Thiazide Diuretics

Thiazide diuretics block the sodium-chloride cotransporter in the distal convoluted tubule, causing mild natriuresis and a lasting fall in blood pressure. They also reduce urinary calcium excretion. They are used in hypertension, mild oedema, hypercalciuric stones and nephrogenic diabetes insipidus.

Members. Hydrochlorothiazide, bendroflumethiazide, chlorothiazide (intravenous), cyclopenthiazide and hydroflumethiazide (obsolete).

Mechanism. Blockade of the luminal sodium-chloride cotransporter increases delivery of sodium to the collecting duct, which increases potassium and hydrogen secretion and so causes hypokalaemia and metabolic alkalosis. Calcium reabsorption rises, so calcium excretion falls. Magnesium wasting occurs and urinary dilution is impaired, which can cause hyponatraemia. Long-term blood pressure lowering is attributed to lower peripheral resistance after the initial volume loss.

Dose response. Blood pressure lowering is flat over about 25 mg of hydrochlorothiazide or 2.5 mg of bendroflumethiazide, while metabolic effects rise with dose.

Pharmacokinetics. Absorbed orally and eliminated unchanged by the kidney. Hydrochlorothiazide has a half-life of 6 to 15 hours and bendroflumethiazide acts for 12 to 18 hours. Action depends on a filtered load, so efficacy falls when eGFR is low.

• Hydrochlorothiazide: widely used, often in fixed combinations with ACE inhibitors or angiotensin receptor blockers.
• Bendroflumethiazide: used mainly in the United Kingdom and some former colonies for hypertension and oedema.
• Chlorothiazide: intravenous option when oral absorption is limited.
• Cyclopenthiazide: low-dose alternative.

• Hypertension: hydrochlorothiazide 12.5 to 25 mg once daily (maximum 50 mg); bendroflumethiazide 2.5 mg each morning.
• Mild oedema: hydrochlorothiazide 25 to 100 mg daily; bendroflumethiazide 5 to 10 mg each morning.
• Hypercalciuric kidney stones: hydrochlorothiazide 12.5 to 50 mg daily with a low-salt diet.
• Nephrogenic diabetes insipidus: hydrochlorothiazide 25 to 50 mg daily, often with amiloride, with a low-sodium diet.
• Selection: thiazide-like drugs are preferred for blood pressure because of stronger outcome data. Hydrochlorothiazide remains acceptable at low dose or in combinations.

Contraindications. Anuria, refractory hypokalaemia, hyponatraemia, hypercalcaemia, symptomatic hyperuricaemia with gout, Addison disease, and severe renal or hepatic impairment (relative).

Adverse effects. Hyponatraemia (older women, low body weight, sometimes severe within weeks), hypokalaemia, hypomagnesaemia, hypercalcaemia, hyperuricaemia and gout, new-onset diabetes or worsening glucose, erectile dysfunction, photosensitivity, pancreatitis and interstitial nephritis. Long-term hydrochlorothiazide use is linked with non-melanoma skin cancer, so advise sun protection and skin checks. A sulphonamide-related reaction can cause acute myopia with angle-closure glaucoma.

Interactions. Lithium toxicity. Digoxin toxicity with hypokalaemia. NSAIDs reduce effect. Corticosteroids and loop diuretics increase potassium loss. Carbamazepine and other hyponatraemia-inducing drugs add risk. Torsades risk with QT-prolonging drugs when potassium is low. Allopurinol hypersensitivity is more likely.

Monitoring. Sodium, potassium, calcium, creatinine and glucose 1 to 2 weeks after starting and at least yearly. Check sodium early in older adults.

Referral and escalation. Severe hyponatraemia (under 125 mmol/L) with confusion, seizures or vomiting requires hospital care.

Special groups. Pregnancy: not used for gestational hypertension or oedema. Breastfeeding: high doses can suppress lactation. Older adults: higher risk of hyponatraemia and falls. Diabetes and gout: use with monitoring. Renal impairment: reduced effect when eGFR is under 30 mL/min/1.73 m2.