• Clinical science

Diuretics

Summary

Diuretics are a group of drugs that increase the production of urine. Diuretics are categorized according to the renal structures they act on and the changes they lead to in the volume and composition of urine, as well as electrolyte balance. Some of these effects are useful in treating disorders such as hypercalcemia, hypocalcemia, and hyperaldosteronism. The most commonly used diuretics with a pronounced diuretic effect are thiazides, loop diuretics, and potassium-sparing diuretics. Osmotic diuretics and carbonic anhydrase inhibitors are used in acute settings to lower intracranial and/or intraocular pressure (e.g., cerebral edema, acute glaucoma). The most serious side effects of the majority of diuretics include volume depletion and excessive changes in serum electrolyte levels (particularly of sodium and potassium), which increases the risk for cardiac arrhythmias.

Overview of diuretics

Summary of diuretic drug effects

Main diuretic agents
Agents Main characteristics and mechanisms Water elimination Effects on serum
pH Na+ K+ Ca2+
Thiazide diuretics
  • Inhibition of Na+-Cl- cotransporters in the early distal tubule
  • Effects compared to loop diuretics
    • Greater loss of potassium
  • ↑ Calcium reabsorption → urine calcium
  • Reduced effectiveness if GFR < 30 mL/min
  • Increased
  • Increased [1]
  • Decreased
  • Decreased
  • Increased

Loop diuretics

  • Significantly increased
  • Increased
  • Normal/slightly decreased
  • Decreased
  • Decreased

Potassium-sparing diuretics

  • Slightly increased
  • Decreased
  • Decreased
  • Increased
  • No change

Osmotic diuretics

  • Affect the entire tubule, but predominantly act on the straight segment of the proximal tubule and the descending loop of Henle
  • ↑ Blood and tubular fluid osmolarity → urine flow and ↓ intracranial/intraocular pressure
  • Significantly increased

Carbonic anhydrase inhibitors

  • Slightly increase
  • Decreased
  • Slightly decreased
  • Slightly decreased
  • No change

Mechanisms of blood acid-base balance changes

Alkalosis

  • Agents: loop diuretics and thiazides
  • Mechanisms
    • Diuresis → volume contraction (i.e., volume loss) ; RAAS ↑ ATII → Na+/H+ exchanger in the PCT HCO3- reabsorption (contraction alkalosis)
    • K+excretion → hypokalemia, leading to the following effects:
      • Induction of H+ excretion (instead of K+ excretion) in exchange for Na+ reabsorption in the collecting duct → ↑ HCO3- reabsorption → alkalosis with paradoxical aciduria
      • Induction of H+/K+-ATPases in all cells; in order to counteract the decrease in serum K+ K+ outflow from the cells in exchange for H+ ↓ serum H+ metabolic alkalosis

Acidosis

References:[2][3][4][5][6]

Thiazide diuretics

Agents

Mechanism of action

Side effects

To avoid hypokalemia, thiazide diuretics may be combined with potassium-sparing diuretics (e.g., aldosterone receptor antagonists).
To remember the side effects of thiazide diuretics, think of “hyperGLUC”: hyperGlycemia, hyperLipidemia, hyperUricemia, and hyperCalcemia.

Indications

Contraindications

Thiazides should be used with caution in patients with prediabetes and diabetes mellitus because they can cause hyperglycemia and changes in glucose concentration.

Interactions

References:[11][6][2][12][13][14][15][16]

Loop diuretics

Agents

Mechanism of action

  • Blockage of Na+-K+-2Cl- cotransporter in the thick ascending loop of Henle
    • Diminishing concentration gradient between the (usually hypertonic) renal medulla and the cortex → concentration of urine is no longer possible → increased diuresis
    • Decreased reabsorption of Ca2+ and Mg2+
  • Increased PGE release (can be inhibited by NSAIDs)
    • Dilation of renal afferent arterioles diuresis
    • General venodilation (rapid venous pooling) → ↓ cardiac preload
  • See “Mechanism of blood pH” changes in “Overview of diuretics” for mechanism of alkalosis.

To recall that loop diuretics cause increased excretion of calcium, think: loops lose calcium!

Side effects

To recall the side effects of loop diuretics, think of “GO PANDA”: Gout, Ototoxicity, low Potassium, Allergy, Nephritis, Dehydration, Alkalosis.

To remember that loop diuretics are ototoxic, imagine a vertical loop of a roller coaster and deafening screams of people passing through it.

Hypokalemia and/or hypomagnesemia can lead to life-threatening arrhythmias!

Indications

Because of the increased risk of hypokalemia and hypovolemia during forced diuresis, rigorous monitoring is necessary.

Contraindications

Contraindications for loop diuretics
Condition Furosemide Torsemide Bumetanide Ethacrynic acid
Anuria
  • Yes
  • Yes
  • Yes
  • Yes
Sulfonamide hypersensitivity
  • Yes
  • Yes
  • Yes
  • No
Hepatic coma or severe electrolyte depletion
  • No
  • No
  • Yes
  • No

History of severe watery diarrhea (caused by the drug)

  • No
  • No
  • No
  • Yes

References:[2][17][18][19][20][21][22][23][24][25][26]

Potassium-sparing diuretics

Agents

To remember that Spironolactone, Triamterene, Eplerenone, and Amiloride are K+-sparing, think of STEAK!

Mechanism of action

Although the molecular pathways differ, both types of potassium-sparing diuretics have very similar clinical effects.

Spironolactone and eplerenone are aldosterone receptor antagonists.

Side effects

Indications

Contraindications

General

Specific

References:[6][14][28][29][30][31]

Osmotic diuretics

Agents

Mechanism of action

Side effects

Indications

Contraindications

References:[3][33]

Carbonic anhydrase inhibitors

Agents

Mechanism of action

  • Inhibition of carbonic anhydrase in the following organs:
    • Kidney (in the proximal convoluted tubule): → ↑ H+ reabsorption and inhibition of Na+/H+ exchange → NaHCO3 diuresis and HCO3- elimination
    • Eyes: ↓ production of aqueous humor
    • Brain: CSF production
    • Acid-base effects: alkalinizes urine and acidifies blood

Side effects

Indications

Contraindications

ACetazolamide causes ACidosis!

References:[35][6]