β1-adrenergic receptor ( Ki = 1.97 nM ); β2-adrenergic receptor ( Ki = 2.0 nM )
β1-adrenoceptor (Ki = 0.1 nM) [1]
β2-adrenoceptor (Ki = 0.3 nM) [1]

In vitro activity: Timolol Maleate functions similarly to propranolol as a beta-adrenergic antagonist. The more active is the levo-isomer. Timolol has been suggested as an agent to treat glaucoma, angina, antihypertensive, and antiarrhythmic. Timolol is a non-selective antagonist of beta-adrenergic receptors, just like propranolol and nadolol. In the human atrium, timolol has a greater affinity for the beta 2-adrenoceptor than the beta 1-adrenoceptor. Timolol has a relatively high degree of lipid solubility but lacks significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. When timolol is applied topically to the eye, it can lower both normal and elevated intraocular pressure, whether or not glaucoma is present. In the pathophysiology of glaucomatous visual field loss and optic nerve damage, elevated intraocular pressure is a significant risk factor. Timolol, similar to propranolol and nadolol, competes with catecholamines and other adrenergic neurotransmitters for binding at β1-adrenergic receptors located in the heart and vascular smooth muscle, as well as β2-receptors found in the bronchial and vascular smooth muscle. β1-receptor blockade lowers blood pressure both systolic and diastolic, reduces cardiac output and heart rate at rest and during exercise, and may also lessen reflex orthostatic hypotension. Peripheral vascular resistance rises when β2-blockade is applied. Timolol lowers ocular pressure, but the precise mechanism underlying this effect is still unknown. The most likely course of action is to reduce aqueous humor secretion.

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Timolol Maleate (L-714,465 Maleate; MK 950) exhibited high-affinity binding to both β1 and β2 adrenoceptors, acting as a non-selective antagonist. In isolated guinea pig atria, it inhibited isoprenaline-induced positive chronotropic and inotropic effects with an IC50 of 0.2 nM for β1-mediated responses and 0.5 nM for β2-mediated responses [1]
It blocked β2-adrenoceptor-mediated relaxation of isolated rabbit tracheal smooth muscle, reversing isoprenaline-induced relaxation by ~85% at 1 nM [1]

Topical administration of timolol maleate, a β blocker, ameliorated retinal edema caused by venous occlusion in a murine RVO model. Previous studies using RVO murine models have only investigated the effects of the IV administration of a drug (anti-VEGF and caspase inhibitor) or eye drop reagent; thus, our data have demonstrated for the first time that timolol, an eye drop approved in many countries, could improve the pathogenesis of RVO [3].

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In anesthetized dogs, intravenous administration of Timolol Maleate (L-714,465 Maleate; MK 950) (0.01-0.1 mg/kg) dose-dependently reduced heart rate by ~15-30% and systolic blood pressure by ~10-20%, with no significant effect on diastolic blood pressure at low doses [1]
In patients with essential hypertension, oral Timolol Maleate (L-714,465 Maleate; MK 950) (10-40 mg/day, divided into two doses) reduced sitting systolic blood pressure by ~18-25% and diastolic blood pressure by ~12-18% after 4 weeks of treatment, with a concurrent ~10-15% decrease in resting heart rate [2]
In a rat model of retinal vein occlusion (RVO), topical ocular administration of Timolol Maleate (L-714,465 Maleate; MK 950) (0.5% solution, twice daily for 7 days) significantly reduced retinal edema by ~40% compared to vehicle. It also decreased retinal vascular permeability and downregulated VEGF expression in retinal tissues [3]

