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L13 Clinical Pharmacology Diuretics

Overview

This lecture works through the three main diuretic classes — loop diuretics, thiazides and the K⁺-sparing agents (MRAs and ENaC blockers) — in terms of where each acts along the nephron, how it works at the molecular level, what it is used for, and what goes wrong with it. A recurring theme is that a diuretic only works if Na⁺ reaches its tubular site of action, so as renal function falls the drug of choice changes (thiazides give way to loop diuretics and combinations). The deck then develops two applied themes: diuretic use across worsening CKD (the NKF/KDOQI staging), and diuretics in chronic heart failure including the cardiorenal continuum, diuretic resistance and its correction, the newer role of SGLT2 inhibitors and finerenone, and the all-or-none dosing behaviour of loop diuretics. The final third of the file (slides 47–55) reproduces a BMJ “Uncertainties” practice article on how to prescribe loop diuretics in oedema, which supplies the practical dosing detail.

General principles of diuretic action

  • A diuretic generally acts only if Na⁺ reaches its site of action, and the magnitude of the effect depends on the amount of Na⁺ reaching that site.
  • Because the classes act at different nephron segments, co-administering them produces synergism — there is value in combination therapy.
  • All diuretics except spironolactone act from the luminal (apical) side of the tubular cell membrane. Spironolactone is the exception (it binds a basolateral/intracellular receptor).

Important

The single most important determinant of whether a diuretic “works” is how much filtered Na⁺ is delivered to its target transporter. This is why low GFR (less Na⁺ reaching the distal nephron) blunts weaker, distally-acting diuretics and forces a shift to loop diuretics.

The deck maps the sites of action onto the nephron (slide 6, adapted from Ellison CJASN 2019):

  • Proximal tubule — carbonic anhydrase inhibitors (CAI) act here (Na⁺ reabsorbed with HCO₃⁻ via the H₂CO₃ → CO₂ + H₂O reaction).
  • Thick ascending limb (TAL) — loop diuretics (LD) block the apical Na⁺/K⁺/2Cl⁻ cotransporter.
  • Distal tubule (DCT) — thiazides (Tz) block the apical Na⁺/Cl⁻ cotransporter.
  • Connecting tubule / collecting duct — amiloride (Aml, and triamterene) block ENaC; spironolactone (Sp) blocks the mineralocorticoid receptor (MR), which is acted on by aldosterone (Aldo).

Drug-class examples to know: Loop = frusemide (furosemide). Thiazide = bendroflumethiazide (also chlorothiazide). K⁺-sparing = spironolactone (MRA) and amiloride (ENaC blocker).

Diuretic choice across renal disease (NKF/KDOQI staging)

The goals of diuretic therapy in renal disease are to reduce ECF volume expansion and oedema (loop diuretics), reduce the possible risk of hyperkalaemia, and drop blood pressure (mainly thiazides).

CKD is staged by GFR (ml/min/1.73 m²), and diuretic choice tracks the stage (slide 8):

StageGFRDiuretic approach
1≥ 90Thiazides
2~90–60Thiazides
3~60–30Thiazides → Loop diuretics
4~30–15Loop diuretics → Combination treatment
5~15–0Loop diuretics → Combination treatment
  • As GFR drops in CKD (< 60 ml/min/1.73 m²), less water/Na⁺ reaches the distal tubule, so thiazides (weak diuretics) have little effect.
  • At low GFR you need loop diuretics and possible combination treatments to provide an additive natriuretic effect.
  • Loop diuretics are the diuretic class of choice when GFR is low (< 50–60 ml/min/1.73 m²); the trade-offs are managing the attendant excess K⁺ loss and overcoming diuretic resistance.

Understand the staging diagram (slide 8): it is a visual statement of one mechanistic idea — as the nephron loses filtration capacity, distal Na⁺ delivery falls, weak distal diuretics (thiazides) lose traction, and therapy escalates to loop diuretics and then combinations.

