A 56-year-old woman with diabetes mellitus and sclerodermi is being treated with insulin, captopril

Fråga: A 56-year-old woman with diabetes mellitus and sclerodermi is being treated with insulin, captopril (Capoten), digoxin (Lanacrist), diltiazem hydrochloride (Cardizem), levothyroxine (Levaxin), ciprofloxacine (Ciproxen), morphine (Dolcontin), flunitrazepam (Rohypnol), buprenorphine (Temgesic) and alpha-toccopherol (vitamin E). Low molecular weight heparin treatment (Fragmin) is planned to begin soon. Do any of these drugs interact with the licensed drug ketanserin (Sufrexal)?

Sammanfattning: Oral administration of ketanserin did not influence the pharmacokinetics of digoxin or digitoxin given intravenously or orally, nor has thyroxine been reported to interact with ketanserin.

However, ketanserin can prolong the QT interval, and the combined use of ketanserin and potassium-depleting diuretics can be harmful. Plasma potassium concentrations should be measured at the beginning of treatment and should be maintained within a normal range.

We did not find any interactions between ketanserin and the other drugs used in the present case (insulin, captopril, diltiazem, ciprofloxacin, morphine, flunitrazepam, buprenorphine or alpha-toccopherol), though formal studes are lacking.

The possibility of prolonged bleeding time during concomitant administration of ketanserin and anticoagulant drugs such as low molecular weight heparin also needs further investigation.

Svar: Ketanserin is a new 5-HT2-receptor antagonist without partial agonist properties. It also possesses weak alpha-1-adrenoreceptor antagonistic activity, which may explain its antihypertensive mechanism of action in patients with essential hypertension. It also inhibits the effects of serotonin on platelets in cardiovascular disease, inhibits vasoconstriction caused by the amine, and when administered intravenously, improves some haemorrheological indices in patients with ischaemic diseases (1). The approved indications are benign hypertension and hypertensive crises in pre-eclampsia and pre- and postoperative hypertension (4).<br><br>The influence of ketanserin on the pharmacokinetics of digoxin was evaluated in 10 healthy volunteers who received a single dose of digoxin, 1.25 mg, by intravenous infusion before and during treatment with ketanserin, 40 mg twice daily, beginning seven days before administration. The same researchers also assessed the pharmacokinetics of intravenous digitoxin one mg during treatment with ketanserin in a similar manner. Plasma concentrations of digoxin and digitoxin were measured for up to 72 hours and 14 days, respectively. Ketanserin caused a slight but nonsignificant prolongation of the digoxin elimination half-life and a reduction in clearance of digitoxin, and also a small increase in Vd. In another study in 12 hypertensive patients with heart failure, trough concentrations of acetyldigoxin (dose: 0.2 mg twice daily) were assessed during treatment with ketanserin 40 mg twice daily. Subsequently, treatment with acetyldigoxin was started at least two months before the study and continued throughout. Trough concentrations of digoxin were assessed during concomitant treatment with a placebo and ketanserin. The study indicated that treatment with ketanserin did not influence the steady-state concentration of digoxin. Furthermore the steady-state values of ketanserin were similar to those reported for treatment with ketanserin alone. The findings of these investigations suggests that ketanserin has no meaningful influence on the pharmacokinetics of digoxin and digitoxin, but since two of the studies were of single-dose administration, more investigations are necessary (2).<br><br>Since ketanserin by itself has been reported by some to slightly increase bleeding time, interaction studies with anticoagulants are desired.<br><br>A harmful interaction between ketanserin and potassium-depleting diuretics resulted in a number of deaths (3). A double-blind, randomised, placebo-controlled trial of ketanserin in patients with intermittent claudication revealed an increased risk for cardiac arrhythmias (with a prolonged QT interval) when ketanserin was administered to patients also receiving potassium-depleting diuretics or antiarrhythmic drugs. This problem was not encountered if a potassium-conserving agent was given with ketanserin, even if the potassium-depleting diuretic was administered concomitantly. Combined administration of ketanserin and antiarrhythmic drugs should be avoided and if the addition of a diuretic is needed to control blood pressure, one that conserves potassium should be used (1,3).<br><br>Extensive analyses of data from large numbers of patients treated with ketanserin who were also receiving other drugs, e.g. thyroxine, failed to detect any clinically relevant drug interactions (1).<br><br>Apart from a possible reduced absorption during concomitant treatment with H2-blockers and antacids, it is unlikely that ketanserin will have any clinically important pharmacokinetic drug interactions related to, for example, altered liver metabolism or displacement from plasma protein binding sites (2). The lack of effect of ketanserin 40 mg twice daily for four weeks on indices of hepatic mono-oxygenase activity provides further evidence that ketanserin is unlikely to influence the metabolism of other drugs metabolised by the liver (1). However, other than those concerning concurrent treatment with beta-blockers, diuretics, digitalis and cimetidine, formal studies are lacking (2). We did not find any interactions reported in patients treated with insulin, captopril, diltiazem, ciprofloxacin, morphine, flunitrazepam, buprenorphine or alpha-toccopherol together with ketanserin.<div id="referenser" style="display:none;">1 Brogden RN, Sorkin EM: Ketanserin: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease. Drugs 1990; 40: 903-949<br>2 Persson B, Heykants J, Hedner T: Clinical pharmacokinetics of ketanserin. Clin Pharmacokinet 1991; 20: 263-279<br>3 Prevention of atherosclerotic complications: controlled trial of ketanserin. Br Med J 1989; 298: 424-430<br>4 Information from the manufacturer Janssen Pharma</div>