L13 Clinical Pharmacology Diuretics

Diuretics and MRAs in Renal Injury and Heart Failure

This is the Year 3 Clinical Pharmacology “vertical thread” lecture (Prof Ivan Sammut) revisiting diuretics in the context of worsening renal function and chronic heart failure (CHF). It builds on the Year 2 antihypertensive lecture, working through the four diuretic classes by their nephron site of action — loop diuretics (frusemide), thiazide diuretics (bendroflumethiazide, chlorothiazide), and the two K⁺-sparing classes (the mineralocorticoid receptor antagonist spironolactone and the ENaC blocker amiloride). For each it covers site/mechanism, pharmacokinetics, therapeutic uses, adverse effects and route of delivery. The recurring clinical threads are: how to stage diuretic choice as GFR falls (NKF/KDOQI), the impact of diuretics on the cardiorenal continuum in CHF, the mechanisms of diuretic resistance and how to overcome them, and the modern roles of SGLT-2 inhibitors and MRAs. The deck closes with a reproduced BMJ practice article on prescribing loop diuretics in oedema. A scope note states the lecture uses biological-sex indices in generalised terms only.

General principles of diuretic action

• Diuretics generally act only if Na⁺ reaches their site of action; the magnitude of the diuretic effect depends on the amount of Na⁺ delivered to that site.
• Acting at different nephron segments can produce synergism, which is the rationale for combining classes.
• All diuretics except spironolactone act from the luminal (tubular) side of the cell membrane — they must get into the tubular fluid to work. Spironolactone instead acts from the basolateral/interstitial side on the intracellular receptor.

Important

Sites of Na⁺ reabsorption and their diuretic targets (proximal → distal):

• Proximal tubule — carbonic anhydrase inhibitors (CAI); Na⁺/H⁺ exchange, HCO₃⁻ recovery via H₂CO₃ → CO₂ + H₂O.
• Thick ascending limb (TAL) — loop diuretics (LD) block the luminal NKCC2 (Na⁺/K⁺/2Cl⁻) cotransporter.
• Distal tubule — thiazides (Tz) block the luminal NCC/ENCC-1 (Na⁺/Cl⁻) cotransporter.
• Connecting tubule / collecting duct — amiloride (Aml, and triamterene) block luminal ENaC; spironolactone (Sp) blocks the mineralocorticoid receptor (MR) that aldosterone (Aldo) activates.
  In every segment the basolateral Na⁺/K⁺-ATPase (3Na⁺ out / 2K⁺ in) provides the gradient that drives luminal Na⁺ entry.

Staging diuretic choice in renal disease (NKF/KDOQI)

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

• Loop diuretics are the class of choice when GFR is low (< 50–60 mL/min/1.73 m²); the attendant excess K⁺ loss must be managed and diuretic resistance overcome.
• As GFR falls 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 loop diuretics ± combination therapy are needed for an additive natriuretic effect.

Important

NKF/KDOQI CKD staging by GFR (mL/min/1.73 m²) and the matched diuretic strategy:

• Stage 1 (GFR ≥ 90): thiazides
• Stage 2 (GFR 90→60): thiazides
• Stage 3 (GFR 60→30): thiazides → loop diuretics
• Stage 4 (GFR 30→15): loop diuretics → combination treatment
• Stage 5 (GFR 15→0): loop diuretics → combination treatment
  “Renal injury” is regarded as beginning around GFR 60.

Loop diuretics — site and mechanism (NKCC2 on the TAL)

Example: frusemide (furosemide).

• 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.
• The TAL NKCC2 normally reabsorbs ~25% of the filtered Na⁺ load, and the downstream nephron lacks the reabsorptive capacity to recover this, so blocking it produces a large diuresis.
• Bottom line: loop diuretics keep fluid and Na⁺/Cl⁻ — as well as K⁺, Ca²⁺ and Mg²⁺ — in the tubule, profoundly increasing their urinary excretion. The high Na⁺ load then delivered to the distal tubule also increases loss of H⁺ and K⁺.

Mechanism of Ca²⁺ and Mg²⁺ loss

In the TAL the combined activity of the apical K⁺ channel (ROMK, recycling K⁺ back to lumen) and basolateral CLC-K2 (Cl⁻ exit) creates a lumen-positive transepithelial potential (~+10 mV) that drives paracellular reabsorption of cations Ca²⁺ and Mg²⁺. Loop diuretics, by shutting NKCC2, abolish this positive potential and therefore increase Ca²⁺ and Mg²⁺ excretion.

Loop diuretic pharmacokinetics (frusemide)

• PO: rapid absorption; max effect 1–2 h; duration 4–6 h.
• IV: onset 2–10 min; max effect ~30 min; duration ~2 h.
• Absolute oral bioavailability is highly variable (~50%), both within and between patients.
• Extensively (>90%) plasma-protein bound.
• Does not pass directly into glomerular filtrate (because it is highly protein-bound); instead it is actively secreted into the proximal tubule by organic anion transporters (OAT1/OAT3). The remaining ~35% is metabolised by glucuronidation.
• Frusemide is a weak organic acid that dissociates to enter cells via OATs, competing with urate and with other drugs/organic anions; this competition promotes accumulation. Tubular uptake follows a concentration gradient.

