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Synopsis: Piretanide1 is a potent ‘loop’ diuretic whose principal site of action is in the thick ascending limb of the loop of Henle. When administered orally or intravenously to healthy volunteers it rapidly increases diuresis and electrolyte excretion, and the effects are short-lived. In comparative studies, piretanide has generally been found to be 5 to 7 times more potent than frusemide (furosemide) but only one-tenth as potent as bumetanide, on a weight-for-weight basis. Piretanide 6 to 12 mg/day, in conventional or sustained release formulations, has been shown to significantly lower elevated blood pressure in a large proportion of patients with mild to moderate hypertension. Comparative trials of up to 3 months duration indicate that at this dosage piretanide is of comparable antihypertensive efficacy as hydrochlorothiazide 50 to 100 mg/day, but has significantly less effect on serum potassium levels. Short term studies in patients with oedema caused by renal, hepatic or cardiac failure demonstrated that piretanide 6 to 9mg is of similar diuretic potency as frusemide 40mg and bumetanide lmg. In medium term trials in patients with congestive heart failure piretanide 6 mg/day produced equivalent symptomatic improvement as frusemide 40 mg/day. When used to treat oedema caused by liver disease, piretanide 12 to 24 mg/day was successful in only about 50% of patients, but spironolactone added to the treatment regimen greatly increased the response rate. Generally, piretanide has been well-tolerated in clinical trials, although the conventional tablet formulation has caused a relatively high incidence of acute adverse effects — these were greatly reduced with the introduction of the sustained release formulation. Serum concentrations of most electrolytes have not shown any consistent adverse trends and hyperuricaemia and hypokalaemia have been encountered infrequently.
Thus, piretanide appears to offer an effective alternative to other ‘loop’ diuretics for the treatment of oedematous diseases and to hydrochlorothiazide for the management of mild to moderate hypertension. However, its relative place in therapy remains to be clarified with wider clinical experience.
Pharmacodynamic Studies: Piretanide is a potent ‘loop’ diuretic with qualitative properties characteristic of this group of drugs and it has a weight-for-weight potency intermediate between bumetanide (the most potent) and frusemide. In healthy volunteers piretanide produces a rapid diuresis, natriuresis, chloruresis and kaliuresis (1 to 2 hours after oral administration and 0.25 to 1 hour after an intravenous injection), the effects of which are short-lived (oral: 4 to 6 hours; intravenous: 2 to 3 hours). At peak saluresis, piretanide reduced fractional free water clearance during hydration by almost 20% and reduced fractional free water reabsorption during hydropenia by approximately 70%. Piretanide has produced no consistent changes in renal plasma flow or glomerular filtration rate in studies in healthy volunteers or in patients with renal insufficiency.
Mean fractional sodium and chloride excretion were increased following piretanide administration by greater than 10-fold, while the fractional excretion of potassium was increased only 2- to 3-fold. Additionally, after single doses of piretanide 3, 6 and 12mg the diuretic and natriuretic effects were found to be dose-dependent whereas the differences in potassium excretion between these doses were not statistically significant.
Following 7 days of high dose piretanide administration (18 mg/day) no clinically significant changes in the plasma or tissue concentrations of sodium or chloride were documented, while plasma potassium concentrations were significantly reduced. However, this reduction was relatively small (from 3.76 to 3.41 mmol/L) and there was no significant change in the tissue concentration of potassium. Administration of a sustained release formulation of piretanide reduced peak diuresis and electrolyte excretion but produced a more prolonged duration of action — overall net salidiuretic effects were comparable with those of a conventional formulation of piretanide.
The urinary excretion of calcium and magnesium, as for sodium and chloride, were greatly increased by piretanide, but changes with respect to phosphate excretion have been conflicting, with both increases and decreases being reported. Similarly, no consistent changes in uric acid excretion have been observed in studies to date. Piretanide has generally had little influence on urinary pH, although in a small number of studies significant decreases have been observed. As a result of its diuretic activity piretanide lowered blood volume by approximately 5 to 10%, but the plasma concentration of antidiuretic hormone was not significantly affected.
In healthy volunteers piretanide 6mg once or twice daily was largely unaccompanied by counter-regulatory changes in the renin-angiotensin-aldosterone system. There is some evidence that plasma renin activity may be slightly increased in elderly hypertensive patients administered piretanide, but plasma aldosterone and catecholamine concentrations were not affected. In a clinical trial in patients with liver cirrhosis and ascites, piretanide produced a positive therapeutic response only in those patients with normal or slightly raised levels of plasma renin activity or plasma aldosterone.
