timolol
Ophthalmic beta-blocker (non-selective beta-adrenergic antagonist)· Brands: Timoptol, Timoptic, Betimol, Istalol, BlocadrenPOTOP
Mechanism of action
Timolol is a non-selective beta-adrenergic antagonist with no intrinsic sympathomimetic, membrane-stabilising or local anaesthetic activity. Applied to the eye it acts mainly on the beta-2 receptors of the ciliary epithelium to reduce cyclic AMP formation and hence aqueous humour secretion, lowering intraocular pressure. It does not affect pupil size or accommodation, so unlike miotics it causes no miosis or dimming of vision. Onset of the ocular hypotensive effect is within about 15 to 30 minutes, with the maximum fall in pressure at roughly 1 to 2 hours. The effect is additive with prostaglandin analogues, alpha-2 agonists and carbonic anhydrase inhibitors, and the drug remains effective on long-term use, though a loss of effect is described in some patients. Oral timolol produces the same class effects as other non-selective beta-blockers, chiefly negative chronotropy, negative inotropy and bronchial smooth muscle constriction.
Pharmacokinetics
Ophthalmic timolol is absorbed partly through the cornea into the aqueous humour and partly into the systemic circulation via the conjunctival and nasal vasculature, so a meaningful fraction escapes first-pass hepatic metabolism and can produce systemic beta-blockade. Aqueous solution is usually given twice daily because the effect on intraocular pressure wanes before 24 hours; the gel-forming solution prolongs contact time and allows once-daily dosing. Systemic absorption is reduced by nasolacrimal occlusion or gentle eyelid closure for one to two minutes after instillation. It is metabolised in the liver, largely by CYP2D6, to inactive metabolites; the elimination half-life is about 3 to 4 hours after oral dosing, and plasma concentrations after ocular use are low but measurable. Timolol and its metabolites are excreted mainly in the urine. Elderly patients and those with renal or hepatic impairment may show greater systemic exposure.
Indications & dosing
Ocular hypertension
Use 0.25% solution; may increase to 0.5% if intraocular pressure remains uncontrolled. Gel-forming solution is available for once-daily dosing.
- adult · TOP: 1 drop BD · Use 0.25% solution; may increase to 0.5% if intraocular pressure remains uncontrolled. Gel-forming solution is available for once-daily dosing.
Open-angle glaucoma
First-line topical therapy. Start with 0.25% solution; titrate to 0.5% if needed. Monitor for systemic beta-blockade, especially in patients with respiratory or cardiac disease.
- adult · TOP: 1 drop BD · First-line topical therapy. Start with 0.25% solution; titrate to 0.5% if needed. Monitor for systemic beta-blockade, especially in patients with respiratory or cardiac disease.
Secondary glaucoma
Used as adjunctive therapy in various secondary glaucomas. Same dosing as for open-angle glaucoma. Consider alternative agents if contraindications to beta-blockers exist.
- adult · TOP: 1 drop BD · Used as adjunctive therapy in various secondary glaucomas. Same dosing as for open-angle glaucoma. Consider alternative agents if contraindications to beta-blockers exist.
Contraindications & precautions
- Bronchial asthma or a history of obstructive airways disease · Ophthalmic timolol can cause bronchospasm due to systemic absorption. Avoid in all patients with reactive airway disease.
- Sinus bradycardia · Beta-blockade further slows heart rate and may precipitate haemodynamic compromise.
- Second or third degree atrioventricular block · Risk of complete heart block and asystole.
- Cardiogenic shock · Negative inotropic effect may worsen shock.
- Overt cardiac failure · Beta-blockade can precipitate decompensation. Use only after stabilisation under specialist care.
- Hypersensitivity to timolol or other beta-blockers · May cause local or systemic allergic reactions.
- Severe peripheral circulatory disorders (e.g. Raynaud's phenomenon, Buerger's disease) · May aggravate ischaemia; use with caution and monitor.
- Diabetes mellitus, particularly labile or insulin-dependent · Beta-blockade can mask tachycardia and other symptoms of hypoglycaemia. Warn patients.
- Systemic absorption can occur; use nasolacrimal occlusion or gently close the eyelids for 2 minutes after instillation to reduce systemic effects.
- Monitor heart rate and blood pressure, especially in patients with cardiovascular disease or those taking oral beta-blockers or calcium channel blockers.
- Avoid abrupt withdrawal; taper if possible to prevent rebound hypertension or angina.
- Warn patients with diabetes that timolol may mask signs of hypoglycaemia and delay recovery.
- Use with caution in patients with myasthenia gravis; beta-blockers may worsen muscle weakness.
- Contact lens wearers should be advised to remove lenses before instillation and wait 15 minutes before reinsertion, as timolol may be absorbed by soft lenses.
