Diuretics
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I now have comprehensive data from Goodman & Gilman's and Braunwald's Heart Disease to provide a thorough overview. Let me compile the full answer.
Diuretics
Diuretics increase urine output by inhibiting sodium (and water) reabsorption at specific sites along the nephron. They are classified by their primary site of action and mechanism.
Classification by Site of Action in the Nephron
| Class | Site | Transporter / Target | Example Drugs |
|---|---|---|---|
| Carbonic anhydrase inhibitors | Proximal tubule | Carbonic anhydrase (HCO3- reabsorption) | Acetazolamide |
| Osmotic diuretics | Proximal tubule + loop of Henle | Osmotic retention of water in lumen | Mannitol |
| Loop diuretics | Thick ascending limb of loop of Henle | NKCC2 (Na+-K+-2Cl- symporter) | Furosemide, Bumetanide, Torsemide, Ethacrynic acid |
| Thiazides | Distal convoluted tubule | NCC (Na+-Cl- cotransporter) | Hydrochlorothiazide, Chlorthalidone, Metolazone |
| K+-sparing (ENaC blockers) | Late distal tubule / collecting duct | ENaC (epithelial Na+ channel) | Amiloride, Triamterene |
| K+-sparing (MR antagonists) | Late distal tubule / collecting duct | Mineralocorticoid receptor | Spironolactone, Eplerenone |
| Vasopressin antagonists (Vaptans) | Collecting duct | V2 receptor (aquaporin-2) | Tolvaptan, Conivaptan |
1. Carbonic Anhydrase Inhibitors
Prototype: Acetazolamide
Mechanism: Inhibits carbonic anhydrase in the proximal tubule, blocking NaHCO3 reabsorption. This results in a bicarbonate-rich, alkaline diuresis.
Effects:
- Increases Na+, HCO3-, and H2PO4- excretion
- Causes hyperchloremic metabolic acidosis with prolonged use (loss of HCO3-)
- Weak diuretic - used mainly for chronic open-angle glaucoma (reduces aqueous humor production) and altitude sickness
Note: Metolazone also has a proximal tubule action (in addition to its distal site), causing greater phosphate loss than traditional thiazides. It is used as an adjunct to loop diuretics in resistant heart failure (HF).
2. Osmotic Diuretics
Prototype: Mannitol
Mechanism: A non-reabsorbable solute that osmotically retains water and solutes (particularly in the proximal tubule and descending limb). It also reduces medullary interstitial tonicity, impairing collecting duct water reabsorption.
Clinical uses: Cerebral edema (reduces intracranial pressure), acute oliguric renal failure, acute glaucoma. Also used in combination with furosemide in acute decompensated HF.
3. Loop Diuretics (Most Potent)
Drugs: Furosemide, Bumetanide, Torsemide, Ethacrynic acid
Mechanism: Compete with Cl- for binding to the NKCC2 transporter on the apical membrane of thick ascending limb (TAL) epithelial cells. This blocks Na+, K+, and Cl- reabsorption, abolishing the medullary concentration gradient.
Key effects:
- Increase fractional excretion of Na+ by up to 20-25% of filtered load
- Enhance free water clearance (water diuresis)
- Effective even in severe renal impairment
- Hypercalciuric (increased Ca2+ excretion - opposite of thiazides)
- Increased K+ and Mg2+ excretion
- Ototoxicity at high doses (especially ethacrynic acid and IV furosemide in renal failure) - due to inhibition of electrolyte transport in the inner ear
- Stimulate renin release via macula densa (block NaCl delivery detection)
- Furosemide also acts as a venodilator within minutes of IV administration (prostaglandin-mediated), reducing pulmonary capillary wedge pressure before diuresis even begins
Adverse effects: Hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalcemia (rare), prerenal azotemia, hyperuricemia (compete with OAT for tubular secretion), ototoxicity
Pharmacokinetics:
- All are highly protein-bound (filtered load is limited; secreted into tubular lumen via OAT1/OAT3 and MRP-4 in the proximal tubule)
- Furosemide: 65% excreted unchanged in urine; oral bioavailability variable (10-100%)
- Bumetanide and torsemide: significant hepatic metabolism; reliably high oral bioavailability
- Short elimination half-lives - "postdiuretic Na+ retention" occurs as tubular drug levels fall; overcome by dietary Na+ restriction or more frequent dosing
Clinical uses: Acute pulmonary edema, chronic HF with volume overload, hypertension in CKD stage 4-5, hypercalcemia, resistant edema
4. Thiazide Diuretics
Drugs: Hydrochlorothiazide (HCTZ), Chlorthalidone, Indapamide, Metolazone
Mechanism: Block the NCC (Na+-Cl- cotransporter) on the apical membrane of the distal convoluted tubule (DCT).
