likely than others to develop drug-induced lupus in response to procainamide

12. 6-Imbalance of endogenous flora: may occur when antimicrobial agents preferentially suppress the growth of one species of microbe, allowing other species to grow vigorously. For example, candidiasis frequently occurs with antibiotic therapy 7-Overdosage: is an exaggerated response to an increased amount of a medication. For example, increased doses of anticoagulants may result in purpura

13. 8-Jarisch-Herxheimer phenomenon: is a reaction due to bacterial endotoxins and microbial antigens that are liberated by the destruction of microorganisms. The reaction is characterized by fever, tender lymphadenopathy, arthralgias, transient macular or urticarial eruptions, and exacerbation of preexisting cutaneous lesions. The reaction is not an indication to stop treatment because symptoms resolve with continued therapy. This reaction can be seen with penicillin therapy for syphilis, griseofulvin or ketoconazole therapy for dermatophyte infections

14. 9-Metabolic effects: Drugs may induce cutaneous changes by their effects on metabolism e.g. isotretinoin may cause xanthomas by increasing lipoproteins 10-Teratogenicity and other effects on thefetus:Thalidomide, retinoids and cytotoxic drugs are proven teratogens and tetracyclines are deposited in developing bones and cause discoloration and enamel hypoplasia of teeth

15. 11-Effects on spermatogenesis: A number of drugs cause oligospermia e.g. estrogens, androgens, cyproterone acetate, colchicine, most monoamine oxidase inhibitors, ketoconazole. Conception should also be avoided after griseofulvin for 3 months as it potentially can damage sperm

16. Clinically • They usually begin 7-20 days after the medication is started • They may involve blood or tissue eosinophilia • They may recur if drugs chemically related to the causative agent are administered

17. During history taking note and detail the following: • All prescription and over-the-counter drugs, including topical agents, vitamins, herbal, laxatives, oral contraceptives, vaccines, homeopathic medicines, etc. as these may not be volunteered as medications • The interval between the introduction of a drug and onset of eruption • Route, dose, duration, and frequency of drug administration • Any improvement after drug withdrawal and any reaction with readministration

18. Determining the morphology of drug eruptions can help the clinician determine the causative medication :

43. Nail changes

45. Rates of reactions to commonly used drugs • Amoxicillin - 5.1% • Trimethoprim sulfamethoxazole - 4.7% • Ampicillin - 4.2% • Semisynthetic penicillin - 2.9% • Blood (whole human) - 2.8% • Penicillin G - 1.6% • Cephalosporins - 1.3% • Quinidine - 1.2% • Gentamicin sulfate - 1%

46. Drugs that commonly cause serious reactions • Allopurinol • Anticonvulsants • NSAIDs • Sulfa drugs • Bumetanide • Captopril • Furosemide • Penicillamine • Thiazide diuretics

47. Drugs unlikely to cause skin reactions

48. Investigations • If history and physical examination are not sufficient for diagnosis, the following investigations may help: • Biopsy e.g. by showing eosinophils in morbilliform eruptions or numerous neutrophils without vasculitis in persons with Sweet syndrome • CBC count with differential may show leukopenia, thrombocytopenia, and eosinophilia in patients with serious drug eruptions

49. Special attention should be paid to the electrolyte balance and renal and/or hepatic function indices in patients with severe reactions such as SJS, TEN, or vasculitis • Urinalysis, stool guaiac tests (for occult blood), and chest radiography are important for patients with vasculitis • Drug reactions, apart from fixed drug eruption, have non-specific clinical features, and it is often impossible to identify the offending chemical with certainty, especially when a patient with a suspected reaction is receiving many drugs simultaneously

50. Treatment • Once the offending drug has been identified, it should be promptly stopped. Failure of a rash to subside on drug withdrawal does not necessarily exonerate it, since traces of the drug may persist for long periods, and some reactions, once initiated, continue for many days without reexposure to the drug • Patients with morbilliform eruptions can continue medication even in presence of rash as the eruption often resolves, especially if the individual is being treated for a serious disease