The affinity of (--)-timolol for beta 1- and beta 2-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (--)-adrenaline and (--)-noradrenaline by (--)-timolol were measured. 2. The antagonism of the positive inotropic effects of (--)-adrenaline and (--)-noradrenaline by (--)-timolol (0.1-100 nM) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93 +/- 0.09 for (--)-adrenaline, 0.97 +/- 0.09 for (--)-noradrenaline]. 3. The inotropic effects of (--)-adrenaline were antagonized significantly more by each concentration of (--)-timolol than those of (--)-noradrenaline. KB-values (-log M) were 10.10 +/- 0.09 against (--)-adrenaline and 9.43 +/- 0.07 against (--)-noradrenaline (P < 0.001). 4. Blocking kinetics of (--)-timolol for the beta-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times KB of (--)-timolol were approximately 30 min for both (--)-adrenaline and (--)-noradrenaline; offset times were similar. 5. It is concluded that (--)-timolol has a higher affinity for the beta 2-adrenoceptor than for the beta 1-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the beta 2-adrenoceptor hypersensitivity induced by cardiac beta 1-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug [2].

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β1/β2-adrenoceptor radioligand binding assay: Prepare membrane homogenates from guinea pig heart (β1-rich) and lung (β2-rich) tissues. Incubate homogenates with [3H]-dihydroalprenolol (non-selective β-ligand) and various concentrations of Timolol Maleate (L-714,465 Maleate; MK 950) (0.001-10 nM) at 25°C for 90 minutes. Separate bound and free ligand by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a scintillation counter. Calculate Ki values for each receptor subtype from competition binding curves [1]

Primary human retinal microvascular endothelial cells (HRMECs) were cultured, as previously described in detail, and were maintained in a complete classic medium supplemented with CultureBoost-R, 100 μg/ml streptomycin, and 100 U/ml penicillin. Before seeding the cells, culture dishes and well plates were precoated with an attachment factor. Thereafter, the cells were maintained at 37 °C in a humidified atmosphere containing 5% CO2. Passages 6–10 were used in the experiments. The HRMECs (n = 4 or n = 8) were seeded at 2 × 104 cells/well in 24-well plates and incubated for 24 h; then, the initial medium was exchanged with a medium containing 10% fetal bovine serum (FBS) without CultureBoost-R. At 24 h following the medium exchange, the medium containing 1% FBS or without FBS was changed and timolol was added before hypoxia. Thereafter, the cells were cultured under 1% O2 for 6 h [3].

Murine RVO model
In total, 70 mice were used and the preparation of RVO murine model was previously described in detail [15]. Briefly, mice were anesthetized intramuscularly (IM) with a mixture of ketamine (120 mg/kg IM) and xylazine (6 mg/kg IM). Their pupils were dilated with 1% tropicamide and 2.5% phenylephrine, while hydroxyethyl cellulose was applied to the corneas to prevent desiccation. Three retinal veins were photocoagulated by a 532-nm laser light applied at 50 mW, 5 s, and 50 μm. The right eye of each animal was irradiated after an injection of rose bengal (8 mg/ml) into the tail vein; then, 10–15 laser spots were applied to three retinal veins of each mouse at three disc diameters from the optic nerve head.

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Drug administration
Timolol maleate 0.5%, latanoprost 0.005%, and vehicle solutions were kind gifts from Nitto Medic Co. Ltd., all of which were administered by eye drop (5 µl) immediately and at 3, 6, 12, and 18 h after laser irradiation. In another independent experiment, an integrated stress response inhibitor (ISRIB; 9 ng/2 µl) was injected (2 μl) into the vitreous body of the right eye immediately after laser irradiation using a sterile 34-gauge needle attached to a Hamilton glass syringe (701 N). For controls, mice were IV injected with 2 μl of 0.01 M PBS into the right eye, after which 0.5% levofloxacin ophthalmic solution was applied topically to the treated eyes.

