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💊 DIURETICS — Clinical Pharmacology

A Hospital-Oriented, Exam-Ready Master Guide

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics, Lippincott Illustrated Reviews Pharmacology, Braunwald's Heart Disease, Comprehensive Clinical Nephrology 7th Ed, Fuster & Hurst's The Heart 15th Ed, Brenner & Rector's The Kidney

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OVERVIEW: THE NEPHRON MAP OF DIURETICS

Clinical Pearl: The further upstream a diuretic acts, the more Na+ it can block - hence loop diuretics are the most potent ("high ceiling").

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CLASS 1: LOOP DIURETICS

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1. Drug Name & Class

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2. Mechanism of Action (Clinical Relevance)

• They inhibit reabsorption of up to 25% of filtered sodium - the highest of any diuretic class
• By blocking NKCC2, they also abolish the lumen-positive electrochemical potential that drives passive reabsorption of Ca²⁺ and Mg²⁺ - hence they increase urinary Ca²⁺ and Mg²⁺ excretion (useful in hypercalcemia)
• They must reach the tubular lumen via proximal tubule secretion - hypoalbuminemia reduces secretion (furosemide is 98% protein-bound), explaining resistance in nephrotic syndrome
• DOSE trial (2011): In acute heart failure, IV furosemide at 2.5x the oral dose gave better decongestion without worsening renal function compared to equivalent oral dosing

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3. Indications

First-Line:

• Acute pulmonary edema (emergency - IV furosemide)
• Acute decompensated heart failure (ADHF) - IV loop diuretics are the primary pharmacologic treatment
• Severe edema refractory to thiazides (cirrhosis, nephrotic syndrome, CKD)

Other Uses:

• Hypercalcemia (with IV saline)
• Hypertensive emergency (with other agents)
• Hyperkalemia (promotes K⁺ excretion)
• Forced diuresis in drug poisonings
• Oliguria/anuria (high-dose IV in AKI/CKD - controversial)
• Bronchopulmonary dysplasia (pediatric)
• Ascites (in combination with spironolactone)

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4. Drug of Choice (DOC) and Why

• DOC for acute pulmonary edema: IV Furosemide - rapid onset (5-10 min IV), potent venodilation (reduces preload) before diuresis even begins
• DOC for ADHF requiring IV therapy: Furosemide IV (most evidence) or Torsemide (higher bioavailability, once-daily dosing, preferred in outpatients)
• DOC for hypercalcemia: Furosemide IV + IV normal saline (increases urinary Ca²⁺ excretion)
• Torsemide preferred over furosemide in patients with cirrhosis or poor GI absorption (more consistent bioavailability)

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5. Adult & Pediatric Dose

Furosemide - Adult:

Furosemide - Pediatric:

Torsemide - Adult:

• Heart failure: 10-20 mg PO/IV once daily (max 200 mg/day)
• Hypertension: 5 mg PO once daily

Bumetanide - Adult:

• 0.5-1 mg IV/PO; max 10 mg/day
• Conversion: Furosemide 40 mg = Bumetanide 1 mg = Torsemide 20 mg

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6. Route of Administration

• IV (preferred in acute settings): Onset 5-10 min; peak 30 min
• PO: Onset 30-60 min; bioavailability of furosemide highly variable (10-100%)
• IM: Acceptable but slower than IV
• Continuous IV infusion: Superior to bolus dosing in resistant cases; avoids peak toxicity

Clinical Pearl: In ADHF, switch from PO to IV furosemide - gut edema reduces oral absorption dramatically. IV dose = ~half the oral dose for most patients (but 2.5× oral dose per DOSE trial for hospitalized patients with chronic furosemide use).

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7. Contraindications

• Anuria (no tubular secretion possible - drug cannot reach its site)
• Severe hypokalemia / hyponatremia (worsens electrolyte imbalance)
• Hypersensitivity to sulfonamides (for furosemide, bumetanide, torsemide - use ethacrynic acid instead)
• Hepatic coma (precipitation of encephalopathy by electrolyte disturbance)
• Concurrent use of ototoxic drugs (aminoglycosides) - relative

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8. Adverse Effects

Common:

• Hypokalemia - most common; causes ECG changes (U waves, flat T waves, prolonged QT)
• Hyponatremia
• Metabolic alkalosis (H⁺ and Cl⁻ lost with Na⁺)
• Hypomagnesemia
• Dehydration / volume depletion / orthostatic hypotension
• Hyperuricemia - competes with uric acid secretion in PCT → precipitates gout
• Hyperglycemia (mild)

Serious / Red Flags:

• Ototoxicity - dose-related, especially with high-dose rapid IV infusion; risk increased with aminoglycosides; permanent deafness possible with ethacrynic acid
  • Prevention: Infuse furosemide no faster than 4 mg/min (max 40 mg/min)
• Hypokalemia-induced arrhythmias - especially dangerous in patients on digoxin
• Hypocalcemia (rare but causes tetany)
• Interstitial nephritis (rare immune-mediated)
• Sulfonamide allergy cross-reaction (rare)