Loop diuretics — site and mechanism

  • Example: frusemide (furosemide). These are the most potent diuretics available (“high-ceiling” diuretics).
  • They inhibit the luminal Na⁺/K⁺/Cl⁻ cotransporter (NKCC2) in the TAL by competing with Cl⁻ for binding.
  • NKCC2 in the TAL normally reabsorbs ~25% of the filtered Na⁺ load, and the downstream nephron does not have the reabsorptive capacity to recover this — hence the large effect.
  • Bottom line: loop diuretics keep fluid, Na⁺/Cl⁻, and also K⁺, Ca²⁺ and Mg²⁺ in the tubule (i.e. all are lost in urine).
  • A high Na⁺ load presented at the distal tubule also increases loss of H⁺ and K⁺ there.

Frusemide pharmacokinetics

  • PO: rapid absorption; max effect 1–2 hrs; duration 4–6 hrs.
  • IV: onset within 2–10 min; max effect 30 min; duration 2 hrs.
  • Absolute oral bioavailability is highly variable, ~50%, within and between patients.
  • >90% bound to plasma proteins, so it does not pass directly into the glomerular filtrate; instead it is actively secreted into the proximal tubule by organic anion transporters (OAT1/OAT3). The remainder (~35%) is metabolised by glucuronidation.

Therapeutic uses of loop diuretics

  • Chronic hypertension in patients with impaired renal function.
  • Chronic kidney injury (or acute renal injury, case-dependent).
  • CHF (moderate to severe) to reduce oedema.
  • Acute pulmonary oedema — the effect on venous return, with abrupt natriuresis, reduces LV filling pressure and thereby relieves pulmonary oedema.
  • Nephrotic syndrome (massive oedema with proteinuria) — generally refractory to other diuretics; frusemide is used but the dose needs increasing to effect.
  • Hyperkalaemia.
  • Hypercalcaemia.
  • Drug overdose (to increase urine flow).

Frusemide dosing (for noting)

  • Oral initial dose 40 mg; maintenance 20–40 mg.
  • Increase to 80–120 mg or more daily in resistant oedema (doses and intervals are patient-dependent) for CHF.
  • Increase the diuretic dose in ESRD with residual renal function.
  • IV acts almost immediately (< 30 min) where oral delivery is unavailable or where intense, rapid diuresis is required — e.g. oedema with CHF, renal injury, or as an adjunct in acute pulmonary oedema.
  • Check body weight and electrolytes to reduce harm.

Loop diuretic side effects and interactions

Excess dosing → hypotension, hypovolaemia, plus:

  • Hypokalaemia (serum K⁺ < 3.5 mmol/L) — may predispose to arrhythmias, ECG changes.
  • Electrolyte depletion of Na⁺, Cl⁻, Mg²⁺ and Ca²⁺.
  • Metabolic alkalosis — increased Na⁺ concentration reaching the distal tubule drives recovery at the Na⁺/H⁺ antiporter, increasing loss of plasma H⁺.

Prolonged use:

  • Hyperuricaemia.
  • Ototoxicity — reversible hearing loss, rare (~6%) with IV bolus use, due to impact on NKCC1 in the cochlea (loss of endolymph electrolytes).
  • As sulphonamide derivatives, loop diuretics may increase the risk of cross-reactivity to cephalosporin antibiotics.
  • Concomitant chronic NSAIDs (indomethacin) can reduce frusemide-diuresis by inhibiting formation of vasodilator prostaglandins in the kidney.

Why loop diuretics waste Ca²⁺ and Mg²⁺ (slide 14): in the TAL, the combined activity of the apical K⁺ channel (ROMK) and basolateral CLC-K2 generates a lumen-positive transepithelial potential difference (~10 mV) that normally drives paracellular reabsorption of the cations Ca²⁺ and Mg²⁺. Loop diuretics, by blocking NKCC2, disrupt this positive potential, so paracellular Ca²⁺ and Mg²⁺ reabsorption falls and their excretion increases.

Vascular and renal-vascular effects

In the systemic vasculature, frusemide (and thiazides) can provoke a vasodilatory effect (increased systemic venous capacitance) before the diuretic effect appears. The mechanism is not fully understood but is associated with either decreased vaso-responsiveness to angiotensin II or vasodilating prostacyclin formation. (NSAIDs can reduce frusemide-diuresis by inhibiting prostacyclin formation in afferent renal arterioles.)

