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Twice daily administration of 70% ethyl alcohol or acidic ear drops (left in each ear for at least 5 minutes) maintains a dry and acidified environment. [7] Such management helps prevent infection in both swimmers and those exposed to warm humid conditions. Attention should be paid to the identification and removal of irritants when patients present with eczematous otitis externa. [1]

References 1. Brook I. Treatment of otitis externa in children. Paediatr Drugs 1999 Oct-Dec; 1 (4): 283-9

2. Rubin J, Yu VL. Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis, and therapy. Am J Med 1988 Sep; 85 (3): 391-8 3. Speight TM, Holford NHG, editors. Avery's drug treatment. 4th ed. Auckland: Adis International Limited, 1997 4. Chandler JR. Pathogenesis and treatment of facial paralysis due to malignant external otitis. Ann Otol Rhinol Laryngol 1972 Oct; 81 (5): 648-58 5. Fauci AS, Braunwald E, Isselbacher KJ, et al., editors. Harrison's principles of internal medicine. 14th ed. New York: McGraw-Hill, 1998 6. Murakami S, Hato N, Horiuchi J, et al. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol1997 Mar; 41 (3): 353-7 7. Marcy SM. Infections of the external ear. Pediatr Infect Dis 1985 Mar-Apr; 4 (2): 192-201

Drug interactions an increasing concern in dermatology The increasing availability of systemic drugs for the treatment of skin diseases is reflected by an increasing necessity to consider drug interactions. Although some drug interactions can have beneficial effects, most induce adverse effects. Patients receiving multiple drugs, including the elderly and patients with various chronic diseases, are at very high risk of developing adverse reactions caused by drug interactions. In general, the most common drug interactions in dermatology involve altered hepatic metabolism, although pharmacodynamic interactions and other pharmacokinetic interactions, such as those involving interference with drug elimination, can also occur. Some of the drugs used in the management of dermatological conditions that are implicated in clinically significant drug interactions include methotrexate, cyclosporin, tetracyclines, rifampicin (rifampin), retinoids and azole antifungals. Awareness of drug-drug interactions is the first step in reducing or eliminating the risk of their occurrence. Some of the most important drug interactions with regard to the therapy of dermatological diseases are shown in table 1.

Interactions may be pharmacodynamic ... Drug interactions can be distinguished as pharmacodynamic and pharmacokinetic reactions. Drug interactions related to the specific pharmacological effects of administered drugs are termed pharmacodynamic interactions. For example, both methotrexate (used in patients with severe psoriasis, psoriatic arthritis or bullous diseases) and trimethoprim inhibit human dihydrofolate reductase. Therefore, the combination

Vol. 16, No. 12; December 4, 2000

of these 2 drugs should be avoided because of the risk of severe myelosuppression.[I] Both retinoids and tetracyclines are used in various dermatological conditions. Concomitant administration of retinoids with tetracycline or minocycline can lead to the development of increased intracranial pressure.[1] Other antimicrobial agents such as erythromycin, cephalosporins and penicillins do not appear to interact with retinoids and may therefore be used as alternatives to tetracyclines in patients requiring concomitant therapy)4] Various other pharmacodynamic drug interactions are possible in the treatment of dermatological disorders. For example, severe GI, renal, hepatic or neuro-toxicity can develop when cyclosporin and colchicine are used concurrently. [1] Photosensitisation and related reactions can also occur in patients receiving psoralen-ultraviolet A (PUVA) therapy and photosensitisers such as griseofulvin, retinoids, quinolones and tetracyclines. [l]

.. . or pharmacokinetic Pharmacokinetic interactions can occur at each step between absorption and elimination. Significant pharmacokinetic drug interactions in dermatology include those occurring during metabolism and elimination. [1]

Cytochrome P450 enzymes often implicated Drug interactions occurring during drug metabolism often involve the cytochrome P450 (CYP) isoenzyme system. The activity of this enzyme system can be induced or inhibited by various factors including drugs. Enzyme induction can result in metabolism of an interacting drug that is more rapid than expected, resulting in decreased plasma drug concentrations of the affected drug;

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~Prugs

~nlfTl~'Y PI'/'iJeCm.\'S

Table 1. Some important drug interactions in the therapy of dermatological diseases[1·3) Drug

Interacting drug

Effect

Pharmacodynamic interactions Methotrexate

Trimethoprim

Both drugs have an antilolate effect potentially resulting in significant bone marrow suppression

