L11 Clinical Pharmacology Diuretics

Overview

Diuretics are drugs acting directly on the kidney to remove excess extracellular fluid and electrolytes by decreasing salt and water reabsorption in the tubules. The lecture builds from the physiology of nephron Na+ handling (a basolateral Na+/K+ ATPase driving Na+ uptake through segment-specific luminal pathways, with water following through aquaporins) to four drug classes defined by where along the nephron they act: osmotic diuretics in the proximal tubule and other water-permeable segments, loop diuretics in the thick ascending limb, thiazides in the distal convoluted tubule, and K+ sparing diuretics in the late distal tubule and collecting duct. Because the site of action determines both potency and which electrolytes besides Na+ are disturbed, each class’s adverse effects follow directly from its mechanism.

Physiological basis of diuretic action

• The kidneys control extracellular fluid volume by adjusting NaCl and H2O excretion; blood pressure is maintained by maintaining fluid volume.
• The kidney filters more than 22 moles of Na+ per day, so NaCl must be reabsorbed by the renal tubules to keep NaCl balance. (The nephron sites figure gives the filtered load as 170 L H2O and 20 M Na+ per day.)
• If NaCl intake/reuptake exceeds output, for example with RAAS activation, hypertension and oedema develop.
• Na+ reabsorption is driven primarily by the Na+/K+ ATPase on the basolateral (blood side) membrane of epithelial cells throughout the nephron. This energy-requiring pump maintains low intracellular Na+ and high intracellular K+.
• Na+ then enters from the lumen passively down its electrochemical gradient, by cell-specific pathways that differ between segments.
• H2O accompanies reabsorbed ions through aquaporin channels to maintain osmotic balance.
• Worked example of a TAL cell: apical NKCC2 brings in Na+, 2Cl- and K+; apical ROMK returns K+ to the lumen; basolateral Na+/K+ ATPase moves 3Na+ out for 2K+ in; basolateral CLC-K2 moves Cl- to blood.

Nephron sites of action and Na+ handling by segment

Going along the nephron, with the class acting at each site and the share of filtered Na+ handled there:

1. Proximal convoluted tubule: osmotic diuretics. Reabsorbs NaCl (given as 67-40% in the lecture figure; the NEJM figure gives 65-70%), K+, H2O, HCO3- (85%), glucose and amino acids. Secretes creatinine, antibiotics, diuretics and uric acid into the tubule. Carbonic anhydrase inhibitors are labelled here but are not a focus of this lecture.
2. Descending limb: osmotic. Reabsorbs H2O, and further down Mg2+ and Ca2+.
3. Thick ascending limb: loop diuretics. Reabsorbs NaCl 25%, plus K+, H2O, Mg2+ and Ca2+.
4. Early distal convoluted tubule: thiazides. Reabsorbs NaCl (about 10% in the lecture figure, about 5% in the NEJM figure and in the thiazide slides), and Ca2+ under the control of PTH.
5. Late distal tubule: osmotic and K+ sparing. Secretes K+ and urea; reabsorbs NaCl 2-5% under aldosterone, plus H2O.
6. Collecting duct and tubules (1-2% of Na+): K+ sparing diuretics and mineralocorticoid receptor antagonists; reabsorbs H2O under ADH.

Key consequence: once a diuretic reaches the tubular fluid, the nephron site at which it acts determines its effect, and also determines which electrolytes other than Na+ will be affected.

How diuretics reach the tubule

• Mannitol is freely filtered at the glomerulus.
• Other diuretics are highly protein bound and therefore are not filtered.
• The proximal tubule secretes and reabsorbs weak acids and bases through organic anion transporters (OATs), which is how most diuretics get into the tubular fluid.
• This shared transport route is the basis of interactions: thiazides compete with uric acid at OAT, other OAT substrates such as probenecid interfere, and frusemide competes with cephalosporins.

Osmotic diuretics: mannitol

Site: proximal tubule and the remainder of the water-permeable tubule. Given IV.

• Pharmacologically inert but osmotically active.
• Freely filtered at the glomerulus but poorly reabsorbed in the proximal tubule.
• Limits reabsorption of water across water-permeable segments: proximal tubule, thin loop of Henle and collecting duct.
• Greatest effect is in the proximal tubule, where most iso-osmotic water reabsorption occurs. The resulting increase in urine volume promotes natriuresis.