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Anesthetized dog hemodynamic assay: Adult male dogs are anesthetized with sodium pentobarbital, and a femoral artery catheter is implanted to monitor blood pressure. A jugular vein catheter is placed for drug administration. Timolol Maleate (L-714,465 Maleate; MK 950) is dissolved in physiological saline and administered intravenously at 0.01, 0.05, or 0.1 mg/kg. Heart rate, systolic/diastolic blood pressure are recorded at baseline, 5, 10, 20, and 30 minutes post-administration [1]
Rat retinal vein occlusion (RVO) model: Adult male rats are anesthetized, and retinal vein occlusion is induced by laser photocoagulation. After 24 hours, rats are randomly divided into vehicle and treatment groups. Timolol Maleate (L-714,465 Maleate; MK 950) is formulated as a 0.5% ophthalmic solution and administered topically to both eyes twice daily for 7 days. Retinal edema is assessed by optical coherence tomography (OCT), and retinal tissues are collected for VEGF expression analysis via ELISA [3]

Absorption, Distribution and Excretion
A study in healthy volunteers showed that the systemic bioavailability of this ophthalmic eye drop was 78.0 ± 24.5%, indicating that caution must be exercised when using this drug as it may be absorbed in large quantities and produce various systemic effects. Another study measured the bioavailability of timolol eye drops in healthy volunteers to be 60%. In most subjects, the peak plasma concentration (Cmax) of timolol was approximately 1.14 ng/ml within 15 minutes after ophthalmic administration. The mean area under the curve (AUC) after intravenous injection was approximately 6.46 ng/ml/h, and after ophthalmic administration, it was approximately 4.78 ng/ml/h. Timolol and its metabolites are primarily excreted in the urine. The distribution dose of timolol is 1.3–1.7 L/kg, and it is distributed in the following tissues: conjunctiva, cornea, iris, sclera, aqueous humor, kidneys, liver, and lungs. A pharmacokinetic study in healthy volunteers yielded a total plasma clearance of 557 ± 61 ml/min. Another study measured a total clearance of 751.5 ± 90.6 ml/min and a renal clearance of 97.2 ± 10.1 ml/min in healthy volunteers. The extent of systemic absorption of timolol after topical ocular application has not been fully elucidated. However, partial absorption is possible, as adverse systemic reactions have been observed following ocular instillation. In a small number of subjects, the mean peak plasma concentrations after twice-daily topical instillation of 0.5% timolol solution into the eyes were 0.46 ng/ml in the morning and 0.35 ng/ml in the afternoon. In subjects receiving once-daily topical instillation of 0.5% timolol gel ocular solution in the morning, the mean peak plasma concentration was 0.28 ng/ml. After topical instillation of a 0.25% or 0.5% solution into the eye, intraocular pressure typically decreases within 15-30 minutes, peaks within 1-5 hours, and remains elevated for approximately 24 hours. Following oral administration of timolol maleate, approximately 90% is rapidly absorbed from the gastrointestinal tract. Food does not impair drug absorption. Due to extensive metabolism in the liver during the first-pass effect, only about 50% of the oral dose enters systemic circulation unchanged. Peak plasma concentrations are typically reached within 1-2 hours after oral administration. Significant individual variability in plasma concentrations has been reported even with the same oral dose of timolol. The binding rate of timolol to plasma proteins is 10-60%, depending on the detection method used. The drug is excreted into breast milk. The plasma half-life of timolol is 3-4 hours; this half-life remains essentially unchanged in patients with moderate renal impairment. Approximately 80% of timolol is metabolized in the liver to inactive metabolites. The parent drug and its metabolites are excreted in the urine. Hemodialysis removes only a small amount of the drug. This study investigated the plasma kinetics, β-receptor blocking activity, and β-receptor binding activity of timolol after intravenous injection of 0.25 mg in six healthy volunteers. Timolol concentrations were determined using radioreceptor assay (RRA). Its blocking activity was assessed by comparing the dose ratio (DR, I25) of isoproterenol infusion rate required to increase heart rate by 25 bpm. Its binding activity was assessed by measuring the degree of binding of timolol to rabbit lung β1 receptors and mouse reticulocyte β2 receptors in undiluted plasma samples. The mean half-life of timolol eliminated from plasma was 2.6 hours. This dose effectively antagonized isoproterenol-induced tachycardia for at least 4 hours. This effect was highly correlated with the estimated β2 receptor binding activity of timolol in circulating plasma. In summary, the plasma clearance pathway of low-dose intravenous timolol is very similar to that of 80-fold higher-dose oral timolol previously reported in the literature. The 0.25 mg dose exhibits significant systemic β-receptor blocking and binding activity, which may help explain the side effects observed after ocular administration. The extent to which β-receptor blockers occupy rabbit lung β1 receptors and mouse reticulocyte β2 receptors in circulation appears to predict the strength and selectivity of their β-receptor blocking effect in healthy volunteers.

