Timolol is a nonselective beta-blocker that available for both topical or systemic administration. Topical timolol is primarily used to reduce intraocular pressure in patients with open-angle glaucoma and ocular hypertension.[1] Topical timolol has also shown to be effecting in treating and minimizing thin, superficial infantile hemangiomas.[2] Systemic administration of timolol can be part of a regimen managing hypertension, myocardial infarction, and migraine prophylaxis.[3][4][5] The use of timolol to treat adult atrial fibrillation is controversial.[6][7]

FDA-Labeled Uses of Topical Timolol:

Open-angle glaucoma

Ocular hypertension

Off-Label Uses of Topical Timolol:

Infantile hemangioma

FDA-Labeled Uses of Systemic Timolol:

Hypertension (not first-line)

Myocardial infarction

Migraine prophylaxis

Off-Label Uses of Systemic Timolol:

Atrial fibrillation (adult)

Open-angle glaucoma and Ocular Hypertension

Open-angle glaucoma characteristically presents with resistance to aqueous humor outflow via the trabecular meshwork.[8] This situation causes a gradual increase in intraocular pressure as the ciliary body continues to secrete aqueous humor. When the intraocular pressure increases beyond normal levels, it is ocular hypertension. If left untreated, this increase in pressure can lead to irreversible damage to the optic nerve and retinal ganglion cells, causing progressive vision loss.[8]

Beta-blockers such as timolol were once first-line treatment for open-angle glaucoma and ocular hypertension, but the recommendation now is that patients first be treated with a topical prostaglandin, such as latanoprost. Topical prostaglandins have demonstrated to be more effective in lowering intraocular pressure and carry a lower risk for systemic side effects when compared to beta-blockers.[9] Timolol is now usually prescribed to patients who may respond insufficiently or have a contraindication to topical prostaglandins. For many patients, clinicians can combine timolol with prostaglandins for an enhanced reduction in intraocular pressure.[10]

Infantile Hemangiomas

Infantile hemangiomas are benign vascular tumors that occur in 4 to 10% of infants. These tumors characteristically have a proliferative phase, followed by involution. The resolution of infantile hemangiomas generally occurs before the age of 4.[2] Infantile hemangiomas are usually asymptomatic but may sometimes ulcerate, cause disfiguration, affect vision, or cause feeding difficulties depending on the location.[11] Topical ophthalmic timolol has demonstrated effectiveness in treating thin, superficial infantile hemangiomas.[2] 

Hypertension

Although previously thought of as first-line therapy for the treatment of hypertension, recent reports have rejected beta-blockers, such as timolol, as a first-line treatment for hypertension in favor of more effective medications including diuretics, calcium-channel blockers, and renin-angiotensin system inhibitors.[12]

Myocardial Infarction

Myocardial infarction is defined as an ischemic infarction to the heart due to a blockage of one or more of the coronary arteries. Beta-blockers, such as timolol, have been shown to increase survival and improve long-term outcomes after myocardial infarction.[13]

Migraine Prophylaxis

Migraines characteristically present as recurrent moderate to severe headaches that can be accompanied by phonophobia, photophobia, and nausea. Migraines can cause severe, unilateral throbbing pain, and physical activity can be an aggravating factor. Timolol has been an effective method for migraine prophylaxis.[14] 

Atrial Fibrillation

Atrial fibrillation is a common rhythm abnormality of the heart. Patients with atrial fibrillation are at an increased risk for many cardiovascular events, including stroke, heart failure, thromboembolism, and cardiovascular-related hospitalizations. Although beta-blockers are among the most common agents used to control heart rate for patients with atrial fibrillation, timolol has not been FDA approved for this purpose, which is perhaps because although timolol is effective at regulating heart rate, it is unlikely to restore sinus rhythm.[15][6][7]

Open-Angle Glaucoma

The exact mechanism of action by which timolol reduces the intraocular pressure in patients with open-angle glaucoma is unknown; however, the thinking is that timolol inhibits beta receptors on the ciliary epithelium. The ciliary epithelium normally functions to increase the production of aqueous humor. Some have proposed that through inhibition of beta receptors, timolol leads to a reduction in the production of aqueous humor and, therefore, reduced intraocular pressure. Researchers have also studied non-adrenergic pathways of timolol in the reduction of intraocular pressure.[16][17][18][19]

Ocular Hypertension

Timolol’s exact mechanism in lowering the intraocular pressure in patients with ocular hypertension is unknown, but it appears to be similar to its mechanism in lowering intraocular pressure for patients with open-angle glaucoma.[18][19][20]

Infantile Hemangioma

The mechanism of how timolol can treat infantile hemangiomas has yet to be fully elucidated. However, the postulated mechanism is that timolol’s effect likely involves antagonism of beta-adrenergic receptors causing multiple processes including vasoconstriction, stimulation of apoptosis, and inhibition of angiogenesis.[21]