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9. Major Drug Interactions

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10. Dose Adjustment in Renal/Hepatic Impairment

• Loop diuretics remain effective in CKD because they still reach the tubular lumen (though secretion is reduced by competing organic acids in uremia)
• Higher doses required: CKD eGFR 30-60 → double usual dose; eGFR <30 → may need 80-160 mg IV per dose
• Torsemide preferred over furosemide in CKD (more consistent bioavailability)
• Loop diuretics continue to work even in severe CKD (unlike thiazides, which lose efficacy at eGFR <30)

• Use with caution - risk of hepatic encephalopathy from hypokalemia and alkalosis
• Spironolactone + furosemide combination preferred (5:2 ratio spironolactone:furosemide) for ascites
• Torsemide preferred over furosemide in cirrhosis

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11. Use in Pregnancy & Lactation

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12. Monitoring Parameters

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13. Patient Counselling Points

1. Take furosemide in the morning (or by 2 PM) - avoid nocturnal urination
2. Weigh yourself daily - report >2 kg weight gain in 2 days (fluid retention)
3. Eat potassium-rich foods - bananas, oranges, potatoes, spinach (if not on K-sparing agent)
4. Avoid NSAIDs - ibuprofen/naproxen blunt the diuretic effect
5. Rise slowly from sitting/lying - orthostatic hypotension risk
6. Do not skip doses without telling your doctor - fluid can reaccumulate rapidly
7. Report immediately: ringing in ears, muscle cramps, weakness (hypokalemia), fainting
8. Avoid alcohol - potentiates hypotension
9. Bring the medication list to every visit - many interactions

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14. Overdose/Toxicity & Antidote

• Severe volume depletion → hypotension, shock
• Severe hypokalemia → paralysis, arrhythmias, cardiac arrest
• Hyponatremia → seizures, coma
• Ototoxicity (with large doses)

• No specific antidote
• IV fluid resuscitation (0.9% NaCl)
• Potassium replacement (IV KCl for severe hypokalemia - monitor ECG)
• Magnesium supplementation
• Monitor electrolytes every 2-4 hours
• Treat arrhythmias as per ACLS

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15. Clinical Pearls & Common Prescribing Mistakes

Clinical Pearls:

1. Furosemide's dual effect in APE: It acts as a venodilator within minutes (before diuresis) - reduces preload acutely
2. "Braking phenomenon": With chronic loop diuretic use, sodium balance resets. A low-salt diet is essential to prevent antinatriuresis from overcoming the drug
3. Torsemide > furosemide in patients with poor gut absorption (cirrhosis, heart failure with gut edema)
4. Furosemide + albumin in hypoalbuminemia: In nephrotic syndrome, infusing albumin with furosemide can improve diuretic response (furosemide is 98% protein-bound; hypoalbuminemia reduces its delivery to the tubule)
5. DOSE trial bottom line: Use 2.5× the home oral dose when admitting with ADHF; high-dose gives better decongestion
6. Post-diuretic Na⁺ retention: Short-acting loop diuretics create a natriuresis window followed by Na⁺ retention. Twice-daily dosing is better than once-daily for this reason

Common Prescribing Mistakes:

• ❌ Using oral furosemide in a decompensated HF patient (gut edema = erratic absorption; switch to IV)
• ❌ Forgetting to replace K⁺ and Mg²⁺ while diuresing aggressively
• ❌ Continuing furosemide in true anuria (no tubular secretion = no effect + wasted drug)
• ❌ Rapid IV push of high-dose furosemide (>4 mg/min) → ototoxicity
• ❌ Co-prescribing furosemide + aminoglycoside without counselling for ototoxicity
• ❌ Not doubling the dose when the first dose has no effect - small increment won't help due to the steep dose-response curve

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16. Clinical Case - Loop Diuretic

• Diagnosis: Acute decompensated heart failure with pulmonary edema
• Problem with oral furosemide: Gut edema in ADHF reduces oral bioavailability - switch to IV
• Dose calculation (DOSE trial): Home dose is 80 mg PO → 2.5× = 200 mg IV; start with 80-160 mg IV bolus, reassess in 2 hours
• Initial management: O₂, sit upright, IV furosemide 80-120 mg IV bolus
• Monitoring: Urine output (target 200-300 mL/hr initially), K⁺ q6h, creatinine q12h, daily weight
• If no response in 2 hours: Double the dose (up to 160 mg IV); consider continuous infusion at 10-20 mg/hr
• K⁺ supplementation: Add IV KCl if serum K⁺ falls below 3.5 mEq/L
• Outcome: Patient passes 1.5 L urine over 4 hours, SpO₂ improves to 96%, dyspnea resolves

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CLASS 2: THIAZIDE DIURETICS

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1. Drug Name & Class

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2. Mechanism of Action (Clinical Relevance)