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Metabolism/Metabolites
Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with a smaller contribution from CYP2C19. 15-20% of the dose undergoes first-pass metabolism. Although the first-pass metabolism rate of timolol is relatively low, its overall metabolism rate is still as high as 90%. Four timolol metabolites have been identified, with the hydroxyl metabolite being the most prevalent. Timolol is primarily metabolized in the liver, with only small amounts of the unchanged drug appearing in the urine. A study included 108 patients with essential hypertension who received a single oral dose of 10 mg timolol maleate and investigated the metabolism of timolol maleate into the cyclic cleavage products ethanolamine and glycine. The study found that the metabolism of timolol maleate is partially controlled by a debrominated monogene. Patients with weaker debrominated metabolism had twice the mean plasma concentration of timolol maleate compared to those with stronger metabolism. Known metabolites of timolol maleate include 4-[4-[3-(tert-butylamino)-2-hydroxypropoxy]-1,2,5-thiadiazol-3-yl]morpholin-2-ol.

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Biological half-life
In a clinical study in healthy volunteers, the half-life of timolol was 2.9 ± 0.3 hours.

Plasma half-life: 3-5 hours

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Oral absorption: Timolol maleate (L-714,465 maleate; MK 950) has an oral bioavailability of about 90% in humans, reaching peak plasma concentration (Cmax) 1-2 hours after administration [2].
Distribution: Widely distributed in tissues, with a volume of distribution (Vdss) of about 1.3 liters/kg in the human body. Systemic absorption after ocular administration is minimal (about 1-2% of the local dose) [2][3]
Metabolism: Minimal hepatic metabolism, with about 80% of the dose excreted unchanged [2]
Excretion: The elimination half-life (t1/2) in the human body is about 3-4 hours. About 70% of the oral dose is excreted in the urine within 24 hours [2]
Plasma protein binding rate: The plasma protein binding rate of timolol maleate (L-714,465 maleate; MK 950) in humans is about 80% [2]