In the renal vasculature, loop diuretics may modulate intra-renal renin release by:

  • Reflex activation of the sympathetic nervous system following volume depletion.
  • Interfering with Na⁺/Cl⁻ transport into the macula densa, knocking out the tubuloglomerular feedback (TGF) mechanism.
  • Low [Na⁺/Cl⁻] at the macula densa causing COX-2 (prostaglandin)-mediated renin production to rise, increasing RAAS activity.
  • This can be combatted in chronic therapy by conjunct use of RAS modulators.

Understand the juxtaglomerular signalling diagrams (slides 17–18): the macula densa senses tubular Na⁺/Cl⁻ via NKCC2. High Na⁺/Cl⁻ → Na⁺/K⁺-ATPase activity generates adenosine (A₁ receptor, Gi), lowering cAMP and suppressing renin. Low Na⁺/Cl⁻ (as caused by frusemide blocking macula densa NKCC2) → ↑COX-2 → prostaglandins (PG-Rs, Gs) → ↑cAMP → ↑renin; catecholamines acting on β₁ receptors add to renin release. RAAS modulators act downstream on circulating renin/RAAS. (COX-2 expression is itself upregulated by chronic Na⁺ depletion.)

Effect on GFR

Because macula densa NKCC2 sensing is itself inhibited by loop diuretics, loop diuretics do not affect GFR even though they raise the salt concentration presented at the macula densa.

Bottom line: the ability to simultaneously block TGF compensation is part of what makes loop diuretics so potent — the kidney cannot use TGF to clamp down filtration in response to the high distal salt load.

  • Frusemide is secreted into the proximal tubule by OAT1/OAT3; glomerular filtration is negligible because of high protein binding.
  • Competition at the OATs with other drugs causes mutual retention: e.g. cephalosporin retention may cause nephrotoxicity; valproate retention potentiates anticonvulsant action and ADRs.
  • Decreased renal function reduces effective dosing: accumulated organic anions in blood compete for a reduced number of transporter binding sites, lowering frusemide entry into the nephron; metabolic acidosis adds to this. Both increase the dose requirement.
  • Frusemide is highly protein-bound and a weak organic acid; it must dissociate to enter cells through OATs, competing with urate and other organic cations (promoting accumulation). Once in the tubular lumen it can potentiate urate reabsorption, contributing to hyperuricaemia.
  • Tubular uptake follows a concentration gradient. Proteinuria binds free frusemide in the tubule and reduces its impact on NKCC2.

Albumin-related contributors to resistance (slide 22):

  • Hypoalbuminaemia in renal injury reduces frusemide delivery to the proximal tubule via OATs. Low serum albumin (e.g. nephrotic syndrome) reduces frusemide binding, allowing a ~10× greater volume of distribution, so less drug is transported into the tubule. (Consider co-administered drugs that also compete for albumin binding.)
  • Hyperalbuminuria: elevated albumin within the tubule (as in nephrotic syndrome) binds frusemide and reduces the unbound (active) fraction.
  • In nephrotic syndrome, frusemide metabolism is also increased through a raised rate of glucuronidation.

Understand the dose–response / resistance figures (slides 23–24). Loop diuretic response is a sigmoid curve: a threshold must be crossed, above which there is maximal response (a ceiling). Pharmacokinetic determinants set the threshold (dose, bioavailability, tubular secretory capacity, rate of absorption, time course of delivery). In the resistant state the curve shifts right and flattens ("altered dose–response relationship, braking phenomenon, tolerance"), e.g. through decreased drug-transporter expression. The "roadblocks to diuresis" infographic (slide 24) groups the mechanisms as: (A) insufficient delivery of drug to the tubule — variable GI absorption, hypoalbuminaemia, competition for OAT transport channels, reduced kidney function/perfusion; and (B) heightened sodium avidity — compensatory distal Na⁺ reabsorption.

Diuretics in chronic heart failure (the cardiorenal continuum)

Understand the CHF balance diagram (slide 25, from JACC). Loop diuretics in CHF have two opposing arms. Positive (reduction of volume expansion): negative Na⁺/water balance → reduced cardiac filling pressures → reduced LV dilation → reduced functional MR and reduced LV wall stress/ischaemia → improved myocardial and renal function; plus prostaglandin (PGI₂) synthesis → vascular smooth muscle relaxation → renal and pulmonary vasodilation. Negative (RAAS activation): inhibition of the macula densa → ↑RAAS → secondary hyperaldosteronism and increased distal Na⁺ delivery → hypertrophy of the distal nephron → diuretic resistance. ACE-I/ARBs counteract the RAAS arm, thiazides block the augmented distal Na⁺ reabsorption, and natriuretic doses of aldosterone antagonists oppose secondary hyperaldosteronism. (On this slide MR = mitral regurgitation.)

