Diuresis and Diuretic Pharmacology

Diuresis and Diuretic Pharmacology

David Ray Velez, MD

Table of Contents

Classes:
Loop Diuretics
Thiazide Diuretics
Potassium-Sparing Diuretics
Carbonic Anhydrase Inhibitors (CAI)
Osmotic Diuretics

General Electrolyte Changes:

    K+ Ca2+ Mg2+ Na+ H+
Loops Furosemide Down Down Down Up Down
Thiazides Hydrochlorothiazide Down Up Down Down Down
K-Sparing Spironolactone Up – Up Down Up
CAI Acetazolamide Down Down Down Down Up

Loop Diuretics

Strongest Diuretic Effect

Agents

  • Furosemide (Lasix) – Most Common
  • Torsemide
  • Bumetanide (Bumex)

Mechanism

  • Acts in the Thick Ascending Limb of the Loop of Henle
  • Inhibits the Na-K-2Cl Carrier in the Luminal Membrane
  • Prevents NaCl Reabsorption
  • Decreased Intracellular Tonicity Prevents Free Water Reabsorption
  • Additional Effects:
    • Directly Inhibits Potassium Reabsorption – Potassium Loss
    • Inhibits the Electrical Gradient that Drives Calcium Reabsorption – Calcium Loss
    • Increased Sodium Delivery to Distal Nephron Increases Na-H Exchange – Hydrogen Loss (Alkalosis)
    • Water Reabsorption Prevented in the Loop of Henle While Sodium is Reabsorbed in More Distal Nephron, Inhibiting Renal Ability to Concentrate Urine – Increase in Sodium Levels

Pharmacokinetics

  • Oral (PO):
    • Onset of Action: 1 Hour
    • Peak Effect: 1-2 Hours
    • Duration: 6-8 Hours
  • Intravenous (IV):
    • Onset of Action: 5 Minutes
    • Peak Effect: 30 Minutes
    • Duration: 2 Hours
  • Excreted in Urine (Minimal Hepatic Metabolism)

Furosemide (Lasix) Dosing

  • Generally Start with Low Dose (10-20 mg) in the ICU and Increase as Tolerated if Necessary
  • May Require BID Dosing
  • 10 mg IV is Approximately Equivalent to 20 mg PO

Side Effects

  • Hypokalemia
  • Hypocalcemia
  • Hypernatremia
  • Metabolic Alkalosis
  • Ototoxicity

Thiazide Diuretics

Relatively Weak Diuretic Effect – DCT Normally Reabsorbs Only 5-10% of the Filtered Sodium Load

Agents

  • Hydrochlorothiazide (HCTZ) – Most Common
    • Only Available PO
  • Chlorothiazide (Diuril)
    • Can Be Given PO or IV
  • Chlorthalidone
  • Indapamide

Mechanism

  • Acts in the Distal Convoluted Tubule (DCT)
  • Inhibits the Na-Cl Transporter in the Luminal Membrane
  • Prevents NaCl Reabsorption
  • Decreased Intracellular Tonicity Prevents Free Water Reabsorption
  • Additional Effects:
    • Increased Sodium Delivery to Distal Nephron Increases Na-K Exchange – Causes Potassium Loss
    • Increased Sodium Delivery to Distal Nephron Increases Calcium Reabsorption Through a Na/Ca Transporter
    • Increased Sodium Delivery to Distal Nephron Increases Na-H Exchange – Causes Hydrogen Loss (Alkalosis)

Pharmacokinetics

  • PO Hydrochlorothiazide:
    • Onset of Action: 2 Hour
    • Peak Effect: 4 Hours
    • Duration: 24 Hours
  • IV Chlorothiazide:
    • Onset of Action: 15 Minutes
    • Peak Effect: 30 Minutes
    • Duration: 2 Hours
  • Excreted in Urine (Not Metabolized)

Dosing

  • PO Hydrochlorothiazide: 25-100 mg Daily or Divided Doses
  • IV Chlorothiazide: 250 mg – 1 g Once-Twice Daily