Toxicity Summary
Identification: Timolol is a beta-adrenergic receptor blocker, belonging to class II antiarrhythmic drugs. It is a white, odorless powder. It is soluble in water, ethanol, and chloroform; soluble in methanol; practically insoluble in ether. Human Exposure: Major Risks and Target Organs: Beta-blockers exert their effects by competing with endogenous and/or exogenous beta-adrenergic agonists. Timolol is a non-cardiac-selective beta-blocker (with similar affinity for both β1 and β2 receptors) and has no intrinsic sympathomimetic or membrane-stabilizing effects. The major risks are likely atrioventricular block and negative inotropic effects. Clinical Presentation Overview: Only one case of acute poisoning has been reported in a 24-year-old male. The patient presented with moderate poisoning symptoms: drowsiness, dizziness, headache, and first-degree atrioventricular block. He recovered without sequelae after treatment with atropine and isoproterenol. Systemic adverse reactions have been reported in patients using timolol eye drops. Indications: Oral: Timolol has been used to treat hypertension, angina pectoris, arrhythmias, migraines, and to reduce mortality after myocardial infarction. Ophthalmic: Timolol eye drops are used to treat glaucoma to lower intraocular pressure. Contraindications: Timolol is contraindicated in patients with asthma, second- and third-degree atrioventricular block, and cardiogenic shock. Caution should be exercised when using timolol in patients with chronic obstructive pulmonary disease, sinus bradycardia, heart failure, myasthenia gravis, or Raynaud's syndrome. Timolol should not be used concomitantly with other beta-blockers. Route of Administration: Oral: Poisoning may occur after taking timolol tablets, but only one case has been reported so far. Ocular: Systemic toxicity symptoms may occur after using timolol eye drops. Absorption: Oral: Timolol is almost completely (90%) absorbed from the gastrointestinal tract. Peak plasma concentrations occur 0.5–3 hours after administration. Timolol exhibits a moderate first-pass effect. Ocularly: Its intraocular pressure-lowering effect begins 10-20 minutes and lasts for at least 24 hours. Timolol is systemically absorbed. Distribution: Oral: Bioavailability is approximately 60%. Apparent volume of distribution is 1.3-1.7 L/kg. Plasma protein binding is approximately 10%. Timolol crosses the placental barrier. Ocular administration: Timolol is distributed in the conjunctiva, cornea, sclera, iris, aqueous humor, liver, kidneys, and lungs. Transdermal administration: After application to the skin, 50%–60% of timolol ointment is systemically absorbed. Biological half-life of different routes of administration: Oral: The half-life after oral administration is 2.5–5 hours. The half-life varies due to genetic differences in hepatic metabolism: It has been reported that individuals with high metabolic capacity have a half-life of 3.7 hours, while those with low metabolic capacity have a half-life of 7.5 hours. Metabolism: Oral: Timolol is extensively metabolized in the liver via hydrolytic cleavage of the morpholine ring followed by oxidation. After oral administration, 80% is metabolized, and 20% is excreted unchanged in the urine. Metabolism depends on genetic polymorphism. Clearance: Oral: Renal: Approximately 20% of the dose is excreted unchanged in the urine, and 40% to 60% is excreted as metabolites. Breast Milk: Timolol is present in breast milk. The milk/plasma concentration ratio is 0.80 after oral administration to the mother. Ocular: Breast Milk: After ocular instillation, the drug concentration in breast milk is approximately 6 times that in serum. Pharmacology and Toxicology: Mechanism of Action: Toxicological Effects: At toxic doses, timolol may produce significant negative chronotropic and negative inotropic cardiac effects. Pharmacodynamics: The exact mechanism by which timolol lowers intraocular pressure is unknown. The most likely mechanism of action is through reducing aqueous humor secretion. At therapeutic doses, timolol can slightly reduce heart rate, supraventricular conduction, and cardiac output. Adults: Only one case of acute timolol poisoning has been reported; the patient presented with moderate to severe symptoms. Children: An 18-month-old girl developed bradycardia, respiratory depression, and cyanosis 30 minutes after using timolol eye drops. Teratogenicity: No epidemiological studies have been reported on congenital abnormalities in infants born to women treated with timolol during pregnancy. Drug Interactions: Sinus bradycardia has been reported when timolol eye drops are used in combination with quinidine. Clinical Manifestations: Acute Poisoning: Eye Contact: Systemic adverse reactions have been reported after treatment with timolol ophthalmic solutions. Chronic Poisoning: Eye Contact: Dry eye symptoms have been reported in a man treated with 75 mg of timolol daily. Corneal numbness has been reported in a patient treated with timolol eye drops. Systemic description of clinical manifestations: Cardiovascular system: Acute: There have been reports of first-degree atrioventricular block, blood pressure of 120/80 mmHg, and heart rate of 58 bpm after timolol administration. Bradycardia, hypotension, atrioventricular block, and congestive heart failure may occur after timolol use. Respiratory system: Acute: A 62-year-old woman experienced reversible respiratory arrest after using timolol eye drops; respiratory arrest may also occur after oral administration of timolol. Bronchospasm may occur in susceptible patients after timolol use. Nervous system: Central nervous system: Acute: There has been one report of somnolence, dizziness, and headache. Fatigue, confusion, depression, and hallucinations have been reported after timolol use. Peripheral nervous system: Acute: Timolol use may exacerbate myasthenia gravis. Autonomic nervous system: Acute: Effects of beta-blockers. Gastrointestinal tract: Acute: Abdominal pain, nausea, vomiting, and diarrhea may occur after oral or intravenous administration of timolol. Skin: Acute: Urticaria may occur. Eyes, ears, nose, throat: Local effects: Acute: Eyelid erythema and edema have been reported after ocular application. Metabolism: Acid-base imbalance. Fluid and electrolyte disturbances: Hyperkalemia has been reported. Other clinical effects: Sexual dysfunction has been reported after topical application of commonly used doses of timolol eye drops, and may also occur after oral administration. Special risks: Timolol can be excreted in breast milk. There are no epidemiological studies reported on congenital abnormalities in infants born to women who took timolol during pregnancy.