PK-driven drug interactions at the OAT

Frusemide competes with other drugs at the OATs, which can cause drug retention: e.g. cephalosporin retention → nephrotoxicity, and valproate retention → potentiated anticonvulsant action and ADRs.

Why dose must rise in renal impairment

With reduced renal function, accumulated organic anions in blood compete for a reduced number of OAT binding sites, cutting frusemide entry into the nephron; metabolic acidosis adds to this. The net effect is a higher dose requirement.

Frusemide — therapeutic uses and dosing

Uses: chronic HTN with impaired renal function; chronic kidney injury (or acute renal injury, case-dependent); moderate-to-severe CHF (to reduce oedema); acute pulmonary oedema (its effect on venous return with abrupt natriuresis reduces LV filling pressure, relieving pulmonary oedema); nephrotic syndrome (massive oedema with proteinuria — generally refractory to other diuretics, so frusemide is used but the dose needs increasing to effect); hyperkalaemia; hypercalcaemia; and in drug overdose (to increase urine flow).

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

Loop diuretics — adverse effects and interactions

Excess dosing can cause hypotension and 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 — the increased Na⁺ concentration reaching the distal tubule drives Na⁺/H⁺ antiporter activity, with increased loss of plasma H⁺.

With prolonged use:

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

Vascular and renal-haemodynamic effects of loop diuretics

Systemic vasculature: frusemide (and thiazides) can produce a vasodilatory effect (increased venous capacitance) before the diuretic effect appears; mechanisms are incompletely understood but are associated with either decreased vascular responsiveness to angiotensin II or vasodilating prostacyclin formation. (NSAIDs reduce frusemide-diuresis partly by inhibiting prostacyclin formation in afferent arterioles.)

Renal vasculature: loop diuretics may modulate intra-renal renin release by:

• reflex sympathetic activation 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 triggering COX-2 (prostaglandin)-mediated renin production, raising RAAS activity.
  This unwanted RAAS activation can be combatted in chronic therapy by conjunct use of RAS modulators.

Understand: how altered Na⁺/Cl⁻ sensing at the macula densa drives renin (slides 16–17)

Juxtaglomerular (JG) cells respond to stimuli signalling volume depletion. High Na⁺/Cl⁻ delivery to the macula densa drives its Na⁺/K⁺-ATPase, generating adenosine (ADO); adenosine acts on JG A₁ receptors via Gi, lowering cAMP and suppressing renin. Conversely, low Na⁺/Cl⁻ (as frusemide produces by blocking macula densa NKCC2) up-regulates COX-2 → prostaglandins (PGs), which act on JG PG receptors via Gs to raise cAMP and stimulate renin. β₁-agonists/catecholamines (via β₁-AR, Gs) and a fall in JG Ca²⁺ also raise renin. COX-2 expression is up-regulated by chronic Na⁺ depletion. Circulating renin output can be reduced pharmacologically by RAAS modulators.

Loop diuretics and GFR

Because macula densa NKCC2 sensing is itself inhibited by loop diuretics, loop diuretics do not lower GFR even though they raise the salt concentration arriving at the macula densa. The bottom line is that the ability to simultaneously block TGF compensation contributes to their potent diuretic effect.

Diuretic resistance — mechanisms

Diuretic resistance is the failure to decongest despite adequate and escalating diuretic doses. Mechanisms cluster into insufficient delivery of drug to the tubule, and heightened sodium avidity / compensatory reabsorption.

PK contributors that worsen resistance:

• Hypoalbuminaemia in renal injury reduces frusemide delivery to the proximal tubule via OATs. Low serum albumin (nephrotic syndrome) reduces frusemide binding, increasing its volume of distribution (×10), so less reaches the tubule. (Co-administered drugs that compete for albumin add to this.)
• Hyperalbuminuria: filtered albumin in the tubule binds free frusemide, reducing the unbound drug available to act on NKCC2 (reduced action in the nephron).
• In nephrotic syndrome, in addition to diminished secretion, frusemide metabolism increases (raised glucuronidation rate).

Understand: the loop-diuretic dose–response relationship and resistance (slide 22)

Plotting sodium excretion against loop-diuretic excretion gives a sigmoid curve: below a threshold little happens; above it response rises steeply to a maximal (ceiling) response. PK determinants (dose, bioavailability, tubular secretory capacity, rate of absorption, time-course of delivery) set where the curve rises. In a diuretic-resistant state the whole curve shifts right and down (blue line): a higher delivery rate is needed to reach threshold, and the maximum is lower — driven by decreased drug-transporter expression (a PK shift) and by an altered dose–response relationship, the braking phenomenon and tolerance (PD shifts).

