Diuretics and Renal Pharmacology

1. Introduction
2. A Brief Nephron Recap
3. The Six Classes of Diuretic
   • Carbonic Anhydrase Inhibitors
   • Osmotic Diuretics
   • Loop Diuretics
   • Thiazide and Thiazide-Like Diuretics
   • Potassium-Sparing Diuretics
   • ADH Antagonists
4. Clinical Uses of Diuretics
5. Diuretic Resistance
6. Drugs and the Kidney
   • Nephrotoxic Drugs
   • Drugs Needing Dose Adjustment in Renal Impairment
7. Treatment of Hyperkalaemia
8. Summary
9. Drug Summary Table
10. Quiz

• Diuresis is the loss of water; natriuresis is the loss of sodium. Most clinically useful diuretics are natriuretics that drag water out of the body with the sodium they excrete.
• Diuretics are most easily learned by where they act along the nephron. The six classes, in order from the start of the tubule to the end, are:
  • carbonic anhydrase inhibitors: drugs that block an enzyme in the proximal convoluted tubule (PCT, the first part of the tubule);
  • osmotic diuretics: they act in the proximal tubule and the loop of Henle;
  • loop diuretics: they act in the thick ascending limb of the loop of Henle (the hairpin-shaped section of tubule after the PCT);
  • thiazides: they act in the distal convoluted tubule (the tubule after the loop);
  • potassium-sparing diuretics: they act in the collecting duct (the final tubule);
  • ADH antagonists: they also act in the collecting duct, where water is reabsorbed under the control of antidiuretic hormone (ADH).
• In England, furosemide and indapamide were the two most prescribed diuretics by number of prescription items in the 12 months to August 2026 (open data from the NHS Business Services Authority Prescription Cost Analysis). Furosemide is a loop diuretic used to relieve fluid retention (oedema) in heart failure and other conditions. Indapamide is a thiazide-like diuretic used for hypertension. Bumetanide, another loop diuretic, is prescribed far less often than furosemide.
• Several common drugs damage the kidney directly or indirectly. They include NSAIDs (non-steroidal anti-inflammatory drugs such as ibuprofen), ACE inhibitors (angiotensin-converting enzyme inhibitors), aminoglycosides (antibiotics such as gentamicin), vancomycin (another antibiotic) and contrast media (the dye given for CT scans and angiograms). Before prescribing, check the glomerular filtration rate (GFR, how much blood the kidneys filter each minute). Adjust the doses of drugs that the kidneys clear. Both are central to safe prescribing.

Introduction

Diuretics are drugs that increase the volume of urine produced. They are among the oldest and most commonly prescribed medicines in the UK formulary, with applications across cardiology (heart disease), nephrology (kidney disease), hepatology (liver disease) and ophthalmology (eye disease). They are also among the easiest drug classes to learn. Each one targets a specific transporter at a specific point along the nephron. Their effects, indications and side effects all follow logically from where they act.

This article assumes the renal physiology covered in The Nephron and Control of Plasma Volume.

A Brief Nephron Recap

The nephron has four main regions. Osmotic diuretics work by osmotic pull in the water-permeable parts of the proximal tubule and loop of Henle, not at a transporter. The other five classes act at five sites along the nephron, in order (the collecting duct appears twice, once for sodium and once for water):

• Proximal convoluted tubule (PCT): reabsorbs around 65% of filtered Na⁺. Site of action of carbonic anhydrase inhibitors.
• Loop of Henle (thick ascending limb): the hairpin-shaped section of tubule after the PCT. It reabsorbs around 25% of filtered Na⁺ via the Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2), a protein that carries all three ions into the cell together. Site of action of loop diuretics.
• Distal convoluted tubule (DCT): reabsorbs around 5% of filtered Na⁺ via the Na⁺/Cl⁻ cotransporter (NCC). Site of action of thiazides.
• Collecting duct: reabsorbs the final 1-2% of filtered Na⁺ via the epithelial sodium channel (ENaC). It also secretes K⁺ into the urine through potassium channels (ROMK and BK channels), and ENaC provides the driving force for this. Aldosterone (the adrenal hormone that makes the kidney keep sodium and lose potassium) regulates both processes. Site of action of potassium-sparing diuretics.
• Collecting duct (water reabsorption): mediated by aquaporin-2 channels (water channels) under the control of antidiuretic hormone (ADH). Site of action of ADH antagonists.

