Xipamide A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy

Publisher Website
Google Scholar
Abstract
Synopsis: Xipamide1 is a diuretic derived from salicylic acid and has a structural resemblance to chlorthalidone. Its pharmacodynamic profile shows a diuretic efficacy is similar to that of frusemide (furosemide) at doses up to 40mg, but the onset and duration of action are comparable to those of hydrochlorothiazide. Xipamide has been studied mostly in the treatment of mild to moderate essential hypertension, with few controlled studies of its use in oedematous states. The efficacy of xipamide 20 to 40mg once daily in patients with mild to moderate hypertension is comparable to that of bendrofluazide 5mg, bumetanide 1mg or hydrochlorothiazide 50mg when used alone in newly treated or previously treated patients. The addition of xipamide 20 to 40mg daily to regimens containing β-blockers, adrenergic neuron-blocking drugs and/or methyldopa has resulted in a further reduction in blood pressure. A few studies in oedematous states suggest that xipamide 40 to 80mg is comparable in efficacy to equal doses of frusemide, and that the side effects of hypokalaemia, hyperuricaemia and increased blood glucose in diabetics or latent diabetics are similar to those of other diuretics. Thus, xipamide is a suitable alternative to other diuretics in the treatment of mild to moderate hypertension and combines the efficacy of frusemide with a less abrupt action in the treatment of oedema. Pharmacodynamic Studies: Although structurally related to chlorthalidone, xipamide is not a thiazide. Diuresis produced by xipamide over a 24-hour period is equivalent to that of an equal dose of frusemide, but the onset and duration of action of xipamide resembles that of hydrochlorothiazide. The natriuretic effect of xipamide is dose related, with a progressive increase in 24-hour sodium excretion up to a dose of 40mg daily, although in one single-dose study in volunteers sodium excretion with xipamide 40mg daily was only marginally greater than that with 20mg daily. Unlike frusemide, xipamide does not result in a ‘rebound’ effect after initial natriuresis, but like frusemide it does produce diuresis in patients with marked renal insufficiency. Urinary sodium/potassium ratios after oral xipamide 20 to 60mg were not significantly different from those after hydrochlorothiazide 50 and 100mg or frusemide 40mg. However, there is some evidence that the sodium/potassium ratio is more favourable with xipamide than with chlorthalidone. Xipamide 40mg, given as a single dose, did not exhibit a kaliuretic effect when creatinine clearance was below about 25 ml/min. Xipamide-induced potassium loss can be prevented by concomitant administration of the potassium-sparing diuretic triamterene, and a combination tablet containing xipamide and triamterene in a ratio of 1: 3 has been developed for clinical use. Studies in healthy subjects demonstrated that xipamide, like hydrochlorothiazide, decreases free water clearance and increases osmolar clearance during maximal water diuresis. Xipamide also behaved similarly to hydrochlorothiazide during maximal hydropenia, thus suggesting that its site of action is on the distal convoluted tubules. However, xipamide resembles frusemide in producing diuresis in renal failure and had an effect additive to that of hydrochlorothiazide in animals — suggesting a mechanism of action somewhat different to that of the thiazides. Pharmacokinetic Studies: Following oral administration of xipamide 20mg, maximum plasma concentrations of around 3 mg/L occur within 1 hour. As calculated by the area under the plasma concentration-time curve (AUC) after intravenous and oral administration, absolute bioavailability is 73%. Xipamide is conjugated with glucuronide and during the first 24 hours after administration 26% of a dose was excreted in the conjugated form and 40 to 55% unchanged. Urinary excretion of radioactivity was 88%, 96 hours after a single dose of 35S-xipamide given orally or intravenously. Elimination half-life in healthy subjects has been reported to be between 5.8 and 8.2 hours after oral administration. In patients with renal impairment, half-life is prolonged. However, since extrarenal clearance remains constant with increasing renal failure and therefore becomes proportionally more important, it is unlikely that xipamide will accumulate to any marked degree in renal failure. Therapeutic Use: Xipamide has most often been studied as an antihypertensive drug in patients with mild to moderate hypertension. Open studies, in which xipamide 10 to 20mg daily was generally administered alone, have suggested that it is an effective antihypertensive drug. At a daily dose of 40mg, or when given at individually titrated optimum dosage, xipamide was superior to placebo. In double-blind crossover trials the efficacy of xipamide 40mg daily was not significantly different from that of bendrofluazide 5mg, bumetanide 1mg or hydrochlorothiazide 50mg daily. In one study, xipamide 20mg was more effective than cyclopenthiazide 0.5mg daily after 6 weeks of treatment. Most of these studies, however, involved only small numbers of patients and were of short duration, thus requiring confirmation in larger and more prolonged comparative studies. Dose-determining studies found no significant difference in antihypertensive efficacy between xipamide 20 and 40mg, although response to the higher dose was more consistent. Similarly no difference between xipamide 10 and 20mg daily was found in a small study, although patient numbers may have been too small to detect any small differences in efficacy that may have existed between the dosages. In patients with mild to moderate hypertension xipamide has been compared with placebo, indapamide and bendrofluazide when added to an existing regimen that did not control blood pressure adequately. The addition of either xipamide 20mg or indapamide 2.5mg daily to nadolol 160mg daily resulted in a significant decrease in blood pressure, although potassium loss was greater with xipamide than with indapamide. Similarly, the addition of xipamide 20 to 40mg to β-blockers, adrenergic neuron-blocking drugs and/ or methyldopa produced a significant fall in blood pressure, although xipamide 20mg was no more effective than a further dose of bendrofluazide 5mg in patients already receiving a β-blocker with or without bendrofluazide 5mg daily. Several studies in small numbers of patients have suggested that xipamide is effective in the treatment of congestive heart failure. In a double-blind study, xipamide 40mg was similar in efficacy to frusemide 25mg in patients receiving digoxin and a controlled sodium intake. Preliminary studies suggest that xipamide is useful in alleviating oedema associated with renal failure and nephrotic syndrome, and appears to be of comparable efficacy to an equal dose of frusemide. Symptomatic improvement of premenstrual syndrome was comparable with xipamide 20mg and frusemide 40mg. Side Effects: Xipamide has generally been well tolerated at dosages used to treat mild to moderate hypertension. The most frequently reported side effects include mild upper gastrointestinal symptoms, anorexia or nausea (incidence 2 to 4%), and tiredness and fatigue (3 to 8%). Dizziness (often postural) and vertigo have also occurred infrequently and were probably related to the extent of reduction in blood pressure. Xipamide, like the thiazide and ‘loop’ diuretics, causes net potassium loss, but this has varied according to the country of investigation. There have been occasional reports of considerable decreases in serum potassium to concentrations as low as 2.2 mmol/L and of symptomatic hypokalaemia. As might be expected, xipamide has caused small increases in average blood urea and serum urate concentrations in some studies, and occasional increases in blood glucose and of plasma lipids in diabetic patients. Dosage and Administration: The usual dose of xipamide in the treatment of mild to moderate hypertension is 20mg daily given as a single dose in the morning. A dose of 40mg may be needed in more severe grades of hypertension. In combination with other antihypertensive drugs the initial dose of xipamide should not exceed 20mg daily. In the treatment of oedema the usual initial dose is 40mg daily which should subsequently be adjusted according to response. Supplementary potassium may be needed to avoid hypokalaemia during long term treatment of cardiac, hepatic or renal oedema.