Acetazolamide

Summary

Acetazolamide is a carbonic anhydrase inhibitor. It works primarily by blocking the actions of carbonic anhydrase in the proximal convoluted tubule, leading to reduced excretion of acidic protons into the urine. As a result, acetazolamide increases blood acidity levels, causing a metabolic acidosis. Clinically, the alkalinization of urine can be useful for treating diseases like salicylate overdoses and cystinuria, while the retention of acidic protons in blood can be useful for treating alkalosis from causes like altitude sickness. Since acetazolamide can decrease production of both CSF production in the brain and aqueous humour in the eye, it can also be used to treat idiopathic intracranial hypertension and glaucoma. However, acetazolamide is also a sulfa drug, so it is important to remember that acetazolamide is contraindicated in patients with sulfa allergies. 

Key Points

• Acetazolamide
  • Mechanism:
    • Carbonic anhydrase inhibitor
      • Increased excretion of bicarbonate/decreased excretion of H+
        • Causes non-anion gap metabolic acidosis (obvious = reduced H+ excretion)
          • Hyperchloremic
        • Carbonic anhydrase within proximal tubule cells synthesizes H+, which is then secreted into tubular fluid and used by brush border carbonic anhydrase to help resorb filtered HCO3-. Carbonic anhydrase inhibitors such as acetazolamide inhibit both membrane-bound and cytoplasmic forms of this enzyme.
      • Acts on proximal convoluted tubule (PCT)
        • Carbonic anhydrase in the lumen of the PCT normally catalyzes the breakdown of carbonic acid (H2Co3), the fusion of H+ and bicarbonate (HCO3-), into CO2 and H20, which can be reabsorbed by the tubule cells and recycled back into bicarbonate. By preventing this recycling process, acetazolamide facilitates the loss of bicarbonate.
  • Indications
    • Idiopathic intracranial hypertension
      • ↓ CSF production
    • Glaucoma
      • ↓ aqueous humor synthesis.
      • Used in both open-angle and angle-closure glaucoma
      • Open-angle glaucoma is characterized by progressive loss of peripheral vision from elevated intraocular pressure. nmolol and other nonselective beta blockers work by diminishing the secretion of aqueous humor by the ciliary epithelium. Acetazolamide, a carbonic anhydrase inhibitor, also decreases aqueous humor secretion by the ciliary epithelium.
    • Altitude sickness (respiratory alkalosis)
      • Your body breathes faster to compensate for the low oxygen content (PiO2) in air at high altitudes. This causes a respiratory alkalosis, which can be compensated for by increasing bicarbonate excretion via acetazolamide.
    • Urinary alkalinization (obvious)
      • Ex: Salicylate overdose, Cystinuria
      • Note that this also promotes formation of calcium phosphate stones (more soluble in acid)
  • Adverse Effects
    • Sulfa drug (allergy)
    • Paresthesias
    • Hyperammonemia
      • Related to decreased H+ excretion, since H+ binds NH3 to form NH4+, which is excreted
    • Hypokalemia
      • May be related to function of H+/K+ ATPases