Therapeutic uses

• Primarily emergency reduction of intracranial pressure, by acutely reducing cerebral intravascular volume, for example in head trauma.
• Also listed in the objectives: IV use restricted to acute conditions, including diuresis in acute renal failure.

Toxicity

• Increased extracellular fluid volume, causing pulmonary congestion with fast infusion rates or in renal injury.
• Hypersensitivity reactions.
• Electrolyte loss.
• Headache, nausea and vomiting.

Loop diuretics: frusemide (furosemide)

Site: thick ascending limb of the loop of Henle. Also called high ceiling diuretics. Other examples: torsemide.

Mechanism

• The most potent diuretics available, drawn from a chemically diverse range of compounds.
• Primarily inhibit the luminal NKCC2 (Na+ K+ 2Cl-) co-transporter by competing with Cl- for its binding site.
• NKCC2 in the TAL can reabsorb about 25% of the filtered Na+ load, and downstream nephron segments do not have the reabsorptive capacity to recover that much filtrate, which is why the effect is so large.
• Secondary effect on the paracellular route: the combined activity of apical ROMK and basolateral CLC-K2 normally creates a lumen-positive transepithelial potential difference of about 10 mV that drives paracellular cation reabsorption (Ca2+, Mg2+, Na+, NH4+). Loop diuretics disrupt this positive potential and so increase excretion of Na+, Ca2+ and Mg2+.
• The high Na+ and Cl- load delivered downstream increases loss of H+ and K+ at the distal tubule and collecting ducts, because Na+ is reabsorbed there in exchange for K+ and H+.

Pharmacokinetics of frusemide

• Oral: rapid absorption, maximum effect at 1-2 hours, duration 4-6 hours.
• IV: onset within 2-10 minutes, maximum effect at 30 minutes, duration 2 hours.
• 90% bound to plasma proteins.
• Does not pass directly into the glomerular filtrate; actively secreted into the proximal tubule by organic acid transporters (OAT1). The remainder (35%) is metabolised by glucuronidation and CYP450 mechanisms.
• Dose-response: frusemide keeps climbing steeply with dose to roughly 12-13 mEq Na+/kg/5 hr (the high ceiling effect), whereas hydrochlorothiazide plateaus at about 6 against a control baseline of about 3.

Therapeutic uses

• Hypertension, effective even in patients with impaired renal function.
• Oedema of cardiac, renal or hepatic origin; maintaining renal function in renal failure.
• Acute pulmonary oedema.
• Hyperkalaemia.
• Symptomatic hypercalcaemia.
• Objectives also list frusemide as a volume unloader in CHF, pulmonary oedema and renal failure.

Side effects and interactions

• Hypovolaemia, dizziness, syncope.
• Hyponatraemia from Na+ loss.
• Hypokalaemia from K+ loss, which may predispose to digoxin toxicity.
• Mg2+ and Ca2+ depletion.
• Metabolic alkalosis.
• Hyperuricaemia from uric acid retention, which may precipitate gout.
• Prolonged use: ototoxicity with hearing loss, from loss of endolymph electrolytes.
• Can increase the renal toxicity of cephalosporin antibiotics, because they compete for the weak organic acid transporters of the proximal tubule.

Thiazide and thiazide-like diuretics: bendroflumethiazide

Site: cortical diluting segment of the distal tubule. Other examples: chlorothiazide.

Mechanism

• Mild to moderate diuretics, because the distal tubule only reabsorbs about 5% of filtered Na+.
• Secreted into the tubule in the proximal tubule, then competitively bind the apical electroneutral eNCC-1 (Na+/Cl- co-transporter) and inhibit Na+/Cl- co-transport and reabsorption.
• eNCC-1 is upregulated by aldosterone.
• Produce a modest increase in Na+ and water excretion, and cause K+ loss by the same downstream mechanism as loop diuretics.
• In the same distal tubule cell, Ca2+ enters apically through the CaT channel and leaves basolaterally via NCX1 in exchange for 3Na+, alongside the basolateral Na+/K+ ATPase and a Cl- channel.