Hypertension

The sympathetic nervous system is essential in the regulation of blood pressure. In normal physiology, beta-1 and beta-2 receptors become activated by endogenous catecholamines. Once these receptors are activated, they stimulate their associated G-protein, thereby activating adenylyl cyclase and leading to an increase in cyclic-AMP (cAMP).[22] This secondary messenger can cause a cascade of reactions in the body, one of them being vasoconstriction and an elevation in blood pressure. Non-selective beta-blockers, such as timolol, block interactions between endogenous catecholamines and prevent the G-protein cascade from occurring, leading to decreased sympathetic tone and therefore decreased blood pressure.[12]

Myocardial Infarction[23][24][25][26]

There are many mechanisms by which beta-blockers can reduce morbidity and mortality in patients after myocardial infarction. For example, beta-blockers can reduce the myocardial demand for oxygen and relieve ischemic chest pain. By blocking the sympathetic receptors in the heart, the heart rate will decrease. This induced bradycardia can lengthen diastole and increase perfusion of the heart. Beta-blockers can inhibit platelet aggregation, thromboxane synthesis, and decrease the rate of atherosclerosis and thromboembolism. They also inhibit cardiac remodeling after myocardial infarction.

Migraine Prophylaxis[14]

The exact mechanism of timolol as migraine prophylaxis is unknown. It likely exhibits its effects through a variety of processes. One proposed mechanism is that a blockage of beta-adrenergic receptors decreases the synthesis and release of norepinephrine, an important intermediate in the pathophysiology of migraines. Another pathway that could contribute to timolol’s migraine prophylactic properties is that beta-blockers can regulate the neuronal firing of periaqueductal gray matter using GABA. Timolol also appears to play a part in regulating the serotonergic system by inhibiting 5-HT, another important mediator in the pathophysiologic pathway of migraines. This modulation of serotonin’s effects also seems to contribute to beta-blockers’ ability to reduce the sensitivity of the auditory system, reducing the frequency of migraine attacks. There is also a hypothesis that beta-blockers play a significant role in reducing the excitability of the visual system in patients with migraines. Beta-blockers, such as timolol, are also thought to reduce the spread of signals through the brain, including the cortical spread as well as the excitability of the ventroposteromedial thalamic nucleus.

Atrial Fibrillation

The autonomic nervous system plays a significant role in the development of atrial fibrillation. Aberrant sympathetic tone can stimulate myocyte contraction and promote irregular rhythms in susceptible patients.[27][28] Beta-blockers help maintain the regular rhythm of the heart by decreasing the autonomic tone, and therefore decreasing sympathetic stimulation of the cardiac myocytes.[7]

Topical Ophthalmic Drop

Ocular Hypertension and Open-Angle Glaucoma

The topical ophthalmic form of timolol comes as a gel or as a solution. When using the gel form, one drop is administered daily to the affected eye. Available doses are 0.25% and 0.5%. When using the solution, one drop of the 0.25% solution is applied to the affected eye twice daily. If the response is inadequate, then the concentration is increased to 0.5% twice daily in the affected eye. Once the intraocular pressure is under control, the patient may decrease the dose to one drop daily.

Infantile Hemangiomas

One drop of 0.5% timolol gel is applied to the affected area 2 to 3 times a day. Treatment continues until improvement is stable.

Systemic

Hypertension

For the treatment of hypertension, dosing is 10 mg of oral timolol twice daily. If the patient’s response is inadequate, then the dose can be increased incrementally to a maximum of 60 mg per day.

Myocardial Infarction

For the secondary treatment of myocardial infarction, the dose is 5 mg of oral timolol twice daily. Dosing can be increased to 10 mg twice daily.

Migraine Prophylaxis

For the prophylactic treatment of migraines, the patient may take 10 mg of oral timolol twice daily. If the response is inadequate, then the dose can be increased to a maximum of 30 mg per day.

Atrial Fibrillation

Clinicians can use timolol to treat atrial fibrillation with an initial dose of 10 mg twice daily. It can then be increased incrementally to a maximum of 30 mg twice daily.

Ocular Side Effects:

• Burning
• Stinging
• Irritation
• Dryness
• Itching
• Watery eyes
• Conjunctival hyperemia
• Blurry vision

Systemic Side Effects[10][29][30]:

• Bronchospasm
• Bronchoconstriction
• Bradycardia
• Depression
• Fatigue
• Confusion
• Hair loss
• Sexual impotence
• Disorientation
• Increased low-density cholesterol levels
• Headache
• Dizziness

The use of timolol is contraindicated in patients with a history of asthma, chronic obstructive pulmonary disease (COPD), and other pre-existing pulmonary conditions.[30] Other contraindications for timolol include underlying cardiovascular conditions, including bradycardia, heart block, or syncope.[31]