Diuretics
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I now have comprehensive information from multiple authoritative textbooks. Here is a thorough overview of diuretics:
Diuretics
Diuretics increase urinary output by decreasing reabsorption of Na+ and water in the renal tubules. Most are highly protein-bound, so they reach the tubular lumen mainly via active secretion through the organic anion transporter in the proximal tubule - this explains why impaired kidney function causes diuretic resistance. - Morgan & Mikhail's Clinical Anesthesiology, 7e
Classification by Site and Mechanism of Action
| Class | Examples | Site of Action | Mechanism |
|---|---|---|---|
| Osmotic diuretics | Mannitol | Proximal tubule, loop of Henle | Increase tubular fluid osmolarity; limit passive water reabsorption |
| Carbonic anhydrase inhibitors | Acetazolamide | Proximal tubule (mainly) | Inhibit H+ secretion and HCO3- reabsorption, reducing Na+ reabsorption |
| Loop diuretics | Furosemide, bumetanide, torsemide, ethacrynic acid | Thick ascending limb of loop of Henle | Inhibit Na+-K+-2Cl- co-transporter (NKCC2) on luminal membrane |
| Thiazide diuretics | Hydrochlorothiazide, chlorthalidone, chlorothiazide, indapamide, metolazone | Distal convoluted tubule (early) | Inhibit Na+-Cl- co-transporter in luminal membrane |
| Potassium-sparing: MR antagonists | Spironolactone, eplerenone, finerenone | Collecting tubule/duct | Compete with aldosterone at mineralocorticoid receptors; decrease Na+ reabsorption and K+ secretion |
| Potassium-sparing: ENaC blockers | Amiloride, triamterene | Collecting tubule | Block epithelial Na+ channels (ENaC) directly; decrease Na+ entry and K+ secretion |
| Aquaretics (vaptans) | Tolvaptan, conivaptan | Collecting duct | Block vasopressin V2 receptors; prevent aquaporin insertion; increase free water clearance |
Source: Guyton & Hall Textbook of Medical Physiology; Braunwald's Heart Disease; Morgan & Mikhail's Clinical Anesthesiology, 7e
1. Osmotic Diuretics (Mannitol)
Mannitol is a six-carbon sugar filtered at the glomerulus but not reabsorbed. Its presence in the tubular lumen osmotically retards water reabsorption in the proximal tubule and loop of Henle. It also increases renal blood flow, activates vasodilatory prostaglandins, and may act as a free radical scavenger. Under acute conditions, up to 25% of the glomerular filtrate can be excreted as urine. - Guyton & Hall
Uses: Cerebral edema (reduces ICP), evaluation of oliguria, prophylaxis against AKI in high-risk patients (though clinical evidence for kidney protection is limited).
2. Carbonic Anhydrase Inhibitors (Acetazolamide)
Inhibit carbonic anhydrase mainly in the proximal tubule, blocking HCO3- reabsorption and H+ secretion. Since H+/HCO3- transport is coupled to Na+ reabsorption via the Na+-H+ exchanger, this causes osmotic Na+, HCO3-, and water diuresis.
Key consequence: Metabolic acidosis due to urinary bicarbonate loss.
Uses: Altitude sickness (prophylaxis), glaucoma (reduces aqueous humor), alkalosis correction, familial periodic paralysis. - Guyton & Hall; Goldman-Cecil Medicine
3. Loop Diuretics
The most potent class - can increase Na+ excretion to 20-25% of filtered load. Furosemide, bumetanide, and torsemide competitively inhibit the NKCC2 symporter in the thick ascending limb. Because they abolish the medullary concentration gradient, they also impair water reabsorption in the collecting duct even in the presence of ADH, producing nearly isotonic urine. - Braunwald's Heart Disease; Guyton & Hall
Additional effects:
- Furosemide acts as a venodilator within minutes of IV dosing (reduces PCWP and right atrial pressure), partly via prostaglandin release - this effect is blocked by indomethacin
- Increased Ca2+ excretion (hypercalciuria) - used in acute hypercalcemia
- Increased K+ excretion - risk of hypokalemia
- Maintain efficacy even with significantly impaired renal function (unlike thiazides)
Key drugs and doses (heart failure):
| Drug | Starting dose | Max daily dose | Duration |
|---|---|---|---|
| Furosemide | 20-40 mg once or twice | 600 mg | 6-8 hr |
| Bumetanide | 0.5-1.0 mg once or twice | 10 mg | 4-6 hr |
| Torsemide | 10-20 mg once | 200 mg | 12-16 hr |
| Ethacrynic acid | 25-50 mg once or twice | 200 mg | 6 hr |
Source: Braunwald's Heart Disease, Table 50.6
4. Thiazide and Thiazide-Like Diuretics
Block the Na+-Cl- co-transporter (NCC) in the early distal convoluted tubule. Increase fractional Na+ excretion to only 5-10% of filtered load. Lose effectiveness when creatinine clearance falls below ~40 mL/min, making them less useful in advanced CKD.
