Timolol, Betaxolol

Mechanism

💊 Commercial Names

Tusoptin, Cusimolol, Timoptol, Betoptic, Cosopt (timolol + dorzolamida).

🔬 Pharmacological Group

Antagonistas de receptores beta-adrenérgicos. Timolol (no selectivo β₁/β₂), Betaxolol (selectivo β₁).

🧪 Standard Presentations

Colirios oftálmicos: Timolol 0.25% y 0.50% (solución y gel de liberación prolongada), Betaxolol 0.25% (suspensión) y 0.5%.

Mechanism of Action

Los betabloqueantes tópicos inhiben los receptores localizados en la superficie basolateral del epitelio no pigmentado del cuerpo ciliar:

• Bloqueo de Receptores β₂-adrenérgicos (Timolol): Los receptores β₂ durales del cuerpo ciliar modulan la producción de humor acuoso de forma constitutiva. El timolol actúa como antagonista competitivo puro. Al bloquear el receptor, inactiva la subunidad estimuladora de la proteína G (G_s), inhibiendo la enzima adenilato ciclasa.
• Disminución de AMPc Intracelular: La inhibición de la adenilato ciclasa reduce los niveles intracelulares de monofosfato de adenosina cíclico (AMPc), lo que inactiva la proteína quinasa A (PKA).
• Reducción de la Secreción Activa: La PKA inactiva deja de fosforilar los canales iónicos y transportadores de membrana celulares (como el intercambiador Na⁺/H⁺ y el cotransportador Na⁺/K⁺/2Cl^-). Esto colapsa el gradiente osmótico activo necesario para la ultrafiltración y secreción de agua desde el estroma ciliar hacia la cámara posterior, reduciendo la tasa de síntesis de humor acuoso entre un 20% y un 30%. El betaxolol, al bloquear selectivamente los receptores β₁, reduce la PIO con menor potencia pero minimiza el bloqueo β₂ pulmonar.

Pharmacokinetics

Quantitative Ocular and Systemic Pharmacokinetics

The Punctal Occlusion Maneuver: Prevention of Systemic Absorption

To mitigate systemic absorption and optimize the intraocular bioavailability of timolol and any other topical ophthalmic drug, the patient must be instructed to perform punctal occlusion: immediately after instillation of the drop, press firmly with the index finger on the inner corner of the eye (over the lacrimal sac and lacrimal puncta) for a minimum of 2 to 3 minutes continuous, keeping the eyelids closed without blinking forcefully. This simple physical maneuver mechanically occludes the tear canaliculi, reducing systemic systemic absorption by up to 60-70% and prolonging the contact time of the drug with the cornea.

Security

Critical Systemic Toxicity: The Danger of Timolol in Respiratory and Cardiac Patients

Free ophthalmic timolol in solution is massively absorbed through the nasal mucosa, reaching the heart and lungs without undergoing first-pass metabolism. In patients with bronchial asthma, severe COPD or bronchial hyperreactivity, systemic blockade of bronchial β₂ receptors causes intense bronchoconstriction of vagal origin that can trigger severe bronchospasm with a fatal outcome. At the cardiac level, timolol decreases the automatism and conduction of the sinus and atrioventricular node by blocking β₁ receptors, inducing extreme bradycardia, second or third degree AV block, and acute congestive heart failure. Its use requires auscultation and exhaustive cardiopulmonary history prior to prescription.

Contraindications

• Absolute: Active bronchial asthma or history of severe chronic obstructive pulmonary disease (COPD); clinically significant sinus bradycardia (<50 bpm); second or third degree atrioventricular block not controlled by pacemaker; cardiogenic shock; decompensated heart failure.
• Relative: Labile or poorly controlled diabetes mellitus (systemic timolol masks the autonomic warning symptoms of hypoglycemia, such as tachycardia, tremor, and sweating); myasthenia gravis (may worsen generalized muscle weakness or ocular symptoms such as eyelid ptosis).

Adverse Effects (ADR)

• Eye Locals: Burning, stinging and tearing sensation of immediate onset (associated with the osmolarity of the eye drops and preservatives); punctate keratitis; corneal hypoesthesia (weak local anesthetic block, increases the risk of inadvertent erosions); dry eyes due to alteration of the tear film.
• Systemic: Bradycardia, arterial hypotension, syncope of vasovagal origin, severe bronchospasm, chronic fatigue, CNS depression, erectile dysfunction, insomnia with nightmares and alteration of the serum lipid profile (decrease in HDL).

Drug Interactions

• Systemic Beta Blockers (Metoprolol, Propranolol): Additive pharmacodynamic effect that can induce profound bradycardia or severe hypotension.
• Calcium Antagonists (Verapamil, Diltiazem): Negative synergism that depresses sinus and cardiac conduction function; risk of sinus arrest or hemodynamic collapse.
• CYP2D6 inhibitors (Quinidine, Fluoxetine, Paroxetine): They inhibit the hepatic metabolism of systemically absorbed timolol, drastically increasing its concentration in the blood and multiplying the risk of beta-blocking adverse effects.