Apart from its diuretic properties, piretanide has been shown to have extrarenal relaxant effects on vascular smooth muscle, which may contribute to its blood pressure lowering effects, and also fibrinolytic and antiplatelet properties similar to those of frusemide.However, the relative contribution of the extrarenal vascular effects of piretanide to its antihypertensive efficacy requires further evaluation.
Piretanide and other ‘loop’ diuretics have been shown to have ototoxic potential in animal experiments, but in the case of piretanide the clinical relevance of these findings awaits clarification, since audiometric testing has rarely been performed.
Pharmacokinetic Studies: When administered in a conventional tablet formulation piretanide 6mg produced peak plasma concentrations of 0.2 to 0.3 mg/L within 1.1 to 1.8 hours. Following 5 days’ treatment with piretanide 6 mg/day no evidence for drug accumulation was observed. Administration of sustained release piretanide 6mg resulted in a 2-fold increase in the time to achieve maximum plasma concentrations, which were reduced by about 50%. The volume of distribution following intravenous administration of piretanide (12mg) was approximately 0.3 L/kg, which indicates limited tissue distribution and is consistent with the high level of protein binding (> 90%) reported for piretanide. Renal clearance accounts for almost half of the total body clearance of 11 to 15 L/h in healthy subjects. Cumulative recovery of unchanged piretanide in the urine has been reported to be between 40 and 75%, with maximal recovery occurring in the first 2 hours. Five metabolites of piretanide have been isolated from the urine but only 1 of these has been identified to date. The elimination half-life of piretanide in healthy volunteers is approximately 1 to 1.7 hours.
In patients with chronic renal insufficiency, large oral doses of piretanide (18 to 96mg) resulted in peak plasma concentrations of 0.5 to 4.2 mg/L within 1 to 2 hours. There was no evidence of drug accumulation following repeat administration of a high dose of piretanide (18mg) 6 hours after the first dose. The volume of distribution of piretanide appears to be slightly increased (0.4 to 0.5 L/kg) and the extent of protein binding decreased (88%). Both the plasma and renal clearances of piretanide were markedly reduced in patients with renal failure, and the elimination half-life was increased to between 1.7 and 9.0 hours. In patients with congestive heart failure, piretanide pharmacokinetics were similar to those in healthy volunteers.
Therapeutic Trials: Clinical trials with piretanide have been performed in oedematous conditions caused by cardiac, renal or liver disease, and also in hypertension and angina. When used as a diuretic to relieve oedema the majority of trials have studied the effects of only a single dose of piretanide.
Dose-finding studies in patients with mild to moderate hypertension have shown that piretanide 6 to 12 mg/day (as either conventional tablets or sustained release capsules) effectively lowers blood pressure (10 to 30%) in a large proportion of patients (60 to 90%). Comparative trials of up to 3 months duration indicate that piretanide 6 to 12 mg/day is of comparable antihypertensive efficacy as hydrochlorothiazide 25mg or 50mg twice daily. In one study piretanide 6 or 12 mg/day reduced blood pressure by a significantly greater amount than a fixed combination of hydrochlorothiazide and amiloride (50mg + 5mg) twice daily. Other medium term comparative trials in patients with mild to moderate hypertension have shown that conventional piretanide and sustained release piretanide produce similar reductions in blood pressure, and that a combination of low dose piretanide (3mg) combined with penbutolol (20mg) is at least as effective as penbutolol 40mg and elicited a better global assessment both from patients and investigators.
In patients with congestive heart failure, piretanide 6 to 9mg administered orally has been found to be of comparable efficacy as bumetanide lmg, frusemide 40mg and hydrochlorothiazide 50mg, while doses of 6 to 12 mg/day were superior to chlorothiazide 1000 to 2000 mg/day. Generally, piretanide tended to produce a more intense acute diuresis but had equivalent 24-hour diuretic activity as frusemide and hydrochlorothiazide (alone or combined with amiloride). Following intravenous administration, piretanide 6 to 12mg produced similar changes to frusemide 20 to 40mg and both drugs at the higher doses were approximately 30% more effective than bumetanide lmg. Short term haemodynamic studies in patients with congestive heart failure demonstrated that the major changes produced by piretanide were reductions in pulmonary wedge, pulmonary arterial and right atrial pressures; however, small reductions in cardiac output have also been noted. The longest of these trials (3 weeks) found a good correlation between haemodynamic and echocardiographic changes and overall clinical response, although haemodynamic improvement usually exceeded diuretic activity by at least 15 hours. During medium term studies, piretanide 6 mg/day produced a similar reduction of the symptoms of congestive heart failure as frusemide 40 mg/day and piretanide plus triamterene (6mg + 50mg) once daily. Long term (up to 3 years) administration of piretanide (up to 24 mg/day) was generally well tolerated and controlled congestive heart failure in 15 patients with moderate to severe disease.
