Diuretics

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Things affect electrolytes concentration

Drug effect
Can Na⁺ help
Exchanger
Charge
Contraction

Diuretic Type	Na⁺	K⁺	Cl^-	HCO₃⁻	Ca²⁺	Uric Acid
Loop (eg, furosemide)	↓↓↓	↓↓	↓↓↓	↑↑ (Cl^- loss, vol. contraction, RAAS $\to↑$ H $^{+}$ secr, $↑$ HCO $_{3}^{-}$ reabs.)	↓ Disrupts TAL lumen potential $\to↓$ Ca reabs.	↑
Thiazide (eg, HCTZ, metolazone)	↓↓	↓ $↑$ Distal Na $\to↑$ K excr (RAAS).	↓↓	↑ Cl- loss, vol. contraction $\to↑$ HCO $_{3}^{-}$ reabs.	↑ $↑$ DCT Ca reabs (Na/Ca exch.).	↑
Potassium sparing (eg, spironolactone, amiloride)	↓ Spiro: $↓$ Aldo effect. Amil: blocks ENaC in CD.	↑	↓ Spiro: $↓$ Aldo-med. NaCl reabs. Amil: $↓$ ENaC activity reduces passive Cl reabs.	↓ $↓$ H $^{+}$ secr (Aldo block/ $↓$ Na reabs).	—	—
Carbonic anhydrase inhibitor (eg, acetazolamide)	↓ Inhibits CA in PCT $\to↓$ NaHCO $_{3}$ reabs.	↓ $↑$ Distal Na $\to↑$ K excr; Met. Acid. $\to$ K wasting.	↑ Hyperchloremic Met. Acid. (HCO $_{3}^{-}$ loss $\to$ compensatory Cl reabs with Na).	↓	↓ $↓$ HCO $_{3}^{-}$ reabs $\to↓$ Ca reabs; Met. Acid. $\to↑$ Ca excr.	—
TAL: Thick ascending limb of Loop of Henle

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

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 lumen
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

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
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

Adverse effects

Loop diuretics

Hypokalemia
Hypomagnesemia
Hypocalcemia
Ototoxicity

Thiazide diuretics

Potassium sparing diuretics

All: hyperkalemia
Spironolactone: gynecomastia, antiandrogen effects

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.