• Low-ceiling: Increasing the dose above therapeutic range gives no additional diuresis (unlike loop diuretics) - hence called "low-ceiling"
• Long-term BP effect: Unlike loop diuretics, thiazides also reduce peripheral vascular resistance with chronic use - the primary mechanism of antihypertensive benefit
• Ca²⁺ retention: Thiazides INCREASE Ca²⁺ reabsorption in the DCT (opposite of loop diuretics) - useful in hypercalciuria and osteoporosis
• Efficacy lost at GFR <30: Thiazides need to be secreted into the tubular lumen; at low GFR, organic acids compete, reducing delivery to their site
• Exception - Metolazone: Works even in severe CKD (eGFR <30); acts at both proximal tubule and DCT

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3. Indications

First-Line:

• Hypertension (Stage 1 and 2) - preferred in JNC/AHA/ACC guidelines, especially in elderly, Black patients, low-renin hypertension
• Heart failure - mild volume overload, outpatient management
• Isolated systolic hypertension in elderly (chlorthalidone - ALLHAT trial)

Other Uses:

• Hypercalciuria / recurrent calcium oxalate kidney stones (increases Ca²⁺ reabsorption)
• Nephrogenic diabetes insipidus (paradoxical antidiuretic effect)
• Osteoporosis (reduces urinary calcium loss)
• Edema - mild, ambulatory patients
• Pre-menstrual edema

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4. DOC and Why

• DOC for uncomplicated essential hypertension: Chlorthalidone (preferred over HCTZ due to longer half-life, better CV outcome data from ALLHAT trial, twice as potent)
• DOC for nephrogenic DI: HCTZ (paradoxically reduces urine volume by ~50% by causing mild Na depletion → reduces GFR → increases proximal tubule water reabsorption)
• DOC for hypercalciuria: Thiazides (HCTZ 25-50 mg/day)

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5. Adult & Pediatric Dose

HCTZ - Adult:

Chlorthalidone - Adult:

• Hypertension: 12.5-25 mg once daily (max 50 mg/day)

Indapamide:

• 1.25-2.5 mg PO once daily

Pediatric (HCTZ):

• 1-3 mg/kg/day PO divided q12h (max 37.5 mg in infants, 100 mg in children)

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6. Route of Administration

• Oral only (no parenteral formulation for HCTZ or chlorthalidone)
• Exception: Chlorothiazide can be given IV
• Best taken in the morning

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7. Contraindications

• Anuria
• Sulfonamide hypersensitivity (structural sulfonamide)
• Severe hypokalemia / hyponatremia
• Gout (relative - hyperuricemia worsens gout)
• Pregnancy (relative - may reduce placental perfusion)
• eGFR <30 mL/min/1.73m² - most thiazides lose efficacy (use metolazone or loop diuretic instead)

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8. Adverse Effects

Common (Mnemonic: GLUCH - see mnemonics section):

• Hypokalemia (less severe than loop diuretics)
• Hyponatremia (most common cause of drug-induced hyponatremia, especially in elderly women)
• Hyperuricemia / Gout
• Hyperglycemia (impairs insulin secretion from pancreatic β-cells; worsens diabetes)
• Hyperlipidemia (↑LDL, ↑triglycerides - mild, transient)
• Hypercalcemia (increases Ca²⁺ reabsorption)
• Hypomagnesemia
• Sexual dysfunction (male - reduced libido, erectile dysfunction)

Serious / Red Flags:

• Severe hyponatremia in elderly women on thiazides (can cause lethargy, seizures, death) - most dangerous ADR
• Pancreatitis (rare)
• Photosensitivity
• Thrombocytopenia (rare, immune-mediated)

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9. Major Drug Interactions

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10. Dose Adjustment in Renal/Hepatic Impairment

• CKD eGFR <30: Most thiazides ineffective - switch to loop diuretics; metolazone exception
• Metolazone: Works in severe CKD; useful as "sequential nephron blockade" when added to loop diuretics
• Hepatic impairment: Use with caution; risk of hypokalemia precipitating hepatic encephalopathy

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11. Use in Pregnancy & Lactation

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12. Monitoring Parameters

• Serum K⁺ - every 1-4 weeks initially, then 3-6 monthly
• Serum Na⁺ - especially in elderly females (highest risk of severe hyponatremia)
• Fasting blood glucose / HbA1c - monitor diabetics closely
• Uric acid - in patients with gout history
• Serum creatinine / BUN - at baseline, periodically
• Serum Ca²⁺ - if on vitamin D supplements
• Lipid panel - periodic (mild effect, usually not clinically significant)
• Blood pressure - at each visit

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13. Patient Counselling Points