Understand: integrated pathophysiology of loop-diuretic resistance (slides 23–24)

The failing heart causes ↓CO and ↑CVP, ↓plasma albumin, ↓RBF and GFR with ↑RAAS and SNS. Mapped onto the nephron: reduced intestinal absorption of loop diuretic; inability to bind albumin; reduced filtration; increased proximal Na⁺ reabsorption; organic acids (e.g. blood urea nitrogen) competitively binding OAT and lowering tubular drug availability; albuminuria binding furosemide at the cotransporter; and distal Na⁺ reabsorption with the braking phenomenon (↑RAAS and SNS). The summary “roadblocks”: (1) variable GI absorption (bioavailability 10–100%, affected by food intake and gut oedema); (2) hypoalbuminaemia; (3) decreased kidney perfusion (low MAP, e.g. heart failure, limits secretion and filtration); (4) competition for transport channels (urea, NSAIDs, albumin-bound drug); (5) reduced kidney function (fewer functional nephrons = fewer sites); plus heightened sodium avidity with compensatory distal reabsorption (ENaC, NCC, HCO₃⁻).

Treating diuretic resistance

Identify poor response as early as possible and adjust dose to eGFR, then escalate in order:

1. Increase dose or frequency if only using 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 raise cardiac output to the kidneys.
5. Restrict water, Na⁺ and interacting medications.

Loop diuretics in CHF — benefits vs harms

Understand: positive vs negative effects of loop diuretics in CHF (slide 25)

Positive (reduction of volume expansion): the loop diuretic drives prostaglandin (PGI₂) synthesis → vascular smooth muscle relaxation → renal and pulmonary vasodilation, and a negative Na⁺/water balance → ↓cardiac filling pressures → ↓LV dilation → ↓functional mitral regurgitation (MR) and ↓LV wall stress/ischaemia → improved myocardial function and improved renal function.
Negative (RAAS activation): inhibition of the macula densa ↑RAAS, producing secondary hyperaldosteronism (→ hypertrophy of the distal nephron) and ↑distal Na⁺ delivery — both feeding diuretic resistance. ACE inhibitors / ARBs counter the RAAS arm; natriuretic doses of aldosterone antagonists oppose the hyperaldosteronism/distal-nephron hypertrophy; thiazide diuretics counter the increased distal Na⁺ delivery.

SGLT-2 inhibitors in heart failure

Understand: SGLT-2 inhibitor effects on urinary Na⁺/water in HF (slide 27)

SGLT-2 inhibitors inhibit SGLT2 and NHE3 in the tubule. In acutely decompensated HF (high sodium avidity) they give a short-term water diuresis; in chronic HF on loop diuretics they cause loop-diuretic potentiation with modest natriuresis → ↓plasma volume. Other effects: ↓dyspnoea (rapid, direct cardioprotective effect), (apparent/relative) erythrocytosis, and overall minimal change in total blood volume or short-term natriuretic peptides.

What is known about combining diuretics with SGLT-2 inhibitors:

• The feared early volume depletion in CHF patients on SGLT-2 inhibitors plus diuretics has not been borne out; diuresis does not appear to be a significant part of empagliflozin’s protective mechanism.
• Early addition of an SGLT-2 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 by SGLT-2 inhibitors may be directly mediated by enhanced glucose deprivation (causing “fuel switching” to more efficient lipid metabolism) and of autophagic flux (cellular repair and removal of cytotoxic debris).

Understand: the initial eGFR "dip" with RAAS- and SGLT2-inhibitors (slide 29)

RAAS inhibitors dilate the efferent arteriole; SGLT2 inhibitors constrict the afferent arteriole — both ↓intraglomerular pressure, so creatinine/cystatin-C commonly rise (an initial eGFR dip) at initiation. This dip is a sign the drugs are protecting the kidney: long-term eGFR is better preserved. Illustrative annual eGFR decline rates: untreated −12 mL/min/yr; RAAS-i only −4.6; SGLT2-i + RAAS-i −1.85 — the combination delaying ESKD by ~15 years (slower GFR decline, ESKD in ~25 vs ~10 years).

Understand: CKD treatment and risk modification framework (slide 30)

Lifestyle base: healthy diet, physical activity, stopping tobacco, weight management, with regular risk-factor reassessment every 3–6 months. First-line drug therapy for most patients: an SGLT2-i continued until dialysis/transplant, plus a RAS inhibitor at maximum tolerated dose aiming for SBP < 120 mmHg if hypertensive, plus statin-based therapy. Targeted therapies for complications: manage hyperglycaemia per KDIGO (GLP-1 RA where indicated); use a non-steroidal MRA (finerenone) in people with diabetes and an indication; a dihydropyridine CCB and/or diuretic for BP; a steroidal MRA if needed for resistant hypertension and eGFR ≥ 45; antiplatelet/ezetimibe/PCSK9i for ASCVD risk; and manage anaemia, CKD-MBD, acidosis and potassium abnormalities. (Cited: CONFIDENCE, NEJM 2025 — finerenone with empagliflozin in CKD and type 2 DM.)

Thiazide diuretics — site and mechanism (NCC/ENCC-1 on the distal tubule)

Examples: bendroflumethiazide, chlorothiazide. A diverse family of thiazide and thiazide-like compounds, all inhibiting NCC1 (eNCC1).