Pharmacokinetics

• A diverse family of thiazide and thiazide-like compounds, all inhibiting NCC1 (eNCC1).
• Oral administration with variable absorption.
• Variable elimination kinetics, so half-lives range from hours to days.
• Excreted into the proximal tubule by OAT in competition with uric acid; transport by OAT1 is needed for the drug to work at all, since it must reach the lumen.
• Affected by other drugs competing for OAT, for example probenecid.
• Eliminated mostly renally or by metabolism.

Therapeutic uses

• Oral delivery.
• Hypertension, used with ACE inhibitors/ARBs and calcium channel blockers; effects go beyond volume unloading.
• Effective monotherapy in elderly hypertensives.
• Can be used in renal disease if GFR is maintained.
• Acute pulmonary hypertension.
• Cheap and effective, so often first-line treatment for hypertension.

Haemodynamics over time
Over weeks of thiazide therapy, blood pressure (systolic and diastolic) falls and returns toward baseline after therapy stops. Plasma volume drops at the start of treatment then partially recovers while still on therapy, and cardiac output dips transiently then returns to baseline on treatment. Total peripheral resistance dips then rises. The point is that the initial fall in BP comes from reduced plasma volume and cardiac output, while the sustained antihypertensive effect on treatment is maintained through reduced peripheral resistance even though plasma volume and cardiac output return toward normal.

Adverse effects (usually at high doses)

• Dehydration and postural hypotension, particularly in the elderly: low BP, high HR.
• Hyponatraemia, usually after prolonged use, causing confusion in the elderly. Increased Na+ loss can also lead to Li+ accumulation in patients on lithium.
• Hypokalaemia and metabolic alkalosis, due to increased Na+ delivery to the distal tubule.
• Uric acid retention, which may precipitate gout.
• K+ loss may prolong the QT interval, particularly alongside other QT extenders such as sotalol; watch for torsade de pointes.
• Hyperglycaemia and impaired glucose tolerance.
• Impotence, which is reversible.

K+ sparing diuretics: spironolactone and amiloride

Site: distal tubules and collecting duct, where aldosterone-regulated Na+/K+ ATPase pumps operate. These are weak diuretics but important in attenuating K+ loss.

Aldosterone physiology to recall

• Aldosterone acts on the distal tubules and collecting ducts to increase plasma Na+ and water retention and to decrease plasma K+.
• It synthesises and activates pumps, promoting Na+ reabsorption from the tubule at the expense of K+ loss, that is, it increases the exchange of Na+ for K+.
• Aldosterone increases Na+/K+ pump synthesis.
• The result is increased blood volume, and therefore increased cardiac output and cardiac workload.
• Molecular pathway: aldosterone crosses to the basolateral mineralocorticoid receptor (MR), the MR translocates to the nucleus, mRNA produces aldosterone-induced proteins (AIP), and these act on the apical K+ channel (K+ efflux into the lumen), on apical ENaC (Na+ influx), and on the basolateral Na+/K+ ATPase (3Na+ out, 2K+ in), supported by mitochondrial ATP.

Spironolactone (MR antagonist)

• An aldosterone antagonist acting through an active metabolic product; competitively binds the mineralocorticoid receptor and prevents its translocation, and also works systemically.
• Binds surface receptors on the basolateral side, so it does not require access to the lumen. It is the one exception to the rule that diuretics act from the luminal side.
• Net renal effect: decreases reabsorption of Na+ and water and decreases loss of K+, so it conserves K+.
• Its action depends on aldosterone levels: the higher the aldosterone level, the greater the diuretic effect.
• Classically associated with the cortical collecting tubule, but MR is now found elsewhere in the cardiovascular and renal system.
• Pharmacokinetics: oral, 70% GI absorption, extensive first-pass hepatic metabolism, extensively plasma protein bound, 100% of metabolites appear in urine.
• Toxicity: hyperkalaemia (avoid excessive K+ supplementation in a patient on spironolactone; look for muscle cramps and weakness, heightened T waves, paraesthesia), androgen-modulating effects reducing testosterone effects because of its steroid structure, gynaecomastia, and GI disturbances.

Amiloride (and triamterene)

• Oral delivery.
• Inhibits the apical epithelial Na+ channel (ENaC), the Na+ flux associated with the aldosterone-sensitive Na+ pump, giving effects similar to spironolactone but by blocking the channel rather than the receptor.
• Relatively weak effects on overall Na+ balance.
• Action is complementary to thiazides: it augments Na+ loss while limiting K+ loss.
• Transported into the lumen at the proximal tubule by organic acid transporters, so unlike spironolactone it does need luminal access.
• Objectives describe it as a weak diuretic used to prevent K+ loss.

