Q4 LONG ANSWER 10M ★ High-yield

Classify diuretics with their sites of action. Describe loop diuretics and the adverse effects of each class.

Pharmacology · 2nd Professional — Para-Clinical

Classification of Diuretics

Class	Site of action	Drugs	Efficacy
Carbonic anhydrase inhibitors	Proximal tubule	Acetazolamide	Weak; self-limiting through acidosis
Osmotic diuretics	Proximal tubule and descending limb	Mannitol	Moderate; obligatory water loss
Loop (high-ceiling) diuretics	Thick ascending limb — Na-K-2Cl cotransporter	Frusemide, torsemide, bumetanide, ethacrynic acid	Most efficacious — up to 25% of filtered sodium
Thiazides	Distal convoluted tubule — Na-Cl cotransporter	Hydrochlorothiazide, chlorthalidone, indapamide, metolazone	Moderate (5–10%); ineffective if GFR is low
Potassium-sparing — aldosterone antagonists	Collecting duct — mineralocorticoid receptor	Spironolactone, eplerenone	Weak alone
Potassium-sparing — sodium channel blockers	Collecting duct — ENaC	Amiloride, triamterene	Weak alone
Vasopressin antagonists	Collecting duct V2	Tolvaptan	Aquaretic — water without sodium

CLINICAL PEARL

Efficacy is set by how much sodium the target segment normally reabsorbs. The thick ascending limb handles about 25% of filtered sodium, so blocking it produces a massive diuresis. The distal tubule handles under 10%, so a thiazide can never match a loop diuretic however large the dose. The collecting duct handles 2 to 3%, which is why potassium-sparing agents are weak diuretics but useful for their potassium effect.

Loop Diuretics in Detail

Inhibit the Na-K-2Cl cotransporter in the thick ascending limb, abolishing the medullary concentration gradient so the urine cannot be concentrated
Also cause loss of calcium and magnesium, since their reabsorption depends on the lumen-positive potential created by potassium recycling — hence their use in hypercalcaemia
Act from the luminal side, so they must be secreted into the tubule; this is why they still work in renal impairment (given a large enough dose) and why they compete with uric acid secretion, causing hyperuricaemia
Intravenous frusemide venodilates within minutes, relieving pulmonary oedema before any urine is passed — a mechanism independent of diuresis
Uses — acute pulmonary oedema, cardiac failure, nephrotic syndrome, cirrhosis with ascites, hypercalcaemia, hyperkalaemia, and acute kidney injury (to convert oliguric to non-oliguric failure, though this does not improve survival)

Adverse Effects BY Class

Class	Adverse effects
Loop	Hypokalaemia, hyponatraemia, hypomagnesaemia, hypocalcaemia, metabolic alkalosis, hypovolaemia, hyperuricaemia and gout, ototoxicity (dose-related, worse with aminoglycosides), hyperglycaemia
Thiazides	The "hypos and hypers" — HYPOkalaemia, HYPOnatraemia, HYPOmagnesaemia; HYPERglycaemia, HYPERuricaemia, HYPERlipidaemia, HYPERcalcaemia. Also impotence and photosensitivity
Potassium-sparing	Hyperkalaemia — dangerous with ACE inhibitors, ARBs, NSAIDs or renal impairment. Spironolactone also causes gynaecomastia, impotence and menstrual irregularity through its antiandrogen effect; eplerenone does not
Acetazolamide	Metabolic acidosis, hypokalaemia, paraesthesiae, renal stones, drowsiness
Mannitol	Initial expansion of plasma volume may precipitate pulmonary oedema in cardiac failure; headache, nausea; contraindicated in anuria

Thiazides retain calcium; loop diuretics lose it — so thiazides are used to prevent recurrent calcium stones and may help osteoporosis, while loop diuretics are used to treat hypercalcaemia. The commonest single point of confusion in the topic

Uses of Individual Agents

Drug	Distinctive uses
Acetazolamide	Glaucoma, acute mountain sickness (by inducing a metabolic acidosis that stimulates ventilation), epilepsy as an adjunct, alkalinisation of urine
Mannitol	Raised intracranial pressure and cerebral oedema; raised intraocular pressure; forced diuresis in some poisonings
Frusemide	Oedematous states; hypercalcaemia; hyperkalaemia
Thiazides	Hypertension; recurrent calcium renal stones; nephrogenic diabetes insipidus (paradoxically reduces urine volume by inducing mild volume depletion)
Spironolactone	Cirrhosis with ascites (the diuretic of choice, since secondary hyperaldosteronism drives the retention), cardiac failure, resistant hypertension, CONN syndrome, hirsutism and acne
Amiloride	With a thiazide or loop diuretic to conserve potassium; lithium-induced diabetes insipidus
Tolvaptan	Hyponatraemia with fluid overload or SIADH; polycystic kidney disease

Diuretics and Potassium

Diuretic	Effect on potassium	Mechanism
Loop and thiazide	HYPOkalaemia	More sodium reaches the collecting duct, where it is exchanged for potassium under aldosterone; volume depletion also raises aldosterone
Spironolactone, eplerenone	HYPERkalaemia	Aldosterone receptor blockade
Amiloride, triamterene	Hyperkalaemia	Block the epithelial sodium channel, so less potassium is exchanged
Acetazolamide	Hypokalaemia	Increased distal sodium delivery with bicarbonate

Combining a loop or thiazide with a potassium-sparing agent balances the effect and is often better than potassium supplements, which are poorly tolerated
Hypokalaemia is dangerous chiefly through arrhythmia, and its risk is multiplied by digoxin and by any QT-prolonging drug

Applied Aspects

Monitor electrolytes and renal function after starting or increasing any diuretic; hypokalaemia and hyponatraemia are the commonest causes of admission related to these drugs
Combine a loop with a thiazide for resistant oedema — "sequential nephron blockade" is markedly synergistic, but causes profound electrolyte loss and needs close monitoring
Give diuretics in the morning, and the second dose by early afternoon, so that nocturia does not destroy sleep and adherence
Spironolactone plus an ACE inhibitor plus NSAIDs is a recognised recipe for lethal hyperkalaemia, particularly in the elderly with impaired renal function
Diuretic resistance may be due to poor adherence, excess salt intake, NSAIDs, gut oedema impairing absorption, or hypoalbuminaemia; look for a cause before escalating the dose
In cirrhotic ascites, spironolactone comes first, with frusemide added in a ratio of about 100:40 mg; reversing the order causes hypokalaemia and precipitates encephalopathy
Correct hypokalaemia before it causes harm — it precipitates digoxin toxicity, arrhythmia and, in cirrhosis, hepatic encephalopathy through increased ammonia production
Ototoxicity of loop diuretics is dose- and rate-related, so intravenous frusemide is given slowly, and the combination with an aminoglycoside is avoided where possible
Weigh the patient daily rather than relying on charts — a loss of about 0.5 to 1 kg a day is a safe target in oedema, and faster loss risks hypovolaemia and renal impairment
Thiazides are ineffective once the GFR falls below about 30, and persisting with them wastes time while the patient remains congested
Metolazone is the exception, retaining activity at low GFR, and is used briefly with a loop diuretic in resistant oedema under close supervision
Acetazolamide is self-limiting — the metabolic acidosis it induces reduces its own effect within a few days, which is why it is a poor diuretic but a useful drug for other purposes
Mannitol is contraindicated in established anuria and in cardiac failure, where the initial plasma expansion can precipitate pulmonary oedema
Ask about NSAID use in any patient whose diuretic seems to have stopped working — they blunt the response by inhibiting renal prostaglandins, and are often bought without prescription

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