Diuretics and Renal Pharmacology

Core

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, nephrology, hepatology and ophthalmology. They are also among the easiest drug classes to learn, because each one targets a specific transporter at a specific point along the nephron, and 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 five distinct regions and the diuretics map onto them in order:

• Proximal convoluted tubule (PCT): reabsorbs around 65% of filtered Na⁺. Site of action of carbonic anhydrase inhibitors.
• Loop of Henle (thick ascending limb): reabsorbs around 25% of filtered Na⁺ via the Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2). 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) and excretes K⁺ via aldosterone-driven Na/K ATPase. Site of action of potassium-sparing diuretics.
• Collecting duct (water reabsorption): mediated by aquaporin-2 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 compensate, so upstream diuretics are not necessarily the most potent.

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. It blocks carbonic anhydrase 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.

Clinical uses are largely outside diuresis itself:

• Glaucoma: reduces aqueous humour production.
• Acute mountain sickness: the metabolic acidosis stimulates respiration.
• Idiopathic intracranial hypertension: reduces CSF production.

Side effects: metabolic acidosis, hypokalaemia, paraesthesiae.

Osmotic Diuretics

Mannitol is filtered at the glomerulus but not reabsorbed. It draws water osmotically into the tubular lumen along the entire nephron, producing a predominantly water diuresis (although some sodium is also lost as the osmotic flow drags solutes with it).

Clinical uses:

• Cerebral oedema (e.g. raised intracranial pressure): mannitol pulls water out of brain tissue across the blood-brain barrier.
• Acute glaucoma.

Side effects: pulmonary oedema in the first few minutes after administration as fluid shifts into the vascular space; hypovolaemia and electrolyte disturbance later. Contraindicated in heart failure and anuria.

Loop Diuretics

Furosemide and bumetanide are the prototypes. 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 that drives water reabsorption further down the nephron. Loop diuretics blunt that gradient and reduce the kidney's concentrating ability.
• NKCC2 normally drives a paracellular potential that drives Ca²⁺ and Mg²⁺ reabsorption. Loop diuretics therefore cause loss of calcium and magnesium as well as sodium and potassium: useful in hypercalcaemia, but a known cause of hypocalcaemia and hypomagnesaemia.

Clinical uses:

• Acute and chronic heart failure: the workhorse drug for relieving pulmonary and peripheral oedema.
• Pulmonary oedema in any setting.
• Decompensated liver disease with refractory ascites (usually combined with spironolactone).
• Nephrotic syndrome with severe oedema.
• Hypercalcaemia (after volume resuscitation).
• 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.
• Metabolic alkalosis (from increased H⁺ loss).
• Hyperuricaemia (gout flare).
• Ototoxicity: 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 at moderate doses.
• Thiazides increase calcium reabsorption (the mechanism is enhanced Na⁺/Ca²⁺ exchange in the distal tubule). They therefore cause hypercalcaemia, in contrast to the hypocalcaemia of loop diuretics.

Clinical uses:

• Hypertension: first-line as part of NICE step 3 of the A-C-D algorithm. NICE prefers thiazide-like (indapamide, chlortalidone) over thiazide (bendroflumethiazide).
• Mild heart failure with preserved renal function.
• Idiopathic hypercalciuria and recurrent calcium stones.
• Nephrogenic diabetes insipidus (paradoxical effect via volume contraction).

Side effects:

• Hypokalaemia, hyponatraemia, hypomagnesaemia.
• Hypercalcaemia.
• Hyperuricaemia: can precipitate gout.
• Hyperglycaemia and worsening glycaemic control in diabetes.
• Hyperlipidaemia.
• 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):

• Spironolactone: the most widely used. Blocks the mineralocorticoid receptor, preventing aldosterone-driven ENaC and Na/K ATPase expression.
• 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 (covered in Hypertension and Heart Failure).
• Resistant hypertension: spironolactone is the standard fourth-line agent.
• Primary hyperaldosteronism (Conn's syndrome).
• Decompensated liver disease with ascites: spironolactone is first-line because secondary hyperaldosteronism is part of the pathophysiology.
• Lithium-induced nephrogenic diabetes insipidus: amiloride blocks the channel through which lithium enters collecting duct cells.

Side effects:

• Hyperkalaemia, particularly when combined with ACE inhibitors, ARBs or NSAIDs. The most important pharmacological caveat.
• Gynaecomastia (spironolactone, because of off-target androgen receptor blockade). Eplerenone avoids this.
• Menstrual irregularities in women on spironolactone.

ADH Antagonists

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

• Tolvaptan: a vasopressin V₂ receptor antagonist. Used for hyponatraemia (especially SIADH) and to slow progression in autosomal dominant polycystic kidney disease.
• Lithium: not licensed as a diuretic, but produces nephrogenic diabetes insipidus as a side effect via downregulation of aquaporin-2. The classical example of a drug that is "diuretic but not natriuretic".

Demeclocycline (a tetracycline) has historically been used for hyponatraemia in SIADH but has been largely replaced by tolvaptan.