Therapeutic uses of the class

• Amiloride commonly used with thiazides (Moduretic replaces Amizide).
• Also combined with frusemide when hypokalaemia is an issue.
• Spironolactone can be used in selected patients with ACE inhibitors/ARBs to treat hypertension.
• Spironolactone in hyperaldosteronism, to combat aldosterone-driven Na+ and H2O retention and K+ loss.
• Oedema in CHF and chronic liver failure. Spironolactone is also indicated in CHF and hypertension.

Important

Every diuretic except spironolactone exerts its effect from the luminal side of the nephron, which is why most of them depend on proximal tubular OAT secretion to work.

Pharmacological summary

• The primary therapeutic goal of a diuretic is to reduce oedema by reducing ECF volume, or to treat hypertension (thiazides).
• Diuretics primarily prevent Na+ entry into the tubule cell.
• Once a diuretic enters the tubular fluid, the nephron site at which it acts determines its effect, and also determines which electrolytes other than Na+ will be affected.
• All diuretics except spironolactone exert their effects from the luminal side of the nephron.
• Recurring consequence of blocking upstream Na+ reabsorption: a high Na+ load reaches the distal Na+/K+ exchange sites, driving Na+ reabsorption at the expense of K+ and H+ loss, hence hypokalaemia with metabolic alkalosis for both loop diuretics and thiazides.

In-class quiz template

Three slides are blank quiz templates: a nephron diagram with four coloured boxes to fill in during class, one per site, each asking for drug class, drug, site and mechanism of action. The four sites are PT/Loop (red), TAL (orange), distal (green), and late distal/collecting duct (purple, with two drugs and two mechanisms). No answers are printed on the slides.

Warning

One of the quiz pages (page 38) was transcribed from text extraction only and not rendered as an image, so its exact box colours, arrow layout and diagram labels could not be confirmed; it is assumed to follow the pattern of the other two quiz pages.

Further reading

• Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th edition, Chapter 25 (Access Medicine, University of Otago library database); the manual’s chapter on diuretics is also listed.
• Golan et al, Principles of Pharmacology: The Pathophysiological Basis of Drug Therapy (2008), Chapter 20.
• Attendant reading on Moodle.

Self-test

1. Define a diuretic as the term is used in this lecture, and state the mechanism by which the therapeutic effect is obtained.
2. Explain how Na+ is reabsorbed along the nephron, naming the pump that drives it and describing how Na+ crosses from lumen into the cell.
3. List the four diuretic classes covered, with the nephron site and the transporter or receptor each targets.
4. State the approximate percentage of filtered Na+ reabsorbed at the proximal convoluted tubule, the thick ascending limb, the distal convoluted tubule and the collecting duct.
5. Explain why most diuretics have to be secreted by proximal tubular organic anion transporters, and name one drug that interferes with this.
6. Describe the mechanism of mannitol, including where in the nephron its greatest effect occurs and why.
7. List the toxicities of osmotic diuretics.
8. Describe how frusemide inhibits NKCC2, and explain why loop diuretics are the most potent class available.
9. Explain how loop diuretics increase Ca2+ and Mg2+ excretion, given that they do not act on a Ca2+ or Mg2+ transporter.
10. Predict the acid-base and K+ consequences of blocking Na+ reabsorption in the thick ascending limb, and explain the mechanism.
11. Compare the oral and IV pharmacokinetics of frusemide (onset, maximum effect, duration).
12. List the therapeutic uses of loop diuretics.
13. Explain why a patient on both a loop diuretic and digoxin needs monitoring, and why prolonged high-dose loop diuretic use can affect hearing.
14. Describe the mechanism of bendroflumethiazide, including which transporter it binds and what upregulates that transporter.
15. Explain why thiazides are only mild to moderate diuretics whereas loop diuretics are high ceiling, referring to the dose-response data.
16. Explain how the haemodynamic basis of the thiazide antihypertensive effect changes between the start of therapy and sustained therapy.
17. List the therapeutic uses of thiazides.
18. A 78-year-old on long-term bendroflumethiazide and sotalol presents with confusion, and an ECG shows a prolonged QT with a run of polymorphic VT. Explain the drug-related mechanism.
19. Describe the renal effects of aldosterone and the molecular steps from receptor binding to changed ion transport.
20. Distinguish the mechanism of spironolactone from that of amiloride, including which side of the cell each acts on.
21. Explain why the diuretic effect of spironolactone depends on the patient’s aldosterone level.
22. List the toxicities of spironolactone and explain why gynaecomastia occurs.
23. Explain why amiloride is combined with a thiazide or with frusemide rather than used alone.
24. List the therapeutic uses of K+ sparing diuretics.
25. State the general principle that links a diuretic’s site of action to the electrolyte disturbances it causes, and name the single drug that does not act from the luminal side.
26. Integrative: a patient with CHF is on frusemide and develops hypokalaemia and metabolic alkalosis. Explain the mechanism, and explain how adding spironolactone addresses both the electrolyte problem and the underlying volume state.