Side Effects

  • Hypokalemia – More Common than with Loop Diuretics
  • Hypercalcemia – Increased Reabsorption
  • Metabolic Alkalosis
  • Gout
  • Acute Angle Glaucoma
  • Skin Sensitivity

Potassium-Sparing Diuretics

Also Known As: Mineralocorticoid/Aldosterone Receptor Antagonist (MRA)

Relatively Weak Diuretic Effect

Agents

  • Spironolactone (Aldactone) – Most Common
  • Amiloride
  • Eplerenone
  • Triamterene

Mechanism

  • Acts in the Distal Convoluted Tubule (DCT)
  • Inhibits Mineralocorticoid/Aldosterone Receptors
    • Aldosterone is a Component of the Renin-Angiotensin-Aldosterone System (RAAS)
  • Prevents Sodium Reabsorption and Potassium Excretion
  • Decreased Intracellular Tonicity Prevents Free Water Reabsorption
  • Additional Effects:
    • Prevents Hydrogen Excretion (Acidosis)
    • Prevents Magnesium Excretion

Pharmacokinetics

  • Slow Onset of Action
  • May Take 48 Hours to See Peak Effect
  • Hepatic Metabolism, Excreted in Urine (Primary) and Bile (Secondary)

Spironolactone (Aldactone) Dosing

  • 5-50 mg PO Daily or Divided Doses

Side Effects

  • Hyperkalemia
  • Metabolic Acidosis
  • Antiandrogen Effects (Gynecomastia, Dysmenorrhea)

Carbonic Anhydrase Inhibitors (CAI)

Relatively Weak Diuretic Effect

Agents

  • Acetazolamide (Diamox)

Mechanism

  • Acts in the Proximal Convoluted Tubule (PCT)
  • Carbonic Anhydrase Inhibitor (CAI)
  • Prevents Breakdown of Carbonic Acid (H2CO3)
  • Prevents Acidification of the Urine and Reabsorption of Bicarbonate – Can Be Used in the Treatment of Metabolic Alkalosis
  • Inhibits Na-H Exchange Preventing Sodium Reabsorption
  • Decreased Intracellular Tonicity Prevents Free Water Reabsorption

Pharmacokinetics

  • Oral (PO):
    • Onset of Action: 1 Hour (Immediate Release), 2 Hours (Extended Release)
    • Peak Effect: 2-4 Hours (Immediate Release), 8-18 Hours (Extended Release)
    • Duration: 8-12 Hours (Immediate Release), 18-24 Hours (Extended Release)
  • Intravenous (IV):
    • Onset of Action: 2-10 Minutes
    • Peak Effect: 15 Minutes
    • Duration: 4-5 Hours
  • Renal Excretion

Acetazolamide (Diamox) Dosing

  • 250-500 mg Once Daily (PO or IV)

Side Effects

  • Hypokalemia
  • Hypocalcemia
  • Metabolic Acidosis
  • Aplastic Anemia
  • Paresthesia
  • Growth Retardation

Osmotic Diuretics

Used More Commonly in the ICU for TBI and Not Specifically for the Diuretic Effects

Agents

  • Mannitol
  • Isosorbide

Mechanism

  • Acts Primarily in the Proximal Convoluted Tubule (PCT) and Loop of Henle Where Water is Freely Permeable
  • Non-Reabsorbable Solute Prevents Water Reabsorption

Mannitol Use in Intracranial Hypertension

  • Used to Decrease ICP in TBI
  • Rheologic Effect:
    • Changes the Shape of RBC’s to Decrease Viscosity, Improve Cerebral Blood Flow, and Decrease ICP
    • The Primary Mechanism of Effect on ICP Occurs within Minutes
  • Osmotic Effect:
    • Causes Osmotic Removal of Fluid from the Brain
    • Secondary Mechanism and Takes Longer (15-30 Minutes)
  • Due to Diuretic Effect, it Should Be Avoided in Hypotensive/Hypovolemic

Pharmacokinetics

  • Onset of Action: 5-10 Minutes
  • Duration: 3-6 Hours
  • Renal Excretion

Mannitol Dosing

  • 25-2.0 g/kg IV

Side Effects

  • Hypovolemia
  • Hyponatremia
  • Hypokalemia