Indapamide

Summary

Synopsis: Indapamide ¹ is an orally active sulphonamide diuretic agent. Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 2.5mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild to moderate hypertension it is as effective as thiazide diuretics and β -adrenergic blocking agents in lowering blood pressure when used as the sole treatment. Indapamide has been successfully combined with β -adrenergic blocking agents, methyldopa, and other antihypertensive agents. While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity.

Thus, indapamide appears to offer a suitable alternative to more established drugs as a ‘first-line’ treatment in patients with mild to moderate hypertension. Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification.

Pharmacodynamic Studies: In dogs, indapamide 0.1 to 3.0 mg/kg did not alter effective renal plasma flow or glomerular filtration rate. Similar findings were reported in healthy volunteers, where single doses of indapamide 10mg and 2.5mg daily given long term also failed to change these parameters significantly. In healthy volunteers and patients with hypertension with or without renal insufficiency, single or multiple doses of indapamide 2.5 to 10mg either increased endogenous creatinine clearance slightly (but significantly) or had no effect. Alterations in mean serum creatinine have rarely occurred during indapamide treatment, but increases in mean blood urea nitrogen have been noted occasionally, the latter probably being a reflection of mild dehydration.

24-Hour urine volumes have not been significantly augmented by low doses (< 2.5mg daily) of indapamide, but moderate to large doses (5 to 30mg) have resulted in clinically significant and dose-related water and electrolyte losses. Following oral administration, the onset of diuresis occurs in 1 to 3 hours, and peak urinary flow at 6 hours. Increased urinary volume from baseline may be noted up to 36 hours after a moderate (10mg) dose of indapamide. In healthy volunteers or oedematous patients large doses (40 to 50mg) have induced a diuresis similar in volume to that of frusemide (furosemide) 40 or 80mg. In greater than half of the trials reported, indapamide 2.5 or 5mg daily has resulted in mean bodyweight losses (an indirect measurement of diuresis) ranging from approximately 0.5 to 2.4kg, which are similar to those noted with bendrofluazide 5mg, hydrochlorothiazide 100mg, or frusemide 40mg, each administered daily. Similar to the benzothiadiazine diuretics, the primary site of the diuretic action of indapamide is the proximal segment of the distal renal tubule, with some activity also apparent in the proximal tubule.

In a limited number of studies, indapamide 2.5 to 5mg daily has been shown to raise plasma renin activity and plasma aldosterone concentrations to an extent similar to that of other diuretic agents and vasodilator drugs (2- to 5-fold).

In healthy volunteers and patients with hypertension, single doses of indapamide 10mg increased the percentage of filtered sodium excreted to 3.4% (p < 0.001), whereas non-parallel studies have shown the percentage of filtered sodium excreted following usual doses of thiazide compounds and frusemide to be 8 and 23%, respectively. Low doses of indapamide (< 1mg) have not resulted in statistically significant episodes of natriuresis, but larger doses ranging from 2.5 to 30mg have increased urinary sodium excretion by 72 to 127 µmol/min. In most studies, indapamide (usually 2.5mg daily) has not altered total exchangeable sodium. Serum sodium concentrations following long term administration of indapamide have generally not been altered.

Indapamide decreases estimated total body potassium, but these changes have been statistically insignificant (≈ 125 mmol). Single doses of indapamide 2.5 to 40mg have consistently increased the rate and quantity of urinary potassium loss in healthy subjects and statistically significant decreases in mean serum potassium concentrations have occurred in approximately 75% of reported clinical trials of indapamide. Although these decreases have usually not exceeded the normal lower physiological limit for serum potassium concentration, some patients have required potassium supplements. In parallel controlled studies, decreases in serum potassium concentrations following indapamide 2.5mg daily were equal in magnitude compared with those with hydrochlorothiazide 50 or 100mg daily.

Urinary chloride excretion is significantly increased by indapamide in a dose-related manner. A single dose of 40mg increased chloride excretion from 7.5 to 25 mmol/hour (p < 0.01), and this increase in urinary excretion was prolonged (up to 72 hours). The single-dose administration of indapamide 2.5mg increased 24-hour urinary chloride loss up to 106.3%, whereas 40mg of the relatively short-acting (≈ 6 hours) agent frusemide increased excretion by 40%. However, serum chloride concentrations seen with indapamide have not resulted in concentrations below the normal range. Bicarbonate ion excretion and serum bicarbonate concentrations appear to be minimally affected by indapamide.