The further upstream a diuretic acts, the larger the fraction of filtered sodium it can affect. But the downstream tubule has time to take up some of the extra sodium. That is why carbonic anhydrase inhibitors, which act at the proximal tubule, are weak, and loop diuretics are the most powerful class.

Diagram: The nephron, with the site of action of each diuretic class labelled along the tubule from the proximal convoluted tubule (PCT) to the collecting duct.

The Six Classes of Diuretic

Carbonic Anhydrase Inhibitors

Acetazolamide is the prototype (the standard example of the class). It blocks carbonic anhydrase (an enzyme that helps the kidney reabsorb bicarbonate) in the proximal tubule, preventing the reabsorption of bicarbonate and, with it, sodium and water. The diuretic effect is modest because the more distal tubule compensates.

Mechanism: blocks PCT carbonic anhydrase → loss of HCO₃⁻, Na⁺ and water in urine → mild metabolic acidosis (too much acid in the blood, because bicarbonate is lost).

Clinical uses are largely outside diuresis itself:

• Glaucoma (raised pressure inside the eye): reduces production of aqueous humour (the fluid in the front of the eye).
• Acute mountain sickness: the metabolic acidosis stimulates respiration.
• Idiopathic intracranial hypertension (raised pressure around the brain with no known cause): reduces CSF production.

Side effects: metabolic acidosis, hypokalaemia (low blood potassium), paraesthesiae (pins and needles).

Osmotic Diuretics

Mannitol is freely filtered at the glomerulus and poorly reabsorbed (less than 10%). It remains in tubular fluid, retaining water osmotically and reducing water reabsorption through water-permeable tubular segments. Mannitol therefore increases urine output and electrolyte excretion.

Clinical uses:

• Cerebral oedema (brain swelling), for example with raised intracranial pressure (high pressure inside the skull): mannitol pulls water out of brain tissue across the blood-brain barrier (the tight lining of the brain capillaries that limits what passes into the brain).
• Acute glaucoma.

Side effects: pulmonary oedema in the first few minutes after administration as fluid shifts into the vascular space; hypovolaemia (low blood volume) and electrolyte disturbance later.

Contraindications to intravenous mannitol in the British National Formulary (BNF, the standard UK prescribing reference) include severe heart failure, severe pulmonary oedema, severe dehydration and anuria (producing no urine).

Loop Diuretics

Furosemide and bumetanide are the prototypes (the standard examples of the class). They block the Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2) in the thick ascending limb of the loop of Henle. The thick ascending limb is responsible for around a quarter of all sodium reabsorption, so loop diuretics are by far the most powerful diuretics available.

Beyond simple natriuresis, blocking NKCC2 has two further consequences worth knowing:

• The thick ascending limb is impermeable to water but generates the medullary concentration gradient (the high salt concentration deep in the kidney) that drives water reabsorption further down the nephron. Loop diuretics blunt that gradient and reduce the kidney's concentrating ability.
• NKCC2 normally helps create a positive electrical charge in the tubular fluid. This charge drives Ca²⁺ and Mg²⁺ reabsorption through the gaps between cells (the paracellular route). Loop diuretics therefore cause loss of calcium and magnesium as well as sodium and potassium. This can lead to hypocalcaemia (low blood calcium) and hypomagnesaemia (low blood magnesium). In hypercalcaemia (high blood calcium), the Society for Endocrinology says loop diuretics are used only if fluid overload develops, because they are not effective for reducing serum calcium.

