Acetazolamide

Mechanism

Pharmacological Group

Non-competitive inhibitor of the enzyme carbonic anhydrase (cytoplasmic type II and luminal membrane-bound type IV isoforms).

Mechanism of Action

Acetazolamide reversibly blocks carbonic anhydrase in the brush border and in the cell cytoplasm of the proximal convoluted tubule. By inhibiting the luminal conversion of HCO₃^- and H⁺ into CO₂ and H₂O, and the subsequent reverse intracellular step:

The lack of intracellular protons (H⁺) stops the functioning of the Na⁺/H⁺ exchanger (NHE3). The immediate consequence is the failure in the reabsorption of Na⁺ and HCO₃^-. This promotes a mild osmotic diuresis rich in sodium bicarbonate, markedly alkalinizing the urine and reducing the reserve of bicarbonate in the blood.

Pharmacokinetics

Key Pharmacokinetics

• Administration: Oral, Intravenous (IV).
• Bioavailability: Close to 100% orally.
• Protein binding: Very high (90-95%), selectively concentrating in erythrocytes and renal cortex.
• Elimination: Unaltered renal excretion by glomerular filtration and active tubular secretion by the organic anion transporter (OAT).
• Half-life: 6 to 9 hours.

Indicators and dose

Clinical Indications

• Open and closed angle glaucoma: Reduces the secretion of aqueous humor by the ciliary processes.
• Prevention and treatment of acute mountain sickness: Induction of metabolic acidosis stimulates the compensatory central respiratory center, increasing ventilation and arterial oxygenation under hypoxia.
• Diuretic-induced metabolic alkalosis: Restores acid-base balance by forcing the excretion of urinary bicarbonate.
• Idiopathic intracranial hypertension (Pseudotumor cerebri): Reduces the production of cerebrospinal fluid in the choroid plexuses.

Dosage and Settings

• Glaucoma: 250 mg to 1000 mg daily orally in divided doses.
• Mountain sickness: 125 mg to 250 mg every 12 hours, starting 24 hours before the ascent.
• Kidney adjustment:
  - CrCl 10-50 mL/min: extend the administration interval to every 12 or 24 hours.
  - CrCl < 10 mL/min: Contraindicated due to ineffectiveness and high risk of systemic toxicity.

Security

Contraindications

• Absolute: Pre-existing severe hyponatremia or hypokalemia; established metabolic or hyperchloremic acidosis; severe adrenal insufficiency (Addison's disease); liver cirrhosis (imminent risk of hepatic encephalopathy secondary to reduced renal excretion of ammonium); documented hypersensitivity to sulfonamides.
• Relative: Severe COPD (compensatory retention of CO₂ is altered by induced metabolic acidosis).

Adverse Effects (ADR)

• Very common: Distal paresthesias in extremities and face (due to inhibition of AC in myelinated sheaths), drowsiness, fatigue.
• Common: Hyperchloremic metabolic acidosis, dysgeusia (metallic taste, especially when consuming carbonated drinks), moderate hypokalemia.
• Serious / Rare: Nephrolithiasis (precipitation of calcium phosphate in alkaline urine), aplastic anemia, agranulocytosis, severe skin rashes (Stevens-Johnson syndrome).

Interactions

• Acetylsalicylic acid (Aspirin): The addition of acidosis can favor the diffusion of non-ionized salicylates to the brain parenchyma, triggering severe central salicylate toxicity.
• Lithium: Significantly increases lithium excretion, reducing its therapeutic efficacy.
• Memantine and Quinidine: As urine becomes alkalinized, renal clearance of these weak bases decreases, increasing their plasma levels and the risk of toxicity.

Pregnancy and Breastfeeding

FDA Category C. Teratogenicity (alterations in extremities) has been demonstrated in animal models at high doses. Avoid in the first trimester. It is excreted in low concentrations in breast milk; Close monitoring of the infant is advised.