Resistant Hypertension Pharmacotherapy

Resistant hypertension is blood pressure over target despite three drugs at maximum tolerated doses, including a long-acting calcium channel blocker, an ACE inhibitor or angiotensin receptor blocker and a thiazide-like diuretic, confirmed by home or ambulatory monitoring. Many cases are apparent resistance from white-coat effect, poor adherence, inadequate doses or interfering substances. True resistance is usually driven by salt retention.

Exclude first. Confirm with ambulatory or home readings, check adherence by pill counts or drug levels where available, use an appropriately sized cuff, and review salt intake.

Interfering substances. NSAIDs, corticosteroids, decongestants, oral contraceptives, ciclosporin, liquorice, khat, cocaine, excess alcohol and some herbal products.

Secondary causes. Primary aldosteronism, renal artery stenosis, chronic kidney disease, obstructive sleep apnoea, phaeochromocytoma and Cushing syndrome.

Optimise the base. Amlodipine 10 mg orally once daily, an ACE inhibitor or angiotensin receptor blocker at full dose (ramipril 10 mg or losartan 100 mg once daily), and chlorthalidone 25 mg or indapamide 2.5 mg orally once daily.

Fourth drug. Spironolactone 25 mg orally once daily, increased to 50 mg daily after 4 weeks if needed. It lowers systolic pressure by about 20 mmHg on average. Check potassium and creatinine at 1 and 4 weeks. Do not start if potassium is over 4.5 mmol/L without close monitoring, or if eGFR is under 30 mL/min/1.73 m2.

If spironolactone is not tolerated. Amiloride 10 mg orally once daily, maximum 20 mg, with the same monitoring; or eplerenone 25 mg orally once daily if gynaecomastia occurs.

Fifth line, usually specialist. Bisoprolol 2.5 to 10 mg once daily, doxazosin 1 mg at night titrated to 4 to 8 mg, clonidine 0.1 mg twice daily (never stop suddenly), hydralazine 25 mg three times daily, or minoxidil 2.5 mg twice daily with a loop diuretic and beta blocker.

Special groups. In pregnancy, none of the mineralocorticoid antagonists is suitable. In older adults, start spironolactone at 12.5 mg. In creatinine clearance under 30 mL/min, use chlorthalidone or a loop diuretic. In hepatic impairment, take care with spironolactone and monitor sodium and potassium weekly for the first month.

Monitoring. Potassium and creatinine at 1 and 4 weeks and after each dose change, then every 3 to 6 months. Stop spironolactone if potassium reaches 6.0 mmol/L, and halve the dose at 5.5 to 5.9 mmol/L.

Aldosterone testing. Measure aldosterone and renin before starting spironolactone where possible, since the test is unreliable on it.

Review. Home pressure at 4 weeks after each change.

Stopping. Taper clonidine over 1 to 2 weeks to avoid rebound hypertension. Reduce drugs gradually if pressure falls under 110 mmHg systolic.

Common errors. Labelling resistance on clinic readings alone, adding more vasodilators without a diuretic, and ignoring NSAID use.

Referral and escalation. Refer to a specialist hypertension service for confirmed resistance on four drugs, suspected secondary causes, or consideration of renal denervation.