Mechanism of Action of Acetazolamide
Acetazolamide acts primarily as a potent carbonic anhydrase inhibitor, preventing the enzyme from catalyzing the reversible reaction of carbon dioxide hydration and carbonic acid dehydration. 1
Primary Mechanism
Acetazolamide specifically inhibits carbonic anhydrase through the following mechanisms:
- Forms a non-competitive inhibitory complex with carbonic anhydrase with a dissociation constant of approximately 10^-8 M 2
- Blocks the enzyme that catalyzes the reversible reaction: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻ 1
- Effective inhibition occurs at concentrations of 10^-4 M, which can be safely achieved in tissues with standard dosing 2
Physiological Effects Based on Site of Action
1. Renal Effects
- Inhibits carbonic anhydrase in the proximal tubule
- Causes bicarbonaturia (renal loss of HCO₃⁻)
- Results in excretion of sodium, potassium, and water 1
- Produces urinary alkalinization and diuresis 1
- Decreases strong ion difference (SID) by increasing renal excretion of sodium without chloride 3
2. Ocular Effects
- Decreases aqueous humor secretion in the eye
- Reduces intraocular pressure, beneficial in glaucoma treatment 1
3. Central Nervous System Effects
- Inhibits carbonic anhydrase in neurons
- Retards abnormal, paroxysmal, excessive neuronal discharge
- Increases seizure threshold in structures like the hippocampus 4
- May modulate neuroinflammation and attenuate high-frequency oscillations 4
- Activates acid-sensing ion channels through acidification of intracellular and extracellular environments 4
4. Respiratory Effects
- Creates tissue respiratory acidosis that improves ventilation
- Produces metabolic acidosis that offsets hyperventilation-induced respiratory alkalosis
- Enhances chemoreceptor response to hypoxic stimuli at altitude 5
- Improves sleep quality through carotid body carbonic anhydrase inhibition 5
Clinical Applications
Acetazolamide's mechanism of action makes it useful for:
- Glaucoma management (through decreased aqueous humor production)
- Epilepsy treatment (as adjunctive therapy)
- Altitude sickness prevention and treatment
- Management of certain types of metabolic alkalosis
- Idiopathic intracranial hypertension
- Diuresis in conditions with abnormal fluid retention 6, 1
Pharmacological Specificity
Acetazolamide demonstrates high specificity for carbonic anhydrase:
- No known effects on other systems at concentrations below 10^-3 M 2
- Non-bacteriostatic sulfonamide with structure and activity distinct from bacteriostatic sulfonamides 1
- Not a mercurial diuretic 1
This carbonic anhydrase inhibition mechanism explains acetazolamide's diverse clinical applications across multiple organ systems, with its effects primarily stemming from the disruption of this fundamental enzymatic pathway.