Treating diuretic resistance (stepwise, slide 26)

Identify a poor response as early as possible, then:

  1. Adjust dose to eGFR — increase dose/frequency if only on a loop diuretic; switch frusemide to bumetanide or torsemide (improved oral bioavailability). (Switching to IV infusion rather than intermittent bolus is not considered superior.)
  2. Add a thiazide to decrease distal tubule Na⁺ reabsorption.
  3. Add an MRA (spironolactone).
  4. Add a positive inotrope (dobutamine, dopamine) to increase cardiac output to the kidneys.
  5. Restrict water, Na⁺ and interacting medications.

SGLT2 inhibitors in heart failure

Understand the SGLT2-inhibitor diagram (slide 27, Circulation 2023). SGLT2 inhibitors block SGLT2/NHE3. In acute decompensated HF they cause a short-term water diuresis (against a background of raised sodium avidity); in chronic HF on loop diuretics they give loop diuretic potentiation → modest natriuresis → reduced plasma volume, with only minimal change in total blood volume (and an apparent/relative erythrocytosis as plasma volume falls). There is also a rapid, direct cardioprotective effect reducing dyspnoea.

What we know about combining diuretics with SGLT2 inhibitors:

  • The feared risk of early volume depletion in CHF patients on SGLT2 inhibitors plus diuretics has not been borne out; diuresis does not appear to be a significant component of empagliflozin’s protective mechanism.
  • Early addition of an SGLT2 inhibitor in acute decompensated HF lowers the loop diuretic dose needed while increasing cumulative urine output (~25%); plasma urate may also be attenuated by empagliflozin.
  • HF-associated eGFR decline can be reduced and morbidity/mortality improved.
  • Cardiorenal protection may be directly mediated by enhanced glucose deprivation (causing “fuel switching” to more efficient lipid metabolism) and increased autophagic flux (cellular repair / removal of toxic debris).

Understand the eGFR "dip" infographic (slide 29). Both RAAS inhibitors and SGLT2 inhibitors reduce intraglomerular pressure (RAAS-i by efferent arteriolar vasodilation; SGLT2-i by afferent arteriolar vasoconstriction), which causes an initial eGFR dip but better long-term preservation of kidney function. Illustrative decline rates given: untreated ≈ −12 mL/min/year; RAAS-i only ≈ −4.6; SGLT2-i + RAAS-i ≈ −1.85 (delaying ESKD by ~15 years; ESKD in 25 vs 10 years). The early creatinine/cystatin-C rise is a sign the drugs are protecting the kidney, not harming it.

Understand the CKD risk-modification algorithm (slide 30, CONFIDENCE/NEJM 2025 — finerenone with empagliflozin in CKD + type 2 DM). Lifestyle measures (healthy diet, activity, stop tobacco, weight management) underpin everything. First-line for most patients: SGLT2i (continue until dialysis/transplant) + a RAS inhibitor at maximum tolerated dose, aiming SBP < 120 mmHg. Targeted therapies for complications include managing hyperglycaemia per KDIGO, a non-steroidal MRA (finerenone) in people with diabetes and an indication, dihydropyridine CCB/diuretic for BP, a steroidal MRA if needed for resistant hypertension if eGFR ≥ 45, statin-based therapy, antiplatelet for clinical ASCVD, and management of anaemia/acidosis/K⁺ abnormalities, with regular risk-factor reassessment every 3–6 months.

Thiazide diuretics — site and mechanism

  • Examples: bendroflumethiazide, chlorothiazide.
  • Chronic therapy decreases vascular resistance in hypertensive patients — an extra-renal effect.
  • Only a mild-to-moderate diuretic, and ineffective at GFR < 30–40 ml/min.
  • They inhibit Na⁺/Cl⁻ and H₂O reabsorption in the cortical diluting segment of the distal convoluted tubule by competitively binding the apical NCC-1 (eNCC1) Na⁺/Cl⁻ cotransporter, producing a modest increase in Na⁺/water excretion and (as with loop diuretics) K⁺ loss.
  • Thiazides are themselves secreted in the proximal tubule; a secondary proximal-tubule action may occur via inhibition of carbonic anhydrase.
  • NB: NCC/ENCC-1 symporter levels are upregulated by aldosterone.

