Timolol

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Adrenergic Beta-Antagonists; Antiarrhythmics; Antiglaucoma Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Ophthalmological preparations > Miotics and antiglaucoma medicines

202-203

71.5-72.5 °C

Solutions of timolol maleate are stable up to a pH of 12. In general, timolol ophthalmic solutions should be protected from light and stored in tight containers at 15-30 °C and protected from freezing. ... Timolol gel-forming ophthalmic solution should be stored at 15-25 °C. /Timolol Maleate/

Timolol maleate tablets should be stored in well closed, light resistant containers at a temperature less than 40 °C, preferably between 15-30 °C. /Timolol maleate/

9.53

8.8

9.2

pKa = 9.21

176.5 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID3047504]

170.43 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

White crystals from ethanol; mp: 201.5-202.5 °C; specific optical rotation: -12.0 deg at 24 °C/405 (concentration by volume = 5 g in 1 N hydrogen chloride); specific optical rotation: 4.2 deg at 25 °C/D; maximum absorption (O.1 N hydrogen chloride): 294 nm (A = 200, 1%, 1 cm); sol in water, ethanol, methanol; sparingly sol in chloroform; very slightly sol in cyclohexane; practically insol in isooctane, ether; stable in soln up to pH 12. /Timolol maleate/

White, odorless, crystalline powder. Slightly soluble in water; freely soluble in ethanol /Timolol hemihydrate/

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P263, P264, P270, P280, P301+P317, P318, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl timolol and timolol maleate, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Timolol and timolol maleate/

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Fraunfelder FT; Ocular Beta-blockers and Systemic Effects. Arch Intern Med 146 (Jun): 1073-74 (1986). The physiological and metabolic systems which contribute to the systemic side effects of timolol maleate when given as ophthalmic drops were described and discussed. The specific reactions ascribed to this medication were also listed. /Timolol maleate/

Jackson CD, Fishbein L; A Toxicological Review of Beta-adrenergic Blockers. Fundam Appl Toxicol 6 (3): 395-422 (1986). The use of various beta-adrenergic blockers has become extensive as they have been found to be efficacious in the treatment of a number of cardiovascular problems including cardiac arrhythmias, angina pectoris, and hypertension. The widespread and chronic use of these drugs has generated a concern for their potential chronic toxicity. Eighteen beta-adrenergic blockers have been reviewed and the available literature pertaining to their potential carcinogenicity, mutagenicity, and teratogenicity has been summarized and compared.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

When used in conjunction with topical miotics, topical dipivefrin, topical epinephrine, and/or systemically administered carbonic anhydrase inhibitors, the effect of timolol maleate in lowering intraocular pressure may be additive. This effect may be used to therapeutic advantage in the treatment of glaucoma. However, the long term efficacy of combined therapy with an adrenergic agonist (eg, dipivefrin, epinephrine) and a beta-adrenergic blocking agent remains to be clearly established. Although topical timolol used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with topical timolol and epinephrine has been reported occasionally. /Timolol maleate/

The possibility of an additive effect on intraocular pressure and/or systemic beta-adrenergic blockade should be considered in patients who are receiving a systemic beta-adrenergic blocking agent and topical timolol concomitantly.

When topical timolol is administered concomitantly with a catecholamine depleting drug (eg, reserpine), the patient should be observed closely for possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, and or postural hypotension.

Concomitant administration of timolol with reserpine may increase the incidence of hypotension and bradycardia as compared with timolol alone, because of reserpine's catecholamine depleting activity. Timolol also is additive with and may potentiate the hypotensive actions of other hypotensive agents (e.g., hydralazine, methyldopa). This effect usually is used to therapeutic advantage, but dosage should be adjusted carefully when these drugs are used concurrently.

For more Interactions (Complete) data for TIMOLOL (8 total), please visit the HSDB record page.

