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Renal Pharmacology: Diuretics

Overview

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I. LOOP DIURETICS (High-Ceiling Diuretics)

Prototype Drugs

• Furosemide (sulfonamide)
• Bumetanide (sulfonamide — ~40× more potent than furosemide)
• Torsemide (sulfonylurea)
• Ethacrynic acid (phenoxyacetic acid — the only non-sulfonamide; for sulfa-allergic patients)

Mechanism of Action

1. Massive ↑ NaCl delivery to distal segments → powerful natriuresis
2. Loss of the lumen-positive electrochemical potential in the TAL → ↑ Mg²⁺ and Ca²⁺ excretion (normally driven by this potential)
3. Abolition of the corticomedullary osmotic gradient → impairs urinary concentrating ability → useful in SIADH

Pharmacokinetics

• All loop diuretics act from the luminal side → must be secreted by the organic acid (OAT) transporter in the proximal tubule to reach the TAL
• Competing anions (uremic toxins, NSAIDs, probenecid) reduce tubular secretion → blunted response in renal failure or nephrotic syndrome (hypoalbuminemia reduces delivery)
• Furosemide oral absorption is highly variable (10–100%); torsemide has nearly complete oral bioavailability
• Torsemide and bumetanide are largely hepatically cleared → preferred when renal function is impaired
• Half-life increases in renal failure (except torsemide)

Pharmacodynamics & Electrolyte Effects

Clinical Indications

1. Pulmonary edema / acute decompensated heart failure — first-line; IV furosemide provides immediate preload reduction even before diuresis
2. Peripheral edema — from heart failure, cirrhosis, nephrotic syndrome, renal failure
3. Hypertension — especially with impaired renal function (eGFR <30); thiazides lose efficacy here, loop diuretics do not
4. Acute hypercalcemia — combined with IV saline, loop diuretics force calciuresis
5. Hyperkalemia — enhance urinary K⁺ excretion (with saline to maintain volume)
6. Acute renal failure — can increase urine flow and K⁺ excretion but do NOT prevent or shorten acute renal failure
7. Anion overdose (bromide, fluoride, iodide) — enhance excretion of these TAL-reabsorbed anions
8. SIADH — loop diuretics destroy the medullary gradient, forcing free water excretion
9. Forced diuresis in drug intoxication (combined with IV saline)

Adverse Effects

Drug Interactions

Typical Doses (Oral)

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II. THIAZIDE DIURETICS

Drugs in This Class

• Hydrochlorothiazide (HCTZ)
• Chlorothiazide (the only IV-available thiazide)
• Bendroflumethiazide
• Methyclothiazide

• Chlorthalidone — t½ ~47 h (binds extensively to RBCs); preferred over HCTZ for cardiovascular outcomes
• Metolazone — retains efficacy even at GFR <30; used for sequential nephron blockade with loop diuretics
• Indapamide — primarily biliary excretion; additional vasodilator properties

Mechanism of Action

• Maximum efficacy is modest (~5% of filtered Na⁺) because 90% of filtered Na⁺ is reabsorbed before reaching the DCT
• Some thiazides (chlorthalidone) retain weak carbonic anhydrase inhibitory activity → minor proximal tubular effects
• NCC expression is regulated by aldosterone
• Mutations in NCC cause Gitelman syndrome (inherited hypokalemic alkalosis with hypomagnesemia and hypocalciuria) — a "pharmacological mimic" of chronic thiazide use

Pharmacokinetics

Pharmacodynamics & Electrolyte Effects

• Loop diuretics → hypercalciuria (loss of lumen-positive potential)
• Thiazides → hypocalciuria (enhanced proximal + DCT Ca²⁺ reabsorption)

Clinical Indications

1. Hypertension — first-line therapy (ALLHAT trial showed thiazide-type diuretics equivalent or superior to ACEi and CCB for most hypertensive patients); mechanism: initial ↓ intravascular volume → later ↓ peripheral vascular resistance
2. Mild heart failure — adjunct
3. Nephrolithiasis (calcium stones, hypercalciuria) — exploit Ca²⁺-retaining effect
4. Nephrogenic diabetes insipidus (NDI) — paradoxical antidiuresis: by ↓ ECF volume, ↑ proximal reabsorption → less fluid reaches collecting duct; used for Li⁺-induced NDI
5. Osteoporosis — ↓ urinary Ca²⁺ loss; fracture risk reduction shown
6. Hypercalciuria — for kidney stone prevention

Adverse Effects

Drug Interactions

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III. POTASSIUM-SPARING DIURETICS

