Pharm 101: Acetazolamide

Classes

Carbonic Anhydrase Inhibitor (CAI)

Pharmacodynamics

• Carbonic anhydrase enzyme is predominantly located in epithelial cells of PCT and catalyses:
  • Dehydration of H2CO3 to CO2 at luminal membrane
  • Subsequent rehydration of CO2 to H2CO3 in cytoplasm of PCT cells
• H2CO3 is converted to H and HCO3 in the cytoplasm, and HCO3 reabsorbed on the interstitial membrane with Na, and H secreted via Na/K transporter on the luminal membrane
• By blocking this enzyme, CAIs blunt NaHCO3 reabsorption and cause diuresis
• They also reduce renal secretion of H in the PCT

Pharmacokinetics

• Well absorbed orally
• An increase in urine pH from HCO3 diuresis occurs within 30 minutes, is maximal at 2 hours, and persists for 12 hours after a single dose
• Excretion by secretion in PCT, therefore dosing must be reduced in renal failure

Clinical uses

• Glaucoma
  • Reduce aqueous humour formation, decreasing intraocular pressure
• Urinary alkalinisation
• Metabolic alkalosis due to excessive diuretic use in heart failure, when replacement of intravascular volume contraindicated
• Acute mountain sickness
  • Decreases CSF formation and pH, which diminishes symptoms of cerebral oedema and increases ventilation

Adverse effects

• Hyperchloraemic metabolic acidosis
  • Due to chronic reduction of HCO3 stores
  • Limits diuretic efficacy of these drugs to 2-3 days
• Renal calculi
  • Increased urinary calcium and phosphate occur during bicarbonaturic response, and these are relatively insoluble at alkaline pH
• Renal K wasting
  • Increased Na (along with HCO3) delivery to the collecting tubule, which creates a lumen-negative electrical potential enhancing K secretion
• Drowsiness and paraesthesiae

Precautions/contraindications

• Renal failure: neurological toxicity
• Hepatic failure:
  • Urinary alkalinisation of urine reduced urinary excretion of NH4, by converting it to rapidly absorbed NH3
  • Leads to hyperammonemia and hepatic encephalopathy in predisposed patients with cirrhosis

Further reading

• Nickson C. High Altitude Illness
• Nickson C. Normal Anion Gap Metabolic Acidosis

References

• Katzung BG. Basic & Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education; 2018. 259-261, 272 p.