• They are mild-to-moderate diuretics and are 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 NCC1 (Na⁺/Cl⁻ cotransporter), producing a modest increase in Na⁺ and water excretion and K⁺ loss (as with loop diuretics).
• Thiazides are secreted in the proximal tubule; a proximal-tubule action may occur as a secondary effect via inhibitory action on carbonic anhydrase.
• Chronic therapy decreases vascular resistance (an extra-renal effect) in hypertensive patients.
• NCC/ENCC-1 expression is up-regulated by aldosterone.

Understand: thiazide site of action at the distal tubule (slide 32)

In the distal convoluted tubule, the apical NCC1 brings Na⁺ and Cl⁻ in (the thiazide target), Ca²⁺ enters apically via CaT, the basolateral Na⁺/K⁺-ATPase (3Na⁺/2K⁺) sets the gradient, and basolateral NCX1 (Ca²⁺ out for 3Na⁺) and a Cl⁻ channel handle exit.

Thiazides — GFR and vascular effects

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

Thiazide pharmacokinetics

• Oral administration with variable absorption; diuresis within one hour.
• Renal elimination mostly, with some glucuronidation.
• Variable elimination kinetics, so half-lives range 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 in the tubule varies with each specific thiazide.

Thiazides — therapeutic uses

Oral delivery, used in: early-stage CKD; HTN (considered after ACEIs are initiated in the absence of co-morbidities; ALLHAT data show value in the elderly); acute pulmonary hypertension; and nephrogenic diabetes insipidus with high urine output (low-dose thiazides paradoxically give a modest fall in urine flow by decreasing intravascular volume, lowering GFR and hence urine volume).

Useful note — thiazides in hypercalciuria / recurrent Ca²⁺ calculi

Thiazides promote distal-tubule Ca²⁺ reabsorption by increasing the number of apical Ca²⁺ (TRPV5) channels, preventing “excess” Ca²⁺ excretion that could otherwise form calculi in the renal ducts. Give with supplemental K⁺ or with amiloride to avoid hypokalaemia. The increased Ca²⁺ reabsorption is also useful in maintaining bone density.

Thiazides — adverse effects

Unwanted effects generally stem from high doses.

• Hypokalaemia — may predispose to digoxin toxicity, and may prolong the QT interval, especially with other QT-extenders (e.g. sotalol).
• Hyponatraemia-provoking, with metabolic alkalosis (increased Na⁺ load at the distal convoluted tubule provoking H⁺ and K⁺ loss); can cause confusion in the elderly, usually after prolonged use; increasing Na⁺ loss may provoke Li⁺ accumulation.
• Hypercalcaemia.
• Hyperuricaemia — may precipitate gout.
• Hyperglycaemia (associated with the hypokalaemia) — impaired glucose tolerance, up to 30% increase, exacerbating diabetes by impairing insulin secretion or peripheral insulin sensitivity (recall K⁺ stimulates insulin secretion in pancreatic β cells, so K⁺ loss impairs it).
• Hypovolaemia — diuresis → dehydration and orthostatic hypotension, particularly in the elderly.
• Also impotence (reversible) and increased urination. Message: treat to effect.

K⁺-sparing diuretics — overview

Two sub-classes act at the distal tubule/collecting duct: mineralocorticoid (MR) antagonists and ENaC channel antagonists.

What aldosterone does (the target of MR antagonists)

Aldosterone acts in the distal tubules and collecting ducts, and also on vasculature and heart. In the kidney it increases plasma Na⁺ and water retention and decreases plasma K⁺ by promoting tubular Na⁺ reabsorption and K⁺ loss (increasing the Na⁺-for-K⁺ exchange). It increases Na⁺/K⁺-ATPase synthesis, raising blood volume and hence cardiac output.

Extra-renal effects of aldosterone in CHF

Cardiac aldosterone receptors and locally produced aldosterone increase in the diseased heart in proportion to CHF severity. Aldosterone is formed by AT-II-induced aldosterone synthase in the failing ventricle and by AT-II-induced production in the adrenal cortex. It promotes vascular and cardiac hypertrophy and fibrosis → arrhythmia, increased afterload. Vascular fibrosis is promoted by a similar mechanism. Clinical value of MR inhibition: in CHF — RALES and TOPCAT trials; in HTN — the PATHWAY-2 study.

Spironolactone (MR antagonist)

• An aldosterone antagonist that competitively binds and prevents translocation of the mineralocorticoid receptor.
• Binds basolateral (interstitial-side) surface receptors — does NOT require access to the lumen (the one exception to luminal action).
• Conserves K⁺ (a K⁺-sparing diuretic); its action is dependent on aldosterone levels — the higher the aldosterone, the greater the effect.

