loop diuretics
Contents
Inhibit NKCC2 in the thick ascending limb (~25% filtered Na⁺). Most potent diuretics. Backbone of acute decongestion but do not improve survival — TRANSFORM-HF (2023). Dose by GFR; frequency by severity.
mechanism
Inhibit Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2), thick ascending limb. Must reach tubular lumen via OAT secretion. Produce dilute, hypotonic urine. Reduce macula densa Cl⁻ → renin release → RAAS activation (the neurohormonal cost).
dosing — IV, by GFR
| eGFR (mL/min) | Furosemide IV | Bumetanide IV | Torsemide IV |
|---|---|---|---|
| > 45 | 80 mg | 2 mg | 40 mg |
| 30–45 | 120 mg | 3 mg | 60 mg |
| < 30 | 160–200 mg | 4–5 mg | 80–100 mg |
- Give q12h minimum; increase to q6h for severe congestion — frequency decongests faster; dose overcomes the GFR threshold
- Alternative: 2.5× home oral dose (DOSE-AHF) — use whichever gives the higher number
- Max single bolus: furosemide 250 mg; bumetanide 12 mg. Infuse furosemide ≤ 4 mg/min (ototoxicity)
- Bolus preferred over infusion — DOSE-AHF: no difference; infusions increase renin activity more
IV → oral: furosemide IV:PO = 1:2 (double the dose); bumetanide and torsemide ≈ 1:1
comparison
| Furosemide | Bumetanide | Torsemide | Ethacrynic acid | |
|---|---|---|---|---|
| Dose equiv | 40 mg | 1 mg | 20 mg | 50 mg |
| PO bioavail | 10–100% (erratic) | 80–100% | 80–100% | variable |
| Half-life | 1.5–2h | 1–1.5h | 3–4h | 2–4h |
| Duration | 4–6h | 4–6h | 6–8h | 6–8h |
| Metabolism | 50% renal, 50% glucuronidation | 50% hepatic | 80% hepatic (CYP2C9) | hepatic |
| Sulfonamide | Yes | Yes | Yes | No |
key points
- Dose ≠ frequency — dose overcomes the natriuretic threshold (rises with falling GFR); frequency prevents post-diuretic sodium rebound (braking phenomenon). Different problems, different solutions
- Loops produce hypotonic urine → tend to cause hypernatraemia, not hyponatraemia (opposite of thiazides)
- Furosemide oral absorption is wildly erratic (10–100%) and worsened by gut oedema — if response is unpredictable, switch to bumetanide or torsemide
- Sigmoidal dose-response — below threshold = no response; above ceiling = toxicity without added benefit. The ceiling provides safety margin at high doses
Allergy to sulfonamide antibiotics (TMP-SMX) does not contraindicate loops. The allergenic N4-arylamine group is absent. Only contraindication is allergy to the specific agent (extremely rare). Ethacrynic acid is the non-sulfonamide alternative (higher ototoxicity).
adverse effects
- Hypokalaemia — target K⁺ > 4.0 in HF; replete with KCl (not gluconate — need the chloride)
- Hypomagnesaemia — must replete Mg²⁺ before K⁺ repletion will work
- Hypochloraemia / metabolic alkalosis — drives diuretic resistance via macula densa
- Ototoxicity — dose-rate dependent; max furosemide 4 mg/min; bumetanide lower risk at high doses
- Hyperuricaemia, hypernatraemia, volume depletion
evidence
- DOSE-AHF (2011) — high dose (2.5×) > low dose; bolus = infusion
- TRANSFORM-HF (2023) — torsemide vs. furosemide: no mortality difference at 12 months