Indapamide

Indapamide is a thiazide like diuretic with a mild direct vasodilator effect, used in hypertension and in stroke prevention after a previous stroke when combined with an angiotensin converting enzyme inhibitor. At the licensed low dose it lowers blood pressure with smaller metabolic effects than higher dose thiazides. It is not used for oedema.

Classification. Thiazide like diuretic (indoline derivative of sulphonamide).

Mechanism. Blocks the sodium chloride cotransporter in the distal convoluted tubule; reduces vascular reactivity to pressor agents and calcium influx into vascular smooth muscle.

Pharmacodynamics. Onset of blood pressure effect within a week, full effect over 8 to 12 weeks; duration 24 hours. Reduces left ventricular mass.

Pharmacokinetics. Almost completely absorbed; bioavailability near 100%. Half life 14 to 18 hours. Extensively metabolised in the liver; about 5% excreted unchanged in urine.

Hypertension, adult.

• 1.5 mg modified release once daily in the morning, or 2.5 mg immediate release once daily.

• Maximum 1.5 mg modified release or 2.5 mg immediate release daily; higher doses add little benefit and cause more electrolyte loss.

Stroke prevention in patients with previous stroke (with perindopril). Indapamide 1.25 mg with perindopril 2 mg once daily, increased after 2 to 4 weeks to indapamide 2.5 mg with perindopril 4 mg once daily; target indapamide 2.5 mg and perindopril 8 mg daily.

Children. Not advised.

Contraindications. Severe kidney impairment (eGFR under 30 mL/min); hepatic encephalopathy or severe hepatic impairment; hypokalaemia; hypersensitivity to sulphonamides.

Warnings. Hyponatraemia (can occur within weeks, especially in older women), hypokalaemia, and QT prolongation. Hypercalcaemia, hyperuricaemia, raised glucose. Photosensitivity. Acute angle closure glaucoma. Non melanoma skin cancer risk with long use.

Adverse effects. Hypokalaemia, hyponatraemia, dizziness, fatigue, rash, muscle cramp, hyperuricaemia, rarely severe skin reactions.

Interactions. Lithium: toxicity. QT prolonging drugs (some antimalarials, macrolides, antipsychotics): torsades risk, especially if potassium is low. Digoxin: hypokalaemia raises toxicity. Corticosteroids and loop diuretics: more potassium loss. Non steroidal anti-inflammatory drugs: reduced effect and kidney injury. Metformin: lactic acidosis if kidney function falls.

Special groups.

• Pregnancy: avoid.

• Breastfeeding: excreted in milk; avoid.

• Patients of African ancestry: good blood pressure response; useful with a calcium channel blocker.

• Older adults: start at the licensed dose; high risk of hyponatraemia, so check sodium early.

• Kidney impairment: avoid at eGFR under 30 mL/min; use with caution at eGFR 30 to 60 mL/min.

• Liver impairment: avoid in severe disease.

Formulations. Tablets 1.25 mg and 2.5 mg (immediate release); modified release 1.5 mg; fixed combinations with perindopril or amlodipine.

Administration. Oral, in the morning with water, with or without food. Swallow modified release tablets whole.

Baseline. Blood pressure, sodium, potassium, calcium, creatinine and eGFR, glucose, urate, ECG if QT prolonging drugs are used.

Monitoring. Sodium, potassium and creatinine 1 to 2 weeks after starting or each dose increase, then every 6 to 12 months. Stop or reduce if sodium falls below 130 mmol/L or potassium below 3.0 mmol/L; correct potassium below 3.5 mmol/L. Blood pressure at 4 weeks.

Stopping. No taper. Hold on sick days with vomiting or diarrhoea.

Common prescribing errors. Using 2.5 mg tablets when a modified release 1.5 mg tablet is intended; combining with QT prolonging antimalarials without a potassium check; using it for oedema; omitting an early sodium check in older women.