Answers

Reveal answers

1. The term is restricted to drugs that have a direct action on the kidney; the therapeutic effect is obtained by removing excess extracellular fluid and electrolytes, through decreased salt and water reabsorption in the tubules.
2. Reabsorption is driven primarily by the Na+/K+ ATPase on the basolateral (blood side) membrane of epithelial cells throughout the nephron, an energy-requiring pump that keeps intracellular Na+ low and K+ high. Na+ then enters from the lumen passively down its electrochemical gradient by cell-specific pathways that differ by segment, and water follows through aquaporins.
3. Osmotic diuretics (mannitol) at the proximal tubule and other water-permeable segments, acting by osmotic force rather than on a transporter; loop diuretics (frusemide) at the thick ascending limb on NKCC2; thiazides (bendroflumethiazide) at the distal tubule on eNCC1; K+ sparing diuretics at the late distal tubule/collecting duct, spironolactone on the mineralocorticoid receptor and amiloride on ENaC.
4. Proximal convoluted tubule 65-70% (the lecture figure gives NaCl 67-40%), thick ascending limb 25%, distal convoluted tubule about 5% (the lecture figure gives about 10%), collecting duct 1-2%.
5. Apart from mannitol, diuretics are highly protein bound and so are not filtered at the glomerulus; they reach the tubular fluid only by proximal tubular secretion of weak acids and bases through organic anion transporters, and all except spironolactone must be in the lumen to act. Probenecid competes for OAT; uric acid competes with thiazides, and cephalosporins compete with frusemide.
6. Mannitol is pharmacologically inert but osmotically active, freely filtered at the glomerulus and poorly reabsorbed in the proximal tubule, so it holds water in the tubule and limits water reabsorption across water-permeable segments (proximal tubule, thin loop of Henle, collecting duct). Its greatest effect is in the proximal tubule because that is where most iso-osmotic water reabsorption occurs; the increased urine volume then promotes natriuresis.
7. Increased extracellular fluid volume with pulmonary congestion at fast infusion rates or in renal injury, hypersensitivity reactions, electrolyte loss, and headache, nausea and vomiting.
8. Frusemide inhibits the luminal NKCC2 co-transporter by competing with Cl- for its binding site. NKCC2 in the TAL can reabsorb about 25% of the filtered Na+ load, and downstream segments lack the reabsorptive capacity to recover that much filtrate, so blocking it produces a very large natriuresis.
9. The combined activity of apical ROMK and basolateral CLC-K2 normally generates a lumen-positive transepithelial potential of about 10 mV, which drives paracellular reabsorption of cations including Ca2+, Mg2+, Na+ and NH4+. Loop diuretics disrupt that positive potential, so paracellular cation reabsorption falls and Ca2+ and Mg2+ excretion rises.
10. A high Na+ and Cl- load is presented downstream to the Na+/K+ exchange sites of the distal tubule and collecting ducts, which reabsorb Na+ at the expense of K+ and H+ loss. The result is hypokalaemia and metabolic alkalosis.
11. Oral: rapid absorption, maximum effect at 1-2 hours, duration 4-6 hours. IV: onset within 2-10 minutes, maximum effect at 30 minutes, duration 2 hours.
12. Hypertension, including in impaired renal function; oedema of cardiac, renal or hepatic origin; maintaining renal function in renal failure; acute pulmonary oedema; hyperkalaemia; symptomatic hypercalcaemia. Also volume unloading in CHF.
13. Loop diuretics cause K+ loss, and hypokalaemia may predispose to digoxin toxicity. Prolonged use causes ototoxicity with hearing loss, attributed to loss of endolymph electrolytes.
14. Bendroflumethiazide is secreted into the tubule at the proximal tubule, then competitively binds the apical electroneutral eNCC-1 Na+/Cl- co-transporter in the cortical diluting segment of the distal tubule, inhibiting Na+/Cl- co-transport and reabsorption. eNCC-1 is upregulated by aldosterone.
