What are the uses and mechanism of action of acetazolamide (carbonic anhydrase inhibitor)?

Acetazolamide: Mechanism of Action and Clinical Uses

Acetazolamide is a potent carbonic anhydrase inhibitor that acts by blocking the enzyme that catalyzes the reversible reaction of carbon dioxide hydration and carbonic acid dehydration, resulting in multiple therapeutic effects including reduction of intraocular pressure, inhibition of abnormal CNS neuronal discharge, diuresis, and prevention of altitude sickness. 1

Mechanism of Action

Acetazolamide specifically inhibits carbonic anhydrase, which leads to several physiological effects:

• Renal effects: Inhibition of carbonic anhydrase in the kidney prevents the reabsorption of bicarbonate ions, leading to:

  • Increased urinary excretion of bicarbonate
  • Increased sodium, potassium, and water excretion
  • Urinary alkalinization
  • Metabolic acidosis 1, 2

• Ocular effects: Decreases aqueous humor secretion in the eye, resulting in reduced intraocular pressure 1

• CNS effects: Reduces abnormal, paroxysmal discharge from central nervous system neurons 1

• Respiratory effects: The induced metabolic acidosis stimulates ventilation, which helps offset respiratory alkalosis at high altitude 3, 4

Clinical Uses

FDA-Approved Indications

1. Glaucoma management

   • Reduces intraocular pressure by decreasing aqueous humor production 1

2. Epilepsy/Seizure disorders

   • Inhibits abnormal neuronal discharge in the CNS 1

3. Edema (cardiac edema)

   • Promotes diuresis through increased excretion of sodium, bicarbonate, and water 1

4. Altitude sickness prevention

   • Recommended dose: 125-250 mg twice daily starting 24 hours before ascent 5
   • Contraindicated in patients with kidney stones, aplastic anemia, sickle cell disease, sulfa allergy, severe hepatic/renal disease, adrenocortical insufficiency, and hyperchloremic acidosis 5

Off-Label Uses

1. Idiopathic intracranial hypertension

   • Reduces cerebrospinal fluid production and intracranial pressure 6

2. CSF leaks and elevated intracranial pressure

   • May help avoid invasive procedures 6

3. Respiratory assistance

   • May aid in ventilator weaning for COPD patients 6
   • Used for sleep apnea, especially at high altitudes (250 mg/day) 5

4. Prevention of methotrexate toxicity and contrast-induced nephropathy 6

5. Reduction of subendocardial ischemia risk at high altitude in patients with coronary artery disease 5

Dosing Considerations

• Standard dosing range: 250-4,000 mg daily divided every 6-12 hours 6
• Altitude sickness prevention: 125-250 mg twice daily starting 24 hours before ascent 5
• Sleep apnea at altitude: 250 mg/day (similar efficacy to higher doses with fewer side effects) 5
• Renal impairment: Administration should not be more frequent than every 12 hours if creatinine clearance is less than 50 mL/min 6

Side Effects and Monitoring

Common Side Effects

• Paresthesias
• Vertigo
• Altered taste
• Allergic dermatitis/conjunctivitis 5

Serious Side Effects

• Kidney stones
• Metabolic acidosis
• Blood dyscrasias
• Stevens-Johnson syndrome
• Serum electrolyte imbalances
• Lethargy
• Suppression of appetite 5

Monitoring Recommendations

• Serum electrolytes
• Renal function
• Acid-base status
• Clinical response 5

Important Precautions

1. Drug interactions:

   • Limit caffeine intake due to potential worsening of side effects 5
   • Avoid combining with other diuretics due to increased risk of dehydration and electrolyte imbalances 5

2. Contraindications:

   • Kidney stones
   • Aplastic anemia
   • Sickle cell disease
   • Sulfa allergy
   • Severe hepatic disease
   • Severe renal disease
   • Adrenocortical insufficiency
   • Hyperchloremic acidosis 5

3. Special populations:

   • Patients with uncontrolled/severe hypertension should avoid high altitude exposure 5
   • Women may have higher risk of acute mountain sickness and may need special consideration 5

Clinical Pearls

• While acetazolamide is effective for altitude sickness prevention, proper acclimatization remains essential (gradual ascent of 300-600m/day above 2500m, rest days, adequate hydration) 5
• The pharmacologic effects of acetazolamide last longer than its 4-8 hour plasma half-life 6
• At typical doses used for altitude sickness prevention (250 mg TID), acetazolamide does not increase cerebral blood flow velocity, contrary to what occurs with higher intravenous doses 7
• Acetazolamide is primarily eliminated unchanged by the kidneys 2