Most studies have shown indapamide to have a hypocalciuric effect approximately equal to that of hydrochlorothiazide in patients with hypertension with normal or elevated serum calcium concentrations. Serum calcium concentrations have not been altered during treatment with indapamide, and urinary phosphate excretion and serum phosphate concentrations have not been appreciably altered. Indapamide 40mg increased (0.05 > p > 0.02) urinary magnesium excretion and decreased serum magnesium concentrations (p < 0.01), and serum concentrations remained decreased for 10 days following this single dose.

The data regarding the effect of indapamide on serum uric acid concentrations is divergent — probably due to varying patient selection criteria in clinical trials. However uncommon, acute gouty arthritis has occurred during treatment with indapamide.

In isolated perfused rat pancreas, high concentrations of indapamide (10 or 100 mg/L) have reduced total insulin secretory response to glucose infusions. Although indapamide 2.5 or 5mg daily for 12 weeks increased blood glucose concentrations similarly to hydrochlorothiazide 50mg twice daily (8.3, 15.8 and 11.6%, respectively) in non-diabetic hypertensive patients, most studies in diabetic and non-diabetic patients with hypertension have not revealed a significant decrease in glucose tolerance with indapamide. Similarly, indapamide has not significantly altered blood glucose concentrations or insulin secretion in hypertensive diabetics who have received it for up to 1 year. As decreased glucose tolerance with thiazide diuretics in non-diabetic patients with hypertension may take up to 2 years to develop, long term studies are required to determine the exact potential indapamide has in inducing this metabolic abnormality. Although the data are limited, indapamide 1 to 4mg daily for up to 24 months has not been reported to increase total cholesterol or triglyceride concentrations, or lower high-density lipoprotein concentrations.

Although the ability of indapamide to relax vascular smooth muscle and decrease peripheral vascular resistance has been demonstrated in various in vitro and in vivo investigations, further study is required to clarify the extent to which the antihypertensive efficacy of indapamide can be attributed to actions other than its diuretic effect.

Indapamide decreased inward calcium current, clonic phasic contractions, and outgoing potassium current in longitudinal muscle strips from isolated rabbit portal vein, and inhibited increases in clonic contractions and calcium influx which could be elicited by angiotensin II. However, the intensity of tonic contractions was not altered. In vitro, cardiovascular smooth muscle preparations decreased action potential amplitude in the presence of indapamide, although resting membrane potential remained unaffected. The decrease in isometric contractions in normally polarised rat portal vein smooth muscle was greater with indapamide than with hydrochlorothiazide or chlorthalidone, and only indapamide decreased the action potential amplitude in this in vitro model when equal concentrations of the 3 agents were used.

In vitro, various concentrations of indapamide have been shown to inhibit vascular smooth muscle contractile responses to assorted vasopressor agents [angiotensin II, adrenaline (epinephrine), tyramine, prostaglandin F_2α, nicotine] and electrical stimulation, while effects on noradrenaline-induced contractions have been inconsistent. Resting tone in arterial and venous smooth muscle has usually not been affected.

The effects of indapamide on in vivo vascular reactivity have been studied both in laboratory animals and in man. In rats, indapamide (usually 10 mg/kg daily) decreased pressor response to oxotremorine, noradrenaline, and tyramine, whereas pretreatment with hydrochlorothiazide 5 mg/kg intraperitoneally did not decrease pressor response to the latter 2 agents. In patients with hypertension, vascular reactivity (i.e. pressor responsiveness) to phenylephrine, noradrenaline, and angiotensin II were decreased after indapamide 2.5 to 5mg daily for 2 to 6 weeks. In small numbers of patients with hypertension, indapamide 2.5mg daily for 6 to 12 weeks was shown to increase muscle blood flow, and decrease limb vascular resistance, total peripheral resistance, and peripheral resistance ‘index’. However, the non-invasive techniques and indirect methods of assessment used in the majority of these studies necessitate cautious interpretation of these findings.

Heart rate, left ventricular end-diastolic or end-systolic volume, ejection fraction, and stroke volume have generally been unaffected by indapamide administration. Similarly, cardiac output has usually remained unchanged or increased. Regression of left ventricular hypertrophy and cardiomegaly have also occurred after long term treatment. No electrocardiographic abnormalities have been reported during indapamide therapy in the absence of metabolic disturbances.

In vitro, indapamide exhibited the greatest inhibitory effect on thromboxane synthesis, and the most stimulatory effect on prostaglandin I₂ (prostacyclin) synthesis when compared with frusemide, hydrochlorothiazide and spironolactone. In patients with hypertension, indapamide 2.5mg daily for 6 weeks increased urinary prostaglandin E₂ excretion (p < 0.025). Some prostaglandins may play a role in the control of blood pressure in man, but the clinical significance of these findings with indapamide is unknown.