Understand: spironolactone's intracellular mechanism (slide 43)

Normally aldosterone crosses the basolateral membrane from the interstitial space, binds the cytoplasmic MR, and the complex enters the nucleus → mRNA → aldosterone-induced proteins (AIP). AIPs up-regulate the apical ENaC (Na⁺ in), the apical K⁺ channel (K⁺ out to lumen), the basolateral Na⁺/K⁺-ATPase (3Na⁺ out / 2K⁺ in) and mitochondrial ATP supply. Spironolactone blocks aldosterone binding to the MR, preventing this whole transcriptional cascade.

Spironolactone PK and toxicity:

• Oral delivery; ~70% GI absorption; extensive first-pass hepatic metabolism to an active product (canrenone); extensively plasma-protein bound; 100% of metabolites appear in urine.
• Toxicity: hyperkalaemia (avoid excess K⁺ supplementation while on spironolactone); androgen-modulating effects from its steroid structure → gynaecomastia; GI disturbances. Use with caution alongside ACEIs, ARBs and non-selective β-blockers.

Indications for an MRA: liver failure, heart failure; as an add-on in diuretic resistance; hyperaldosteronism (primary & secondary); resistant hypertension; proteinuria. Spironolactone forms an effective natriuretic when given to patients with high aldosterone levels or with loop/thiazide diuretics on board, and is advocated in HF with reduced ejection fraction (HFrEF).

Amiloride (ENaC blocker)

• Inhibits the ENaC channels (which operate under the influence of aldosterone) in the collecting duct / late distal tubule.
• Transported into the lumen by organic acid transporters at the proximal tubule (so, unlike spironolactone, it does act from the luminal side).
• Its action is complementary to thiazides, and used with them it augments Na⁺ loss but limits K⁺ loss. Oral delivery. (Triamterene shares this ENaC-blocking action.)

BMJ Practice article — “How to prescribe loop diuretics in oedema” (Anisman, Erickson, Morden, BMJ 2019;364:l359)

The deck reproduces this article in full. Its clinically load-bearing points:

Loop diuretics behave like an on/off switch

Loop diuretics respond in an all-or-none fashion: for a given individual a single dose is either subtherapeutic or therapeutic. There is no way to titrate the effect gradually up or down. The PK is unusual — they show an almost vertical (sigmoid) dose–response rise between “fully off” and “fully on”, unlike the standard hyperbolic curve of most drugs (slide 55, Figs 1–2). A dose above the therapeutic threshold gives maximal diuresis; a dose below it does little. It is the intratubular (not serum) concentration that determines whether the threshold is reached; GFR and/or proteinuria indicate the likelihood of achieving effective intratubular concentrations.

• Choosing a loop diuretic: UK NICE does not direct one loop over another. Authors suggest torsemide as loop of choice (typical starting dose 10–20 mg; some start lower). Potential torsemide advantages over furosemide: higher potency, longer and more predictable bioavailability, lower HF readmission, aldosterone inhibition, less hypokalaemia, less cardiac fibrosis, and absence of damaging low-thiamine levels. Bumetanide is favoured when minimising fluid infusion is critical (its IV form is ~40× more concentrated than furosemide). Ethacrynic acid (high ototoxicity risk) is reserved for documented sulfa-diuretic allergy.

Equivalent doses of loop diuretics (Box 3)

80 mg PO furosemide ≈ 40 mg IV furosemide ≈ 20 mg PO or IV torsemide ≈ 1 mg PO or IV bumetanide ≈ 100 mg PO or IV ethacrynic acid.

Four common myths about loop diuretics (Box 4)

• “Avoid oral diuretics in oedema (absorption compromised)” — Fact: absorption may be slower with gut oedema, but the overall absorbed dose and diuretic effect are essentially the same.
• “Don’t use loops with a sulfa allergy” — Fact: all loops except ethacrynic acid contain a sulfa moiety, but most patients allergic to sulfonamide antibiotics are not allergic to loops; antibiotic sulfa allergy is not an absolute contraindication.
• “IV drip beats bolus for severe oedema” — Fact: the largest trial showed no difference in any outcome between bolus and continuous infusion (meta-analysis of 10 trials agreed).
• “Stop diuresis if creatinine is rising” — Fact: some rise in urea/creatinine may be unavoidable or even a sign of effective diuresis; an ESCAPE sub-study found aggressive diuresis with haemoconcentration correlated with a significant 180-day mortality benefit.

