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Loop Diuretics

(Based on KD Tripathi Pharmacology framework, supplemented by Katzung and Lippincott)

Definition

Loop diuretics are the most potent diuretic agents available. They act primarily on the thick ascending limb (TAL) of the loop of Henle, inhibiting the Na⁺/K⁺/2Cl⁻ cotransporter and producing copious diuresis even in patients with poor renal function.

Members / Classification

Drug	Class	Oral Daily Dose
Furosemide (Lasix)	Sulfonamide derivative	20-80 mg
Bumetanide	Sulfonamide derivative	0.5-2 mg
Torsemide	Sulfonamide derivative	5-20 mg
Ethacrynic acid	Phenoxyacetic acid derivative	50-200 mg

Note: Furosemide is the prototype and most widely used. Bumetanide is 40x more potent than furosemide on a mg-to-mg basis. Ethacrynic acid is the only non-sulfonamide loop diuretic - it is used in patients with sulfonamide allergy.

Relative potency (equivalent doses):

Furosemide 20 mg = Torsemide 10 mg = Bumetanide 0.5 mg = Ethacrynic acid ~50 mg

Site of Action

The thick ascending limb (TAL) of the loop of Henle, which normally accounts for 25-30% of filtered NaCl reabsorption. This is why loop diuretics are the most efficacious - no downstream segment can compensate for such a large sodium load.

Mechanism of Action

Loop diuretics inhibit the NKCC2 (Na⁺/K⁺/2Cl⁻) cotransporter located on the luminal membrane of the TAL of Henle's loop.

Consequences of NKCC2 inhibition:

NaCl reabsorption in the TAL is blocked
The lumen-positive potential (generated by K⁺ recycling back into the lumen) is abolished - this positive potential normally drives passive reabsorption of Ca²⁺ and Mg²⁺, so both are excreted in urine
Osmolarity of the renal medullary interstitium falls, reducing the gradient for water reabsorption from the descending limb - further enhancing diuresis
Increased Na⁺ delivery to the collecting duct stimulates Na⁺/K⁺ exchange, causing K⁺ and H⁺ wasting

Important: Loop diuretics must reach the tubular lumen via proximal tubular secretion to be effective. NSAIDs and probenecid compete for this secretory pathway and can reduce their efficacy.

Venodilatory effect: Before diuresis begins, loop diuretics induce acute venodilation via prostaglandin synthesis, reducing left ventricular filling pressure. This explains their rapid benefit in acute pulmonary edema even before urine output increases.

Pharmacokinetics

Feature	Furosemide	Bumetanide	Torsemide	Ethacrynic acid
Bioavailability	Variable (10-90%)	~80-100%	~80-100%	Good
Onset (IV)	5 min	5 min	10 min	5 min
Duration	2-6 hours	~6 hours	4-6 hours	2-4 hours
Elimination	Renal	50% renal / 50% hepatic	Mainly hepatic	Hepatic
Route	Oral / IV / IM	Oral / IV	Oral / IV	Oral / IV

Brand name "Lasix" comes from "lasts six" hours - the approximate duration of action of furosemide.

Pharmacological Actions / Effects

1. Diuresis

Causes massive natriuresis and chloruresis - greatest of all diuretics
Effective even in renal failure (unlike thiazides)
Dose-response follows a sigmoidal ("S"-shaped) curve with a threshold, steep slope, and ceiling effect

2. Electrolyte Changes

Urine: Increased Na⁺, Cl⁻, K⁺, H⁺, Ca²⁺, Mg²⁺ excretion
Plasma: Hypokalemia, hypomagnesemia, hypochloremia, metabolic alkalosis, possible hyponatremia

3. Calcium Excretion

Loop diuretics increase urinary Ca²⁺ excretion (opposite of thiazides which decrease it)
This is exploited in treating hypercalcemia

4. Uric Acid

Loop diuretics compete with uric acid for proximal tubular secretion, reducing uric acid excretion → hyperuricemia

5. Hemodynamic Effects

Venodilation reduces preload rapidly (via prostaglandins)
Reduction of pulmonary congestion and left ventricular filling pressures

Therapeutic Uses (Indications)

