Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic used in hypertension and in mild to moderate oedema from heart failure, liver or kidney disease. At low doses it lowers blood pressure with little more diuresis; higher doses add metabolic harm without extra benefit in hypertension. It is cheap and widely available and works well in patients of African ancestry. Many fixed combination tablets contain it.

Classification. Thiazide diuretic (benzothiadiazine); sulphonamide derivative.

Mechanism. Blocks the sodium chloride cotransporter in the distal convoluted tubule, increasing sodium, chloride and water excretion and raising potassium and magnesium loss. It reduces urinary calcium loss. Long term blood pressure effect also involves reduced vascular resistance.

Pharmacodynamics. Diuresis begins within 2 hours, peaks at 4 to 6 hours, and lasts 6 to 12 hours. Blood pressure effect builds over 2 to 4 weeks. Little effect when eGFR is under 30 mL/min.

Pharmacokinetics. Oral bioavailability 60 to 80%. Half life 6 to 15 hours. Not metabolised; excreted unchanged in urine by tubular secretion. Crosses the placenta and enters breast milk.

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 (little added benefit above 25 mg and more metabolic harm).

Oedema (heart failure, cirrhosis, nephrotic syndrome), adult. 25 to 100 mg daily as a single dose or in 2 divided doses, or on alternate days; maximum 200 mg daily for a short time. Reduce to the lowest effective maintenance dose.

Nephrogenic diabetes insipidus and calcium stones (specialist). 25 mg once or twice daily for diabetes insipidus; 25 mg twice daily for stone prevention with high urinary calcium.

Children. 1 to 2 mg/kg daily as a single dose or in 2 divided doses; maximum 37.5 mg daily under 2 years and 100 mg daily from 2 to 12 years. Neonates and infants under 6 months: up to 3 mg/kg daily in 2 divided doses.

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

Warnings. Hyponatraemia (common in older women, can be severe within days), hypokalaemia, hypomagnesaemia, hypercalcaemia, hyperuricaemia and gout, and worsening glucose tolerance. Long term use raises the risk of non melanoma skin cancer, so advise sun protection and skin checks. Acute angle closure glaucoma and acute myopia (within hours to weeks). May precipitate hepatic encephalopathy.

Adverse effects. Dizziness, postural hypotension, hyponatraemia, hypokalaemia, hyperuricaemia, raised glucose and lipids, erectile dysfunction, photosensitivity, rarely pancreatitis or blood dyscrasias.

Interactions. Lithium: levels rise (toxicity). Digoxin: hypokalaemia increases toxicity. Non steroidal anti-inflammatory drugs: reduced effect and kidney injury. Drugs that prolong QT (for example some antimalarials and macrolides): hypokalaemia raises the risk of arrhythmia. Corticosteroids and loop diuretics: more potassium loss. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers: first dose hypotension and kidney injury if volume depleted; useful pairing for blood pressure.

Special groups.

• Pregnancy: avoid for hypertension; may reduce placental perfusion and cause foetal electrolyte disturbance. Used for oedema only if essential.

• Breastfeeding: small amounts in milk; large doses can suppress lactation. Low dose is acceptable.

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

• Older adults: start 12.5 mg daily; high risk of hyponatraemia and falls.

• Kidney impairment: little effect when eGFR is under 30 mL/min; loop diuretic needed; monitor creatinine.

• Liver impairment: small shifts in fluid and electrolytes can trigger encephalopathy; use lowest dose.

Formulations. Tablets 12.5, 25, 50 mg; combinations with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, amiloride or calcium channel blockers.

Administration. Oral, in the morning with or without food, to avoid night time urination.

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

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 2 to 4 weeks. Skin check yearly in long term users.

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

Common prescribing errors. Starting at 50 mg; giving in the evening; combining with lithium; missing hyponatraemia in older patients; continuing it when eGFR falls below 30 mL/min and expecting an effect; omitting sodium and potassium checks.