Key effects:
- Increase Na+ excretion by only 5-10% of filtered load (weaker than loop diuretics)
- Decrease free water clearance (tend to cause hyponatremia)
- Hypocalciuric (increase Ca2+ reabsorption - used in hypercalciuria and osteoporosis)
- Lose effectiveness when creatinine clearance <40 mL/min
- Hypokalemia and metabolic alkalosis (increased Na+ delivery to collecting duct drives K+ and H+ secretion)
- Hyperuricemia, hyperglycemia, hyperlipidemia
Clinical uses: Hypertension (first-line), mild heart failure, hypercalciuria/nephrolithiasis, nephrogenic diabetes insipidus (paradoxically reduce urine volume)
5. Potassium-Sparing Diuretics
a) ENaC Blockers
Drugs: Amiloride, Triamterene
Mechanism: Directly block the epithelial Na+ channel (ENaC) in the late distal tubule and collecting duct, reducing Na+ entry into cells (and thus K+ secretion).
Effects: Modest natriuresis, hyperkalemia, metabolic acidosis. Used in combination with loop or thiazide diuretics to prevent hypokalemia.
b) Aldosterone (Mineralocorticoid Receptor) Antagonists
Drugs: Spironolactone, Eplerenone
Mechanism: Compete with aldosterone for the mineralocorticoid receptor (MR). Aldosterone normally increases ENaC activity, Na+/K+-ATPase synthesis, and mitochondrial ATP production in collecting duct cells. Blocking MR reduces Na+ reabsorption and K+ secretion.
Key points:
- Spironolactone also has anti-androgen effects (gynecomastia, menstrual irregularities)
- Eplerenone is more selective for MR (fewer hormonal side effects)
- Both are cardioprotective and renoprotective via non-epithelial MR blockade
- Especially useful in secondary hyperaldosteronism (e.g., cirrhosis with ascites, HF)
- Major adverse effect: Hyperkalemia - avoid with K+ supplements or in renal failure
6. Vasopressin Antagonists (Vaptans / Aquaretics)
Drugs: Tolvaptan (V2-selective), Conivaptan (V1a/V2)
Mechanism: Block the V2 receptor in the collecting duct, preventing AVP-mediated insertion of aquaporin-2 water channels. This causes a water diuresis without natriuresis (electrolyte-free water excretion).
Uses: Euvolemic or hypervolemic hyponatremia (serum Na+ ≤125 mEq/L) in HF, SIADH, cirrhosis (after failure of fluid restriction). FDA-approved (tolvaptan, conivaptan) for clinically significant hyponatremia.
Electrolyte Effects Summary
| Class | Na+ | K+ | Ca2+ | Mg2+ | HCO3- | Uric acid |
|---|---|---|---|---|---|---|
| Carbonic anhydrase inhibitors | ++ | + | NC | V | ++ lost | Retained |
| Loop diuretics | +++ | ++ lost | ++ lost | ++ lost | + lost | Retained |
| Thiazides | + | ++ lost | - retained | + lost | + lost | Retained |
| K+-sparing (ENaC/MR) | + | - retained | NC | NC | - acidosis | NC |
Diuretic Resistance
When diuretics fail to produce expected natriuresis, consider:
- Non-compliance with Na+ restriction (dietary intake overrides diuretic effect)
- Reduced renal perfusion (HF, cirrhosis) shifting dose-response curve right
- Postdiuretic Na+ retention (short half-life agents)
- NSAID use (blocks prostaglandin-mediated actions of loop diuretics)
- Combination strategies: Adding a thiazide (especially metolazone) to a loop diuretic causes sequential nephron blockade and dramatically increases natriuresis (used in resistant HF)
Clinical Uses at a Glance
| Indication | First Choice | Alternatives |
|---|---|---|
| Hypertension | Thiazide (chlorthalidone) | Loop (if CKD), K+-sparing |
| Heart failure (volume overload) | Loop (furosemide) | + thiazide if resistant |
| Acute pulmonary edema | IV furosemide | Bumetanide, torsemide |
| Cirrhosis / ascites | Spironolactone | + furosemide |
| Hypercalcemia | Loop diuretic + saline | - |
| Hypercalciuria / stones | Thiazide | - |
| Nephrogenic DI | Thiazide | Amiloride |
| Hyponatremia (euvolemic/hypervolemic) | Tolvaptan/Conivaptan | Fluid restriction |
| Glaucoma / altitude sickness | Acetazolamide | - |
| Cerebral edema | Mannitol | - |
Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics, Ch. 29 | Braunwald's Heart Disease, Ch. 50 | Brenner and Rector's The Kidney, Ch. 50
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