Mechanism of Action of Indapamide
Indapamide works through a dual mechanism: it inhibits the sodium-chloride transporter in the distal tubule of the kidney (causing diuresis) and directly reduces peripheral vascular resistance through vascular effects, likely related to calcium channel modulation. 1, 2
Primary Renal Mechanism
Indapamide blocks the sodium-chloride cotransporter in the distal convoluted tubule, leading to increased excretion of sodium, chloride, and water, which reduces intravascular volume and contributes to blood pressure lowering. 1
This diuretic action occurs in the cortical diluting segment of the distal tubules, as demonstrated by free water clearance studies. 3
The natriuresis induced by indapamide causes upregulation of the epithelial sodium channel (ENaC), which is aldosterone-sensitive and can enhance acid secretion in the cortical collecting tubule, potentially leading to metabolic alkalosis. 1
Direct Vascular Effects
Indapamide demonstrates a direct vascular action that decreases peripheral vascular resistance independent of its diuretic effect. 3, 4
The drug alters vascular reactivity to calcium and other vasoconstrictive agonists, suggesting calcium channel modulation as part of its mechanism. 3, 5
Hemodynamic studies show indapamide significantly decreases total peripheral resistance (15%) and mean blood pressure (16%) without significant effects on cardiac output, heart rate, or rhythm. 3
Unique Pharmacological Features
Indapamide has a prolonged duration of action of approximately 36 hours, which is longer than traditional thiazide diuretics and allows for once-daily dosing. 1
The drug has a biphasic elimination pattern with a terminal half-life of approximately 14-16 hours in whole blood. 2, 3
Indapamide is preferentially and reversibly taken up by erythrocytes with a whole blood/plasma ratio of 6:1 at peak concentration, and 71-79% is bound to plasma proteins. 2
Clinical Implications of Dual Mechanism
At the standard antihypertensive dose of 2.5 mg daily, indapamide produces only limited diuresis, yet maintains effective blood pressure reduction, supporting the contribution of its direct vascular effects. 4, 6
The combination of diuretic and vasodilatory actions results in blood pressure reduction without significant adverse hemodynamic effects on cardiac function or renal blood flow. 3
Indapamide maintains efficacy in patients with renal impairment down to eGFR of 30 mL/min/1.73m², though diuretic effects decline as renal function decreases. 1, 2