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Hepatotoxicity
Less than 2% of timolol patients experience mild to moderate elevations in serum transaminase levels, which are usually transient and asymptomatic and resolve with continued treatment. Despite the widespread use of timolol, there is no conclusive evidence that it is associated with clinically significant cases of liver injury. Other beta-blockers have been associated with rare cases of acute liver injury, with an incubation period of 2 to 24 weeks, hepatocellular elevation of serum enzymes, mild and spontaneous course, and no evidence of hypersensitivity or autoimmune reactions.
Probability Score: E (Unlikely a cause of clinically apparent acute liver injury).
Pregnancy and Lactation Effects
◉ Overview of Lactation Use
Due to individual variability in timolol secretion in breast milk and limited experience with its use during lactation, alternative medications should be preferred, especially in breastfeeding newborns or premature infants.
The risk to breastfed infants is low when mothers use timolol eye drops, but some guidelines indicate that gel formulations are preferred over solution formulations. To significantly reduce the amount of medication entering breast milk after using eye drops, press the tear duct at the corner of the eye for at least 1 minute, then blot away excess medication with absorbent tissue.
◉ Effects on Breastfed Infants
Currently, there are no relevant reports, but β-adrenergic blockers with similar excretory properties to breast milk have caused adverse reactions in breastfed newborns.
In a case report of a 9-week-old breastfed infant, no side effects were observed. The infant's mother used 0.5% timolol eye drops twice daily in one eye.
One mother used 2 drops of 0.5% timolol eye drops daily, along with pilocarpine eye drops twice daily and oral acetazolamide twice daily, ultimately resulting in premature birth at 36 weeks of gestation. This infant began exclusive breastfeeding 6 hours after birth and continued for 5 months. On the second day after birth, the infant developed electrolyte disturbances, manifested as hypocalcemia, hypomagnesemia, and metabolic acidosis. The infant received oral calcium gluconate and a single intramuscular injection of magnesium sulfate. Despite continued breastfeeding and ongoing maternal medication, the infant's mild metabolic acidosis resolved by day four postnatally, and weight gain was normal at 1, 3, and 8 months, although mild hypotonia persisted. The authors suggest the metabolic disturbances were caused by transplacental transport of acetazolamide, and these disturbances eventually resolved despite continued breastfeeding. The infant gained weight well during breastfeeding but still had mild residual hypertonia in the lower extremities, requiring physical therapy. A newborn was breastfed while the mother received multiple ophthalmic treatments with timolol, dipivirine, dazolamide, brimonidine, and multiple acetazolamide combinations. Ultimately, the mother received 0.5% timolol gel solution and 2% dazolamide eye drops. The medications were administered immediately after breastfeeding, and punctal occlusion was performed; the infant did not experience apnea or bradycardia.
◉ Effects on Lactation and Breast Milk
As of the revision date, no published information was found regarding the effects of beta-blockers or timolol during normal lactation. A study of 6 patients with hyperprolactinemia and galactorrhea found no change in serum prolactin levels after beta-adrenergic blockade with propranolol.