1. Take in the morning - prevent nighttime urination
2. Do not take salt substitutes (KCl-based) without medical advice
3. Sun protection - photosensitivity; use sunscreen
4. Report: muscle weakness, cramps (hypokalemia), excessive thirst (hyperglycemia), joint pain (gout)
5. Diabetics: Check blood sugar more frequently - thiazides can worsen glycemia
6. Gout patients: Inform doctor before starting - may precipitate gout attack
7. Long-term therapy: Don't stop suddenly - BP will rebound
8. Hydration: Drink adequate fluids; avoid alcohol

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14. Overdose/Toxicity

• Primarily electrolyte disturbances: severe hyponatremia, hypokalemia
• Volume depletion, hypotension
• No antidote - supportive care: IV fluids, electrolyte replacement

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15. Clinical Pearls & Common Prescribing Mistakes

Pearls:

1. Chlorthalidone > HCTZ for hypertension (twice as potent, longer-acting, better cardiovascular outcome data from ALLHAT - reduced stroke by 15% vs amlodipine/lisinopril)
2. Thiazide + K-sparing diuretic combination prevents hypokalemia (e.g., HCTZ + amiloride = co-amilozide/Moduretic)
3. Metolazone + furosemide = "sequential nephron blockade" - used for diuretic resistance; blocks both DCT and TAL → potent synergistic diuresis
4. Nephrogenic DI paradox: Mild Na depletion → reduced GFR → increased PCT reabsorption → decreased delivery to collecting duct → less free water lost
5. Thiazides conserve calcium (unlike loop diuretics) - preferred in patients with osteoporosis

Common Prescribing Mistakes:

• ❌ Using HCTZ when chlorthalidone is available (chlorthalidone has better outcomes)
• ❌ Using thiazides in eGFR <30 (they won't work)
• ❌ Prescribing thiazides to a gout patient without prophylaxis
• ❌ Missing severe hyponatremia in elderly women on thiazides (check Na⁺ at 2 weeks)
• ❌ Starting thiazide in a patient already on lithium without monitoring Li⁺ levels

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16. Clinical Case - Thiazide

• Diagnosis: Stage 2 hypertension, T2DM, recurrent hypercalciuria/stones
• First choice for uncomplicated HTN + Black ethnicity or age >55: Chlorthalidone 12.5-25 mg PO OD (JNC/AHA guideline preferred thiazide)
• Added benefit here: Thiazide INCREASES Ca²⁺ reabsorption → reduces urinary calcium → prevents recurrent kidney stones - dual benefit
• Concern: T2DM - thiazides worsen glycemia; monitor HbA1c, consider low dose (12.5 mg)
• Monitor: BP at 4 weeks, K⁺ and Na⁺ at 2 weeks, uric acid, fasting glucose
• Patient counselling: Take in morning, potassium-rich diet, report muscle cramps or excessive thirst

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CLASS 3: POTASSIUM-SPARING DIURETICS

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1. Drug Name & Class

• Spironolactone - steroidal, nonselective
• Eplerenone - steroidal, selective (no antiandrogenic effects)
• Finerenone - nonsteroidal MRA (newest, approved for CKD in DM)

• Amiloride - direct epithelial Na⁺ channel (ENaC) blocker
• Triamterene - direct ENaC blocker

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2. Mechanism of Action (Clinical Relevance)

Spironolactone / Eplerenone:

• Competitively block aldosterone receptors (mineralocorticoid receptors, MR) in principal cells of the collecting duct and late distal tubule
• By blocking aldosterone, they reduce synthesis of epithelial Na⁺ channels (ENaC) and Na⁺/K⁺-ATPase → less Na⁺ reabsorption, less K⁺ secretion
• Beyond diuresis: MRAs block cardiac and vascular fibrosis mediated by aldosterone (RALES, EPHESUS, EMPHASIS-HF trials) → reduced mortality in HFrEF

Amiloride / Triamterene:

• Directly block ENaC (epithelial Na⁺ channels) in the luminal membrane of collecting duct principal cells
• Aldosterone-independent mechanism

• These drugs prevent K⁺ loss - useful when combined with K-wasting diuretics
• The diuretic effect is WEAK (only 2-3% of filtered Na⁺ is handled here)
• Primary value of MRAs in HF is anti-fibrotic/neurohormonal blockade, not diuresis

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3. Indications

Spironolactone:

• Heart failure (HFrEF) - reduce mortality (RALES trial: 30% mortality reduction)
• Hyperaldosteronism (primary - Conn syndrome; secondary)
• Cirrhotic ascites - first-line (in combination with furosemide in 100:40 mg ratio)
• Resistant hypertension (4th-line add-on)
• Edema from secondary hyperaldosteronism
• Hirsutism / PCOS (off-label - antiandrogenic effect)

Eplerenone:

• Post-MI heart failure (EPHESUS trial)
• HFrEF (EMPHASIS-HF trial)
• Preferred over spironolactone in males (no gynecomastia)

Amiloride:

• Combined with thiazides/loop diuretics to prevent hypokalemia
• Lithium-induced nephrogenic DI (blocks Li⁺ entry via ENaC into tubular cells)
• Liddle syndrome (constitutive ENaC activation)

