Chlorthalidone

Chlorthalidone is a long acting thiazide like diuretic used in hypertension and in oedema. It is more potent than hydrochlorothiazide at the same milligram dose, has a half life of about 2 days, and gives smooth control of blood pressure through the full 24 hours. It keeps some activity at lower eGFR than other thiazides. It is available in East Africa as a single agent and in combination with azilsartan or atenolol in some markets.

Classification. Thiazide like diuretic (phthalimidine sulphonamide).

Mechanism. Blocks the sodium chloride cotransporter in the distal convoluted tubule; also inhibits carbonic anhydrase weakly and has vasodilator effects.

Pharmacodynamics. Onset within 2 to 3 hours, peak at 2 to 6 hours, diuresis lasts 24 to 72 hours. Blood pressure effect builds over 2 to 4 weeks. Lowers cardiovascular events in hypertension.

Pharmacokinetics. Bioavailability about 65%. Half life 40 to 60 hours. Concentrates in red cells. About 70% excreted unchanged in urine.

Hypertension, adult.

• Start 12.5 mg once daily in the morning.

• Increase to 25 mg once daily after 2 to 4 weeks.

• Maximum 50 mg daily (rarely needed; adverse effects rise steeply).

Oedema, adult. 25 to 100 mg once daily, or 100 to 200 mg on alternate days; maximum 200 mg daily; lowest effective maintenance dose.

Hypertension in advanced chronic kidney disease (eGFR 15 to 30 mL/min), adult. Start 12.5 mg once daily, increase to 25 mg, then 50 mg as needed; monitor potassium and creatinine closely.

Children. Not established; specialist use of 0.5 to 1 mg/kg once daily has been reported.

Contraindications. Anuria; refractory hyponatraemia, hypokalaemia or hypercalcaemia; Addison disease; symptomatic hyperuricaemia or gout flares; hypersensitivity to sulphonamide derived drugs; severe hepatic impairment.

Warnings. Hyponatraemia, hypokalaemia and hypomagnesaemia, more frequent than with hydrochlorothiazide at equal doses; hyperuricaemia and gout; raised glucose; hypercalcaemia. Non melanoma skin cancer risk with long use. Acute angle closure glaucoma. Because the effect lasts for days, adverse effects also persist after stopping.

Adverse effects. Hypokalaemia, hyponatraemia, dizziness, hyperuricaemia, glucose intolerance, erectile dysfunction, photosensitivity, rarely pancreatitis.

Interactions. Lithium: toxicity. Digoxin: hypokalaemia raises toxicity. Non steroidal anti-inflammatory drugs: reduced effect and kidney injury. QT prolonging drugs: hypokalaemia raises arrhythmia risk. Corticosteroids and loop diuretics: more potassium loss. Antidiabetic drugs: higher doses of insulin or oral agents may be needed.

Special groups.

• Pregnancy: avoid for hypertension.

• Breastfeeding: excreted in milk; avoid or use only low doses with infant monitoring.

• Patients of African ancestry: good response as monotherapy; first line with a calcium channel blocker.

• Older adults: start 12.5 mg daily or on alternate days; high risk of hyponatraemia.

• Kidney impairment: effective down to eGFR of about 15 mL/min but needs close monitoring.

• Liver impairment: use the lowest dose; avoid in severe disease.

Formulations. Tablets 12.5, 25, 50 mg; combination with atenolol, azilsartan or other agents in some markets.

Administration. Oral once daily in the morning; if alternate day dosing is used, write the days.

Baseline. Blood pressure, sodium, potassium, calcium, creatinine and eGFR, urate, glucose, history of gout.

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. Skin check yearly in long term users.

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

Common prescribing errors. Giving 50 mg as the start dose; assuming equal milligram potency to hydrochlorothiazide; missing the long half life when adverse effects persist; using it with lithium.