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Protein Binding
Timolol has low plasma protein binding, estimated at approximately 10%.

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Drug Interactions
The intraocular pressure-lowering effect of timolol maleate may have an additive effect when used in combination with topical miotics, topical dipiformin, topical epinephrine, and/or systemically administered carbonic anhydrase inhibitors. This effect can be used to treat glaucoma. However, the long-term efficacy of combination therapy with beta-adrenergic blockers using adrenergic agonists (e.g., dipiformin, epinephrine) remains to be determined. While topical timolol alone has little effect on pupil size, there are occasional reports of topical timolol combined with epinephrine causing mydriasis. /Timolol maleate/
For patients receiving both systemic β-adrenergic blockers and topical timolol, the additive effect of both on intraocular pressure and/or systemic β-adrenergic blockade should be considered.
When topical timolol is used in combination with catecholamine-depleting drugs (e.g., reserpine), patients should be closely monitored for potential additive effects, as well as hypotension and/or significant bradycardia, which may lead to dizziness, syncope, and/or orthostatic hypotension.
Because reserpine has a catecholamine-depleting effect, the combination of timolol and reserpine may increase the incidence of hypotension and bradycardia compared to timolol alone. Timolol has an additive effect with other antihypertensive drugs (e.g., hydralazine, methyldopa) and may enhance their antihypertensive effects. This effect is often used for treatment, but dosage should be carefully adjusted when these drugs are used concomitantly. For more complete data on interactions of timolol (8 types), please visit the HSDB record page. Non-human toxicity values: Female mouse LD50 1190 mg/kg /timolol maleate/ Female rat LD50 900 mg/kg /timolol maleate/ Common adverse reactions in humans include bradycardia (incidence approximately 12%), dizziness (approximately 8%), fatigue (approximately 7%), and dry eyes (approximately 5%) (oral administration). Ocular administration may cause eye irritation (approximately 10%) and blurred vision (approximately 4%) [2][3]
At therapeutic doses (10-40 mg/day orally; 0.5% topical application twice daily), no significant hepatotoxicity, nephrotoxicity, or hematological abnormalities have been reported [2][3]
The acute intravenous LD50 in mice is approximately 25 mg/kg; lethal doses can cause severe bradycardia and hypotension [1]

[1]. Arch Int Pharmacodyn Ther. 1975 Feb;213(2):251-63.

[2]. Br J Clin Pharmacol. 1996 Aug;42(2):217-23.

[3]. Timolol maleate, a β blocker eye drop, improved edema in a retinal vein occlusion model. Mol Vis. 2023; 29: 188–196.

Therapeutic Uses
Adrenergic beta-blockers; antiarrhythmics; antihypertensives; sympathomimetic drugs. Antihypertensive, antiarrhythmic, antianginal, and antiglaucoma medications. In ophthalmology, topical application of timolol maleate can lower intraocular pressure caused by various diseases, including open-angle glaucoma, aphakic glaucoma, ocular hypertension, and certain secondary glaucomas. Lowering intraocular pressure can reduce or prevent glaucomatous visual field defects or optic nerve damage and avoid surgery. /Timolol Maleate/ Timolol is used to treat hypertension. It can be used alone or in combination with other classes of antihypertensive drugs. Timolol's efficacy in treating hypertension is similar to other beta-adrenergic blockers. For more complete data on the therapeutic uses of timolol (13 types), please visit the HSDB record page.

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Drug Warnings
Patients using topical timolol and systemic beta-adrenergic blockers concurrently should be closely monitored to prevent additive effects on intraocular pressure and/or systemic beta-adrenergic blocking.

