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Diuretic TypeNa+K+HCO3Ca2+Uric Acid
Loop (eg, furosemide)↓↓↓↓↓↑↑
Thiazide (eg, HCTZ, metolazone)↓↓
Potassium sparing (eg, spironolactone, amiloride)
Carbonic anhydrase inhibitor (eg, acetazolamide)

Carbonic anhydrase inhibitors


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

Thiazide diuretics


Agents

  • Hydrochlorothiazide (HCTZ)
  • Chlorthalidone
  • Chlorothiazide
  • Metolazone

Mechanism of action

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  • 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+
    • Decreased intracellular sodium levels increase the activity of the basolateral Na+/Ca2+ exchanger in the cells of the distal convoluted tubule. Sodium is transported into, and calcium out of, the cell, resulting in decreased intracellular calcium concentration that leads to increased reabsorption from the lumen via luminal Ca2+ channels. Calcium reabsorption may also be increased because of increased uptake of sodium and calcium in the proximal tubule as a result of sodium depletion.

Use thiazide with loop diuretics

Loop diuretics function by inhibiting the Na+-K+-2Cl- cotransporter in the ascending limb of the loop of Henle to block sodium absorption and encourage the excretion of sodium and water in the urine. However, the sodium excretion caused by loop diuretics is limited by the reabsorption of sodium in the distal convoluted tubule; the Na-Cl cotransporter in the distal tubule counteracts some of the effect of loop diuretics by absorbing much of the sodium that is not absorbed in the loop of Henle. Inhibition of the Na-Cl cotransporter with metolazone prevents reabsorption of the increased sodium delivered to the distal tubule, significantly increasing total sodium excretion.

Loop diuretics


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+
      • Normally, Na+-K+-2Cl-cotransporter can cause positive potential in lumen because of K+ channel, which drives calcium out of lumenPasted image 20240322220231.png
  • Increased PGE release (can be inhibited by NSAIDs)
    • Dilation of renal afferent arterioles → diuresis
    • General venodilation (rapid venous pooling) → ↓ cardiac preload

Potassium-sparing diuretics


Agents

  • Aldosterone receptor antagonists: spironolactone, eplerenone
    • Eplerenone has a low affinity for progesterone and androgen receptors and thus has fewer antiandrogenic adverse effects (e.g., gynecomastia) than spironolactone.
    • Spironolactone and eplerenone are aldosterone receptor antagonists.
  • Epithelial sodium channel blockers: triamterene, amiloride

Mechanism of action

  • Androgen and progesterone receptor antagonistPasted image 20241201151050.png

Adverse effects


Loop diuretics

Thiazide diuretics

Potassium sparing diuretics

Carbonic anhydrase inhibitors

  • Hyperammonemia with paresthesias
  • Proximal renal tubular acidosis → hyperchloremic, nonanion gap metabolic acidosis
  • Hypokalemia
    • Caused by increased sodium delivery to the distal nephron and its reabsorption there in exchange for potassium.
  • Sulfonamide hypersensitivity
  • Calcium phosphate stone formation (alkaline urine promotes precipitation)
    • Because paracellular calcium (Ca2+) reabsorption is coupled to Na+ reabsorption in the proximal tubule, urinary Ca2+ excretion is slightly increased (total serum Ca2+ is slightly reduced).

Osmotic diuretics

  • Hypernatremia
  • Pulmonary edema
    • Mannitol is an osmotic diuretic, it increases osmolarity of blood and extracts fluid from intracellular compartments into Extracellular compartment. This leads to ECF expansion, and volume overload before diuresis begins.