Dorzolamide, Brinzolamide, Acetazolamide

Mechanism

💊 Commercial Names

Trusopt, Azopt, Diamox (oral), Simbrinza (coformulated with brimonidine).

🔬 Pharmacological Group

Inhibitors of soluble and membrane-bound carbonic anhydrase (types II and IV). Sulfonamides.

🧪 Standard Formulations

Eye drops: dorzolamide 2.0%, brinzolamide 1.0% (suspension). Acetazolamide 250 mg tablets and injection.

Mechanism of Action

The active secretion of aqueous humor depends on the osmotic gradient generated by the active transport of bicarbonate (HCO₃^-) and sodium:

• Blockade of Carbonic Anhydrase II (CA-II) and IV: CAIs reversibly and competitively inhibit this highly metabolically active enzyme in non-pigmented ciliary epithelial cells.
• Inhibition of the Carbon Dioxide Hydration Reaction: The rate of the following intraocular reversible chemical reaction is suppressed:

  CO₂ + H₂O AC H₂CO₃ H⁺ + HCO₃^-

• Collapse of Active Sodium and Water Transport: By drastically decreasing basal cellular production of hydrogen ions (H⁺) and bicarbonate (HCO₃^-), cotransport is inhibited for sodium (Na⁺) and water towards the posterior chamber. Aqueous humor secretion falls between 40% and 50% in the case of oral acetazolamide, and 20% in the case of topical dorzolamide/brinzolamide.

Pharmacokinetics

Quantitative Ocular and Systemic Pharmacokinetics

Security

Systemic Acetazolamide Toxicity: Metabolic Acidosis and Hypokalemia

Oral or intravenous administration of acetazolamide massively inhibits carbonic anhydrase in the renal proximal convoluted tubule. By blocking the tubular reabsorption of bicarbonate, a massive excretion of carbonates coupled to sodium and water (mild osmotic diuresis) occurs, predictably inducing a hyperchloremic metabolic acidosis with a normal anion gap (no-gap). To compensate for the negative renal load, distal tubular secretion of potassium increases, causing severe hypokalemia that predisposes to arrhythmias and muscle intolerance. Biweekly monitoring of serum electrolytes is required for prolonged treatments.

Contraindications

• Absolute: Documented hypersensitivity to sulfonamides (risk of cross-reaction mediated by T lymphocytes, including anaphylaxis and toxicodermias); severe renal failure (Cl_cr < 30 mL/min - risk of lethal metabolic acidosis due to systemic accumulation of acetazolamide); severe liver failure (risk of hepatic encephalopathy due to ammonia accumulation).
• Relative: Pre-existing corneal endothelial insufficiency (gutted cornea or low endothelial cell density - AC is vital for the dehydrating endothelial pump, topical IACs can trigger irreversible corneal edema).

Adverse Effects (ADR)

• Ocular Sites: Dysgeusia / Bitter metallic taste in the pharynx after instillation (due to the passage of eye drops to the nasolacrimal duct and contact with the taste buds of the tongue); intense dural burning (dorzolamide acid); transient blurred vision (brinzolamide suspension); allergic follicular conjunctivitis.
• Systemic (Mainly Acetazolamide): Distal paresthesias in hands and feet (due to mild dural acidosis); phosphocalcium renal lithiasis (alkaline urine with low citrate excretion); idiopathic blood dyscrasias (aplastic anemia, agranulocytosis); fatigue, depression, weight loss, nausea and repeated vomiting.

Drug Interactions

• High-Dose Salicylates (Aspirin): Coadministration with systemic acetazolamide may shift the balance of aspirin toward its diffusible non-ionized form in the brain, inducing fulminant salicylic acid toxicity in the CNS.
• Loop diuretics (Furosemide): Potentiation of the risk of severe hypokalemia of renal origin.