Diuretics

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 diuretic agents

Overview of diuretic effects

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

• Agents: carbonic anhydrase inhibitors and potassium-sparing diuretics
• Mechanisms
  • Carbonic anhydrase inhibitors: via decreased HCO₃⁻ reabsorption
  • Potassium-sparing diuretics
    • Hyperkalemia → influx of K⁺ to the cells in exchange for H⁺ via H⁺/K⁺exchanger → acidosis
    • Aldosterone blockers specifically inhibit renal K⁺ and H⁺ secretion

Agents

• Hydrochlorothiazide (HCTZ)
• Chlorthalidone
• Chlorothiazide
• Metolazone

Mechanism of action

• Inhibition of Na⁺-Cl^- cotransporters ; in the early distal convoluted tubule; → ↑ excretion of Na⁺ (saluresis) and Cl^- → ↓ diluting capacity of nephron and ↑ excretion of potassium; (kaliuresis) and ↓ excretion of calcium → diuresis
• Increased reabsorption of Ca²⁺
• Hyperpolarization of smooth muscle cells → vasodilation
• Hyperpolarization of pancreatic beta cells → decreased insulin release ^[8]
• See “Mechanism of blood pH” changes in “Overview of diuretics” for mechanism of alkalosis.

Side effects ^[9]

• Hypokalemia and metabolic alkalosis
• Hyponatremia ^[10]
• Hypomagnesemia
• Hypercalcemia
• Hyperglycemia ^[11]
• Hyperlipidemia (↑ cholesterol, triglycerides)
• Hyperuricemia
• Allergic reactions (sulfonamide hypersensitivity)

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

• Hypertension
• Chronic edema secondary to congestive heart failure; , cirrhosis, and kidney disease
• Prevention of calcium kidney stones, idiopathic hypercalciuria
• Osteoporosis
• Nephrogenic diabetes insipidus ^[12][13]
• Sequential nephron blockade

Contraindications

• Hypersensitivity (including hypersensitivity to any sulfonamide medications) ^[14]
• Gout
• Anuria
• Severe hypokalemia

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

Interactions

• Glucocorticoids: increased hypokalemia
• Carbamazepine: increased hyponatremia
• Lithium: increased hyponatremia ^[15]
• ACE inhibitors: hypotension (especially first-dose hypotension)
• Propranolol: increased hyperlipidemia and hyperglycemia
• NSAIDs: decreased diuretic effect
• Increased effects of digitalis , methotrexate, and lithium

Agents

• Sulfonamides: furosemide, torsemide, bumetanide
• Other: ethacrynic acid

Mechanism of action ^[16]

• 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 ^[17]

• Metabolic imbalances
  • Hypokalemia, hypomagnesemia, hypocalcemia, hypochloremia, hyponatremia (moderate)
  • Metabolic alkalosis
  • Hyperuricemia/gout
  • Hyperglycemia
• Ototoxicity (potentially permanent hearing damage): especially high risk with ethacrynic acid
• Dehydration/hypovolemia
• Sulfonamide hypersensitivity (except ethacrynic acid, which can be used for diuresis in patients with allergies to sulfonamides) →; rash, interstitial nephritis

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 ^[18]

• Hypertension
• Edema
  • Cardiac (acute and congestive heart failure, peripheral edema, lung edema)
  • Renal (nephrotic syndrome)
  • Hepatic (liver cirrhosis)
• Renal failure (acute and chronic)
• Hypercalcemia
• Forced diuresis
  • Definition: massive diuresis for forced renal elimination of (toxic) substances
  • Implementation: IV administration of large amounts of fluids in combination with loop diuretics
  • Indications: hypercalcemic crisis, severe hyperkalemia, rhabdomyolysis, intoxication (e.g., lithium)
• Sequential nephron blockade ^[19]
  • Used to overcome resistance to diuretic treatment
  • Method: combination of loop diuretics and thiazides → restoration of diuretic effects

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

Contraindications

Agents

• Aldosterone receptor antagonists: spironolactone, eplerenone
• Epithelial sodium channel blockers: triamterene, amiloride

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.

