Mechanism of Action of Acetazolamide
Acetazolamide primarily works as a potent carbonic anhydrase inhibitor that prevents the conversion of carbon dioxide and water to carbonic acid and its subsequent dissociation to bicarbonate and hydrogen ions. 1
Primary Mechanism
Carbonic Anhydrase Inhibition: Acetazolamide is a non-bacteriostatic sulfonamide that specifically inhibits the enzyme carbonic anhydrase, which catalyzes the reversible reaction involving the hydration of carbon dioxide and dehydration of carbonic acid 1
Enzyme Specificity: It acts as a noncompetitive inhibitor of multiple carbonic anhydrase subtypes in humans 2
Physiological Effects Based on Target Tissues
Kidney Effects
- Inhibits carbonic anhydrase in the kidney, disrupting the reversible reaction of CO2 hydration/carbonic acid dehydration 1
- Results in renal loss of bicarbonate ions (HCO3-), which carries out sodium, water, and potassium 1
- Causes alkalinization of urine and promotes diuresis 1
- Increases reabsorption of ammonia by renal tubules due to urinary alkalinization 1
- Acts in the proximal convoluted tubule to reduce sodium reabsorption 3
Eye Effects
- Decreases secretion of aqueous humor in the eye 1
- Results in reduced intraocular pressure, beneficial in glaucoma 1
Central Nervous System Effects
- Retards abnormal, paroxysmal, excessive discharge from central nervous system neurons 1
- Acidifies intracellular and extracellular environments, activating acid-sensing ion channels 2
- Increases seizure threshold in critical structures such as the hippocampus 2
- Decreases cerebrospinal fluid (CSF) production, useful in treating raised intracranial pressure 4, 5
- Inhibits brain/choroid plexus CA II, IV, VA, and XII isoforms, leading to decreased CSF secretion 5
Respiratory Effects
- Creates metabolic acidosis that stimulates ventilation, particularly useful at high altitude 6
- Offsets hyperventilation-induced respiratory alkalosis at altitude 6
- Allows chemoreceptors to respond more fully to hypoxic stimuli 6
Clinical Applications Based on Mechanism
- Glaucoma: Reduces intraocular pressure by decreasing aqueous humor production 1
- Epilepsy: Controls certain convulsive disorders by inhibiting abnormal neuronal discharge 1, 2
- Edema: Promotes diuresis in cases of abnormal fluid retention (e.g., cardiac edema) 1
- Idiopathic Intracranial Hypertension: Reduces CSF production and controls intracranial pressure 5
- Altitude Sickness: Multiple mechanisms including metabolic acidosis, improved ventilation, better sleep quality, and diuresis 6, 7
- Heart Failure: Enhances decongestion when used with loop diuretics by inhibiting sodium reabsorption in the proximal tubule 3
Potential Side Effects Related to Mechanism
- Paresthesias and altered taste due to effects on neural tissue 7, 4
- Metabolic acidosis from renal bicarbonate loss 7, 8
- Electrolyte imbalances from diuretic effect 7
- Kidney stones from urinary alkalinization 7, 8
- Periorbital myokymia (rare) through unknown mechanisms 4
Acetazolamide's diverse therapeutic applications stem from its fundamental action as a carbonic anhydrase inhibitor, with different clinical effects manifesting based on the specific tissue distribution of carbonic anhydrase isoforms throughout the body.