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4. DOC and Why

• DOC for cirrhotic ascites: Spironolactone (± furosemide) - aldosterone levels are high in cirrhosis; MRAs target the pathophysiology directly
• DOC for primary hyperaldosteronism (bilateral adrenal hyperplasia): Spironolactone or eplerenone - medical management of non-surgical cases
• DOC for HFrEF (EF ≤35%) to reduce mortality: Spironolactone (RALES) or eplerenone (EMPHASIS-HF) - added to ACEi/ARB + beta-blocker

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5. Adult & Pediatric Dose

Spironolactone - Adult:

Eplerenone - Adult:

• Post-MI HF: 25 mg/day → titrate to 50 mg/day
• Hypertension: 50 mg OD (max 100 mg/day)

Amiloride - Adult:

• 5-10 mg/day PO (max 20 mg/day)

Pediatric (Spironolactone):

• 1-3 mg/kg/day PO divided q6-12h (max 100 mg/day)

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6. Route of Administration

• Oral only for all potassium-sparing diuretics
• Spironolactone: Take with food (increases bioavailability by ~30%)
• Onset of spironolactone: Slow (2-3 days to full effect) - accounts for aldosterone receptor resynthesis time

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7. Contraindications

• Hyperkalemia (K⁺ >5.5 mEq/L) - absolute
• Severe renal impairment (eGFR <30) - high risk of dangerous hyperkalemia
• Anuria
• Concurrent use of ACEi + ARB + MRA (triple RAAS blockade = very high hyperkalemia risk)
• Addison's disease (already has low aldosterone - MRA can cause severe hyponatremia and hyperkalemia)

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8. Adverse Effects

Common:

• Hyperkalemia - most dangerous; life-threatening if severe
• Hyponatremia
• Metabolic acidosis (mild - reduced H⁺ excretion)

Spironolactone-Specific (antiandrogenic effects):

• Gynecomastia in males (most common reason for switching to eplerenone)
• Menstrual irregularities / dysmenorrhea in women
• Decreased libido, impotence in males
• Breast tenderness

Serious / Red Flags:

• Severe hyperkalemia → peaked T waves, widened QRS, ventricular fibrillation → cardiac arrest
• Hyponatremia in cirrhosis

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9. Major Drug Interactions

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10. Dose Adjustment in Renal/Hepatic Impairment

• Avoid in eGFR <30 mL/min (hyperkalemia risk is prohibitive)
• If eGFR 30-49: use cautiously with close K⁺ monitoring (check at 1, 4, 8 weeks)
• Finerenone: has less hyperkalemia risk than spironolactone, approved down to eGFR 25 in DM-CKD

• Spironolactone is the preferred agent in cirrhosis (high aldosterone state)
• Risk of hepatic encephalopathy from hyponatremia - monitor carefully
• Reduce dose if Na⁺ <125 mEq/L → suspend

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11. Use in Pregnancy & Lactation

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12. Monitoring Parameters

• Serum K⁺ at baseline, 1 week, 4 weeks, then every 3-6 months
• Serum Na⁺ - especially in cirrhosis
• Serum creatinine - at baseline and with any dose change
• ECG - if K⁺ rises >5.5 (peaked T waves = K⁺ toxicity)
• Blood pressure - at each visit
• Gynecomastia - clinical examination in males on spironolactone

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13. Patient Counselling Points

1. Avoid potassium-rich salt substitutes (they are KCl - can cause dangerous hyperkalemia)
2. Avoid NSAIDs - increase hyperkalemia risk
3. Take spironolactone with food - improves absorption
4. Report immediately: palpitations, muscle weakness, tingling (hyperkalemia warning signs)
5. Males: Gynecomastia is common with spironolactone - report to consider switching to eplerenone
6. Don't miss K⁺ blood tests - essential safety monitoring
7. Inform all prescribers about this drug (risk with ACEi/ARB combination)

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14. Overdose/Toxicity

• Primary threat: Severe hyperkalemia → cardiac arrest
• Management: IV calcium gluconate (membrane stabilization), insulin + dextrose, sodium bicarbonate, salbutamol (all shift K⁺ intracellularly), Kayexalate or patiromer (remove K⁺), dialysis if severe
• Monitor on continuous cardiac monitor

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15. Clinical Pearls & Common Prescribing Mistakes

Pearls:

1. Spironolactone in HF is anti-fibrotic, not primarily diuretic - the mortality benefit (RALES: 30% relative risk reduction) comes from blocking aldosterone-mediated myocardial fibrosis
2. Ascites dosing ratio: Spironolactone:Furosemide = 100:40 mg (maintains normokalemia while achieving diuresis)
3. Spironolactone onset is slow (2-3 days) - do not titrate too quickly; requires time for aldosterone receptors to be re-synthesized
4. Eplerenone = clean MRA: No sex hormone side effects; preferred in males and post-MI
5. Amiloride in Lithium-DI: Lithium enters collecting duct cells via ENaC; amiloride blocks ENaC → prevents Li⁺ intracellular accumulation → treats nephrogenic DI
6. Finerenone (2021): First nonsteroidal MRA; approved for CKD + T2DM (FIDELIO-DKD trial) - reduces renal progression and CV events