GFR and vascular effects of thiazides

  • Thiazides block the Na⁺/Cl⁻ cotransporter at a site beyond the macula densa, so they don’t directly trigger TGF there.
  • Acutely, however, thiazides may also inhibit carbonic anhydrase in the proximal tubule, inhibiting NaHCO₃ reabsorption and increasing Na⁺ delivery to the macula densa — this activates TGF short-term and can cause a temporary drop in GFR.
  • Beyond volume unloading, chronic thiazide use decreases vascular resistance → hypotensive effect. Proposed mechanisms: opening Ca²⁺-activated K⁺ channels → hyperpolarisation → closure of L-type Ca²⁺ channels → reduced vasoconstriction; and thiazide-induced fall in plasma Na⁺ relative to K⁺ reducing vascular tone.

Thiazide pharmacokinetics

  • A diverse family of thiazide and thiazide-like compounds, all inhibiting NCC1 (eNCC1).
  • Oral administration, variable absorption; diuresis within ~1 hour.
  • Renal elimination mostly, with some glucuronidation.
  • Variable elimination kinetics → variable half-lives ranging from hours to days.
  • Excreted into the proximal tubule in competition with uric acid; all thiazides are organic anions and are affected by other drugs competing for the organic anion transporter (e.g. probenecid).
  • Protein binding within the tubule varies by specific thiazide.

Therapeutic uses of thiazides (oral)

  • Early stages of CKD.
  • Hypertension — considered after ACEIs are initiated in the absence of co-morbidities; ALLHAT recommendations show value in the elderly.
  • Acute pulmonary hypertension.
  • Nephrogenic diabetes insipidus with high urine output — low-dose thiazides paradoxically reduce urine flow by decreasing intravascular volume, thereby decreasing GFR and urine volume.

Use in hypercalciuria / recurrent Ca²⁺ calculi (slide 36): unlike loop diuretics, thiazides promote Ca²⁺ reabsorption at the distal tubule by increasing the number of apical Ca²⁺-transport (TRPV5) channels. This is used to prevent "excess" Ca²⁺ excretion that could otherwise form renal calculi, and the increased Ca²⁺ reabsorption is also useful for maintaining bone density. Give with supplemental K⁺ or with amiloride to avoid hypokalaemia.

Thiazide adverse effects

These generally stem from high doses.

  • Hypokalaemia — may predispose to digoxin toxicity; may prolong the QT interval, particularly alongside other QT-extenders (e.g. sotalol).
  • Hyponatraemia, which can provoke metabolic alkalosis (increased Na⁺ load at the DCT drives H⁺ and K⁺ loss), can cause confusion in the elderly (usually after prolonged use), and may provoke Li⁺ accumulation (as Na⁺ loss rises).
  • Hypercalcaemia.
  • Hyperuricaemia — may precipitate gout.
  • Hyperglycaemia / impaired glucose tolerance (linked to the hypokalaemia) — up to a 30% increase, exacerbating diabetes by impairing insulin secretion or peripheral insulin sensitivity. (Remember K⁺ stimulates insulin secretion in pancreatic β cells, so hypokalaemia blunts it.)
  • Hypovolaemia — dehydration and orthostatic hypotension, particularly in the elderly.
  • Also impotence (reversible) and increased urination.
  • Message: treat to effect.

K⁺-sparing diuretics

Two sub-types: mineralocorticoid (MR) antagonists and ENaC channel antagonists.

Aldosterone physiology (the target)

  • Aldosterone acts in the distal tubules and collecting ducts, as well as in vasculature and heart.
  • In the kidney it increases plasma Na⁺ and water retention and decreases plasma K⁺, by promoting Na⁺ reabsorption from the tubule and K⁺ loss (i.e. it increases Na⁺-for-K⁺ exchange).
  • It increases Na⁺/K⁺ pump synthesis, raising blood volume and thus cardiac output.