Adverse effects
- Ocular stinging or burning on instillation
- Blurred vision
- Conjunctivitis
- Bradycardiaserious
- Bronchospasmserious
- Hypotensionserious
- Fatigue
- Depression
- Masking of hypoglycaemic symptomsserious
- Keratitisserious
Renal & hepatic adjustment
- eGFR 0–30: No specific dose change is defined for ophthalmic timolol. Systemic absorption from eye drops is small and renal clearance of unchanged drug is minor, so severe renal impairment (eGFR below 30) rarely alters exposure. If oral timolol is used, monitor heart rate and blood pressure closely and follow local formulary guidance.
- Hepatic impairment (mild): No dose adjustment needed for ophthalmic use. Timolol is extensively metabolised in the liver, so small changes in hepatic function have little effect at eye-drop doses.
- Hepatic impairment (moderate): No routine ophthalmic dose change. Monitor for systemic beta-blockade (bradycardia, fatigue, dizziness) because hepatic metabolism may be reduced.
- Hepatic impairment (severe): Use with caution. Plasma timolol from eye drops can rise in cirrhosis and portal-systemic shunting. Use the lowest effective dose, monitor pulse and blood pressure at each review, and consider an alternative agent if systemic effects appear.
Monitoring, pregnancy & toxicity
- Pulse rate and blood pressure · Before starting, 1 to 2 weeks after any change, then at each routine review
- Respiratory status: wheeze, breathlessness, cough, history of asthma or COPD · Before starting and at every review; stop if bronchospasm develops
- Intraocular pressure and therapeutic response · 4 to 6 weeks after starting, then as directed by the eye clinic
- Symptoms of systemic beta-blockade: fatigue, dizziness, cold extremities, reduced exercise tolerance, masked hypoglycaemia symptoms in diabetes · At each review
- Ocular surface effects: dry eye, stinging, blurred vision, punctate keratitis · If symptoms develop
- Adherence, drop technique and punctal occlusion · At each review
- Pregnancy: Timolol eye drops are absorbed systemically and can affect the fetus. Beta-blockers in late pregnancy have been associated with fetal growth restriction, neonatal bradycardia and neonatal hypoglycaemia, so timolol should be used only when the expected benefit outweighs the risk. Use the lowest effective dose, apply punctal occlusion for 1 to 2 minutes after each drop to reduce systemic absorption, and involve the obstetric team early. Labetalol is often preferred when a systemic beta-blocker is needed in pregnancy. Practice varies by region and local formulary.
- Toxicity: Bradycardia, hypotension, dizziness, syncope, fatigue after excessive dosing or accidental ingestion of eye drops, especially in children or older adults · Stop timolol. Give atropine for symptomatic bradycardia, lie the patient flat and give IV fluids for hypotension. Glucagon is used for refractory bradycardia or hypotension, with isoprenaline, adrenaline or temporary pacing as escalation. Arrange urgent medical assessment.
- Toxicity: Bronchospasm or acute severe wheeze, particularly in people with asthma or COPD · Stop timolol. Give oxygen, nebulised salbutamol and ipratropium, and systemic corticosteroids as indicated. Seek urgent respiratory or emergency care.
- Toxicity: High-degree heart block, acute cardiac failure or pulmonary oedema · Cardiac monitoring, atropine, inotropic support (for example isoprenaline or adrenaline) and transcutaneous or transvenous pacing may be required. Manage in a high-dependency or intensive care setting.
- Toxicity: CNS depression, confusion, seizures and hypoglycaemia, mainly after oral overdose, since timolol is lipophilic and crosses the blood-brain barrier · Supportive care with airway protection, IV glucose for hypoglycaemia, benzodiazepines for seizures, and close monitoring of pulse, blood pressure, blood glucose and conscious level. Contact a poisons information service or local toxicology unit for advice.
Clinical notes
Timolol eye drops are a first-line option for open-angle glaucoma and ocular hypertension, commonly used with a prostaglandin analogue when a single agent is insufficient. Prescribers must take a respiratory and cardiac history before starting: timolol is generally avoided in asthma, severe COPD, sinus bradycardia, second or third degree heart block and decompensated heart failure, since enough drug is absorbed systemically to provoke bronchospasm, bradycardia, hypotension, fatigue and, rarely, masking of hypoglycaemia in diabetes. It can also mask thyrotoxicosis and cause ocular irritation, blurred vision, dry eye and, uncommonly, corneal or periocular reactions. Because the patient may already take an oral beta-blocker, the combined systemic load needs review, and interactions with verapamil, diltiazem, digoxin and CYP2D6 inhibitors should be considered. Patients should be shown correct instillation with punctal occlusion, advised not to touch the bottle tip to the eye, and told to remove soft contact lenses before use if the preparation contains benzalkonium chloride. Abrupt withdrawal of systemic beta-blockade should be tapered rather than stopped; ocular therapy is generally continued perioperatively but the anaesthetist should be informed. Practice and product availability vary by country, and the gel-forming solution, preservative-free unit doses and fixed combinations differ between formularies.
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BNF; local formulary; manufacturer's summary of product characteristics (SmPC); national glaucoma guidance such as NICE or equivalent