Generic Name: Timolol Maleate (ophthalmic)
Drug Class: Non-selective beta-adrenergic receptor blocker (β-blocker)
Formulations:
– Timolol 0.25% eye drops
– Timolol 0.5% eye drops
– Timolol 0.25% gel-forming solution
– Timolol 0.5% gel-forming solution
Route: Ophthalmic (topical ocular)
Indications: Open-angle glaucoma, ocular hypertension
Therapeutic Effect: Reduction of intraocular pressure (IOP) through decreased aqueous humor production
Timolol is a widely used topical β-blocker prescribed to manage elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension. While the compound does not directly affect visual function, its pressure-lowering effect reduces the risk of optic nerve damage and visual field loss. Although administered to the eye, timolol can be absorbed systemically and mimic the adverse effects associated with oral beta-blockers.
2. Indications
2.1 Primary Indications
Open-angle glaucoma:
Used to lower elevated IOP in patients with chronic open-angle glaucoma to slow the progression of optic neuropathy.
Ocular hypertension:
Indicated to prevent optic nerve damage in patients with consistently high intraocular pressure but no current glaucomatous damage.
2.2 Adjunctive Indications
– May be used in combination with other intraocular pressure-lowering agents such as prostaglandin analogs, alpha agonists, and carbonic anhydrase inhibitors.
– May be considered when monotherapy with other agents is inadequate.
3. Dosage and Administration
3.1 Available Strengths
– Timolol 0.25% (2.5 mg/mL)
– Timolol 0.5% (5 mg/mL)
– Also available in gel-forming formulations that enhance contact time with the ocular surface
3.2 Recommended Dosage
Solution Form
Adults:
– One drop of 0.25% or 0.5% in the affected eye(s) twice daily
– If IOP is not controlled adequately, dosage may be increased to 0.5% twice daily
– Once IOP is stabilized, maintenance may be achieved with once daily dosing
Gel-forming Solution
– One drop of 0.25% or 0.5% in the affected eye(s) once daily, typically in the morning
– This formulation requires only once-daily dosing due to its prolonged ocular retention
Pediatric Use
– Use with caution in children over 2 years
– Start with the lowest available strength (0.25%)
– Close systemic monitoring required
3.3 Administration Technique
– Wash hands thoroughly before use
– Tilt head back and pull down lower eyelid
– Instill one drop into the conjunctival sac
– Avoid blinking and close the eye gently for 1–2 minutes
– Apply gentle pressure to the nasolacrimal duct to minimize systemic absorption
– Wait at least 5 minutes before administering another eye drop if using multiple agents
– Contact lenses must be removed before instillation and reinserted after 15 minutes
4. Mechanism of Action
Timolol is a non-selective β1 and β2 adrenergic receptor blocker. Its main ocular effect is a reduction in intraocular pressure via the following mechanisms:
– Inhibits sympathetic stimulation of β2 receptors in the ciliary body
– Reduces aqueous humor production
– Minimal effect on aqueous outflow pathways
– IOP reduction occurs within 30 minutes, peaks at 1 to 2 hours, and lasts up to 24 hours
There is no significant miosis, blurred vision, or night blindness, which makes it different from miotic agents such as pilocarpine.
5. Pharmacokinetics
Absorption:
– Rapid absorption through conjunctival and nasal mucosa
– Systemic bioavailability up to 78% despite topical administration
– Gel formulation has prolonged ocular contact, resulting in lower systemic peak levels
Distribution:
– Timolol is lipophilic and widely distributed throughout body tissues, including ocular tissues and CNS
– Passes through the blood-ocular and blood-brain barriers
Metabolism:
– Extensively metabolized by the liver via cytochrome P450 2D6
– Undergoes first-pass metabolism when systemically absorbed
Excretion:
– Primarily excreted via the kidneys
– Terminal half-life approximately 2.5 to 5 hours
– Duration of therapeutic ocular effect exceeds plasma half-life due to receptor binding
6. Contraindications
– Bronchial asthma or a history of asthma
– Severe chronic obstructive pulmonary disease (COPD)
– Sinus bradycardia
– Second- or third-degree atrioventricular block
– Overt cardiac failure or cardiogenic shock
– Hypersensitivity to timolol or other β-blockers
– Concurrent use of systemic β-blockers is generally avoided to prevent additive effects
7. Warnings and Precautions
7.1 Respiratory Effects
– Topical timolol can cause bronchospasm, especially in patients with asthma or obstructive airway disease
– May be life-threatening even with ophthalmic doses
– Use is contraindicated in asthma and severe COPD
7.2 Cardiovascular Effects