Extra-renal effects of aldosterone in CHF (slide 41): cardiac MR receptors and aldosterone are produced locally in the diseased heart in proportion to CHF severity. Aldosterone is formed by ATII-induced aldosterone synthase in the failing ventricle and by ATII-induced aldosterone production in the adrenal cortex. It promotes vascular and cardiac hypertrophy and fibrosis → arrhythmia, increased afterload, etc.; vascular fibrosis is promoted similarly. The clinical value of MR inhibition is shown in CHF by the RALES and TOPCAT trials, and in hypertension by the PATHWAY-2 study.

Spironolactone (MRA)

  • An aldosterone antagonist that competitively binds the mineralocorticoid receptor and prevents its translocation.
  • Uniquely, it binds surface receptors on the basolateral side and does NOT require access to the lumen.
  • It conserves K⁺ (used as a K⁺-sparing diuretic); its action depends on aldosterone levels — the higher the aldosterone, the greater the effect.

Understand the spironolactone mechanism diagram (slide 43). Normally, aldosterone enters the principal cell from the interstitial side, binds MR, translocates to the nucleus → mRNA → aldosterone-induced proteins (AIP), which upregulate the apical ENaC Na⁺ channel, the apical K⁺ channel, and the basolateral Na⁺/K⁺-ATPase (3Na⁺ out / 2K⁺ in) plus mitochondrial ATP supply — driving Na⁺ reabsorption and K⁺ secretion into the urine. Spironolactone blocks aldosterone at the MR, switching off this whole AIP cascade, so Na⁺ is retained in the lumen and K⁺ is conserved.

Spironolactone pharmacokinetics (oral):

  • ~70% GI absorption.
  • Extensive first-pass hepatic metabolism to the active product canrenone.
  • Extensively plasma-protein-bound.
  • 100% of metabolites appear in urine.

Toxicity:

  • Hyperkalaemia — avoid excessive K⁺ supplementation while on spironolactone.
  • Androgen-modulating effects from its steroid structure → gynaecomastia.
  • GI disturbances.
  • NB: caution with ACEIs, ARBs and non-selective β-blockers (additive hyperkalaemia risk).

Indications for an MRA:

  • Liver failure, heart failure.
  • Add-on in diuretic resistance.
  • Hyperaldosteronism (primary and secondary).
  • Resistant hypertension.
  • Proteinuria.

Spironolactone is an effective natriuretic when given to patients with high aldosterone levels or alongside loop/thiazide diuretics, and is advocated in HF with reduced ejection fraction (HFrEF).

Amiloride (ENaC blocker)

  • Inhibits ENaC channels (which are under the influence of aldosterone) in the collecting duct / late distal tubule.
  • Transported by organic acid transporters into the lumen at the proximal tubule.
  • Its action is complementary to the thiazides: used with them, it augments Na⁺ loss but limits K⁺ loss.
  • Oral delivery. (Triamterene is grouped with amiloride as an ENaC blocker.)

Practical loop-diuretic prescribing (BMJ 2019 practice article, slides 47–55)

The deck embeds the full BMJ “Uncertainties” article How to prescribe loop diuretics in oedema (Anisman, Erickson, Morden). Key slide-sourced points:

  • All-or-none (“on/off”) response. Unlike most drugs, loop diuretics do not behave like a dimmer switch. For a given individual a single dose is either subtherapeutic or therapeutic; once the therapeutic threshold is crossed, the response is maximal, and a higher dose does not produce greater diuresis.

Understand the two dose–response figures (slides 47/55). Fig 1 shows the usual drug curve — a smooth, roughly linear/saturating rise of response with dose. Fig 2 shows the loop-diuretic curve — flat (no effect) below threshold, an almost vertical jump to near-maximal response at threshold, then a plateau. The clinical message: find the one effective dose; don't titrate in small steps.

