Diuretic Therapy - Complete Notes (KDT 2nd MBBS Pharmacology)

1. Classification of Diuretics (MOA-based)

2. DIURETIC THERAPY - Complete Overview

Mechanism of Action (by class)

• Aldosterone antagonists (spironolactone, eplerenone): Block cytosolic mineralocorticoid receptors → reduce synthesis of aldosterone-induced proteins → decrease Na⁺ channels and Na⁺/K⁺ ATPase in the collecting duct → less Na⁺ reabsorption, less K⁺ secretion.
• Epithelial Na⁺ channel blockers (amiloride, triamterene): Directly block ENaC channels on apical membrane of collecting duct.

Adverse Effects of Diuretics

Therapeutic Uses of Diuretics

Complications of Diuretic Therapy

1. Electrolyte imbalances - most common: hypokalemia (loop, thiazides), hyperkalemia (K⁺-sparing)
2. Hyponatremia - especially thiazides; loop diuretics can cause it too
3. Metabolic alkalosis - loop and thiazides (loss of Cl⁻ and H⁺); metabolic acidosis with acetazolamide/K⁺-sparing
4. Volume depletion / prerenal azotemia - excessive diuresis, especially in elderly
5. Hyperuricemia / gout - loop and thiazides (compete with uric acid for secretion; ECF contraction enhances urate reabsorption)
6. Hyperglycemia - thiazides and loop diuretics (hypokalemia impairs insulin release)
7. Ototoxicity - loop diuretics (especially rapid IV furosemide, ethacrynic acid; worse with aminoglycosides)
8. Diuretic resistance - occurs with chronic loop diuretic use due to: tubular hypertrophy in distal segments, decreased renal perfusion, hypoalbuminemia (furosemide is heavily protein-bound), reduced proximal tubular secretion (NSAIDs, probenecid competition)
9. Hypomagnesemia - loop diuretics; can cause cardiac arrhythmias, refractory hypokalemia

Precautions with Diuretics

• Monitor electrolytes (Na⁺, K⁺, Mg²⁺, Cl⁻) regularly, especially with high doses
• Avoid K⁺-sparing + ACE inhibitor/ARB combination without careful monitoring - risk of life-threatening hyperkalemia
• Pregnancy: thiazides and loop diuretics generally avoided (except specific indications); can reduce placental blood flow
• Renal impairment: increase furosemide dose (less secretion into tubule); thiazides ineffective if GFR <30
• Hepatic cirrhosis: loop diuretics can precipitate hepatic encephalopathy (rapid electrolyte shifts, alkalosis → NH₃ ↑); start low, use with spironolactone
• Diabetes mellitus: thiazides and loop diuretics worsen glucose tolerance
• Gout: use with caution; loop and thiazide diuretics raise serum uric acid
• Ototoxicity: avoid rapid IV furosemide boluses; avoid concurrent aminoglycosides or cisplatin
• NSAIDs: reduce efficacy of loop diuretics by inhibiting prostaglandin synthesis (prostaglandins mediate part of the venodilatory and diuretic response)
• Lithium toxicity: diuretics reduce lithium clearance; avoid combination or monitor lithium levels closely

3. HIGH-CEILING DIURETICS - Uses

1. Acute pulmonary edema - IV furosemide is first-line; acts within 5-15 min via venodilation even before diuresis begins
2. Chronic congestive heart failure - reduce volume overload, relieve pulmonary and peripheral edema
3. Edema of nephrotic syndrome - only diuretics effective against massive edema
4. Edema/ascites of liver cirrhosis - used with spironolactone
5. Hypertension with CKD (GFR <30 mL/min) - thiazides fail; loop diuretics are the choice
6. Hypercalcemia (emergency) - given with IV saline; furosemide inhibits tubular Ca²⁺ reabsorption → calciuresis
7. Forced diuresis - in drug overdose (barbiturates, salicylates) to hasten renal elimination
8. Acute renal failure (oliguric phase) - to convert oliguria to non-oliguria (does not improve prognosis, but may ease fluid management)
9. Hyperkalemia - adjunct to increase K⁺ excretion
10. SIADH - furosemide combined with hypertonic saline (furosemide prevents further water retention)
11. Cerebral edema (adjunct to mannitol)
12. Transfusion-associated circulatory overload

4. FUROSEMIDE - Complete Pharmacology

Mechanism of Action

• This transporter normally moves 1 Na⁺, 1 K⁺, and 2 Cl⁻ from the tubular lumen into the cell, powered by the basolateral Na⁺/K⁺-ATPase gradient.
• Furosemide enters tubular fluid via proximal tubule secretion (OAT1/OAT3 on basolateral side, MRP4 on luminal side) and binds the Cl⁻-binding site of NKCC2 from the luminal side.
• Effect on TAL: Blocks Na⁺, K⁺, Cl⁻ reabsorption (~25% of filtered load)
• Destroys medullary gradient: The TAL is the site that generates the hyperosmotic medullary interstitium necessary for urine concentration. Furosemide abolishes this gradient → inability to concentrate urine → large volume of isotonic urine excreted
• Increases K⁺ secretion distally: Increased Na⁺ delivery to the collecting duct stimulates aldosterone-driven K⁺ secretion → hypokalemia
• Inhibits Ca²⁺ and Mg²⁺ reabsorption in TAL (both depend on the lumen-positive voltage generated by K⁺ back-leak) → hypocalcemia, hypomagnesemia
• Direct venodilatory action: Within minutes of IV administration, furosemide increases prostaglandin synthesis (PGE₂, PGI₂) → venodilation → reduced preload (this occurs before significant diuresis)

