Timolol

Timolol, belonging to the beta blocker acts as a nonselective beta-adrenergic blocker. Timolol works by decreasing pressure in the eye. Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and beta(2)-receptors in the vascular and bronchial smooth muscle.

This medication is used to treat the high pressure inside the eye due to glaucoma (open-angle type) or another eye disease (such as ocular hypertension). Lowering high pressure inside the eye helps to prevent blindness. This medication work by decreasing the amount of fluid within the eye.

The onset of action of timolol occurs within 20 minutes of the administration of an ophthalmic dose. The Duration of Action for timolol was about 24 hours. The Tmax was found within 15 minutes following the administration of timolol by the ophthalmic route and Cmax was about 1.14 ng/ml.

Timolol is available in the form of an ophthalmic solution, ophthalmic gel-forming solution, and tablets.

• Timolol tablets to be swallowed whole with water.

• To instill the eye drops or eye gel: Tilt the head back and, pressing the finger gently on the skin just beneath the lower eyelid, pull the lower eyelid away from the eye to make a space. Drop the medicine into this space. Let go of the eyelid and then gently close the eyes. Do not blink. Keep the eyes closed and apply pressure to the inner corner of the eye with the finger for 1 or 2 minutes to allow the medicine to be absorbed by the eye.

Timolol is approved for the treatment of open-angle glaucoma, ocular hypertension, Hypertension, myocardial infarction, and migraine prophylaxis.

Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate.

The reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis

Timolol is a nonselective beta-blocker available for both topical as well as systemic administration. Topical timolol is primarily used to reduce intraocular pressure in patients with open-angle glaucoma and ocular hypertension.

Timolol is approved for use in the following clinical indications mentioned below:

• For Topical :

• Open-angle glaucoma and Ocular Hypertension:

Open-angle glaucoma characteristically presents with resistance to aqueous humor outflow via the trabecular meshwork. This situation causes a gradual increase in intraocular pressure as the ciliary body continues to secrete aqueous humor. When 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.

Beta-blockers such as timolol were once the 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 effectiveness in lowering intraocular pressure and carry a lower risk for systemic side effects when compared to beta-blockers. 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.

Although not approved, there have been certain off-label uses documented for Topical Timolol. These include:

• 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. Infantile hemangiomas are usually asymptomatic but may sometimes ulcerate, cause disfiguration, affect vision, or cause feeding difficulties depending on the location. Topical ophthalmic timolol has demonstrated effectiveness in treating thin, superficial infantile hemangiomas.

• For Systemic:

• 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.

• Myocardial Infarction:

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

• Migraine Prophylaxis:

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

Although not approved, there have been certain off-label uses documented for Systemic Timolol. These include:

• Atrial Fibrillation:

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

Timolol is available in the form of an ophthalmic solution, ophthalmic gel-forming solution, and tablets.

Topical Ophthalmic Drop:

• Ocular Hypertension and Open-Angle Glaucoma:

The topical ophthalmic form of timolol comes as a gel or solution. One drop is administered daily to the affected eye when using its gel form. 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, 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 to 20 mg of oral timolol twice daily. If the patient’s response is inadequate, 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, the dose can be increased to 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.

• Angina:

For off-label treatment of angina, the dose is 10 to 60 mg orally each day taken two or three times daily.

Timolol can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Timolol is available in various dosage strengths:

For Tablets : 5 mg, 10mg , 20mg

For Ophthalmic solution : 0.25%, 0.5%

Timolol is available in the form of an ophthalmic solution, ophthalmic gel-forming solution, and tablets.

Timolol should be used in the treatment of open-angle glaucoma, ocular hypertension, Hypertension, myocardial infarction, and migraine prophylaxis. along with appropriate dietary restrictions

• Open-angle glaucoma: Avoid caffeine, saturated fats, trans fatty acids, and salt in their daily diet, glaucoma patients should also consider avoiding any foods they’re allergic to.

• Hypertension:- It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

• Myocardial infarction:- No more than 25 to 35 percent of your daily calories should come from total fat (including saturated fat). Less than 7 % of your daily calories should come from saturated fat. Avoid trans fats and Consume less than 200 milligrams a day of dietary cholesterol.

• Migraine:- Some commonly triggered diets include: Baked food with yeast, such as sourdough bread, bagels, doughnuts, coffee cake, Chocolate, Cultured dairy products (like yogurt and 0kefir), Tomatoes, Vegetables like onions, pea pods, some beans, corn, and sauerkraut, Vinegar and Alcohol must be avoided.