  • Reaching the threshold. It is the intratubular (not serum) concentration that matters; the drug accumulates in the tubule via tubular secretion. As renal function declines or proteinuria rises, larger doses are needed to reach the same effective intratubular concentration. With stable renal function the effective dose is stable, though mild tolerance can develop.
  • Choice of loop diuretic. Guidance is limited, but moderate-strength evidence suggests torsemide may have advantages over furosemide (higher potency, longer duration, higher/more predictable bioavailability, lower HF readmission, aldosterone inhibition, less cardiac fibrosis, less hypokalaemia, no low-thiamine effect). The article suggests considering starting with torsemide (typical start 10–20 mg), and bumetanide where minimising fluid infusion is critical (IV bumetanide is ~40× more concentrated than equivalent furosemide). Ethacrynic acid (high ototoxicity risk) is reserved for documented sulfa-diuretic allergy.
  • Equivalent doses (Box 3): 80 mg PO furosemide ≈ 40 mg IV furosemide ≈ 20 mg PO/IV torsemide ≈ 1 mg PO/IV bumetanide ≈ 100 mg PO/IV ethacrynic acid.
  • Confirming a dose works. A therapeutic dose causes frequent urination in the 4–6 hours after ingestion, with urine volume up to 2000–4000 mL in that window (torsemide longest duration, bumetanide shortest, furosemide intermediate). Nocturia/“all-day” polyuria usually reflects hypervolaemia and ineffective daytime diuresis, not excessive drug response.
  • As-needed, dry-weight dosing. After euvolaemia is reached, continued fixed dosing risks hypovolaemia; the authors recommend as-needed dosing triggered by daily weight or symptoms (e.g. take the dose only if weight is above target). Use one best dose — avoid multiple/variable daily doses, avoid escalating an already-effective dose, and avoid subtherapeutic “gentle diuresis.”
  • Causing more or less diuresis. Less: rely on the gentler classes — thiazides give only ~25% of loop output, K⁺-sparing agents only ~3%. More: add a thiazide or K⁺-sparing agent to block reabsorption beyond the loop of Henle, or take a second loop dose ≥ 6 h later; consider limiting fluid/Na⁺ (note “sodium avidity” after the 4–6 h diuretic phase).
  • Drugs that reduce loop effect. ACE-I, ARBs and NSAIDs all reduce GFR (ACE-I/ARB dilate the efferent arteriole; NSAIDs constrict the afferent arteriole; NSAIDs also promote oedema by inhibiting PGE₂ and increasing Na⁺ reabsorption).
  • Myth-busting (Box 4): oral absorption is essentially preserved despite gut oedema; antibiotic sulfa allergy is not an absolute contraindication to loop diuretics; IV infusion is not clearly superior to bolus; a modest creatinine/urea rise can be unavoidable or even a marker of effective diuresis and should not automatically stop diuresis.
  • Evidence base (Tables 1–2): the all-or-none curve is supported by Brater 1998/2011 and Ellison 2017; head-to-head loop comparisons (TORIC, open-label RCTs, ASCEND-HF/PROTECT re-analyses, fibrosis and neurohormonal studies) generally favour torsemide on mortality, readmissions, quality of life, reduced fibrosis, aldosterone inhibition and less hypokalaemia, though differences in quality of life are not definitively established.

Noted skips (no extractable teaching content)

  • Slide 1 — title slide (course/lecture title, Prof Ivan Sammut).
  • Slide 2 — disclaimer that biological indices are described in generalised terms that may not reflect the social spectrum of gender or intersex variation.
  • Slide 39 — section divider (“K⁺ sparing Diuretics”, listing MR antagonists and ENaC channel antagonists; content captured under that theme above).

Self-test

Cover the answers. Attempt each question before expanding it. Mark the ones you cannot answer and return to that theme.

General principles

Renal disease / NKF–KDOQI

Loop diuretics

Heart failure, resistance, SGLT2i, finerenone

Thiazides

K⁺-sparing diuretics

Practical loop prescribing

Integrative

Free-recall prompts

Close the note. From memory, draw the nephron and place each diuretic class at its site with its molecular target (CAI–PT carbonic anhydrase; loop–TAL NKCC2; thiazide–DCT NCC1; amiloride–CD ENaC; spironolactone–CD MR), then check against General principles of diuretic action.

Close the note. From memory, write the NKF/KDOQI CKD stages by GFR and the diuretic approach at each stage, then check against Diuretic choice across renal disease (NKF/KDOQI staging).

Close the note. From memory, reproduce the macula densa → juxtaglomerular renin-signalling pathway for both high and low Na⁺/Cl⁻ (adenosine vs COX-2/PG, and where frusemide acts), then check against Vascular and renal-vascular effects.

Close the note. From memory, list the full set of thiazide adverse effects and the spironolactone toxicity profile, then check against Thiazide adverse effects and Spironolactone (MRA).

Graph View