Loop Diuretic

Indications

Symptomatically reduce pulmonary and Peripheral Edema
1. Congestive Heart Failure
2. Nephrotic Syndrome
3. Renal Insufficiency (GFR<30%)
  1. Other Diuretics (e.g. Thiazide Diuretics) are ineffective at low GFR
  2. Loop Diuretics (esp. Furosemide) may be used to prevent weight gain between Dialysis runs
Emergency Management of Pulmonary Congestion (Lasix)
1. Left Ventricular Dysfunction (CHF)

Contraindications

Sulfonamide Allergy

Precautions

All Loop Diuretics except Torsemide need to be dosed twice daily for effect
Loop Diuretics are associated with significant Electrolyte abnormalities and volume depletion (FDA black box warning)
Loop Diuretics have a threshold dose, below which they have no effect
Loop Diuretics have a ceiling dose, above which increasing dose has little effect
1. Better in these cases to increase frequency at the ceiling dose

Mechanism

Loop Diuretics are the most potent Diuretics
Potently inhibits reabsorption of Sodium and chloride
1. Action at ascending loop of Henle in glomerulus (Inhibits Na+/K+/Cl+ co-transporter)
2. Results in increased urinary Sodium and water excretion
Direct Venodilation in Pulmonary Edema
1. Reduces venous return (Preload)
2. Reduces Central Venous Pressure
3. Synergistic effect with Morphine and Nitroglycerin
Reduces Intravascular Volume
1. Reduces Cardiac Output
2. Beware Hypotension in Myocardial Infarction

Preparations
Relative Potency (40 to 20 to 1)

Furosemide (Lasix) 40 mg IV (equivalent to 80 mg oral, but variable bioavailability)
Torsemide (Demadex) 20 mg IV (equivalent to 20 mg oral)
Bumetanide (Bumex) 1 mg IV (equivalent to 1 mg oral)
References
1. Pham (2017) Card Fail Rev 3(2):108-122 +PMID: 29387462 [PubMed]

Preparations
Bumetanide (Bumex)

Oral dosing (adults)
1. Start: 0.5 to 1 mg orally twice daily
2. Maximum: 10 mg/day
3. Duration: 4-6 hours
Intravenous dosing (adults)
1. Start: 1 mg IV/dose (Max: 4-8 mg/dose)
Intravenous Infusion (adults)
1. Load: 1 mg IV
2. Rate: 0.5 to 2 mg/hour IV

Preparations
Furosemide (Lasix)

Precautions
1. Lasix (named for LAst SIX) is only effective for 6 hours
2. Optimal dosing is given at least twice daily (patient otherwise is Sodium avid 18 hours/day)
3. Half-life: 1 to 1.5 hours
4. Highly variable bioavailability on oral ingestion (varies between 10 and 90%)
  1. Increased bioavailability when taken with meals
  2. Gastrointestinal absorption is markedly decreased in severe edema
  3. Contrast with Torsemide which has excellent and consistent bioavailability
5. Higher doses (2-3x) required for Nephrotic Syndrome
6. Renal dysfunction results in decreased response and increased half-life
  1. Only 15-20% of Furosemide dose is delivered to the renal tubule in stage 5 CKD
Oral Dosing (adults)
1. Start: 20-40 mg orally daily to twice daily
2. Maximum: 600 mg/day (rare to exceed 400 mg/day)
3. Peak effect at 1 to 1.5 hours after oral dose
4. Duration: 6-8 hours
Intravenous Dosing
1. Intravenous dose is typically one half of oral dose (in exacerbations, the oral dose is often used IV)
2. Administer slowly over 1-2 minutes
  1. Doses higher than 80 mg should infuse slowly to avoid Ototoxicity
3. Bolus: 20-40 mg IV (0.5-1.0 mg/kg, max 2 mg/kg)
4. Infusion: 0.25 to 0.75 mg/kg/hour
5. Onset: Diuresis starts within 10 minutes
6. Peak effect in 10-30 minutes
7. Duration: 6 hours
8. Peak Diuretic effect of repeat dosing is 25% of the first dose
  1. Compensatory Sodium retention may be overcome by frequent IV doses or continuous infusion
9. Maximum effective dose (ceiling dose)
  1. Chronic Kidney Disease or Nephrotic Syndrome: 80 to 200 mg
  2. Congestive Heart Failure or Cirrhosis: 40-80 mg
Intravenous Infusion
1. Background
  1. More effective at maintaining a constant increased Urine Output with less adverse effects (e.g. Ototoxicity)
  2. Maximum diuresis at 3 hours after continuous infusion started
2. Loading dose: 40-200 mg
  1. Loading doses higher than 80 mg should infuse slowly to avoid Ototoxicity
3. Infusion dose
  1. Start: 10-20 mg/hour IV
  2. Maximum: 40 mg/hour IV
  3. Very high dose Furosemide infusions (4 mg/min) risk Ototoxicity

