Introduction
Timolol is a non-selective beta-adrenergic receptor blocking agent that belongs to the class of medications known as beta-blockers. First approved by the FDA in 1978, it has established itself as a cornerstone therapy in both cardiovascular and ophthalmic medicine. Timolol is available in both oral and ophthalmic formulations, serving distinct therapeutic purposes across these delivery systems.
Mechanism of Action
Timolol competitively blocks beta-1 and beta-2 adrenergic receptors. In cardiovascular applications, this results in:
- Decreased heart rate (negative chronotropy)
- Reduced myocardial contractility (negative inotropy)
- Diminished cardiac output
- Lowered blood pressure
In ophthalmic use, timolol reduces intraocular pressure by decreasing aqueous humor production through inhibition of beta-adrenergic receptors in the ciliary body. The ophthalmic formulation may also slightly increase aqueous outflow.
Indications
FDA-approved indications:- Oral formulation: Hypertension, angina pectoris, myocardial infarction prophylaxis
- Ophthalmic solution: Elevated intraocular pressure in ocular hypertension, open-angle glaucoma
- Migraine prophylaxis
- Essential tremor
- Secondary prevention of variceal bleeding in portal hypertension
Dosage and Administration
Oral formulation:- Hypertension: 10-20 mg twice daily, maximum 60 mg/day
- Angina: 15-30 mg divided into 2-3 doses daily
- Myocardial infarction prophylaxis: 10 mg twice daily
- 1 drop of 0.25% or 0.5% solution in affected eye(s) twice daily
- Some formulations allow once-daily dosing
- Hepatic impairment: Use with caution; consider dose reduction
- Renal impairment: Use with caution in severe impairment
- Elderly: Initiate at lower end of dosing range
- Pediatrics: Safety and efficacy not established for oral form
Pharmacokinetics
Absorption:- Oral: Well absorbed (90%) but undergoes significant first-pass metabolism (25-30% bioavailability)
- Ophthalmic: Systemic absorption occurs through nasolacrimal duct
- Protein binding: Approximately 60%
- Volume of distribution: 1.3-1.7 L/kg
- Crosses blood-brain barrier and placenta
- Extensive hepatic metabolism via CYP2D6
- Metabolites are pharmacologically inactive
- Half-life: 2-5 hours (oral)
- Primarily renal excretion (20% unchanged)
- Dialyzable: Yes
Contraindications
- Bronchial asthma or history of bronchospasm
- Severe chronic obstructive pulmonary disease
- Sinus bradycardia or sick sinus syndrome
- Second- or third-degree heart block
- Cardiogenic shock
- Decompensated heart failure
- Hypersensitivity to timolol or components
Warnings and Precautions
Cardiac effects: May precipitate heart failure in susceptible patients Respiratory: Can cause bronchospasm in patients with reactive airway disease Withdrawal syndrome: Abrupt discontinuation may exacerbate angina or cause MI Diabetes: Masks hypoglycemic symptoms and may alter glucose metabolism Thyrotoxicosis: May mask clinical signs of hyperthyroidism Ophthalmic use: Systemic absorption can cause cardiovascular and pulmonary effects Myasthenic conditions: May exacerbate muscle weaknessDrug Interactions
Contraindicated combinations:- Other beta-blockers (additive effects)
- Calcium channel blockers (verapamil, diltiazem) - risk of bradycardia and heart block
- Antiarrhythmics (disopyramide, amiodarone): Increased risk of bradycardia
- Insulin and oral hypoglycemics: Enhanced hypoglycemic effect
- Sympathomimetics: Antagonized effects
- CYP2D6 inhibitors (fluoxetine, paroxetine): Increased timolol concentrations
- Clonidine: Exaggerated rebound hypertension upon withdrawal
Adverse Effects
Common (≥1%):- Cardiovascular: Bradycardia, hypotension
- Central nervous system: Fatigue, dizziness, depression
- Gastrointestinal: Nausea, diarrhea
- Respiratory: Dyspnea (especially in susceptible patients)
- Ophthalmic: Local irritation, burning, blurred vision
- Heart block or arrhythmias
- Bronchospasm
- Exacerbation of heart failure
- Severe hypotension
- Hallucinations or psychosis
- Peyronie's disease (with oral formulation)
Monitoring Parameters
Baseline assessment:- Complete blood count, renal and hepatic function
- Electrolytes
- ECG (heart rate, conduction intervals)
- Pulmonary function tests (if indicated)
- Intraocular pressure measurements
- Heart rate and blood pressure
- Signs of heart failure
- Respiratory status
- Glucose monitoring in diabetics
- Ophthalmologic examinations
- Adverse effect assessment
Patient Education
Administration instructions:- Take oral medication at same times daily
- For eye drops: Wash hands before use, avoid touching dropper tip, wait 5 minutes between different eye medications
- Do not discontinue abruptly without medical supervision
- Rise slowly from sitting/lying position to prevent dizziness
- Be cautious with alcohol consumption
- Inform all healthcare providers about timolol use
- Carry medical identification indicating beta-blocker use
- Shortness of breath or wheezing
- Unusual fatigue or swelling
- Slow heart rate or dizziness
- Depression or mood changes
- Vision changes or eye discomfort
References
1. Frishman WH. Timolol: A new beta-adrenergic blocking agent. Am J Cardiol. 1978;41(4):721-727. 2. Zimmerman TJ, Kaufman HE. Timolol: A beta-adrenergic blocking agent for the treatment of glaucoma. Arch Ophthalmol. 1977;95(4):601-604. 3. Timolol prescribing information. FDA-approved labeling. 4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill Education; 2017. 5. McEvoy GK, ed. AHFS Drug Information. American Society of Health-System Pharmacists; 2023. 6. Becker DE. Basic and clinical pharmacology of beta-adrenergic blocking drugs. Anesth Prog. 1984;31(4):185-191.