Common Prescribing Mistakes:

• ❌ Prescribing spironolactone with ACEi+ARB together ("triple RAAS blockade") → fatal hyperkalemia
• ❌ Not checking K⁺ before starting in CKD patients
• ❌ Giving spironolactone to a pregnant woman (teratogenic)
• ❌ Using high-dose spironolactone in cirrhosis with Na⁺ <125 (risk of acute hyponatremia)
• ❌ Forgetting the slow onset - impatient titration

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16. Clinical Case - K-Sparing Diuretic

• Question: Should we add an MRA?
• RALES trial criteria met: HFrEF EF <35%, NYHA III-IV, on ACEI + BB → add spironolactone 25 mg/day
• Caution: eGFR 52 → acceptable (>30); K⁺ 4.2 → acceptable (<5.0); monitor K⁺ at 1 week
• Not eplerenone here? Either works; eplerenone preferred in males to avoid gynecomastia, but cost is higher
• Also add furosemide 40 mg PO BD for the symptomatic edema
• Monitoring plan: K⁺ and creatinine at 1 week, 4 weeks; daily weight
• Outcome: K⁺ rises to 4.8 (acceptable); NYHA improves to Class II; edema resolves over 4 weeks

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CLASS 4: CARBONIC ANHYDRASE INHIBITORS

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1. Drug Name & Class

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2. Mechanism of Action

• Increased urinary HCO₃⁻, Na⁺, K⁺, water excretion
• Reduced aqueous humor production (in the eye)
• Metabolic acidosis (self-limiting; HCO₃⁻ stores deplete → loss of efficacy after 2-3 days)

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3. Indications

• Acute angle-closure glaucoma (reduce IOP acutely before surgery)
• Altitude sickness / Acute mountain sickness (prophylaxis and treatment - stimulates respiratory alkalosis compensation)
• Idiopathic intracranial hypertension (pseudotumor cerebri)
• Metabolic alkalosis in mechanically ventilated patients (when ventilator cannot correct)
• Urinary alkalinization (in salicylate/phenobarbital overdose)
• Epilepsy (adjunct - especially catamenial epilepsy, petit mal)
• Familial periodic hypokalemic paralysis

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4. Dose

• Glaucoma: 250-1000 mg/day PO in divided doses; 500 mg IV for acute attack
• Altitude sickness: 125-250 mg PO q12h, starting 24h before ascent
• IIH: 500-2000 mg/day PO
• Alkalosis: 250-375 mg PO/IV q8-12h

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5. Adverse Effects & Contraindications

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CLASS 5: OSMOTIC DIURETICS

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1. Drug Name & Class

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2. Mechanism of Action

• Non-reabsorbable osmotically active solutes
• Act in proximal tubule and descending loop - limit water reabsorption by creating osmotic gradient in tubular lumen
• Extract water from intracellular compartments → expand ECF volume before diuresis
• Reduce medullary tonicity → limit ADH-driven water reabsorption
• Increase urinary excretion of nearly all electrolytes (Na⁺, K⁺, Ca²⁺, Mg²⁺, HCO₃⁻)

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3. Indications

• Cerebral edema / raised ICP (traumatic brain injury, post-neurosurgery) - reduces brain mass
• Acute angle-closure glaucoma (reduces IOP rapidly)
• Prevention/treatment of AKI in surgeries (renal transplant, cardiac, vascular - controversial)
• Dialysis disequilibrium syndrome - prevents osmotic shift of water into brain during dialysis
• Hemolytic transfusion reactions - forced diuresis to flush free Hgb
• Drug overdose - forced diuresis (combined with alkalinization for salicylates)
• Cystic fibrosis - inhaled mannitol (FDA approved) to improve mucus clearance

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4. Dose

• Cerebral edema: 0.25-2 g/kg IV over 30-60 min; may repeat q4-8h
• Acute glaucoma: 1.5-2 g/kg IV over 30-60 min
• AKI prevention: 0.5-1 g/kg IV pre-procedure

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5. Adverse Effects & Contraindications

• Initial ECF expansion (before diuresis) → acute pulmonary edema (most dangerous)
• Dehydration / volume depletion (if used excessively)
• Electrolyte disturbances (hypo/hypernatremia, hypokalemia)
• Rebound increased ICP (paradoxically in some patients - rare)

• Pulmonary edema / Congestive heart failure (ECF expansion can be catastrophic)
• Active intracranial bleeding (ECF expansion may worsen)
• Anuria (cannot excrete mannitol → accumulates → dangerous ECF expansion)
• Severe dehydration

