Loop Diuretics
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Direct answer
Loop diuretics (furosemide, bumetanide, torasemide, ethacrynic acid) inhibit the Na-K-2Cl cotransporter of the thick ascending limb of the loop of Henle, producing the most powerful diuresis available — hence "high-ceiling". They are the drugs of choice in acute pulmonary oedema, refractory or renal-failure oedema, nephrotic syndrome and hypercalcaemia, and they retain efficacy at low glomerular filtration rates where thiazides fail. Their signature toxicities are ototoxicity (dose-rate-dependent, potentiated by aminoglycosides), hypokalaemic metabolic alkalosis, hypocalcaemia and hypomagnesaemia.
What you must remember
- Site: Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb, where 25 per cent of filtered sodium is reabsorbed — the basis of their power.
- Furosemide 20–40 mg orally (bioavailability only about 50 per cent and erratic); torasemide is nearly completely absorbed — switch to it when oral furosemide fails.
- Intravenous furosemide relieves pulmonary oedema within minutes through venodilatation before any urine flows.
- Electrolyte signature: hypokalaemia, hypomagnesaemia, hypocalcaemia (opposite of thiazides), metabolic alkalosis, hyponatraemia with excessive use.
- Ototoxicity follows rapid intravenous injection (keep the rate at or below 4 mg/min) and is synergistic with aminoglycosides and cisplatin; ethacrynic acid is the most ototoxic and the non-sulfonamide option.
- They remain effective in chronic kidney disease — doses must rise as filtration falls, which is why 500 mg furosemide is legitimate in advanced renal failure.
- Combination with thiazide (or metolazone) produces sequential nephron blockade for resistant oedema — powerful and dangerous for electrolytes.
- Loop diuretics with normal renal function need morning dosing to avoid nocturia; sustained potassium loss requires supplementation or a potassium-sparing partner.
How to work through acute pulmonary oedema
A 70-year-old arrives breathless, pink frothy sputum, saturations 84 per cent, jugular veins engorged. The order of steps shows the pharmacology. Sit her upright and give oxygen first — position does what no drug can in seconds. Then furosemide 40 mg intravenously (80 if on chronic diuretics): its earliest action is venodilatation, shifting blood from the chest to the periphery and dropping preload before diuresis starts; this is also why sublingual or intravenous nitrates are given simultaneously. Third, watch potassium over the next days — each day of 80 mg can strip several millimoles, and the patient is usually already on a losing diet; hypokalaemia in a patient on digoxin is arrhythmia waiting. Fourth, if she was already on 80 mg twice daily at home and remains congested, the options are dose escalation, adding metolazone 5 mg for sequential blockade, or switching to intravenous therapy to bypass erratic absorption — each with daily electrolytes. Fifth, ask why the oedema happened: in a normal-ventricle patient with nephrotic syndrome, diuretic strategy differs from heart failure because intravascular volume may already be contracted. The examinable point threading all five steps is that loop diuretics are haemodynamic drugs in the first hour and tubular drugs thereafter.
Where students slip
The classic confusion is electrolyte direction: loop diuretics lose calcium (the thick ascending limb reabsorbs calcium paracellularly down the electrical gradient that NKCC2 maintains), so they treat hypercalcaemia, while thiazides retain calcium and precipitate it — reversing these two facts is one of the most common single-best-answer errors in renal pharmacology. The second slip is ototoxicity prevention: writing "give slowly" without the number — the safe rate is 4 mg/min or less for furosemide. Third, candidates forget that furosemide is a sulfonamide and, more relevantly, that ethacrynic acid is the answer when sulfa allergy is genuine. Finally, in the cirrhotic ascites algorithm, spironolactone comes before furosemide (100:40 ratio) — reaching for furosemide first in ascites is a mark-losing reflex.
Frequently asked questions
Why do loop diuretics work in renal failure while thiazides fail?
Filtered drug still reaches the luminal thick ascending limb when given in high doses, whereas thiazides need a functioning distal tubule with adequate delivery — a GFR-dependent difference the exam expects you to state.
How does intravenous furosemide relieve pulmonary oedema before diuresis?
It releases vasodilator prostaglandins and acts directly on veins, rapidly reducing preload; the renal effect follows within 20–30 minutes.
Which electrolyte disturbance distinguishes loops from thiazides?
Loops cause hypocalcaemia and hypomagnesaemia by abolishing the lumen-positive gradient that drives paracellular calcium and magnesium reabsorption; thiazides do the reverse.
Why is ethacrynic acid occasionally preferred?
It is the only loop diuretic that is not a sulfonamide, so it is chosen when sulfa cross-reactivity is a genuine concern — at the price of the highest ototoxicity.
What is sequential nephron blockade?
Adding metolazone or a thiazide to a loop diuretic blocks distal compensation, producing a brisk diuresis for resistant oedema — reserved for monitored inpatients because hyponatraemia and hypokalaemia follow quickly.