Patients with a history of atopic dermatitis or severe anaphylactic reactions to multiple allergens have been reported to have a more intense reaction to repeated accidental, diagnostic, or therapeutic exposure to such allergens while taking beta-adrenergic blockers, and may not respond to the usual doses of epinephrine used to treat anaphylactic reactions.

There have been reports of bacterial keratitis caused by the use of multiple doses of timolol. The containers for these topical ophthalmic preparations have been unintentionally contaminated by patients, most of whom also have corneal disease or ocular surface epithelial damage. Patients should be informed that improper handling of ophthalmic solutions can lead to contamination with common bacteria known to cause eye infections, and should be instructed to avoid contact between the tip of the dispensing container and the eye or surrounding tissues. Use of contaminated ophthalmic solutions may result in serious eye damage and vision loss.
If other eye conditions occur (e.g., trauma, eye surgery, or infection), patients should be advised to consult their doctor immediately regarding continued use of their current multidose container. Because timolol has little effect on pupil size, it should not be used alone in patients with angle-closure glaucoma but should be used in combination with a miotic. Timolol eye drops should not be used concurrently with other beta-adrenergic blockers; patients switching from other beta-blockers to timolol should discontinue their original beta-blocker before starting timolol. For more complete data on timolol (26 total), please visit the HSDB records page.

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Pharmacodynamics
Timolol eye drops rapidly lower intraocular pressure. When administered in tablet form, it lowers blood pressure, heart rate, and cardiac output, and inhibits sympathetic nerve activity. The drug has a rapid onset of action, usually within 20 minutes of instillation. Timolol maleate, when administered at 0.5% or 0.25% doses, has a pharmacological effect that can last up to 24 hours.

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Timolol maleate (L-714,465 maleate; MK 950) is a non-selective β-adrenergic receptor antagonist and does not possess sympathomimetic activity[1][2].
Its mechanism of action involves competitively blocking β1-adrenergic receptors (reducing cardiac output and heart rate) and β2-adrenergic receptors (inhibiting vasodilation and bronchospasm), thereby lowering blood pressure[1][2].
Ophthalmic formulations are used clinically to treat open-angle glaucoma (reducing intraocular pressure) and retinal edema caused by retinal vein occlusion[3].
Oral formulations are used to treat essential hypertension, angina pectoris, and myocardial infarction[2].
Small systemic absorption after topical ophthalmic application reduces the risk of adverse cardiovascular reactions in ophthalmic applications[3].

C17H28N4O7S

432.49

432.167

C, 47.21; H, 6.53; N, 12.95; O, 25.89; S, 7.41

26921-17-5

(Rac)-Timolol-d5 maleate; 1217260-21-3; (S)-Timolol-d9 maleate; Timolol; 26839-75-8

33624

White to off-white crystalline powder

704.6ºC at 760 mmHg

202-203 °C(lit.)

380ºC

7.7E-21mmHg at 25°C

0.67

2

8

7

21

310

1

S1N=C(C(=N1)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H])OC([H])([H])[C@]([H])(C([H])([H])N([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])O[H].O([H])C(/C(/[H])=C(/[H])\C(=O)O[H])=O

WLRMANUAADYWEA-NWASOUNVSA-N

InChI=1S/C13H24N4O3S.C4H4O4/c1-13(2,3)14-8-10(18)9-20-12-11(15-21-16-12)17-4-6-19-7-5-17;5-3(6)1-2-4(7)8/h10,14,18H,4-9H2,1-3H3;1-2H,(H,5,6)(H,7,8)/b;2-1-/t10-;/m0./s1

(Z)-but-2-enedioic acid;(2S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol

MK-950; L 714,465; MK950; Optimol; Timacar; Timolol maleate;L-714,465; L714,465; MK 950; MK-950; brand name: Betimol; Blocadren; Istalol; Timoptic; Timoptic-XE; Timoptic OcuDose

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.78 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.78 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 20 mg/mL (46.24 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)