Pharmacokinetic Studies: In healthy volunteers, bioavailability of indapamide after a 5mg dose was estimated to be 93%. Peak concentrations of indapamide occurred approximately 0.5 to 2 hours after oral administration and remained relatively constant for up to 8 hours. Mean steady-state blood concentrations of 89 and 158.5 µg/L occurred after 4 daily doses of indapamide 2.5 and 5mg, respectively.

In vitro, indapamide accumulated in vascular smooth muscle and the red cell binding of indapamide was found to be high. The red cell to plasma ratio of radioactivity after in vitro incubation of whole blood with ¹⁴C-indapamide ranged up to 9: 1, and in vivo ratios obtained in man following treatment with indapamide were similar (5.7: 1). Indapamide binds predominantly (98%) to the carbonic anhydrase fraction of the red cell, but the activity of this enzyme remains intact. In man, indapamide is 76 to 79% protein bound.

Human studies have shown indapamide to be excreted 60 to 70% renally, with about 7% as unchanged drug, and the remainder as metabolic products. Up to 19 metabolites of indapamide have been detected in urine. The renal clearance of indapamide has been estimated to be 1.71 ml/min; therefore, hepatic clearance is responsible for the greatest portion of the total systemic clearance (20 to 23.4 ml/min). Faecal elimination accounts for 16 to 23% of an orally administered dose. The elimination half-life of indapamide has been estimated to range from 13.9 to 17.8 hours in healthy subjects.

Indapamide does not significantly accumulate in patients with renal insufficiency or failure following long term treatment. Pharmacokinetic data in patients with hepatic dysfunction are lacking. Indapamide is not dialysable.

Therapeutic Trials: In open and placebo-controlled studies in patients with mild to moderate hypertension, indapamide (usually 2.5mg daily) has been shown to be an effective antihypertensive agent, lowering resting systolic and diastolic blood pressures by 10 to 20%. Maximum blood pressure-lowering effect occurred most frequently at the second or third month of therapy, and indapamide generally lowered blood pressure to 95mm Hg or less in 60 to 80% of these patients.

In parallel group and crossover comparisons, indapamide 2.5mg daily was approximately equal in antihypertensive efficacy to other diuretic agents, including hydrochlorothiazide 50mg (alone or in combination with amiloride 5mg), bendrofluazide 5mg, chlorthalidone 100mg, chlorothiazide 500mg, or pindolol 10 or 15mg, atenolol 100mg, or metoprolol 200mg daily. In a few small studies, indapamide 2.5mg daily displayed a superior blood pressure-lowering effect when compared with cyclopenthiazide 0.5mg or methyldopa 500mg, each administered daily. Therapeutic regimens combining indapamide with a β-adrenoceptor blocking agent or methyldopa have exerted good antihypertensive efficacy and have been well tolerated. Decreases in serum potassium concentrations were generally of equal magnitude when indapamide was compared with other diuretic agents. Indapamide has also been proven effective in reducing blood pressure in a small number of patients with renal insufficiency or failure (on haemodialysis).

In patients with oedema due to unknown causes, congestive heart failure, or hepatic disease, indapamide 2.5 to 20mg daily was an effective diuretic agent, with both lower and moderately high doses (2.5, 5 and 10mg) being approximately equal in effectiveness to hydrochlorothiazide 100mg daily. Hypokalaemia was a common complication of moderate to high dose indapamide treatment in these patients, with reported incidences ranging from 25 to 40%. Further studies are required before the efficacy of indapamide in the treatment of oedema (and whether it offers any advantages over existing diuretics in this setting) can be clearly stated.

Side Effects: The most common side effect reported during indapamide therapy is hypokalaemia (serum potassium < 3.5 mmol/L); 1.2 to 3 and 7% of patients manifest laboratory signs and/or clinical symptoms of hypokalaemia with indapamide 2.5 or 5mg daily, respectively. Although central nervous system effects, fatigue, orthostatic hypotension, and gastrointestinal side effects have also occurred during indapamide therapy, they have been infrequent and minor in severity. Sexual dysfunction said to be associated with indapamide treatment has been reported only rarely.

Dosage and Administration: The recommended initial daily dose of indapamide for the treatment of hypertension or oedema is 2.5mg daily, administered orally. The dose may be increased to 5mg daily if an appropriate antihypertensive effect has not occurred after 1 to 2 months of treatment. Likewise, an inadequate diuretic response after 1 week of treatment with this dose in oedematous patients is indicative of a need for an increase in dosage. Indapamide should probably be used with caution in patients with impaired renal or hepatic function. Indapamide is capable of inducing hypokalaemia and possibly other metabolic abnormalities and, as with other diuretics, laboratory and clinical monitoring of patients at appropriate intervals is advised.