• Determining if a dose works: ask about the response — therapeutic dosing produces frequent urination in the 4–6 h after ingestion (urine volume up to 2000–4000 mL in that window). Torsemide has the longest duration in that window, bumetanide the shortest, furosemide intermediate. A higher dose above threshold will not give greater diuresis; a dose below threshold won’t substantially change output. No short-term increase in urine output (or “I pee all day and all night”) suggests a subtherapeutic dose that should be increased until the threshold is reached. Note: loop-diuretic diuresis (frequent urination for 4–6 h) is distinct from hypervolaemia’s continuous polyuria (worse lying down at night); nocturia usually indicates ineffective daytime diuresis, not excess response.
• As-needed, dry-weight dosing: once euvolaemic, continued fixed dosing risks hypovolaemia, so dose as-needed against a dry weight. Box 5 dosing errors to avoid: prescribing multiple different daily doses; variable doses; increasing an already-effective dose; or using subtherapeutic doses for “gentle diuresis” (keeping a switch off is essentially a placebo). Daily weighing is recommended in Scottish, American and European HF guidelines, though no trial has shown daily weights improve outcomes; visible oedema or breathlessness can serve as triggers.
• Causing less diuresis: loop effect cannot be gently titrated; other classes are less potent — thiazides may give only ~25% of a loop’s urine output, and K⁺-sparing diuretics on their own only ~3% — useful for “gentle” diuresis in mild hypervolaemia.
• Causing more diuresis: add a thiazide or K⁺-sparing diuretic to block reabsorption beyond the loop of Henle, or give a second loop dose ≥6 h later. Note sodium avidity: the kidneys aggressively retain Na⁺ after the 4–6 h diuretic phase, so Na⁺ ingested after a loop dose noticeably blunts the effect.
• Drugs that reduce loop effect: ACE-I and ARBs (dilate the efferent arteriole, reducing glomerular pressure head) and NSAIDs (constrict the afferent arteriole, reducing flow; also directly increase oedema via inhibition of prostaglandin E₂ synthesis with increased Na⁺ reabsorption) — all reduce GFR.

Understand: the comparative evidence tables (slides 52–54)

Table 1 summarises the evidence for the all-or-none dose–response curve (Brater 1998, Brater 2011, Ellison 2017 review articles), all showing a sigmoid/threshold curve. Table 2 compares loops, dominated by torsemide-vs-furosemide trials — e.g. TORIC (2002, 1377 patients: 1-year mortality 2.2% torsemide vs 4.5% furosemide, favouring torsemide); a 2001 open-label trial (234 patients: significantly fewer HF readmissions on torsemide, 17% vs 32%); torsemide may inhibit aldosterone and correlate with reduced cardiac fibrosis; torsemide and bumetanide are 90–100% bioavailable (more predictable than furosemide’s variable 10–100%); and long-term furosemide can cause low thiamine (worsening HF).

Slides noted as reference/administrative (not core pharmacology content)

Slide 50 (BMJ p4) is mostly the reference list, “how patients were involved”, additional educational resources and patient-information boxes, and slide 51 (BMJ p5) is references only — these are cited sources/admin material rather than new examinable content and are not expanded above.

Decorative / scope slides

Slide 1 is the title card (Prof Ivan Sammut). Slide 2 is a scope/terminology disclaimer (the lecture uses biological-sex indices in generalised terms; gender-spectrum and intersex variation are covered elsewhere). Slide 39 is a section divider for “K⁺-sparing Diuretics” but carries the two sub-class names (MR antagonists; ENaC antagonists), captured above.

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Self-test

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

General principles & nephron sites

Why must Na⁺ reach a diuretic's site of action for it to work, and which single diuretic is the exception to luminal action?

Diuretics generally act only if Na⁺ is delivered to their site, and the size of the effect depends on the Na⁺ load reaching that site. All diuretics except spironolactone act from the luminal side; spironolactone acts from the basolateral/interstitial side on the intracellular MR.

Match each diuretic class to its transporter/receptor target and nephron segment.

CAI → proximal tubule (carbonic anhydrase); loop diuretics → NKCC2, thick ascending limb; thiazides → NCC/ENCC-1, distal tubule; amiloride/triamterene → ENaC, connecting tubule/collecting duct; spironolactone → mineralocorticoid receptor, connecting tubule/collecting duct.

Why do thiazides become ineffective and loop diuretics become the class of choice as GFR falls?

As GFR drops (< ~60 mL/min/1.73 m²), less Na⁺/water reaches the distal tubule, so thiazides (weak diuretics acting there) have little effect. Loop diuretics are the choice at GFR < 50–60 mL/min, with combination treatment added at lower GFR for an additive natriuretic effect.

State the NKF/KDOQI diuretic strategy for each CKD stage by GFR.

Stage 1 (≥90) and Stage 2 (90→60): thiazides; Stage 3 (60→30): thiazides → loop diuretics; Stage 4 (30→15): loop diuretics → combination; Stage 5 (15→0): loop diuretics → combination.

Loop diuretics

Describe the mechanism of frusemide at the TAL and why it is so potent.

It competes with Cl⁻ for binding to the luminal NKCC2 cotransporter in the thick ascending limb, blocking reabsorption of ~25% of the filtered Na⁺ load; the downstream nephron cannot recover this, so a large diuresis follows (a “high-ceiling” diuretic).

Why do loop diuretics increase Ca²⁺ and Mg²⁺ excretion?

ROMK (apical K⁺ recycling) plus basolateral CLC-K2 normally create a lumen-positive transepithelial potential (~+10 mV) that drives paracellular Ca²⁺/Mg²⁺ reabsorption. Blocking NKCC2 abolishes this positive potential, so Ca²⁺ and Mg²⁺ are lost.

How does frusemide reach its luminal site of action given it is >90% protein-bound?

It is too protein-bound to be filtered, so it is actively secreted into the proximal tubule by OAT1/OAT3; ~35% is cleared by glucuronidation.