Pharmacokinetics

• Oral bioavailability: Variable (~60%, range 10-100%) - absorption from GI tract is unpredictable, especially in CHF (gut wall edema)
• Protein binding: ~98% (mainly albumin) - therefore less active in hypoalbuminemia
• Onset: PO: 30-60 min; IV: 5-10 min (venodilation within minutes)
• Duration: PO: 4-6 hrs; IV: 2-3 hrs
• Elimination: ~65% excreted unchanged in urine via renal tubular secretion; remainder glucuronide-conjugated in kidney; t½ ~1.5 hrs (prolonged in renal failure)
• Dose: Oral 20-80 mg OD/BD; IV 20-200 mg; pediatric 1-2 mg/kg

Indications / Therapeutic Uses

1. Edema states: CHF, nephrotic syndrome, hepatic cirrhosis (with spironolactone)
2. Acute pulmonary edema (LVF) - IV, drug of first choice
3. Hypertension - particularly with CKD (GFR <30) or resistant hypertension
4. Hypercalcemia - with IV normal saline infusion
5. Hyperkalemia - to increase K⁺ excretion
6. Forced diuresis - barbiturate and salicylate overdose
7. Acute renal failure - to maintain urine output
8. SIADH - with hypertonic saline
9. Anion exchange resin toxicity (adjunct)
10. Transfusion reactions with circulatory overload

Adverse Effects of Furosemide

• Hypokalemia - most common; can precipitate digitalis toxicity, cardiac arrhythmias
• Hyponatremia - dilutional or depletion type
• Hypochloremic metabolic alkalosis - Cl⁻ loss; H⁺ loss via K⁺/H⁺ exchange at collecting duct
• Hypomagnesemia - causes refractory hypokalemia; cardiac arrhythmias
• Hypocalcemia - unlike thiazides; can worsen in patients with hypoparathyroidism
• Hyperuricemia - competes with uric acid for tubular secretion; ECF contraction increases urate reabsorption → can precipitate gout
• Hyperglycemia - hypokalemia impairs insulin secretion; less severe than thiazides

• Dose-dependent, usually reversible (rarely permanent)
• Furosemide alters ionic composition of endolymph (the endocochlear potential depends on NKCC1 in stria vascularis)
• More common with: rapid IV bolus, high doses, concurrent aminoglycosides/cisplatin, renal failure
• Ethacrynic acid is most ototoxic among loop diuretics

• Volume depletion → prerenal azotemia
• Interstitial nephritis (rare, allergic)

• Furosemide is a sulfonamide derivative → cross-sensitivity with sulfa drugs possible
• Skin rash, eosinophilia, DRESS syndrome (rare)
• Interstitial nephritis

• Postural hypotension / dizziness (volume depletion)
• Muscle cramps (electrolyte disturbances)
• Bone marrow depression (rare)
• Photosensitivity
• GI disturbances (nausea, vomiting, diarrhea)

Drug Interactions of Furosemide

Precautions with Furosemide

1. Monitor electrolytes (K⁺, Na⁺, Mg²⁺) regularly
2. Hypokalemia: supplement KCl in patients on digoxin; add K⁺-sparing diuretic if needed
3. Renal impairment: dose may need to be increased (reduced proximal secretion into lumen); monitor creatinine
4. Hepatic cirrhosis: risk of hepatic encephalopathy due to alkalosis → NH₃ levels rise; use low doses with spironolactone
5. Diabetes mellitus: monitor blood glucose
6. Gout history: avoid or use with allopurinol
7. Avoid rapid IV bolus (>4 mg/min) to minimize ototoxicity; infuse slowly or as short infusion
8. Sulfa allergy: cross-reactivity possible (ethacrynic acid is the non-sulfonamide alternative)
9. Pregnancy category C: use only if benefits outweigh risks; can cause fetal electrolyte imbalance
10. Hypoalbuminemia (nephrotic, cirrhosis): reduced protein binding → less drug delivered to tubular lumen; may require higher doses or albumin co-administration
11. NSAIDs: avoid concurrent use (blunt diuretic response and venodilatory effect)

5. Furosemide in Left Ventricular Failure (LVF) - Pharmacological Basis

Pathophysiology of Acute LVF

How Furosemide Helps in LVF (Dual Mechanism)

• Furosemide stimulates synthesis of prostaglandins (PGE₂, PGI₂) in the vasculature
• These prostaglandins cause systemic venodilation → increased venous capacitance → reduces venous return to the heart → reduced preload
• LVEDP falls (one study: from 20 to 15 mm Hg within 5-15 minutes); pulmonary capillary wedge pressure decreases
• Venous capacitance increases by ~50%
• This phase is blocked by: NSAIDs (inhibit prostaglandin synthesis) and ACE inhibitors
• This explains why IV furosemide is beneficial in acute pulmonary edema even before urine flow begins

• Furosemide inhibits NKCC2 in TAL → massive natriuresis and water excretion
• Blood volume decreases → further reduction in preload and LVEDP
• Pulmonary venous pressure falls → resorption of pulmonary edema fluid → relief of dyspnea

Net Hemodynamic Effects

• Reduced preload (venous return, LVEDP, pulmonary capillary pressure)
• Little direct change in cardiac output (Frank-Starling predicts minimal CO change at high filling pressures)
• Combined with a vasodilator (e.g., isosorbide dinitrate) - best outcomes in acute LVF

Cautions in Acute LVF

• High-dose IV furosemide (>80 mg rapid bolus) - associated with more adverse outcomes than high-dose nitrates in comparative trials (adverse event rate 46% vs 25%)
• Preferred approach: lower dose titrated to PCWP ~16 mmHg; can give as IV infusion rather than rapid bolus
• Monitor hemodynamic and biochemical parameters during therapy
• Avoid if ECV depletion or preload-dependent right heart failure is suspected (rule out with volume bolus)

Summary Table - Furosemide at a Glance