What is the mechanism of action of indapamide (thiazide-like diuretic)?

Mechanism of Action of Indapamide

Indapamide works through a dual mechanism of action: it primarily inhibits the sodium-chloride transporter in the distal tubule of the kidney and also has direct vascular effects through calcium channel antagonist-like properties. 1, 2

Primary Mechanism: Renal Effects

• Indapamide is classified as a thiazide-like diuretic, specifically a non-thiazide sulfonamide diuretic, that acts at the cortical diluting segment of the distal tubules 3, 2
• It inhibits the sodium-chloride transporter in the distal tubule, leading to increased sodium and chloride excretion (natriuresis) 4
• This natriuretic effect results in water excretion and reduction of intravascular volume, contributing to its antihypertensive properties 4
• The diuretic-induced natriuresis causes upregulation of the epithelial sodium channel (ENaC), which is aldosterone-sensitive 4
• Enhanced ENaC activity increases cortical collecting tubule acid secretion, which can cause metabolic alkalosis 4

Secondary Mechanism: Vascular Effects

• Unlike traditional thiazides, indapamide has additional direct vascular effects that contribute to its antihypertensive efficacy 2, 5
• It shows an alteration in vascular reactivity to calcium and other agonists, suggesting direct vascular action 2
• These calcium antagonist-like vasorelaxant activities help maintain its long-term antihypertensive efficacy 5, 6
• Hemodynamic studies show indapamide significantly decreases total peripheral resistance (15%) in addition to its diuretic effects 2

Pharmacokinetic Properties

• Indapamide is rapidly and completely absorbed from the gastrointestinal tract, with peak blood concentrations occurring approximately 2 hours after administration 1, 2
• It has a long duration of action (approximately 36 hours) compared to traditional thiazide diuretics 3, 1
• The drug is extensively metabolized by the liver with only about 7% excreted unchanged in urine 1, 2
• It has a terminal half-life of approximately 14-16 hours in whole blood 1, 2
• Indapamide is preferentially taken up by erythrocytes with a whole blood/plasma ratio of approximately 6:1 at peak concentration 1
• Approximately 76% of indapamide in plasma is reversibly bound to plasma proteins 1, 2

Clinical Implications

• At therapeutic doses (2.5-5 mg daily), indapamide causes a mean decrease in serum potassium of 0.5-0.6 mEq/L 1, 3
• It may increase uric acid levels by approximately 1 mg/100 mL 1, 3
• Unlike some diuretics, indapamide has little or no effect on glomerular filtration rate or renal plasma flow in hypertensive patients 1
• It maintains efficacy in patients with varying degrees of renal impairment, although diuretic effects generally decline as renal function decreases 1

Unique Features Compared to Traditional Thiazides

• Indapamide has a longer duration of action (36 hours) than most traditional thiazide diuretics 3, 4
• It demonstrates minimal adverse effects on glucose and lipid metabolism compared to conventional thiazides 5, 6
• The sustained-release formulation provides smoother pharmacokinetics, avoiding unnecessary plasma peak concentrations that may be associated with side effects 6
• It has been shown to be effective in protecting against hypertensive target-organ damage in the heart and kidneys 6

Understanding indapamide's dual mechanism of action explains why it remains effective as an antihypertensive agent even at doses that produce minimal diuresis, making it a valuable option for treating hypertension and edema.