Clinical Uses of Diuretics

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

• Hypertension: thiazide-like diuretics (indapamide) first; spironolactone for resistant disease.
• Heart failure with reduced ejection fraction: loop diuretic (furosemide) for symptoms; spironolactone or eplerenone for prognosis; SGLT2 inhibitor for additional benefit.
• Pulmonary oedema: 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: loop diuretic (thiazides become ineffective once eGFR falls below around 30 mL/min). Avoid potassium-sparing agents because of hyperkalaemia risk.
• Hyponatraemia: tolvaptan in SIADH.
• Hypercalcaemia: loop diuretic after fluid resuscitation.
• 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, all worth understanding:

• Furosemide is highly bound to albumin and reaches its tubular site of action by being secreted into the proximal tubule via organic anion transporters, not by glomerular filtration. Anything that competes with this transport; reduced renal blood flow in heart failure, reduced functioning nephrons in CKD; reduces drug delivery.
• Hypoalbuminaemia in nephrotic syndrome reduces the carrier for furosemide, again limiting tubular delivery.
• Gut wall oedema in heart failure reduces oral absorption; intravenous administration bypasses this.
• Distal nephron remodelling 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.

Drugs and the Kidney

Nephrotoxic Drugs

Some drugs cause direct damage to the kidney; others reduce its function indirectly. The distinction matters because direct nephrotoxins damage previously healthy kidneys, while indirect agents are usually only problematic in patients whose kidneys are already vulnerable.

Direct (true) nephrotoxins:

• Aminoglycosides (gentamicin, amikacin): classical proximal tubular toxicity. The MHRA recommends therapeutic drug monitoring.
• Vancomycin.
• Aciclovir: crystal nephropathy if dehydrated.
• Iodinated contrast media, particularly in pre-existing CKD.
• Cisplatin.
• Tenofovir.

Drugs that worsen renal function indirectly (especially in established renal disease, dehydration or sepsis):

• NSAIDs: reduce prostaglandin-mediated afferent arteriolar dilation.
• ACE inhibitors and ARBs: reduce angiotensin II-mediated efferent arteriolar constriction. Particularly hazardous in bilateral renal artery stenosis.
• Diuretics: volume depletion.
• Metformin: not directly nephrotoxic, but accumulates and can cause lactic acidosis if eGFR falls below 30 mL/min.

The combination of NSAID + ACE inhibitor + diuretic ("the triple whammy") in a dehydrated or septic patient is a recurring cause of preventable acute kidney injury.

Drugs Needing Dose Adjustment in Renal Impairment

Many drugs require dose reduction in renal impairment, with the BNF as the standard reference. The general principles are:

• Avoid direct nephrotoxins where possible.
• Reduce dose or extend interval for renally cleared drugs: aminoglycosides, vancomycin, low-molecular-weight heparins, digoxin, lithium, methotrexate, gabapentin, opioids (morphine, codeine).
• Avoid drugs that accumulate in renal failure: metformin (if eGFR < 30), nitrofurantoin (if eGFR < 45), tetracyclines (except doxycycline).
• Use Cockcroft-Gault rather than eGFR for narrow-therapeutic-index drugs (digoxin, gentamicin, vancomycin), as recommended in the BNF.

Treatment of Hyperkalaemia

Severe hyperkalaemia is a medical emergency because of the risk of fatal arrhythmias (peaked T waves, broadened QRS, sine-wave pattern, asystole). The management has three pharmacological steps, taught at pre-clinical level as "protect, shift, remove":

Hyperkalaemia: protect, shift, remove

Protect the heart: intravenous calcium gluconate stabilises the cardiac membrane (no effect on potassium itself).

Shift potassium into cells: intravenous insulin with dextrose, plus nebulised salbutamol.

Remove potassium from the body: volume resuscitation and a loop diuretic; oral potassium binders (sodium zirconium cyclosilicate, patiromer; calcium polystyrene sulfonate is older and now second-line); haemodialysis if refractory.

The shift therapies act within minutes but are temporary; potassium will re-emerge unless removed. Renal physicians or critical care should be involved early in any patient with K⁺ > 6.5 mmol/L or with ECG changes.

Summary

• Diuretics are best learned by their site of action along the nephron: PCT (CAIs), loop (loop diuretics), DCT (thiazides), collecting duct (potassium-sparing and ADH antagonists).
• Loop diuretics (furosemide) are the most powerful class: the workhorse for symptomatic heart failure, pulmonary oedema, ascites and severe oedema.
• Thiazide-like diuretics (indapamide) are first-line for hypertension. They cause "hypos and hypers": hypokalaemia, hyponatraemia, hypomagnesaemia; hypercalcaemia, hyperuricaemia, hyperglycaemia, hyperlipidaemia.
• Potassium-sparing diuretics (spironolactone, eplerenone, amiloride) are used in heart failure, resistant hypertension and primary hyperaldosteronism. The major risk is hyperkalaemia.
• Direct nephrotoxins (aminoglycosides, vancomycin, NSAIDs, contrast) and indirect agents (ACE inhibitors, diuretics, NSAIDs) commonly cause AKI; the "triple whammy" of NSAID, ACE inhibitor and diuretic is a recurring cause.
• Hyperkalaemia management is "protect, shift, remove": calcium gluconate, insulin/dextrose with salbutamol, then diuresis or potassium binders.

Drug Summary Table

The diuretics in nephron order.

Reviewed by: Dr. Marcus Judge

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