A patient on frusemide is started on a cephalosporin and becomes nephrotoxic. What is the mechanism?

Frusemide and the cephalosporin compete at the proximal-tubule OATs; reduced cephalosporin secretion causes its retention and accumulation, producing nephrotoxicity. (Valproate retention via the same route potentiates anticonvulsant action and ADRs.)

Why does the effective frusemide dose need to rise as renal function declines?

Accumulated organic anions in blood compete for a reduced number of OAT binding sites, lowering frusemide secretion into the nephron; metabolic acidosis compounds this — so a higher dose is required.

List the loop-diuretic adverse effects, separating excess-dosing from prolonged-use effects.

Excess dosing: hypotension, hypovolaemia, hypokalaemia (arrhythmia/ECG risk), electrolyte depletion (Na⁺/Cl⁻/Mg²⁺/Ca²⁺), metabolic alkalosis. Prolonged use: hyperuricaemia, ototoxicity (reversible, ~6%, IV bolus, via cochlear NKCC1), sulphonamide cross-reactivity with cephalosporins, and reduced diuresis with chronic NSAIDs.

Why does ototoxicity occur with loop diuretics, and why is it usually reversible?

Loop diuretics affect NKCC1 in the cochlea, causing loss of endolymph electrolytes; the hearing loss is rare (~6%), associated with IV bolus use, and reversible.

Explain why loop diuretics do NOT lower GFR despite raising salt delivery to the macula densa.

Macula densa NKCC2 sensing is itself blocked by the loop diuretic, so tubuloglomerular feedback cannot fire to constrict the afferent arteriole; blocking TGF compensation both preserves GFR and adds to the potent diuresis.

Distinguish the adenosine pathway from the COX-2 pathway in macula-densa control of renin.

High Na⁺/Cl⁻ drives the macula densa Na⁺/K⁺-ATPase → adenosine → JG A₁ receptor (Gi) → ↓cAMP → renin suppressed. Low Na⁺/Cl⁻ (as frusemide produces) → ↑COX-2 → prostaglandins → JG PG receptor (Gs) → ↑cAMP → renin stimulated.

Diuretic resistance

Define diuretic resistance and give two PK mechanisms by which nephrotic syndrome worsens it.

Failure to decongest despite adequate, escalating doses. In nephrotic syndrome: hypoalbuminaemia reduces frusemide delivery via OATs and raises its volume of distribution (×10); filtered tubular albumin binds free frusemide (reducing unbound drug at NKCC2); plus increased frusemide glucuronidation.

Describe how the loop-diuretic dose–response curve shifts in a resistant state and the two categories of cause.

The sigmoid Na⁺-excretion curve shifts right and down: a higher delivery rate is needed to reach threshold and the maximum is lower. Causes are PK (decreased drug-transporter expression) and PD (altered dose–response, braking phenomenon, tolerance).

List the stepwise treatment of diuretic resistance in order.

Adjust dose to eGFR; increase loop dose/frequency or switch frusemide to bumetanide/torsemide; add a thiazide; add an MRA (spironolactone); add a positive inotrope (dobutamine/dopamine); restrict water, Na⁺ and interacting drugs.

Thiazides

Describe the thiazide mechanism and the GFR limit below which they fail.

They competitively block the apical NCC1 (Na⁺/Cl⁻ cotransporter) in the cortical diluting segment of the distal convoluted tubule, giving a modest natriuresis with K⁺ loss; ineffective at GFR < 30–40 mL/min.

Why can thiazides cause a temporary drop in GFR acutely?

Acutely they may also inhibit proximal carbonic anhydrase, reducing NaHCO₃ reabsorption and increasing Na⁺ delivery to the macula densa, which activates TGF short-term and transiently lowers GFR.

Explain the proposed vascular mechanism of thiazides' chronic hypotensive effect.

Beyond volume unloading, thiazides may open Ca²⁺-activated K⁺ channels → hyperpolarisation → closure of L-type Ca²⁺ channels → reduced vasoconstriction; thiazide-induced loss of plasma Na⁺ relative to K⁺ may also reduce vascular tone.

Why are thiazides useful in recurrent calcium calculi, and what must be co-prescribed?

They increase distal-tubule Ca²⁺ reabsorption by up-regulating apical TRPV5 channels, reducing the Ca²⁺ excretion that forms calculi (also helps bone density). Give with supplemental K⁺ or amiloride to avoid hypokalaemia.

A patient on a thiazide and digoxin develops an arrhythmia. What electrolyte mechanism links the two?

Thiazide-induced hypokalaemia predisposes to digoxin toxicity and may prolong the QT interval (worse with other QT-extenders such as sotalol).

Why do thiazides impair glucose tolerance?

Thiazide-induced hypokalaemia impairs insulin secretion (K⁺ normally stimulates secretion from pancreatic β cells) and reduces peripheral insulin sensitivity, giving up to a 30% rise in glucose intolerance and exacerbating diabetes.

