Thiazide Like Diuretics

Thiazide-like diuretics share the sodium-chloride cotransporter blockade of thiazides but lack the benzothiadiazine ring. They include chlortalidone, indapamide, metolazone and xipamide. Outcome studies in hypertension and after stroke support chlortalidone and indapamide, which makes them the preferred diuretics for blood pressure control.

Mechanism. Blockade of the distal sodium-chloride cotransporter, which increases sodium and chloride excretion and raises potassium and hydrogen ion loss in the collecting duct. Indapamide has additional vasodilator and calcium channel effects. Metolazone also acts at the proximal tubule, which explains its synergy with loop diuretics.

Duration and potency. Chlortalidone has a half-life of 40 to 60 hours and gives more 24-hour blood pressure reduction than hydrochlorothiazide at similar doses. Indapamide has a half-life of about 14 to 18 hours, with sustained-release forms that give 24-hour effect at low dose. Metolazone acts for 12 to 24 hours.

Metabolic profile. Low-dose indapamide has minimal effect on glucose and lipids. Chlortalidone causes more hypokalaemia than hydrochlorothiazide.

Pharmacokinetics. Chlortalidone binds to red cells, which prolongs action. Indapamide is extensively metabolised in the liver with renal elimination of metabolites. Metolazone is partly renally cleared.

• Chlortalidone: hypertension, oedema, long action; outcome data in older adults; effective in advanced chronic kidney disease for blood pressure in some studies.
• Indapamide: hypertension, stroke prevention with an ACE inhibitor; outcome data in patients over 80 years.
• Metolazone: for resistant oedema with a loop diuretic.
• Xipamide: hypertension and oedema.

• Hypertension: chlortalidone 12.5 mg daily, increased to 25 mg; indapamide 1.5 mg sustained release or 2.5 mg each morning.
• After stroke or transient ischaemic attack: indapamide 2.5 mg with perindopril 4 mg daily, increased to 8 mg.
• Oedema in heart failure: chlortalidone 25 to 100 mg daily.
• Resistant oedema: metolazone 2.5 to 5 mg orally once daily or 30 minutes before the loop diuretic dose, for 2 to 3 days, with daily sodium and potassium checks. Maximum 20 mg daily under specialist care.
• Selection: first-line thiazide-like diuretic for hypertension. Use metolazone only with close monitoring because severe hyponatraemia and hypokalaemia are frequent.

Contraindications. Anuria, hyponatraemia, refractory hypokalaemia, hepatic encephalopathy, severe renal failure (indapamide and metolazone, with eGFR under 30 mL/min/1.73 m2 as a usual limit), and history of hypersensitivity to sulphonamide derivatives.

Adverse effects. Hyponatraemia, hypokalaemia, hypomagnesaemia, hypercalcaemia, hyperuricaemia, hyperglycaemia, postural hypotension, rash, and with indapamide, QT prolongation when potassium is low. Metolazone can produce rapid fluid and electrolyte loss.

Interactions. Lithium levels rise. Digoxin toxicity follows hypokalaemia. NSAIDs reduce effect. Corticosteroids and loop diuretics add potassium loss. Torsades de pointes risk rises when indapamide is combined with QT-prolonging drugs.

Monitoring. Sodium, potassium, creatinine and glucose 1 to 2 weeks after starting, then yearly. Daily sodium and potassium during metolazone combinations.

Referral and escalation. Severe hyponatraemia or hypokalaemia with arrhythmia needs hospital care.

Special groups. Older adults: strong benefit but higher hyponatraemia risk, so start at the lowest dose. Pregnancy: avoid. Breastfeeding: avoid at higher doses. Hepatic impairment: use with caution. Diabetes: monitor glucose.