Distinctive features (compared to loop diuretics):
- Decrease free water clearance (can worsen hyponatremia)
- Increase Ca2+ reabsorption in the distal nephron - useful in nephrolithiasis (calcium stones) and osteoporosis prevention
- Well established in reducing cardiovascular events and mortality in hypertension (multiple RCTs)
- Metolazone (a thiazide-like quinazoline) is used in combination with furosemide in diuretic-resistant patients
Source: Braunwald's Heart Disease; Guyton & Hall
5. Potassium-Sparing Diuretics
Mineralocorticoid Receptor Antagonists (MRAs)
Spironolactone, eplerenone, and finerenone block aldosterone receptors in the collecting tubule/duct, reducing Na+ reabsorption and K+ secretion. They shift K+ from cells to ECF, risking hyperkalemia. Particularly useful in:
- Primary hyperaldosteronism
- Heart failure (RALES trial: spironolactone reduced mortality in severe HF; EMPHASIS trial: eplerenone reduced mortality in mild HF)
- Secondary hyperaldosteronism (cirrhosis, nephrotic syndrome)
Finerenone (a non-steroidal MRA) appears to have attenuated hyperkalemia risk compared to steroidal MRAs. - Guyton & Hall; Braunwald's Heart Disease
ENaC Blockers
Amiloride and triamterene directly block epithelial Na+ channels in the collecting tubule, decreasing Na+ entry and K+ secretion. Used for hypertension and edema, often combined with other diuretics to prevent hypokalemia. - Guyton & Hall
Contraindication for all K+-sparing diuretics: Serum K+ >5.5 mEq/L; GFR <45 mL/min (use with caution down to <30 mL/min in heart failure). - Goldman-Cecil Medicine
6. Aquaretics (Vasopressin V2 Antagonists)
Tolvaptan (V2-selective) and conivaptan (V1a/V2) block ADH receptors, preventing aquaporin channel insertion into collecting duct cells. This increases free water clearance without affecting Na+ excretion - a pure water diuresis (aquaresis). FDA-approved for clinically significant hyponatremia (serum Na+ ≤125 mEq/L) resistant to fluid restriction. - Braunwald's Heart Disease
Adverse Effects Summary
| Class | Key Side Effects | Contraindications |
|---|---|---|
| Thiazides | Hypokalemia, hyponatremia, hypomagnesemia, hyperuricemia/gout, insulin resistance, new-onset T2DM, hyperlipidemia, photosensitivity, erectile dysfunction | Gout |
| Loop diuretics | Hypokalemia, ototoxicity (potentiated by aminoglycosides), interstitial nephritis, potentiate succinylcholine | Hepatic coma |
| K+-sparing (MRAs) | Hyperkalemia, spironolactone-specific: gynecomastia, menstrual irregularities | K+ >5.5 mEq/L, GFR <45 mL/min |
| Carbonic anhydrase inhibitors | Metabolic acidosis, hypokalemia, kidney stones (uric acid/calcium phosphate), sulfa allergy reactions | Sulfa allergy, significant hepatic or renal disease |
| Osmotic (mannitol) | Volume expansion initially, dehydration/hypernatremia if excessive, nephrotoxicity in high doses | Anuria, severe HF, hyponatremia |
Source: Goldman-Cecil Medicine, Table 463
Clinical Applications
| Condition | Preferred Diuretic(s) |
|---|---|
| Hypertension | Thiazides (first-line), loop diuretics in CKD |
| Heart failure (fluid overload) | Loop diuretics; add MRA for mortality benefit |
| Cirrhosis/ascites | Spironolactone + furosemide |
| Nephrotic syndrome | Loop diuretics ± thiazide combination |
| Acute hypercalcemia | Loop diuretics (increase Ca2+ excretion) |
| Calcium nephrolithiasis | Thiazides (increase Ca2+ reabsorption) |
| Cerebral edema / raised ICP | Mannitol |
| Altitude sickness | Acetazolamide |
| Hyponatremia (euvolemic/hypervolemic) | Vaptans (tolvaptan, conivaptan) |
| Diuretic resistance | Loop + thiazide combination (metolazone + furosemide) |
| Primary hyperaldosteronism | Spironolactone |
Diuretic Resistance
Resistance occurs when the response to loop diuretics is blunted. Causes include: reduced tubular secretion (impaired organic anion transport in CKD), neurohormonal activation (RAAS, aldosterone excess), increased Na+ reabsorption in downstream nephron segments, and poor adherence to sodium restriction. Management involves combination therapy at different tubular sites - typically adding a thiazide (or metolazone) to a loop diuretic. - Goldman-Cecil Medicine; Brenner & Rector's The Kidney
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