What is the appropriate starting dose of indapamide for an adult with essential hypertension, and what are its contraindications, cautions, required monitoring, common adverse effects, drug interactions, and alternative antihypertensive options?

Indapamide for Essential Hypertension

Starting Dose

For adults with essential hypertension, start indapamide at 1.5 mg once daily using the modified-release formulation, which is the preferred option endorsed by current guidelines. 1 Alternatively, the immediate-release formulation can be initiated at 2.5 mg once daily. 1

• The modified-release 1.5 mg formulation delivers a smoother pharmacokinetic profile that avoids unnecessary plasma peak concentrations while maintaining 24-hour efficacy. 2
• Both formulations are taken once daily in the morning due to the drug's approximately 36-hour duration of action. 1
• Indapamide is rapidly and completely absorbed from the gastrointestinal tract, reaching maximal blood levels in approximately 2.3 hours, and food or antacids do not reduce bioavailability. 3

Role in Treatment Algorithm

Indapamide should be considered as first-line therapy in patients aged >55 years when a calcium channel blocker is not suitable due to edema, intolerance, or evidence of heart failure. 1

• For most patients with confirmed hypertension (BP ≥140/90 mmHg), current guidelines recommend initial dual combination therapy rather than monotherapy. 1
• The preferred three-drug combination when step 3 therapy is needed consists of an ACE inhibitor (or ARB) + calcium channel blocker + indapamide. 1
• In black patients of African or Caribbean origin, indapamide should be considered as part of initial combination therapy with a calcium channel blocker. 1
• Do not use indapamide as monotherapy in patients <55 years old without specific contraindications to ACE inhibitors or ARBs, as these are preferred first-line agents in this age group. 1

Contraindications and Cautions

Absolute contraindications:

• Severe renal impairment (though indapamide shows little accumulation even in renal impairment compared to other diuretics). 3
• Severe hepatic dysfunction (hepatic clearance is the dominant route of elimination). 3
• Hypersensitivity to sulfonamide-derived drugs. 3

Use with caution in:

• Patients with history of gout or hyperuricemia. 1
• Elderly patients who have heightened risk of hyponatremia. 4
• Patients with diabetes mellitus, though indapamide has a favorable metabolic profile compared to conventional thiazides. 2, 5

Required Monitoring

Before initiating therapy, obtain:

• Serum electrolytes (sodium, potassium). 1
• Renal function (creatinine, eGFR). 1
• Serum uric acid level. 1

Within 2-4 weeks of initiation or dose escalation, recheck:

• Serum potassium and sodium. 1
• Renal function. 1
• Serum calcium levels. 1
• Uric acid. 1

Monitor particularly for:

• Hypokalemia (though less frequent than with conventional thiazides at usual doses). 5, 6
• Hyponatremia, especially in elderly patients. 4
• Changes in glucose metabolism in diabetic patients, though indapamide does not typically induce deleterious effects on carbohydrate metabolism. 5

Common Adverse Effects

Indapamide is generally well tolerated with mild and rare side effects. 5

• Electrolyte disturbances (hypokalemia, hyponatremia) occur less frequently than with conventional thiazides at standard antihypertensive doses. 5, 6
• Dizziness and headache may occur, particularly during initial therapy. 7
• Fatigue and muscle cramps related to electrolyte changes. 6
• Importantly, long-term administration does not typically induce significant changes in electrolyte balance at the 2.5 mg daily dose, possibly related to its limited diuretic activity at this dose. 5
• No tachyphylaxis has been observed during long-term treatment, nor withdrawal syndrome at discontinuation. 5

Drug Interactions

When combining indapamide with other antihypertensives:

• Indapamide has been successfully combined with beta-blockers, ACE inhibitors, ARBs, and calcium channel blockers. 5, 6
• When initiating combination therapy, consider reducing the usual dose of other agents by 50% initially. 1
• Do not combine with other potassium-depleting agents without careful monitoring of serum potassium. 1

Other significant interactions:

• NSAIDs may reduce the antihypertensive effect. 6
• Lithium clearance may be reduced, increasing lithium toxicity risk. 6
• Corticosteroids may increase potassium loss. 6

Mechanism and Clinical Efficacy

Indapamide has a dual mechanism of action:

• Diuretic effect at the cortical diluting segment of the distal tubules. 3, 2
• Direct vascular effect that decreases vascular reactivity and peripheral vascular resistance. 3, 2, 5

Clinical effectiveness:

• Effectively reduces arterial blood pressure in approximately two-thirds of patients with mild to moderate hypertension. 5
• Blood pressure reduction is rapid in onset (within 1-2 weeks), reaches 65% of maximum by 1 month, and achieves maximum effect after 3-4 months. 5
• Provides 24-hour efficacy with once-daily dosing. 2
• Has been shown to protect against hypertensive target-organ damage in the heart and kidney. 2

Alternative Antihypertensive Options

When indapamide is not suitable, consider:

For patients <55 years or with diabetes/CKD:

• ACE inhibitors or ARBs are preferred first-line agents. 8

For patients >55 years:

• Calcium channel blockers (long-acting dihydropyridines) are an alternative first-line option. 8, 1

Other thiazide-like diuretics:

• Chlorthalidone 12.5-25 mg daily is the preferred thiazide diuretic in many guidelines due to its prolonged half-life and proven cardiovascular disease reduction. 4
• Chlorthalidone has superior 24-hour blood pressure reduction compared to hydrochlorothiazide but carries higher risk of hypokalemia. 4

For resistant hypertension (Step 4):

• Low-dose spironolactone 25 mg once daily if serum potassium <4.6 mmol/L. 8
• Alpha-blockers or beta-blockers if further diuretic therapy is not tolerated or contraindicated. 8

Common Pitfalls to Avoid

• Do not discontinue indapamide automatically when eGFR decreases to <30 mL/min/1.73 m², as it demonstrates effectiveness even in advanced CKD, unlike hydrochlorothiazide. 4
• Do not assume metabolic abnormalities are inevitable—indapamide at standard doses has a favorable metabolic profile and rarely causes significant electrolyte disturbances. 5
• Do not use indapamide as monotherapy in younger patients (<55 years) when ACE inhibitors or ARBs are more appropriate first-line agents. 1
• Do not neglect to check baseline and follow-up electrolytes, particularly in elderly patients who are at higher risk for hyponatremia. 1, 4