The lecture has been given on Dec. 5th, 2010 by Dr. Darseem.

1. Drug reactions

2. Almost any drug can cause a cutaneous reaction. Many inflammatory skin conditions can be caused or exacerbated by drugs. A drug reaction can be included in the differential diagnosis of most skin diseases.

3. Mechanisms These are many and various being related both to the properties of the drug and to a variety of host factors. Some mechanisms involved in drug reactions. -Pharmacological Caused by over dosage or failure to excrete or metabolize. Cumulative effects. Altered skin ecology. -Allergic IgE-mediated Cytotoxic Immune complex-mediated Cell-mediated -Idiosyncratic -Exacerbation of pre-existing skin conditions

4. Non-allergic drug reactions: Some drug reactions are a result of overdosage , others to the accumulation of drugs, or to unwanted pharmacological effects, e.g. stretch marks from systemic steroids. Other reactions are idiosyncratic (an odd reaction peculiar to one individual), or a result of alterations of ecological balance. Cutaneous reactions can be expected from the nature of some drugs. These are normal but unwanted responses. For example: -Mouth ulcers frequently occur as a result of the cytotoxicity of methotrexate.

5. -Silver-based preparations, given for prolonged periods, can lead to a slate-grey color of the skin (argyria). -Acute vaginal candidiasis occurs when antibiotics remove the normal resident bacteria from the female genital tract and so foster colonization by yeasts. -Dapsone or rifampicin, given to patients with lepromatous leprosy, may cause erythema nodosum leprosum as the immune response to the bacillus is re-established. They affect many, or even all, patients taking the drug at a sufficient dosage for a sufficient time.

6. Allergic drug reactions: Occur in only a minority of patients and even with low doses. Usually appear after the latent period required for an immune response. Chemically related drugs may cross-react. Fortunately, allergic drug reactions present in only a limited number of forms; urticaria and angioedema, vasculitis, erythema multiforme, or a morbilliform erythema. Rarer allergic reactions include bullae, erythroderma, pruritus, toxic epidermal necrolysis and the hypersensitivity syndrome reaction. This syndrome includes the triad of fever, rash (from morbilliform to exfoliative dermatitis) and internal involvement (hepatitis, pneumonitis, nephritis and haematological abnormalities).

7. Most patients with infectious mononucleosis develop a morbilliform rash if ampicillin is administered. Penicillin is a common cause of severe anaphylactic reactions, which can be life-threatening. Minocycline can accumulate in the tissues and produce a brown or grey color in the mucosa, sun-exposed areas or at sites of inflammation, as in the lesions of acne. Minocycline can rarely cause the hypersensitivity syndrome reaction, hepatitis, worsen lupus erythematosus, or elicit a transient lupus-like syndrome.

8. Some common reaction patterns and drugs which can cause them: 1.Toxic (reactive) erythema; This common type of drug eruption, looking sometimes like measles or scarlet fever, and sometimes showing prominent urticarial or erythema multiforme-like elements. Itching and fever may accompany the rash. Drugs include antibiotics (especially ampicillin), sulphonamides and related compounds (diuretics and hypoglycaemics), barbiturates, phenylbutazone and para-aminosalicylate (PAS).

10. 2. Urticaria Many drugs may cause this but salicylates are the most common, often working non-immunologically as histamine releasers. Antibiotics are also often to blame. Insect repellents and nitrogen mustards can cause urticaria on contact. Urticaria may be part of a severe and generalized reaction (anaphylaxis) that includes bronchospasm and collapse.

12. 3. Erythema multiforme Target-like lesions appear mainly on the extensor aspects of the limbs, and bullae may form. In the Stevens–Johnson syndrome, the patients are often ill and the mucous membranes are severely affected. Sulphonamides, barbiturates, lamotrigine and phenyl- butazone are known offenders.

14. 4. Purpura Itchy brown petechial rash on dependent areas that is characteristic reactions. Thrombocytopenia and coagulation defects should be excluded. Thiazides, sulphonamides, phenylbutazone, sulphonylureas, barbiturates and quinine are among the drugs reported to cause purpura.

16. 5. Bullous eruptions Some of the reactions noted above can become bullous. Bullae may also develop at pressure sites in drug- induced coma.

18. 6. Eczema This is not a common pattern and occurs mainly when patients sensitized by topical applications are given the drug systemically. Penicillin, sulphonamides, neomycin, phenothiazines and local anaesthetics should be considered.

20. 8. Exfoliative dermatitis The entire skin surface becomes red and scaly. This can be caused by drugs (particularly phenylbutazone, PAS, isoniazid and gold), but can also be caused by widespread psoriasis and eczema.

21. 9. Fixed drug eruptions Round, erythematous or purple, and sometimes bullous plaques recur at the same site each time the drug is taken. Pigmentation persists between acute episodes. The glans penis seems to be a favored site. Paracetamol, trimethoprim-sulfa, Non-steroidal anti-inflammatory drugs (NSAIDs; including aspirin), antibiotics, systemic antifungal agents and psychotropic drugs are possible offenders.

