Dorzolamide, Brinzolamide, Acetazolamide

Mechanism

💊 Commercial Names

Trusopt, Azopt, Diamox (oral), Simbrinza (coformulación con Brimonidina).

🔬 Pharmacological Group

Inhibidores de la enzima anhidrasa carbónica soluble e unida a membrana (tipo II y IV). Sulfonamidas.

🧪 Standard Presentations

Colirios: Dorzolamida 2.0%, Brinzolamida 1.0% (suspensión). Acetazolamida comprimidos 250 mg e inyectable.

Mechanism of Action

La secreción activa de humor acuoso depende del gradiente osmótico generado por el transporte activo de bicarbonato (HCO₃^-) y sodio:

• Bloqueo de la Anhidrasa Carbónica II (AC-II) y IV: Los IAC inhiben reversible y competitivamente esta enzima de alta actividad metabólica en las células del epitelio ciliar no pigmentado.
• Inhibición de la Reacción de Hidratación del Dióxido de Carbono: Se suprime la velocidad de la siguiente reacción química reversible intraocular:

  CO₂ + H₂O AC H₂CO₃ H⁺ + HCO₃^-

• Colapso del Transporte Activo de Sodio y Agua: Al disminuir drásticamente la producción celular basal de iones hidrógeno (H⁺) y bicarbonato (HCO₃^-), se inhibe el cotransporte de sodio (Na⁺) y agua hacia la cámara posterior. La secreción de humor acuoso cae entre un 40% y un 50% en el caso de la acetazolamida oral, y un 20% en el caso de dorzolamida/brinzolamida tópicas.

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.