Retinoids

Tetracyclines

Possible increased risk of intracranial hypertension

Azathioprine

Allopurinol

Increased plasma concentrations of azathioprine's active metabolite 6'mercaptopurine with increased risk of bone marrow suppression

Cyclosporin

Ketoconazole 8

Increased blood concentrations of cyclosporin

Cyclosporin

Erythromycin b

Increased blood concentrations of cyclosporin

G riseofu Ivin

Oral contraceptives

Reduced hormonal concentrations in plasma leading to reduced/loss of contraceptive efficacy

Methotrexate

Retinoids

Increased risk 01 hepatotoxicity"

Methotrexate

NSAIDs

Increased plasma methotrexate concentrations (NSAIDs may inhibit renal elimination of methotrexate, possibly by inhibiting renal prostaglandin synthesis and reducing renal perfusion)

Rifampicin (rilampin)

Oral contraceptives

Reduced hormonal concentrations in plasma leading to reduced/loss of contraceptive efficacy

Pharmacokl netic interactions

Increased plasma concentration of dapsone metabolite (hydroxylamine derivative) associated with methaemoglobinaemia and agranulocytosis a Other azole antifungals (e.g. fluconazole, itraconazole) have been implicated but possibly to a lesser extent. b Interaction appears to be less problematic with other macrolides such as clarithromycin. c Mechanism 01 interaction unclear and may involve a pharmacodynamic component. Rifampicin

Dapsone

conversely, enzyme inhibition may result in elevated plasma concentrations as the drug remains in the circulation longer before metabolism to inactive compounds.[l] In dermatology, some of the most important drug interactions mediated by the CYP system are those involving cyclosporin, erythromycin and azole antifungals. Azole derivatives, particularly ketoconazole, can inhibit the metabolism of drugs that are substrates for the isoenzymeCYP3A4 such as cyclosporin. Concomitant use of cyclosporin and ketoconazole has resulted in significantly elevated blood concentrations of cyclosporin. [1,3] Likewise, erythromycin can significantly increase blood concentrations of cyclosporin, presumably by inhibiting its hepatic metabolism. [3] Another important interaction in dermatology can occur with concurrent use of azathioprine (used in systemic lupus erythematosus and dermatomyositis) and allopurinol. Allopurinol inhibits the metabolism of 6-mercaptopurine (active metabolite of azathioprine) and thus leads to enhanced cytotoxicity and increased risk of bone marrow suppression. If required concomitantly, the dosage of azathioprine should be reduced by one-quarter to one-third.[l,3] Conversely, griseofulvin and rifampicin (rifampin) induce the metabolic activity of various CYP isoenzymes, resulting in a number ofdinically significant

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drug interactions, such as reduced efficacy of oral contraceptives.[l] Rifampicin and the sulfone derivative dapsone are recommended by the World Health Organization as combined therapy for lepromatous leprosy. However, these drugs must be used together with caution because rifampicin induces the metabolism of dapsone to a hydroxylamine derivative, a powerful oxidant that can cause methaemoglobinaemia and agranulocytosis. [1] Retinoids and methotrexate are generally not recommended for concomitant administration because of an increased risk of hepatotoxicity, although the mechanism of this interaction is unclear. [1]

Elimination can be affected too Various drugs can affect the elimination of others. For example, inhibition of prostaglandin synthesis by NSAIDs may disturb the renal tubular elimination of methotrexate, leading to accumulation of this drug in plasma and, in some cases, destruction of renal parenchyma. [3,5] The renal clearance of antiviral agents such as aciclovir, ganciclovir, foscarnet and cidofovir is reduced by probenecid and can potentiate the risk of adverse events by increasing plasma antiviral concentrations. [1]

VoL 16, No. 12; December 4, 2000

15

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References 1. TC, Merk HF. Important drug interactions in dermatology. Drugs 2000 Feb; 59 (2): 181-92 2. British National Formulary. No. 39. London: The Pharmaceutical Press, 2000 Mar: 578-614 3. AHFS Drug Information. Bethesda: American Society of Health-Systems Pharmacists, 1999

4. Andersen WK, Feingold DS. Adverse drug interactions clinically important for the dermatologist. Arch Dermatol 1995; 131: 468-73 5. Randat 1M, Marchbank CR, Dudley MN. Interactions of fluoroquinolones with other drugs: mechanisms, variability, clinical significance, and management. Clin Infect Dis 1992; 14: 272-84

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