Clinical uses:

• Acute and chronic heart failure: the workhorse drug for relieving pulmonary and peripheral oedema.
• Pulmonary oedema (fluid in the lungs) caused by acute heart failure. NICE advises intravenous diuretic therapy for people with acute heart failure.
• Decompensated liver disease (cirrhosis with complications) with ascites (fluid in the abdomen). Spironolactone is the usual first-line diuretic (the one tried first), and a loop diuretic is added if more rapid diuresis is needed.
• Nephrotic syndrome (a kidney condition with heavy protein loss in the urine and low blood albumin) with severe oedema.
• Hypercalcaemia, but only if fluid overload develops after intravenous saline. Loop diuretics are not effective for reducing serum calcium, so saline and then bisphosphonates (drugs that slow bone breakdown, which lowers blood calcium) are the main treatment.
• Resistant hypertension in patients with renal impairment, where thiazides become ineffective.

Side effects are predictable from the mechanism:

• Hypovolaemia and hypotension.
• Hypokalaemia, hypomagnesaemia, hypocalcaemia, hyponatraemia (low blood sodium).
• Metabolic alkalosis (too little acid in the blood), from increased H⁺ loss.
• Hyperuricaemia (raised blood uric acid), which can trigger a gout flare (a painful, inflamed joint).
• Ototoxicity (damage to hearing): rare but increased with rapid IV administration and with co-administered aminoglycosides.

Thiazide and Thiazide-Like Diuretics

Bendroflumethiazide (a true thiazide) and indapamide (a thiazide-like diuretic; chlortalidone is another) block the Na⁺/Cl⁻ cotransporter (NCC) in the distal convoluted tubule.

Two important pharmacological points distinguish them from loop diuretics:

• The DCT reabsorbs only around 5% of filtered sodium, so thiazides are moderate-potency diuretics, not powerful ones. They reach a ceiling effect (a dose above which little extra diuresis is gained) at moderate doses.
• Thiazides increase calcium reabsorption (the mechanism is enhanced Na⁺/Ca²⁺ exchange in the distal tubule). They can therefore cause or worsen hypercalcaemia (high blood calcium). Loop diuretics have the opposite effect on calcium and increase its loss in the urine.

Clinical uses:

• Hypertension: when starting or changing diuretic treatment, NICE prefers a thiazide-like drug such as indapamide to a conventional thiazide such as bendroflumethiazide. NICE sets out hypertension drug treatment in steps. At step 1 the choice depends on age, ethnicity and diabetes. It is usually an ACE inhibitor, an ARB (angiotensin II receptor blocker) or a calcium-channel blocker (CCB, a blood pressure drug such as amlodipine). A thiazide-like diuretic is offered at step 1 if a CCB is not tolerated, for example because of ankle oedema, or if there is evidence of heart failure. At step 3, a thiazide-like diuretic is part of the standard combination with an ACE inhibitor or ARB and a CCB.
• Oedema (fluid retention), including fluid retention in heart failure: the BNF lists oedema as an indication for bendroflumethiazide.
• Idiopathic hypercalciuria (too much calcium in the urine, with no known cause) and recurrent calcium stones (kidney stones). NICE advises considering a thiazide for adults with recurrent stones that are mostly calcium oxalate and who have hypercalciuria, after their sodium intake is restricted to no more than 6 g a day.
• Nephrogenic diabetes insipidus (a condition in which the kidneys do not respond to ADH, so they pass large volumes of dilute urine). The effect is paradoxical: the loss of sodium and water shrinks the blood volume (volume contraction), so the kidney reabsorbs more fluid upstream and passes less urine.

Side effects:

• Hypokalaemia, hyponatraemia, hypomagnesaemia.
• Hypercalcaemia.
• Hyperuricaemia: can precipitate gout.
• Hyperglycaemia (high blood glucose) and worsening control of blood glucose in diabetes.
• Hyperlipidaemia (raised blood cholesterol and other fats).
• Erectile dysfunction.

The rule of thumb is that thiazides cause "hypos and hypers": hypokalaemia, hyponatraemia, hypomagnesaemia; hypercalcaemia, hyperuricaemia, hyperglycaemia, hyperlipidaemia.