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MASTER COMPARISON TABLE — All Diuretic Classes

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MNEMONICS FOR QUICK REVISION

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1. Loop Diuretic ADRs: "OHHHH DAMMIT"

• Ototoxicity
• Hypokalemia
• Hyponatremia
• Hypomagnesemia
• Hyperglycemia (mild)
• Hyperuricemia / gout
• Dehydration
• Alkalosis (metabolic)
• Metabolic disturbances
• Metabolic alkalosis
• Interstitial nephritis (rare)
• Tetany (hypocalcemia, rare)

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2. Thiazide ADRs: "GLUCH + H"

• Gout (hyperuricemia)
• Lipids ↑ (hyperlipidemia)
• Uric acid ↑
• Calcium ↑ (hypercalcemia - retains Ca)
• Hyperglycemia / hypokalemia / hyponatremia
• Hypomagnesemia

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3. K-Sparing ADRs: "SPEGH"

• Spironolactone causes gynecomastia
• Periods irregular (menstrual disturbance)
• Electrolyte: hyperkalemia (main risk)
• Gyn effects (antiandrogenic)
• Hyponatremia

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4. Diuretic Sites on the Nephron: "People Always Love Diuretics Carefully"

• PCT = carbonic anhydrase inhibitors (Proximal)
• Ascending Loop = loop diuretics
• Loop descending = osmotic diuretics (also PCT)
• DCT = thiazides (Distal)
• Collecting duct = K-sparing

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5. Loop Diuretics Members: "FEBT"

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6. Conversion (Loop Diuretics equivalence):

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7. Potassium effect quick recall:

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8. Thiazides - Unique actions remembered by "CHID":

• Calcium retention (good for osteoporosis / stones)
• Hyperuricemia
• Ineffective in eGFR <30
• Diabetes worsening (hyperglycemia)

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9. Spironolactone clinical uses: "ARCH"

• Ascites (cirrhosis - first-line)
• Resistant hypertension
• Conn syndrome (hyperaldosteronism)
• Heart failure (reduce mortality)

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10. Mannitol contraindications: "PAC"

• Pulmonary edema
• Anuria
• CHF (congestive heart failure)

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QUICK REFERENCE - EXAM BULLETS

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💊 DIURETICS — Concise Clinical Pharmacology

OPD · IPD · Emergency · Internship · University Exams

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📍 NEPHRON MAP — Anchor Every Drug Here First

PCT (65% Na)         Loop/TAL (25% Na)      DCT (5-8% Na)      Collecting Duct (2-3%)
     ↓                      ↓                     ↓                      ↓
Acetazolamide          LOOP DIURETICS          THIAZIDES           K-SPARING
Mannitol            (Furosemide, Torsemide)  (HCTZ, Chlorthalidone) (Spiro, Amiloride)

Rule: The more upstream the site → the more Na⁺ blocked → the more potent the diuretic. Loop > Thiazide > K-sparing in diuretic potency.

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🔵 CLASS 1 — LOOP DIURETICS

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Drug Class & Members

Furosemide 40 mg = Torsemide 20 mg = Bumetanide 1 mg

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Mechanism of Action

Also abolish the lumen-positive potential → increase urinary Ca²⁺ and Mg²⁺ excretion (clinically useful in hypercalcaemia).

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Main Indications

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Drug of Choice (DOC)

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Adult Dose

⚠️ DOSE Trial Key Point: In hospitalised ADHF, give 2.5× the oral dose IV → better decongestion without harming kidneys.

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Major Contraindications

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Serious Adverse Effects (Red Flags) 🚩

⚠️ Infuse furosemide no faster than 4 mg/min to prevent ototoxicity.

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Important Drug Interactions

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Patient Counselling Points

1. Take in the morning (or before 2 PM) — avoid waking up at night to urinate
2. Weigh daily — report >2 kg gain in 2 days (fluid returning)
3. Eat potassium-rich foods — bananas, oranges, spinach, potatoes (if not on K-sparing drug)
4. Avoid NSAIDs — they block the diuretic effect
5. Rise slowly from bed — risk of fainting (orthostatic hypotension)
6. Report immediately: ringing in ears (ototoxicity), muscle cramps/weakness (hypokalemia), excessive thirst/dizziness
7. Diabetics: monitor blood sugar more frequently
8. Do not stop suddenly without telling your doctor

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🏥 Clinical Case

A 68-year-old male with ischemic cardiomyopathy (EF 28%), on oral furosemide 80 mg/day at home, presents to casualty with acute dyspnea, SpO₂ 87%, bilateral crackles, and raised JVP.

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🟡 CLASS 2 — THIAZIDE DIURETICS

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Drug Class & Members

Chlorthalidone > HCTZ for hypertension: longer half-life, better CV outcomes (ALLHAT trial).

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Mechanism of Action

Ca²⁺ retention: Thiazides INCREASE Ca²⁺ reabsorption in the DCT — opposite of loop diuretics. (Exam-favourite!)