• Aldosterone receptor antagonists (spironolactone, eplerenone)
  • Competitively bind to aldosterone receptors in the late distal convoluted tubule and the collecting duct → inhibition of the effects of aldosterone → decreased Na⁺ reabsorption and K⁺ excretion; ; ; → diuresis
  • Decreased H⁺ excretion → acidosis
  • Evolving hyperkalemia induces H⁺/K⁺-ATPases in all cells; to counteract the increase in serum K⁺ → K⁺ enters cells in exchange for H⁺ → amplifies acidosis
  • Spironolactone also acts (nonspecifically) on sex hormone receptors → endocrine side effects (see section “Gonads” in “General endocrinology” for more information about hormonal effects of spironolactone)
• Epithelial sodium channel blockers (triamterene, amiloride): direct inhibition of the epithelial sodium channels (ENaC) in the distal convoluted tubule and the collecting duct → reduced Na⁺ reabsorption and reduced K⁺ secretion → diuresis

Spironolactone and eplerenone are aldosterone receptor antagonists.

Side effects

• General side effects
  • Metabolic and electrolyte imbalances, such as hyperkalemia; , hyponatremia, and metabolic acidosis, can lead to cardiac arrhythmias
  • Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Spironolactone-specific side effects: endocrine disturbances
  • Men: antiandrogenic effects (e.g., gynecomastia, erectile dysfunction)
  • Women: amenorrhea

Indications

• Hypertension (especially if hypokalemia is also present)
• Ascites/edema due to congestive heart failure, nephrotic syndrome, or cirrhosis of the liver (mainly spironolactone)
• Hyperaldosteronism (Conn syndrome)
• Nephrogenic diabetes insipidus (amiloride) ^[20]
• Hypokalemia
• Hyperandrogenic states, e.g., polycystic ovary syndrome (spironolactone)

Contraindications

General

• Anuria and/or renal insufficiency
• Preexisting hyperkalemia
• Addison disease
• Combination with other potassium-sparing diuretics or potassium supplements

Specific

• Spironolactone: Use with caution in patients with CHF with either of the following:
  • GFR < 30 mL/min
  • Creatinine ≥ 2.5 mg/dL (men) or ≥ 2 mg/dL (women)
• Eplerenone
  • Concomitant use of strong CYP3A4 inhibitors
  • Patients with hypertension with concomitant type II diabetes mellitus and microalbuminuria or with renal insufficiency (serum creatinine > 2.0 mg/dL for men or > 1.8 mg/dL for women; or creatinine clearance < 50 mL/min)
  • Creatinine clearance < 30 mL/min
• Amiloride: diabetic nephropathy

Agents

• Mannitol
• Urea ^[21]

Mechanism of action

• Increase the osmolality of:
  • Serum: ↑ shift of water into the intravascular space → ↑ binding of water → ↓ intracranial and intraocular pressure
  • Glomerular filtrate: ↑ tubular fluid osmolarity → ↑ binding of water → ↑ urine production
• No saluresis

Side effects

• Dehydration
• Initial cardiac volumetric strain
• Metabolic and electrolyte imbalances
  • Effective glomerular filtration → hypernatremia
  • Ineffective glomerular filtration or administration of very high doses → ↑ plasma osmolality → ↑ extracellular fluid volume → pulmonary edema; , potassium fluctuations, hyponatremia or hypernatremia, and/or metabolic acidosis

Indications

• Elevated ICP (e.g., cerebral edema)
• Acute glaucoma
• Prevention of acute renal injury in cases of oliguria
• Forced renal excretion of substances(e.g., drugs or toxins)

Contraindications

• Anuria
• Progressive heart failure
• Severe pulmonary edema
• Severe dehydration

Agents

• Acetazolamide

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 → compensatory hyperventilation; disinhibition of central chemoreceptors → ↑ oxygenation
  • Eyes: ↓ production of aqueous humor
  • Brain: ↓ CSF production
  • Acid-base effects: alkalinizes urine and acidifies blood

Side effects

• Hyperammonemia with paresthesias
• Proximal renal tubular acidosis → hyperchloremic, nonanion gap metabolic acidosis
• Hypokalemia
• Sulfonamide hypersensitivity
• Calcium phosphate stone formation (alkaline urine promotes precipitation)
• Neuropathy

Indications

• Acute glaucoma
• Altitude sickness (counteracts respiratory alkalosis)
• Idiopathic intracranial hypertension
• Metabolic alkalosis
• Prevention of cystine kidney stones

Contraindications

• Hyperchloremic metabolic acidosis
• Severe renal insufficiency
• Adrenocortical insufficiency
• Hyponatremia, hypokalemia
• Hepatic disease or insufficiency ^[22]
• Long-term use in glaucoma

ACetazolamide causes ACidosis.