Potassium-Sparing Diuretics

Two subtypes act on the late distal tubule and collecting duct, both reducing Na⁺ reabsorption without driving K⁺ excretion. They are weak diuretics on their own but are useful in combination with thiazides or loop diuretics, both for added diuresis and to offset hypokalaemia.

Aldosterone antagonists (mineralocorticoid receptor antagonists, MRAs): drugs that block the receptor that aldosterone acts on.

• Spironolactone: the most widely used. Blocks the mineralocorticoid receptor, so aldosterone can no longer switch on the production (expression) of ENaC and the Na/K ATPase pump (the sodium-potassium pump, a protein that uses energy to move sodium out of the cell and potassium in).
• Eplerenone: more selective for the mineralocorticoid receptor, fewer endocrine side effects.

ENaC blockers:

• Amiloride: directly blocks the epithelial sodium channel.
• Triamterene: same mechanism, less commonly used in the UK.

Clinical uses:

• Heart failure: spironolactone and eplerenone reduce mortality in HFrEF (heart failure with reduced ejection fraction). In HFrEF the left ventricle ejects a smaller proportion of its blood with each beat than normal. HFrEF is covered in Hypertension and Heart Failure.
• Resistant hypertension (blood pressure that stays high despite three blood pressure drugs, one of them a thiazide-like diuretic): NICE advises considering low-dose spironolactone as the fourth drug (step 4). This is for people whose blood potassium is 4.5 millimoles per litre (mmol/L) or lower. If the blood potassium is higher than 4.5 mmol/L, NICE advises considering an alpha-blocker or beta-blocker (drugs that block the receptors that adrenaline acts on) instead. Sodium, potassium and renal function are checked within 1 month of starting spironolactone.
• Primary hyperaldosteronism (Conn's syndrome): a disorder of the adrenal gland in which too much aldosterone is made.
• Decompensated liver disease with ascites: spironolactone is first-line because the body makes extra aldosterone in cirrhosis (secondary hyperaldosteronism), which makes the kidney hold on to sodium.
• Lithium-induced nephrogenic diabetes insipidus (the kidney stops responding to ADH in a patient taking lithium, a mood-stabilising drug): amiloride blocks the channel through which lithium enters collecting duct cells.

Side effects:

• Hyperkalaemia (high blood potassium), particularly when combined with ACE inhibitors, ARBs or NSAIDs. This is the most important caution when prescribing these drugs.
• Gynaecomastia (breast tissue growth in men) with spironolactone, because it also blocks androgen (male sex hormone) receptors. Eplerenone is less likely to cause it, but the BNF lists gynaecomastia as an uncommon side effect of eplerenone.
• Menstrual irregularities in women on spironolactone.

ADH Antagonists

Antidiuretic hormone (ADH) drives water reabsorption from the collecting duct via aquaporin-2 channels. The principles are explained in Control of Plasma Osmolarity. Drugs that block this action produce a free-water diuresis: the kidney loses water without losing significant sodium.

• Tolvaptan: a vasopressin V₂ receptor antagonist (it blocks the V₂ receptor on collecting duct cells that ADH, also called vasopressin, normally acts on). It is licensed for hyponatraemia (low blood sodium) caused by SIADH (the syndrome of inappropriate antidiuretic hormone secretion, in which too much ADH is released). It is started in hospital or under specialist supervision, and the sodium is monitored closely because correcting it too fast can cause serious neurological harm. It is also used to slow the progression of autosomal dominant polycystic kidney disease (ADPKD, an inherited condition in which cysts enlarge the kidneys). NICE recommends it for ADPKD only if chronic kidney disease is stage 2 or 3 at the start and the disease is progressing rapidly. Liver function must be monitored.
• Lithium (a mood-stabilising drug): not licensed as a diuretic, but it can cause nephrogenic diabetes insipidus as a side effect. It does this by reducing the number of aquaporin-2 channels (downregulation), so the kidney cannot concentrate urine. It is the classical example of a drug that is "diuretic but not natriuretic", meaning it increases water loss without increasing sodium loss.