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Main Indications

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Drug of Choice (DOC)

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Adult Dose

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Major Contraindications

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Serious Adverse Effects (Red Flags) 🚩

⚠️ High-yield exam fact: Thiazides cause hyponatremia (elderly women), hypokalaemia, hyperglycaemia, hyperuricaemia, hypercalcaemia — "GLUCH" mnemonic below.

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Important Drug Interactions

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Patient Counselling Points

1. Take in the morning — prevents nocturia
2. Potassium-rich diet — if not on K-sparing agent
3. Sun protection — photosensitivity; apply sunscreen
4. Diabetics — check blood sugar more frequently; thiazides can raise glucose
5. Gout patients — report joint pain immediately
6. Elderly women — report confusion, excessive weakness (hyponatremia warning)
7. Avoid salt substitutes (KCl-based) without medical advice
8. Do not stop suddenly — BP will rebound

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🏥 Clinical Case

A 56-year-old woman with T2DM and recurrent kidney stones (calcium oxalate) presents with BP 158/96 mmHg, eGFR 78, K⁺ 4.1, no target organ damage.

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🟢 CLASS 3 — POTASSIUM-SPARING DIURETICS

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Drug Class & Members

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Mechanism of Action

Beyond diuresis (MRAs): Block aldosterone-mediated cardiac and vascular fibrosis → reduce mortality in heart failure (RALES, EPHESUS, EMPHASIS-HF trials).

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Main Indications

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Drug of Choice (DOC)

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Adult Dose

Spironolactone onset = 2–3 days (wait for aldosterone receptors to be re-synthesised before judging effect).

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Major Contraindications

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Serious Adverse Effects (Red Flags) 🚩

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Important Drug Interactions

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Patient Counselling Points

1. Avoid potassium-rich salt substitutes (they contain KCl — can cause dangerous hyperkalemia)
2. Do not take K⁺ supplements without explicit medical advice
3. Avoid NSAIDs — increase risk of high potassium
4. Take spironolactone with food — improves absorption by ~30%
5. Report immediately: palpitations, muscle weakness, tingling (all signs of hyperkalemia)
6. Males on spironolactone: Breast tenderness/swelling (gynecomastia) — tell your doctor; alternative available (eplerenone)
7. Do not miss blood tests — K⁺ must be checked at 1 week, 4 weeks, then every 3–6 months
8. Tell all your doctors — dangerous if combined with ACE inhibitors + ARBs

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🏥 Clinical Case

A 74-year-old male with HFrEF (EF 30%), NYHA Class III, already on ramipril 10 mg + carvedilol 25 mg BD. Serum K⁺ = 4.3, creatinine = 1.3 mg/dL, eGFR = 54. BNP = 920. Still breathless and has ankle oedema.

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🟣 CLASS 4 — CARBONIC ANHYDRASE INHIBITORS

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🏥 Clinical Case

A 28-year-old trekker planning to climb to 4500 m in 2 days asks for prevention of altitude sickness.

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🟠 CLASS 5 — OSMOTIC DIURETICS

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🏥 Clinical Case

A 35-year-old man is brought to casualty after a road traffic accident. CT head shows diffuse cerebral oedema. GCS = 9. BP 150/90.

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📊 MASTER COMPARISON TABLE

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🧠 MNEMONICS — QUICK REVISION

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1. Loop Diuretic ADRs → "OHH DAMMIT"

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2. Thiazide ADRs → "GLUCH"

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3. K-Sparing (Spironolactone) ADRs → "MAGIC"

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4. Spironolactone uses → "ARCH"

• A — Ascites (cirrhosis)
• R — Resistant hypertension
• C — Conn's syndrome (primary hyperaldosteronism)
• H — Heart failure (HFrEF — reduces mortality)

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5. Loop Diuretic Members → "FEBT"

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6. K⁺ Rule — Easiest to Remember:

"Loop and Thiazide = Lose K⁺" / "K-sparing = Keep K⁺"

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7. Thiazide Unique Properties → "CHID"

• C — Calcium retained (good for stones, osteoporosis)
• H — Hyperuricemia (precipitates gout)
• I — Ineffective in eGFR <30
• D — Diabetes worsening (hyperglycemia)

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8. Mannitol Contraindications → "PAC"

• P — Pulmonary oedema
• A — Anuria
• C — CHF (Congestive Heart Failure)

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9. Loop Equivalence — "40-20-1"

Furosemide 40 mg = Torsemide 20 mg = Bumetanide 1 mg

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10. Diuretic Sites (Proximal → Distal) → "PALTC"

• P — PCT = acetazolamide, mannitol
• A — Ascending loop = loop diuretics
• L — Loop descending = mannitol (also)
• T — Thin/distal = thiazides (DCT)
• C — Collecting duct = K-sparing

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🔑 HIGH-YIELD EXAM BULLETS (1-LINERS)

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