K⁺-sparing diuretics & aldosterone

Describe spironolactone's mechanism and why it is the exception to luminal-side action.

It competitively binds the mineralocorticoid receptor and prevents its translocation, blocking the aldosterone-induced transcription of ENaC, the apical K⁺ channel and Na⁺/K⁺-ATPase. It binds the receptor from the basolateral/interstitial side, so it does not need to reach the tubular lumen; its effect is greater the higher the aldosterone level.

Contrast the mechanism and luminal access of amiloride versus spironolactone.

Amiloride directly blocks luminal ENaC in the collecting duct/late distal tubule and is delivered into the lumen by proximal organic-acid transporters (luminal action). Spironolactone blocks the intracellular MR from the basolateral side and needs no luminal access.

Give the key PK facts and main toxicities of spironolactone.

~70% GI absorption; extensive first-pass metabolism to the active metabolite canrenone; extensively protein-bound; 100% renal excretion of metabolites. Toxicities: hyperkalaemia (avoid excess K⁺), gynaecomastia (androgen-modulating steroid structure), GI disturbance; caution with ACEIs/ARBs/non-selective β-blockers.

Why are MRAs valuable in CHF beyond their renal effect?

Aldosterone (produced locally in the diseased heart via AT-II-induced aldosterone synthase) promotes cardiac and vascular hypertrophy and fibrosis, causing arrhythmia and increased afterload; MR inhibition opposes this (evidence: RALES, TOPCAT in CHF; PATHWAY-2 in HTN).

SGLT-2 inhibitors & integrative

Why does eGFR commonly dip when an SGLT2 inhibitor or RAAS inhibitor is started, and why is this reassuring?

RAAS inhibitors dilate the efferent arteriole and SGLT2 inhibitors constrict the afferent arteriole, both lowering intraglomerular pressure; the resulting creatinine rise/eGFR dip reflects pressure reduction and predicts better long-term preservation of kidney function.

What happens to loop-diuretic requirement and urine output when an SGLT2 inhibitor is added early in acute decompensated HF?

The loop-diuretic dose needed falls while cumulative urine output rises (~25%) via loop-diuretic potentiation; plasma urate may also be attenuated by empagliflozin, and the feared early volume depletion has not been borne out.

Integrative: a CHF patient on escalating frusemide stops responding. Using the cardiorenal continuum, explain why, and outline how MRAs, thiazides and ACE-I/ARBs each counter a specific arm.

Loop diuretics activate RAAS via macula densa inhibition → secondary hyperaldosteronism (distal-nephron hypertrophy) and increased distal Na⁺ delivery, both producing resistance; low CO/perfusion, hypoalbuminaemia and OAT competition reduce drug delivery. MRAs (e.g. natriuretic-dose spironolactone) oppose the hyperaldosteronism/distal hypertrophy; thiazides block the increased distal Na⁺ reabsorption; ACE-I/ARBs suppress the RAAS arm.

From the BMJ practice article

Explain why loop diuretics behave as an "all-or-none" switch and the practical consequence for dosing.

Their dose–response curve is steeply sigmoid: a single dose is either below threshold (little effect) or above it (maximal diuresis), set by intratubular (not serum) concentration. So the effect cannot be gently titrated; the task is to find the one dose that crosses threshold, then dose as-needed against a dry weight.

State the equivalent loop-diuretic doses and the comparative bioavailability that favours torsemide/bumetanide.

80 mg PO furosemide ≈ 40 mg IV furosemide ≈ 20 mg PO/IV torsemide ≈ 1 mg PO/IV bumetanide ≈ 100 mg PO/IV ethacrynic acid. Torsemide and bumetanide are 90–100% bioavailable vs furosemide’s variable 10–100%.

How do you tell, at the bedside, whether a loop-diuretic dose is therapeutic, and how is this distinguished from hypervolaemic polyuria?

A therapeutic dose causes frequent urination in the 4–6 h after ingestion (up to 2000–4000 mL). Hypervolaemia instead causes continuous polyuria worse lying down at night; nocturia signals ineffective daytime diuresis, not over-response.

Address the myth "stop diuresis when creatinine rises."

Some rise in urea/creatinine may be unavoidable or even mark effective diuresis; an ESCAPE sub-study linked aggressive diuresis with haemoconcentration to a significant 180-day mortality benefit, so a rising creatinine alone is not a reason to stop.

Free-recall prompts

Close the note. From memory, draw the nephron and place each diuretic class at its transporter/receptor and segment, including the basolateral Na⁺/K⁺-ATPase in each cell. Check against General principles of diuretic action.

Close the note. Write out the full loop-diuretic adverse-effect list (excess-dosing vs prolonged-use) with the mechanism of each, then check against Loop diuretics — adverse effects and interactions.

Close the note. Reproduce the stepwise treatment ladder for diuretic resistance and, for each step, the resistance mechanism it targets. Check against Treating diuretic resistance and Diuretic resistance — mechanisms.

Close the note. From memory, list the thiazide adverse effects (the "hyper-" and "hypo-" series) with one mechanism each, then check against Thiazides — adverse effects.