What is indapamide?

What is Indapamide

Indapamide is a thiazide-like diuretic (specifically a non-thiazide sulfonamide indoline derivative) used primarily for treating hypertension, with a unique dual mechanism combining diuretic effects and direct vasodilation. 1, 2

Drug Classification and Chemistry

• Indapamide represents the first of a new class of antihypertensive/diuretics called indolines, chemically distinct from traditional thiazides because it lacks the thiazide ring system and contains only one sulfonamide group 2
• The chemical name is 4-Chloro-N-(2-methyl-1-indolinyl)-3-Sulfamoylbenzamide with a molecular weight of 365.84 2
• It is classified as a thiazide-like diuretic rather than a true thiazide due to its structural differences 1

Mechanism of Action

• Indapamide works through a dual mechanism: it inhibits the sodium-chloride transporter in the distal tubule (causing natriuresis and diuresis) while simultaneously producing direct vasodilation that decreases peripheral vascular resistance 1, 3
• The diuretic effect occurs at the cortical diluting segment of the distal tubules, similar to thiazides 3
• Unlike conventional thiazides, indapamide has significant antivasoconstrictive effects that reduce vascular reactivity to calcium and other agonists, contributing substantially to its blood pressure-lowering action 4, 5

Pharmacokinetics

• Indapamide has a longer duration of action (approximately 36 hours) compared to traditional thiazide diuretics, allowing once-daily dosing 1
• Peak blood concentrations occur within 2 hours after oral administration 2
• The drug is preferentially and reversibly taken up by erythrocytes with a whole blood/plasma ratio of 6:1 at peak concentration 2
• 71-79% is reversibly bound to plasma proteins 2
• The half-life in whole blood is approximately 14 hours, with a terminal half-life of excretion of 26 hours 2
• It is extensively metabolized, with only 7% excreted unchanged in urine; 70% of the dose is eliminated renally and 23% via the gastrointestinal tract 2, 3

Clinical Indications

• Primary indication: Treatment of hypertension 1, 2
• Secondary indication: Management of edema 2
• Used in heart failure for controlling sodium and water retention 1
• Recommended as a replacement diuretic in resistant hypertension (step 2 treatment) 1
• Has demonstrated stroke reduction when combined with ACE inhibitors in patients with cerebrovascular disease 1

Dosing

• Standard dosing: 2.5 mg once daily or 1.5 mg modified-release once daily 6
• Usual daily dose ranges from 2.5-5 mg once daily 1
• Initial dosing typically starts at 2.5 mg 1
• Maintains efficacy down to estimated glomerular filtration rates (eGFRs) of 30 mL/min/1.73m² 1
• The 1.5 mg sustained-release formulation provides equivalent efficacy to 2.5 mg immediate-release with improved tolerability 7

Guideline-Recommended Position in Hypertension Management

• Preferred over conventional thiazides: When diuretic treatment is initiated or changed, indapamide (along with chlorthalidone) is preferred over conventional thiazides like bendroflumethiazide or hydrochlorothiazide 6
• Step 1 treatment: For patients aged >55 years or Black patients of any age, if a calcium channel blocker is unsuitable or if heart failure risk exists, indapamide is a first-line option 6
• Step 2 treatment: If blood pressure is not controlled with an ACE inhibitor/ARB plus calcium channel blocker, indapamide should be added 6
• Step 3 treatment: The combination of ACE inhibitor or ARB, calcium channel blocker, and indapamide represents the standard triple therapy 6

Advantages Over Other Diuretics

• Superior cardiovascular outcomes data: Both indapamide and chlorthalidone have substantially more cardiovascular disease risk reduction data than hydrochlorothiazide 8, 9
• Metabolic profile: Indapamide does not induce deleterious effects on carbohydrate and lipid metabolism, unlike some other diuretics 4, 10
• Lower electrolyte disturbance: At the 2.5 mg dose, indapamide produces limited diuretic activity with less frequent significant changes in electrolyte balance compared to higher-dose conventional thiazides 4
• Longer duration of action: The 36-hour duration allows consistent 24-hour blood pressure control with once-daily dosing 1

Important Adverse Effects and Monitoring

• Hypokalemia: At daily doses of 2.5 mg and 5 mg, mean decreases in serum potassium of 0.5 and 0.6 mEq/L respectively can occur 1, 2
• Hyperuricemia: May increase uric acid levels by approximately 1 mg/100 mL 1, 2
• Electrolyte monitoring: Regular monitoring of potassium, sodium, and other electrolytes is recommended, particularly in patients at risk for imbalances 1
• Generally well tolerated with mild and rare side effects 4

Clinical Efficacy

• Effectively reduces blood pressure in approximately two-thirds of patients with mild to moderate hypertension 4
• Blood pressure reduction is rapid in onset (within 1-2 weeks), reaches 65% of maximum effect by 1 month, and achieves maximum reduction after 3-4 months 4
• No tachyphylaxis observed during long-term treatment, and no withdrawal syndrome at discontinuation 4
• Successfully combined with beta-blockers, methyldopa, ACE inhibitors, and other antihypertensive agents with additive effects 2, 4

Common Pitfalls to Avoid

• Do not assume interchangeability with hydrochlorothiazide: Indapamide has a distinct mechanism and longer duration of action that makes it superior for cardiovascular risk reduction 8, 9
• Do not neglect electrolyte monitoring: Despite having a better metabolic profile than some diuretics, potassium monitoring remains essential, especially at higher doses 1
• Do not discontinue in stable patients: For patients already well-controlled on bendroflumethiazide or hydrochlorothiazide, continuation is acceptable, but indapamide should be preferred for new initiations 6