Indication	Notes
Acute pulmonary edema	Drug of choice; IV furosemide gives rapid relief via venodilation + diuresis
Cardiac edema / CHF	Chronic fluid management in heart failure
Renal edema / nephrotic syndrome	Effective even with low GFR
Hepatic ascites	Usually combined with spironolactone
Hypertensive emergencies	Especially with renal impairment
Hypercalcemia	Along with IV saline infusion to enhance Ca²⁺ excretion
Hyperkalemia	Enhances urinary K⁺ excretion
Acute renal failure	Converts oliguric to non-oliguric ARF; increases urine flow
Anion overdose (bromide, fluoride, iodide)	TAL is the site where these anions are reabsorbed
Forced diuresis	Drug/toxin poisoning management

Adverse Effects / Toxicity

1. Electrolyte Disturbances (Most Common)

Hypokalemia - most common; causes muscle weakness, arrhythmias, digoxin toxicity
Hypomagnesemia - urinary Mg²⁺ loss; can worsen cardiac arrhythmias
Metabolic alkalosis (hypokalemic, hypochloremic)
Hyponatremia - less common than with thiazides
Hypocalcemia - rare (usually compensated by PTH)

2. Volume Depletion

Acute hypovolemia - hypotension, shock, cardiac arrhythmias; risk with aggressive diuresis

3. Ototoxicity

Reversible or permanent hearing loss (sensorineural), tinnitus, vertigo
Particularly with rapid IV infusion, high doses, or combined with aminoglycoside antibiotics
Ethacrynic acid causes the most ototoxicity among loop diuretics

4. Hyperuricemia / Gout

Competes with uric acid for tubular secretion → may precipitate acute gout attacks

5. Hyperglycemia

Less pronounced than with thiazides, but may impair glucose tolerance

6. Hypotension

Especially on standing (orthostatic hypotension)

7. Allergy

Sulfonamide-based agents (furosemide, bumetanide, torsemide) - rarely cross-react with sulfonamide antibiotics (structurally different)
Ethacrynic acid - used when sulfonamide allergy is a concern

Drug Interactions

Interacting Drug	Effect
Aminoglycosides	Additive ototoxicity
Digoxin	Hypokalemia from loop diuretics → increased digoxin toxicity
NSAIDs	Inhibit prostaglandin synthesis → reduce loop diuretic efficacy
Probenecid	Competes for proximal tubular secretion → reduces loop diuretic action
Corticosteroids	Additive hypokalemia
Antihypertensives	Additive hypotension
Lithium	Reduced lithium clearance → lithium toxicity
Potassium-sparing diuretics	Counteract hypokalemia (used therapeutically in combination)

Contraindications

Anuria (not responding to diuretics)
Severe dehydration / hypovolemia
Hepatic coma (risk of worsening electrolyte imbalance)
Hypersensitivity (to sulfonamides for furosemide/bumetanide/torsemide)
Severe hypokalemia/hyponatremia (unless corrected first)

Furosemide - Prototype Drug Summary

Feature	Details
Drug class	Loop diuretic, sulfonamide derivative
Mechanism	Inhibits NKCC2 in TAL of loop of Henle
Route	Oral, IV, IM
Onset (IV)	5 minutes
Duration	2-6 hours
Dose	20-80 mg/day oral; 20-40 mg IV
Elimination	Primarily renal
Special feature	Venodilation precedes diuresis; effective in renal failure

Comparison: Loop vs. Thiazide Diuretics

Feature	Loop Diuretics	Thiazides
Site of action	Ascending limb of loop of Henle	Distal convoluted tubule
Potency	Highest	Moderate
Calcium excretion	Increased	Decreased
Use in renal failure	Yes	No (ineffective if GFR <30)
Ototoxicity	Yes	No
Duration	Short (2-6 hrs)	Longer (6-12 hrs)

Key Points for Exam

Loop diuretics act on the TAL by blocking NKCC2 (Na⁺/K⁺/2Cl⁻ cotransporter)
They are the most potent diuretics (25-30% of NaCl filtered load reabsorbed at TAL)
Furosemide is prototype; ethacrynic acid is the only non-sulfonamide
They increase Ca²⁺ and Mg²⁺ excretion - contrast with thiazides
Drug of choice for acute pulmonary edema - acts by venodilation even before diuresis
Major ADR: Hypokalemia and ototoxicity (especially ethacrynic acid)
NSAIDs reduce loop diuretic efficacy
Effective even in renal failure - a key advantage

Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed.; Lippincott Illustrated Reviews: Pharmacology - aligned with KD Tripathi classification framework

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