In patients with renal insufficiency the salidiuretic effects of piretanide seem to be less pronounced but generally more prolonged than in healthy subjects, the extent of the difference depending on the severity of renal impairment. Increased doses of piretanide are therefore required to obtain a clinically significant response in this type of patient. Raising the piretanide dosage 8-fold (48mg) only partially restored salidiuretic efficacy in patients with renal failure, to approximately 30% of its maximal effects at a dose of 6mg in patients with normal or slightly reduced glomerular filtration rates. Piretanide 18mg twice daily and bumetanide 3mg twice daily equally increased salidiuresis in patients with renal insufficiency, while in a single-dose study piretanide 12mg was marginally less effective than frusemide 80mg. Similarly, in a 3-day study, piretanide and frusemide, administered at a dose ratio of 6mg to 40mg (the dose administered being dependent upon the severity of renal failure), produced equivalent changes for most parameters, although urinary volume was increased fractionally more by frusemide. Piretanide has also been used in patients with stable renal transplants and a dose of 9mg was of similar efficacy as lmg of bumetanide over a period of 3 days. In a single-dose study in 6 patients with nephrotic syndrome, piretanide 12mg was more effective than frusemide 80mg during maximal water diuresis, but these dosages produced comparable changes during hydropenia.
Clinical trials with piretanide in patients with liver disease have been of short duration. Intravenous piretanide 6mg was found to be as effective as frusemide 20mg over a 3-day period in the largest study to date, and in a single-dose study in 6 patients with liver cirrhosis, intravenous piretanide 9mg induced diuretic effects comparable to bumetanide 0.5mg. However, in another trial, piretanide 12 to 24 mg/day administered orally to patients with liver cirrhosis and associated ascites produced a response rate of only about 50%. The number of patients responding to diuretic therapy was greatly increased by the addition of spironolactone 150 mg/day to their drug regimen. These data suggest that piretanide may not be a suitable first-line choice for patients with liver cirrhosis and ascites but may be useful in combination with spironolactone.
Side Effects: Short term trials indicate that piretanide has generally been well tolerated. Using a conventional tablet formulation in comparative studies the incidence of side effects has been the same or less than the other diuretics employed. However, in a 12-week open trial of 210 patients with mild to moderate hypertension, the incidence of some of the more common acute reactions such as pronounced diuresis (10%), nausea (5.2%), and thirst (4.8%) were more frequent than previously reported for other ‘loop’ diuretics such as bumetanide and frusemide. Recent data using a newer sustained release formulation of piretanide have shown a greatly decreased incidence of these acute side effects. There have been no consistent adverse changes in laboratory values. Serum levels of most important electrolytes have not significantly altered during clinical trials with piretanide and a low incidence of hypokalaemia has been recorded. In comparative trials in patients with congestive heart failure, renal or liver disease, piretanide has had no greater effect on potassium homeostasis than other diuretics such as bumetanide, frusemide, hydrochlorothiazide (alone or combined with amiloride), chlorothiazide, and triamterene. There is evidence that it has lesser kaliuretic potential than frusemide or chlorothiazide in patients with congestive heart failure, and than hydrochlorothiazide in patients with hypertension. Changes in blood uric acid concentrations have been variable, but isolated cases of hyperuricaemia have been noted. The effects of piretanide on carbohydrate metabolism appear to be minimal, with most studies reporting little change in blood glucose concentrations.
In a 12-week study in patients with mild to moderate hypertension, piretanide 12 mg/day was found to alter a number of indices of lipid metabolism and its effects were generally greater than those of hydrochlorothiazide (100 mg/day) despite having a lesser effect on potassium balance. However, in therapeutic trials published to date no clinically important changes in serum cholesterol or serum triglycerides have been documented.
Dosage and Administration: For the treatment of oedema in adults the recommended starting dose using conventional tablets is 6 mg/day. If necessary, this dosage may be increased. Results from patients with renal disease suggest that much greater dosages may be necessary (30 to 60mg) when glomerular filtration rates are severely reduced. Piretanide is also available as sustained release capsules (6mg); the recommended dosage with this formulation is 1 capsule daily, but further doses may be administered if necessary to achieve a desired level of diuresis. For the clinical management of mild to moderate hypertension in adults, the recommended starting dosage is 9 mg/day using conventional tablets or 1 to 2 sustained release capsules (6mg) daily. The maintenance dosage in adults is usually 1 capsule daily. At present insufficient data are available for dosage recommendations in children. The usual precautions for other ‘loop’ diuretics and for drugs which lower blood pressure apply to piretanide.
KeywordsCongestive Heart Failure Sustained Release Hydrochlorothiazide Frusemide Bumetanide
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