Pasted image 20240322215128.png

Carbonic anhydrase inhibitors

Agents

Acetazolamide

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

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.

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

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).

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.