Thiazide Diuretics
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Direct answer
Thiazides (hydrochlorothiazide, chlorthalidone, indapamide) inhibit the sodium-chloride cotransporter in the distal convoluted tubule, producing mild sustained diuresis that makes them first-line antihypertensives with unmatched stroke-prevention data. Beyond blood pressure they treat mild oedema, nephrogenic diabetes insipidus (paradoxical antidiuresis) and calcium kidney stones; their metabolic costs are hypokalaemia, hyponatraemia, hyperuricaemia, hyperglycaemia, hypercalcaemia and dyslipidaemia, which is why gout, significant hyponatraemia and lithium therapy are their classic problem areas.
What you must remember
- Site of action: distal convoluted tubule Na-Cl cotransporter (NCC); onset within 1–2 hours, duration 12–24 hours; efficacy collapses when glomerular filtration rate falls below about 30 mL/min.
- Chlorthalidone 12.5–25 mg outperformed comparators in ALLHAT and has a 40–60 hour half-life; indapamide 1.25–2.5 mg is metabolically neutral.
- Hypokalaemia is dose-related — check potassium at 1–2 weeks; combine with a potassium-sparing agent or ACE inhibitor when it drifts down.
- Thiazides are the commonest cause of drug-induced hyponatraemia, especially in elderly women.
- Hyperuricaemia can precipitate gout — a history of gout is a relative contraindication.
- They worsen glucose tolerance modestly (hypokalaemia reduces insulin secretion) but rarely justify stopping treatment in a diabetic.
- Hypercalcaemia follows increased distal calcium reabsorption — the same mechanism that makes them useful in calcium stone formers.
- Thiazides raise serum lithium by increasing proximal lithium reabsorption — a dangerous interaction in psychiatric patients.
- In nephrogenic diabetes insipidus, volume contraction enhances proximal water reabsorption and paradoxically reduces urine volume.
A typical outpatient problem
A 68-year-old woman started on hydrochlorothiazide 25 mg four weeks ago returns with dizziness; her sodium is 126 mmol/L and she has been drinking her usual tea plus extra water. Manage it as a sequence. First, recognise the syndrome — thiazide hyponatraemia typically appears within the first two to four weeks, in older women, and can be distinguished clinically from syndrome of inappropriate antidiuretic hormone by urine osmolality and urine sodium interpreted together, though overlap exists. Second, stop the thiazide; most cases resolve with fluid restriction over days. Third, avoid rapid correction — the goal is under 8–10 mmol/L in 24 hours, since osmotic demyelination follows overcorrection just as it follows the hyponatraemia itself. Fourth, choose her replacement antihypertensive with the chapter's logic: a calcium channel blocker or an ACE inhibitor, neither of which disturbs sodium. Fifth, use the episode to review the whole thiazide profile — her potassium was 3.3, uric acid at the upper limit, and she had a past gout attack, meaning this drug was always a poor fit. The case compresses every listed adverse effect into one chart and explains why the modern starting dose is 12.5 mg, not 50.
Where students slip
Students routinely call thiazides the diuretics of choice in chronic kidney disease — they are not; below a glomerular filtration rate of about 30 mL/min they fail, and loop diuretics (or metolazone add-on) take over. The second slip is forgetting the two "paradoxical" indications: diabetes insipidus, where a diuretic reduces urine volume, and calcium stones, where a diuretic lowers urinary calcium. The third is the lithium interaction, which appears repeatedly in pharmacology papers as a single-best-answer on rising lithium levels. A smaller mark-loser: thiazides (except chlorthalidone and indapamide being sulfonamide-derived) can cause sulfa allergy cross-reaction — mention it, but do not overstate the clinical risk.
Frequently asked questions
Why are thiazides first-line in hypertension despite weak diuresis?
Their antihypertensive action persists long after diuresis fades through arteriolar dilatation, and trials show unmatched stroke reduction at low cost — the reason guidelines across the world retain them.
Why do thiazides reduce urine volume in diabetes insipidus?
By inducing mild volume depletion they increase proximal sodium and water reabsorption, delivering less filtrate to the diluting segments — a paradoxical antidiuretic effect in both nephrogenic and central types.
Which electrolyte abnormalities follow thiazide therapy?
Hypokalaemia, hyponatraemia, hypomagnesaemia, hypercalcaemia (increased distal calcium reabsorption) and metabolic alkalosis — a pattern opposite to loop diuretics' hypocalcaemia.
When do thiazides stop working as diuretics?
Once glomerular filtration rate falls below roughly 30 mL/min, little drug reaches the distal tubule lumen; switching to a loop diuretic or adding metolazone restores response.
What happens to lithium on a thiazide?
Serum lithium rises because sodium and lithium are handled similarly proximally — the dose of lithium must be reduced and levels monitored, or the interaction causes tremor, confusion and toxicity.