15. The distal tubule handles only about 5% of filtered Na+, so the maximum achievable natriuresis is small; the dose-response curve for hydrochlorothiazide plateaus at about 6 mEq Na+/kg/5 hr, whereas frusemide continues to climb to about 12-13, against a control baseline of about 3.
16. At the start of therapy blood pressure falls through a drop in plasma volume and a transient fall in cardiac output. On continued therapy plasma volume partially recovers and cardiac output returns to baseline, yet blood pressure stays lowered, because the sustained effect is maintained through reduced total peripheral resistance.
17. Oral use for hypertension in association with ACE inhibitors/ARBs and calcium channel blockers, with effects beyond volume unloading; effective monotherapy in elderly hypertensives; use in renal disease if GFR is maintained; acute pulmonary hypertension. They are cheap and effective and often first-line for hypertension.
18. Prolonged thiazide use causes hyponatraemia, which produces confusion in the elderly. Thiazide-induced K+ loss prolongs the QT interval, and this is compounded by sotalol as another QT extender, precipitating torsade de pointes.
19. Aldosterone acts on the distal tubules and collecting ducts to increase plasma Na+ and water retention and decrease plasma K+, by synthesising and activating pumps that increase exchange of Na+ for K+, and by increasing Na+/K+ pump synthesis; this raises blood volume and therefore cardiac output and workload. Molecularly, aldosterone binds the basolateral mineralocorticoid receptor, the receptor translocates to the nucleus, mRNA yields aldosterone-induced proteins, and these act on the apical K+ channel, apical ENaC and the basolateral Na+/K+ ATPase.
20. Spironolactone is a competitive aldosterone antagonist that binds the mineralocorticoid receptor on the basolateral (blood) side and prevents its translocation, so it does not need access to the lumen and also acts systemically. Amiloride blocks the apical epithelial Na+ channel ENaC from the luminal side, and must be transported into the lumen at the proximal tubule by organic acid transporters.
21. Spironolactone works only by antagonising aldosterone at the mineralocorticoid receptor, so the more aldosterone signalling there is to block, the greater the diuretic effect; the higher the aldosterone level, the greater the effect.
22. Hyperkalaemia (avoid excessive K+ supplementation; watch for muscle cramps and weakness, heightened T waves, paraesthesia), androgen-modulating effects that reduce testosterone effects, gynaecomastia, and GI disturbances. The androgen and gynaecomastia effects arise from its steroid structure.
23. Amiloride has relatively weak effects on overall Na+ balance, so alone it is a poor diuretic. Its action is complementary to thiazides: it augments Na+ loss while limiting K+ loss, and it is also combined with frusemide when hypokalaemia is a problem.
24. Amiloride with thiazides (Moduretic replaces Amizide); amiloride with frusemide where hypokalaemia is an issue; spironolactone with ACE inhibitors/ARBs in selected hypertensive patients; spironolactone in hyperaldosteronism to combat aldosterone-driven Na+ and water retention and K+ loss; oedema in CHF and chronic liver failure.
25. Diuretics primarily prevent Na+ entry into the tubule cell, and once a diuretic is in the tubular fluid the nephron site at which it acts determines its effect and which electrolytes other than Na+ are affected. Spironolactone is the only one that does not act from the luminal side.
26. Frusemide blocks NKCC2 in the TAL, so a large Na+ and Cl- load reaches the distal tubule and collecting duct, where Na+ is reabsorbed in exchange for K+ and H+, producing hypokalaemia and metabolic alkalosis. Spironolactone blocks the mineralocorticoid receptor driving that distal Na+ for K+ exchange, so it decreases K+ loss while also decreasing Na+ and water reabsorption, adding to volume unloading; it is indicated in CHF and in oedema of CHF, and is combined with frusemide when hypokalaemia is an issue.