24. 10. Acneiform eruptions Lithium, iodides, bromides, oral contraceptives, androgens or glucocorticosteroids, antituberculosis and anticonvulsant therapy may cause an acneiform rash.

26. 11. Lichenoid eruptions These resemble lichen planus, but not always very closely as mouth lesions are uncommon and as scaling and eczematous elements may be seen. Consider antimalarials, NSAIDs, gold, phenothiazines and PAS.

28. 12. Toxic epidermal necrolysis In adults, this ‘scalded skin’ appearance is usually drug-induced (e.g. sulphonamides, barbiturates, phenylbutazone, oxyphenbutazone, phenytoin, carbamazepine, lamotrigine or penicillin). 13. Hair loss This is a predictable side-effect of acitretin and cytotoxic agents, an unpredictable response to some anticoagulants, and sometimes seen with antithyroid drugs. Diffuse hair loss may occur during, or just after, the use of an oral contraceptive.

31. 14. Hypertrichosis This is a dose-dependent effect of diazoxide,minoxidil and cyclosporin A. 15. Pigmentation Chloasma may follow an oral contraceptive plus sun exposure. Large doses of phenothiazines impart a blue-grey colour to exposed areas. Heavy metals can cause a generalized browning. Clofazimine makes the skin red. Mepacrine turns the skin yellow. Minocycline turns leg skin a greenish grey color.

32. Presentation Some drugs and the reactions they can cause: Antibiotics Penicillins and sulphonamides are among the drugs most commonly causing allergic reactions. These are often morbilliform, but urticaria and erythema multiforme are common too. Viral infections are often associated with exanthems, and many rashes are incorrectly blamed on an antibiotic when, in fact, the virus was responsible.

33. Penicillamine Like penicillin itself, this can cause morbilliform eruptions or urticaria, but the drug has also been incriminated as a cause of -haemorrhagic bullae at sites of trauma, -extrusion of elastic tissue through the skin, -pemphigus.

34. Oral contraceptives The hair fall that may follow stopping the drug is like that seen after pregnancy (telogen effluvium). Chloasma, hirsutism, erythema nodosum, acne and photosensitivity are other reactions.

35. Gold Its side-effects range from pruritus to morbilliform eruptions, to curious papulosquamous eruptions such as pityriasis rosea or lichen planus. Erythroderma, erythema nodosum, hair fall and stomatitis may also be provoked by gold.

36. Steroids Cutaneous side-effects from systemic steroids include a ruddy face, cutaneous atrophy, striae, hirsutism, an acneiform eruption and a susceptibility to cutaneous infections, which may be atypical.

37. Anticonvulsants There may be cross-reactivity between phenytoin, carbamazepine and phenobarbitol. -Skin reactions are common and include erythematous, morbilliform, urticarial and purpuric rashes. -Toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, the hypersensitivity syndrome reaction and a lupus erythematosus-like syndrome are rare. -A phenytoin-induced pseudolymphoma syndrome has also been described in which fever and arthralgia are accompanied by generalized lymphadenopathy and hepatosplenomegaly and, sometimes, some of the above skin signs. -Long-term treatment with phenytoin may cause gingival hyperplasia.

38. Course If a reaction occurs during the first course of treatment, it characteristically begins late, often about the ninth day, or even after the drug has been stopped. In such cases, it has taken that lag time to induce an immune reaction. In previously exposed patients the common morbilliform allergic reaction starts 2–3 days after the administration of the drug. The speed with which a drug eruption clears depends on the type of reaction and the rapidity with which the drug is eliminated.

39. Treatment The first approach is to withdraw the suspected drug. This is not always easy as sometimes a drug is necessary and there is no alternative available. At other times the patient may be taking many drugs and it is difficult to know which one to stop. The decision to stop or continue a drug depends upon the nature of the drug, the necessity of using the drug for treatment, the availability of chemically unrelated alternatives, the severity of the reaction, and the probability that the drug is actually causing the reaction.

40. Non-specific therapy depends upon the type of eruption. In urticaria, antihistamines are helpful. In some reactions, topical or systemic corticosteroids can be used, and applications of calamine lotion may be soothing.

41. Anaphylactic reactions require special treatment to ensure that the airway is not compromised (e.g. oxygen, assisted respiration or even emergency tracheostomy). One or more injections of adrenaline (epinephrine) (1 : 1000) 0.3–0.5 mL should be given subcutaneously or intramuscularly in adults before the slow (over 1 min) intravenous injection of chlorphenamine maleate (10–20 mg diluted in syringe with 5–10 mL of blood). Although the action of intravenous hydrocortisone (100 mg) is delay for several hours it should be given to prevent further deterioration in severely affected patients. Patients should be observed for 6 h after their condition is stable, as late deterioration may occur.

42. Desensitization, seldom advisable or practical, may rarely be carried out when therapy with the incriminated drug is essential and when there is no suitable alternative (e.g. with some anticonvulsants, antituberculous and antileprotic drugs). An expert, usually a physician with considerable experience of the drug concerned, should supervise desensitization.

43. Thanks