A. ENaC Blockers: Amiloride & Triamterene

• Weak diuretics (1–3% fractional Na⁺ excretion) — used primarily to prevent K⁺ loss from loop/thiazide therapy
• Amiloride also blocks Li⁺ entry via ENaC → useful for lithium-induced NDI; treats Liddle syndrome (constitutively active ENaC)
• Triamterene is partially metabolized in the liver; can form kidney stones (triamterene crystals)

B. Mineralocorticoid Receptor (MR) Antagonists: Spironolactone, Eplerenone, Finerenone

• Spironolactone: Steroidal MR antagonist; also weakly anti-androgenic → gynecomastia, menstrual irregularity — a distinguishing adverse effect
• Eplerenone: More selective MR antagonist → fewer sex hormone side effects; shorter t½; preferred post-MI
• Finerenone: Nonsteroidal MR antagonist; may cause less hyperkalemia; approved for CKD in type 2 diabetes (reduces albuminuria and cardiovascular events)
• Efficacy is proportional to endogenous aldosterone levels (unlike ENaC blockers)
• Slow onset and offset (24–48 h) — due to genomic mechanism
• KEY USE: Added to standard therapy in HFrEF → reduces mortality (RALES trial: spironolactone; EPHESUS: eplerenone)
• Aldosterone promotes myocardial fibrosis, vascular fibrosis, baroreceptor dysfunction — additional non-renal effects beyond diuresis

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IV. CARBONIC ANHYDRASE INHIBITORS

• Act in the PCT: inhibit luminal and cytoplasmic carbonic anhydrase → ↓ H⁺ secretion → ↓ NaHCO₃ reabsorption → alkaline urine, metabolic acidosis
• Self-limiting diuresis because the resulting acidosis limits further HCO₃⁻ excretion
• Main uses: Glaucoma (↓ aqueous humor formation), altitude sickness (prophylaxis/treatment), metabolic alkalosis, epilepsy (minor)
• Adverse effects: Hypokalemia, metabolic acidosis, phosphate wasting, paresthesias/drowsiness (high doses), hypersensitivity (DRESS syndrome), contraindicated in cirrhosis (↓ NH₄⁺ excretion → hyperammonemia)

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V. OSMOTIC DIURETICS

• Freely filtered, poorly reabsorbed → osmotically retain water in tubule lumen
• Main uses: Cerebral edema, ↓ IOP (glaucoma), dialysis disequilibrium syndrome, oliguric states, cystic fibrosis (mannitol inhaler)
• Contraindicated in: Pulmonary edema, anuric states, active intracranial bleeding (mannitol, urea)
• Adverse effects: Transient volume expansion (dangerous in CHF, pulmonary edema), hyponatremia, dehydration/hypernatremia if water loss exceeds electrolyte loss

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VI. SGLT2 INHIBITORS (Emerging Renal Diuretics)

• Inhibit SGLT2 in the PCT → ↓ glucose and Na⁺ reabsorption (90% of glucose reabsorption normally occurs here)
• Result in glucosuria, osmotic diuresis, modest natriuresis
• Primary indication: T2DM, but now first-line for HFrEF and CKD due to cardiorenal protection (EMPA-REG, CREDENCE trials)
• t½ of dapagliflozin: 10–12 h
• Not effective in advanced CKD (eGFR <30, some <45)

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VII. DIURETIC RESISTANCE

1. Diminished oral bioavailability (furosemide)
2. Impaired tubular secretion — OAT competition from uremic toxins, hypoalbuminemia (drug bound to albumin → less free drug secreted)
3. "Braking phenomenon" — compensatory ↑ Na⁺ reabsorption post-diuretic dose by RAAS/SNS activation
4. Distal tubular hypertrophy and remodeling — ↑ DCT and CD transporters compensate for chronic loop blockade

• Switch to IV (continuous infusion)
• Add a thiazide or metolazone (sequential nephron blockade — profound synergistic diuresis)
• Add an MR antagonist
• Correct hypoalbuminemia
• Restrict dietary Na⁺

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Summary Comparison: Loop vs. Thiazide

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• Katzung's Basic and Clinical Pharmacology, 16th Ed., Ch. 15, pp. 401–429
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Ch. 29, pp. 580–600
• Lippincott Illustrated Reviews: Pharmacology, Ch. 8 & 9, pp. 293–297
• Braunwald's Heart Disease, Ch. on diuretics in HF
• Harrison's Principles of Internal Medicine, 21st Ed. (images)Your credits are exhausted. Your daily credits reset tomorrow, or you can purchase a top-up for more.