Demeclocycline (a tetracycline antibiotic) can also be used for hyponatraemia caused by SIADH, if fluid restriction alone does not restore the sodium concentration or is not tolerable. Demeclocycline is thought to act by blocking the effect of ADH on the kidney tubule. In renal impairment it should be avoided unless the potential benefit outweighs the risk, because it can accumulate.

Clinical Uses of Diuretics

The clinical role of each class can be summarised by the standard indications:

• Hypertension: prefer a thiazide-like drug such as indapamide when a diuretic is started or changed; this is not a universal step 1 choice. Consider low-dose spironolactone for resistant hypertension if the blood potassium is 4.5 mmol/L or lower.
• Heart failure with reduced ejection fraction (the heart pumps out too small a proportion of its blood with each beat): a loop diuretic (furosemide) relieves congestion and fluid retention. NICE advises offering four drug groups together. They are an ACE inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist (MRA, such as spironolactone or eplerenone) and an SGLT2 inhibitor (sodium-glucose cotransporter-2 inhibitor, such as dapagliflozin or empagliflozin).
• Pulmonary oedema from acute heart failure: intravenous furosemide.
• Liver disease with ascites: spironolactone first; loop diuretic added if needed.
• Nephrotic syndrome: high-dose loop diuretic, sometimes given intravenously because oral absorption is reduced.
• Chronic kidney disease: a loop diuretic is used. Thiazides usually work poorly once the estimated glomerular filtration rate (eGFR) falls below around 30 mL/min: the BNF says bendroflumethiazide and indapamide are ineffective when the creatinine clearance is below 30 mL/min. However, chlortalidone still lowered blood pressure in a trial in stage 4 chronic kidney disease, and a thiazide can still be added to a loop diuretic (see Diuretic Resistance). Potassium-sparing agents carry a high risk of hyperkalaemia in renal impairment, so monitor the blood potassium closely. The BNF advises avoiding spironolactone and amiloride in severe renal impairment.
• Hyponatraemia (low blood sodium) caused by SIADH: fluid restriction is the mainstay of treatment. Tolvaptan is a specialist option, started in hospital or under specialist supervision. The sodium is monitored closely because correcting it too fast can cause osmotic demyelination (serious damage to nerve cells in the brain).
• Hypercalcaemia: intravenous saline first, then bisphosphonates if needed. A loop diuretic is used only if fluid overload develops.
• Cerebral oedema: mannitol.
• Glaucoma and idiopathic intracranial hypertension: acetazolamide.

Diuretic Resistance

Patients with severe heart failure, nephrotic syndrome or advanced CKD often appear to "stop responding" to standard doses of furosemide. Several mechanisms contribute:

• Furosemide is highly bound to albumin in the blood. It reaches its site of action by being secreted into the proximal tubule by organic anion transporters (proteins in the tubule wall that carry acidic drugs from the blood into the tubular fluid), not by glomerular filtration. Anything that interferes with this transport reduces the amount of drug that reaches the tubule. Examples are reduced renal blood flow in heart failure and fewer functioning nephrons in CKD.
• Hypoalbuminaemia (low blood albumin) in nephrotic syndrome may reduce the amount of furosemide carried to the kidney, because furosemide travels bound to albumin. How much this matters is not settled: trials of albumin infusion have given conflicting results. Enzymes in the urine called serine proteases may also activate ENaC and so increase sodium reabsorption in the collecting duct.
• Gut wall oedema in heart failure reduces oral absorption; intravenous administration bypasses this.
• Distal nephron remodelling (structural changes in the later part of the nephron) with chronic loop diuretic use increases sodium reabsorption downstream, blunting net diuresis. Adding a thiazide or thiazide-like agent to a loop diuretic ("sequential nephron blockade") can overcome this.
• High dietary salt intake simply replaces sodium as fast as it is excreted.

Preview the Diuretics and Renal Pharmacology quiz