Preparations
Torsemide (Demadex)

Background
1. Oral Bioavailability 80-90% consistently, even in severe edema (contrast with Furosemide)
2. Once daily dosing (contrast with all other Loop Diuretics)
3. Half-life: 3 to 4 hours (doubled in hepatic dysfunction)
Oral Dosing (adults)
1. Start: 10-20 mg orally daily
2. Maximum: 200 mg/day
3. Duration: 12-16 hours
Intravenous Dosing (adults)
1. Start: 10 mg IV
2. Maximum: 100-200 mg/day
Intravenous Infusion (adults)
1. Load: 20 mg
2. Rate: 5-20 mg/hour

Preparations
Ethacrynic Acid (Edecrin)

Oral Dosing
1. Start: 25 mg orally daily
2. Maximum: 200-400 mg divided 2-3 times daily
Intravenous Dosing
1. Start: 0.5 to 1 mg/kg IV up to 100 mg/dose

Adverse Effects

Risk of central volume depletion (Dehydration, Hypotension and contraction alkalosis)
Renal dysfunction
1. Minimize dosage when starting an ACE Inhibitor
2. Avoid NSAIDs
Hypersensitivity (esp. Sulfonamide)
1. Ethacrynic Acid is the only non-sulfonamide Loop Diuretic
Electrolyte abnormalities
1. Metabolic Alkalosis
2. Hypokalemia
3. Hypomagnesemia
4. Hypocalcemia
5. Hyponatremia
6. Hyperosmolality
Ototoxocity
1. Typically reversible (but permanent Deafness may occur)
2. Risk Factors
  1. Higher Loop Diuretic serum concentrations (esp. high dose Furosemide)
  2. Renal dysfunction
  3. Concurrent Aminoglycoside use
  4. More common with Ethacrynic Acid

Mechanism
Loop Diuretic Resistance

Renal Insufficiency
1. Renal Toxin (e.g. NSAID) decreases GFR
2. NSAIDs
Decreased Diuretic oral absorption
Structural changes in the Kidney
1. Normal aging
2. Distal tubular hypertrophy (long term use)
  1. Consider adding a Thiazide Diuretic
  2. Counters distal tubular reabsorption
  3. Significantly boosts Loop Diuretic effect
Increased Dietary Sodium intake
1. CHF patient is an avid Sodium retainer
2. Sodium is common in most foods
  1. Chicken Noodle soup = 1200 meq
  2. Milk 122 meq
  3. Big Mac 1010 meq
  4. Canned Spinach 910 meq

Drug Interactions

Warfarin
1. Furosemide displaces Warfarin from Protein binding and increases Warfarin levels and INR
Cyclosporine
1. Cyclosporine decreases Uric Acid excretion, and increased gout risk when used with Furosemide

References

Won Oh (2015) Electrolyte Blood Press 13(1):17-21 +PMID: 26240596 [PubMed]