– Risk of bradycardia, hypotension, atrioventricular block, and cardiac failure
– Patients with underlying heart disease should be monitored closely
– Withdrawal should be gradual in case of systemic symptoms
7.3 Masking of Hypoglycemia
– May obscure signs and symptoms of hypoglycemia in patients with diabetes mellitus
– Caution required in insulin-dependent diabetics
7.4 Thyrotoxicosis
– Timolol may mask clinical signs of hyperthyroidism such as tachycardia
– Sudden withdrawal could precipitate a thyroid storm in these patients
7.5 Surgical Considerations
– β-blockers may alter responses to anesthesia and catecholamine stimulation
– Inform the anesthesiologist before surgical procedures
7.6 Contact Lens Users
– Preserved formulations contain benzalkonium chloride, which can accumulate in soft contact lenses
– Patients should remove lenses prior to administration and wait at least 15 minutes before reinserting
8. Adverse Effects
8.1 Local Ocular Effects
– Transient stinging or burning sensation
– Dry eyes
– Conjunctival hyperemia
– Blurred vision
– Photophobia
– Eyelid inflammation
– Keratitis
– Diplopia
– Decreased corneal sensitivity
– Foreign body sensation
– Eye discharge
8.2 Systemic Effects (Due to Absorption)
– Fatigue
– Dizziness
– Depression
– Headache
– Nausea
– Cold extremities
– Bradycardia
– Hypotension
– Bronchospasm
– Dyspnea
– Sexual dysfunction
– Insomnia or vivid dreams
Systemic adverse reactions may mimic those seen with oral β-blocker therapy and occur especially in elderly or debilitated patients.
9. Drug Interactions
9.1 With Other Beta-Blockers
– Additive systemic β-blockade may occur with oral or other topical β-blockers
– Not recommended to use with oral timolol or systemic propranolol
9.2 With Calcium Channel Blockers
– Increased risk of AV block or hypotension when used with verapamil or diltiazem
– Use with caution and monitor cardiac function
9.3 With Clonidine
– May exacerbate rebound hypertension upon withdrawal of clonidine
– Avoid abrupt cessation of clonidine if co-administered
9.4 With Antidiabetic Agents
– May enhance hypoglycemia and mask warning signs such as tachycardia
– Close glucose monitoring is necessary
9.5 With CYP2D6 Inhibitors
– Paroxetine, fluoxetine, and other SSRIs may increase plasma levels of timolol via CYP2D6 inhibition
– Dose adjustment or close monitoring may be required
10. Use in Specific Populations
10.1 Pregnancy
– Use only if clearly needed
– Animal studies have shown adverse effects, but adequate human data is lacking
– Risk of fetal bradycardia or growth restriction if systemically absorbed
10.2 Lactation
– Excreted in breast milk in small amounts
– Potential for systemic β-blockade in infants
– Breastfeeding is not recommended during treatment with ophthalmic timolol
10.3 Pediatric Use
– Safety and efficacy have not been fully established
– Rare cases of apnea and bradycardia have been reported in neonates
– Only used when absolutely necessary with close observation
10.4 Geriatric Use
– Increased risk of systemic adverse effects
– Use lowest effective dose with appropriate monitoring
11. Monitoring Parameters
– Intraocular pressure: baseline and periodic measurements
– Visual field testing in glaucoma patients
– Heart rate and blood pressure
– Respiratory status in at-risk individuals
– Blood glucose in diabetic patients
– Signs of local irritation or ocular surface disease
12. Overdose Management
Symptoms:
– Bradycardia
– Hypotension
– Bronchospasm
– Cardiac arrest
– Fatigue, dizziness, or syncope
Management:
– Supportive care with oxygen and intravenous fluids
– Atropine for bradycardia
– Glucagon or isoproterenol for cardiac depression
– Salbutamol or other β2 agonists for bronchospasm
– Hospitalization may be necessary for severe systemic symptoms
– Hemodialysis is not effective due to extensive tissue distribution
13. Storage and Handling
– Store at room temperature (15–25°C)
– Protect from light and moisture
– Do not refrigerate unless specified by manufacturer
– Discard 28–30 days after opening, even if solution remains
– Do not touch the dropper tip to any surface to avoid contamination
14. Clinical Considerations
– Timolol is often used as first-line therapy or added when prostaglandins fail to control IOP
– Systemic side effects are more likely in elderly, children, and patients with comorbidities
– Nasolacrimal occlusion and eyelid closure reduce systemic absorption
– Gel-forming preparations allow for once-daily administration and reduce systemic exposure
– Tachyphylaxis or reduced efficacy may occur with prolonged use
– Patients should be educated to monitor for signs of systemic effects and report adverse reactions promptly
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