The dietary restriction should be individualized as per patient requirements

Timolol may be contraindicated in the following:

• Asthma, Chronic obstructive pulmonary disease

Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease

• Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock

Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with sinus bradycardia; second or third-degree atrioventricular block; overt cardiac failure; cardiogenic shock

• Hypersensitivity Reactions

Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this product in the past.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Potentiation of Respiratory Reactions Including Asthma

Timolol Maleate Ophthalmic Solution 0.5% contains timolol maleate; and although administered topically, it can be absorbed systemically. Therefore, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate

• Cardiac Failure

Sympathetic stimulation may be essential for the support of the circulation in individuals with diminished myocardial contractility, and its inhibition of beta-adrenergic receptor blockade may precipitate more severe failure.

In patients without a history of cardiac failure, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Timolol Maleate Ophthalmic Solution 0.5% should be discontinued

• Obstructive Pulmonary Disease

Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of the bronchospastic disease [other than bronchial asthma or a history of bronchial asthma in which Timolol Maleate Ophthalmic Solution 0.5% is contraindicated] should, in general, not receive beta-blocking agents, including Timolol Maleate Ophthalmic Solution 0.5%

• Increased Reactivity to Allergens

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

• Potentiation of Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

• Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or in diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

• Masking of Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

PRECAUTIONS:

General:

Because of the potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timolol, alternative therapy must be considered.

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by the patients who, in most cases, had a concurrent corneal disease or disruption of the ocular epithelial surface.

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).

Angle-closure glaucoma:

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Timolol maleate has little or no effect on the pupil. TIMOLOL should not be used alone in the treatment of angle-closure glaucoma.

Anaphylaxis:

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Muscle Weakness:

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms

Drinking alcohol while taking the timolol can increase drowsiness and dizziness which in turn increase the risk of accidental injury.

Timolol use in breastfeeding patients is not recommended.

Teratogenic Effects: Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on the postnatal development of offspring.

Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies on pregnant women. Timolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Potassium-Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium when taken along with timolol, can lead to an increase in blood potassium levels.

Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to the molecule Timolol can be categorized as:

Common Adverse effects:

• Blurred vision
• burning or stinging in the eye.

Less Common adverse effects:

• Arm, back, or jaw pain
• Blisters
• Hives
• Welts, Or Itching
• Blue Lips, Fingernails, Or Skin Burning
• Crawling
• Itching
• Numbness
• Prickling
• "Pins And Needles," Or Tingling Feelings
• Change In Vision
• Chest Pain Or Discomfort
• Chest tightness or heaviness
• Confusion about identity, place, and time continues ringing or buzzing or other unexplained noise in the ears
• Coughing that sometimes produces frothy pink sputum
• Depression
• Noisy breathing
• Difficulty with chewing, swallowing, or talking
• Dilated neck veins
• Discharge
• Excessive tearing
• Disturbed color perception
• Double vision
• Drooping eyelids
• Dry or itching eyes etc.

Rare adverse effects:

• Acid or sour stomach
• Belching
• Body aches or pain
• Diarrhea
• Dry mouth
• Ear congestion
• Hearing loss
• Heartburn, etc.

Post Marketing Experience:

The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium and decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.

The clinically relevant drug interactions of Timolol are briefly summarized here:

Beta-Adrenergic Blocking Agents:

Patients who are receiving a beta-adrenergic blocking agent orally and Timolol should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

Calcium Antagonists:

Caution should be used in the co-administration of beta-adrenergic blocking agents, such as Timolol, and oral or intravenous calcium antagonists because of the possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration must be avoided.

Catecholamine-Depleting Drugs:

Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.

Digitalis and Calcium Antagonists:

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

CYP2D6 Inhibitors:

Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine) and timolol.

Clonidine:

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension, which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

The common side effects of Timolol includes the following:

Eye irritation, double vision, headache, depression, dizziness, nausea, etc.

The use of Timolol should be prudent in the following group of special populations:

Pregnancy

• Teratogenic Effects:

Pregnancy Category C: Teratogenicity studies have been performed on animals. Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on the postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies on pregnant women. Timolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers:

Timolol has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from Timolol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use:

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

• The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of molecule Timolol
• There have been reports of inadvertent overdosage with Timolol resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily.

Pharmacodynamics:

• Timolol, when administered through the ophthalmic route, rapidly decreases intraocular pressure. When administered in tablet form, it reduces the blood pressure, heart rate, and cardiac output and reduces sympathetic activity. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose.
• Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses.
• Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise and a decrease in both systolic and diastolic blood pressure.

Pharmacokinetics:

• Absorption:

The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5, indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers.

The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration.

• Distribution:

Timolol is distributed to the following tissue: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung i.e., 1.3 - 1.7 L/kg.

The plasma protein binding of timolol is not extensive and is estimated to be about 10%.

• Metabolism:

Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19. 15-20% of a dose undergoes first-pass metabolism. Despite its relatively low first-pass metabolism, timolol is 90% metabolized. Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant.

• Elimination:

Timolol and its metabolites are mainly found excreted in the urine.

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