Mild-to-moderate elevations in serum aminotransferase levels occur in less than 2% of patients on timolol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its wide spread use, timolol has not been convincingly linked to instances of clinically apparent liver injury. Other beta-blockers have been implicated in rare instances of acute liver injury with a latency to onset ranging from 2 to 24 weeks, a hepatocellular pattern of serum enzyme elevations and a mild, self-limiting course without evidence of hypersensitivity or autoimmune reactions.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 240(SRC), determined from a log Kow of 1.83(2) and a regression-derived equation(3), indicates that timolol is expected to have moderate mobility in soil(SRC). Volatilization of timolol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.3X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Timolol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.4X10-8 mm Hg(SRC), determined from a fragment constant method(5).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 240(SRC), determined from a log Kow of 1.83(2) and a regression-derived equation(3), indicates that timolol is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.3X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 1(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), timolol, which has an estimated vapor pressure of 1.4X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase timolol may be removed from the air by wet and dry deposition(SRC).

IDENTIFICATION: Timolol is an adrenergic beta-receptor blocking agent and a Class II antiarrhythmic drug. The drug is a white, odorless powder. Soluble in water, alcohol, in chloroform; soluble in methanol; practically insoluble in ether. HUMAN EXPOSURE: Main risks and target organs: Beta-blocking agents exert their effects by competing with endogenous and/or exogenous beta-adrenergic agonists. Timolol is a non-cardioselective beta-blocker (it has similar affinity for beta1 and beta2 receptors) and it has no intrinsic sympathomimetic or membrane stabilizing effect. The main risks might be an impairment of atrioventricular conduction and a negative inotropic effect. Summary of clinical effects: Only one case of acute poisoning after ingestion in a 24 year old man has been reported. The patient showed moderate toxic symptoms: drowsiness, vertigo, headache, and first degree atrioventricular block which was treated with atropine and isoproterenol. The patient recovered without sequelae. Adverse systemic effects have been reported in patients treated with timolol eye drops. Indications: Oral administration: Timolol has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmias, migraine and for the reduction of mortality following myocardial infarction. Ocular administration: Ophthalmic solutions of timolol are used in the treatment of glaucoma to reduce intraocular pressure. Contraindications: Timolol is contraindicated in patients with asthma, second and third degree AV block, and cardiogenic shock. Timolol should be used cautiously in patients with chronic obstructive pulmonary diseases, sinus bradycardia, cardiac failure, myasthenia gravis, Raynaud's syndrome. Timolol should not be administered with other beta-blockers. Routes of entry: Oral: Poisoning after ingestion of timolol tablets may occur but only one case has been actually reported. Eye: Systemic toxic symptoms may occur after treatment with timolol eye drops. Absorption by route of exposure: Oral: Timolol is almost completely (90%) absorbed from the gastrointestinal tract. The peak plasma concentration occurs 0.5-3 hours after ingestion. Timolol is subject to a moderate first pass effect. Ocular: The onset of the ocular hypotensive action occurs after 10-20 minutes and lasts for at least 24 hours. Timolol is absorbed systemically. Distribution by route of exposure: Oral: Bioavailability is about 60%. Apparent volume of distribution is 1.3 - 1.7 L/kg. Plasma protein binding is approximately 10%. Timolol crosses the placenta Ocular: Timolol is distributed in conjunctiva, cornea, sclera, iris, aqueous humor, liver, kidney and lung. Transdermal: After cutaneous application of timolol ointment, 50 to 60% is absorbed systemically. Biological half-life by route of exposure: Oral: After oral administration, the half-life is 2.5 - 5 hours. The half-life varies according to genetic differences in hepatic metabolism: half-lives of 3.7 and 7.5 hours were reported in extensive and poor metabolizers, respectively. Metabolism: Oral: Timolol is extensively metabolized in the liver by hydrolytic cleavage of the morpholino ring with subsequent oxidation. Following an oral dose, 80% is metabolized and 20% is eliminated unchanged in urine. Metabolism is dependent on genetic polymorphism. Elimination by route of exposure: Oral: Kidney: About 20% of the dose is eliminated unchanged in the urine and 40 to 60% as metabolites. Breast milk: Timolol is present in breast milk. Following a maternal oral dose, the milk/plasma ratio is 0.80. Ocular: Breast milk: Following ocular instilation, the concentration in breast milk was approximately 6 times higher than in serum. Pharmacology and toxicology: Mode of action: Toxicodynamics: At toxic doses, timolol may exert a pronounced negative chronotropic and negative inotropic cardiac effect. Pharmacodynamics: The exact mechanism whereby timolol reduces ocular pressure is still not known. The most likely action is by decreasing the secretion of aqueous humor. At therapeutic doses, timolol slightly decreases heart rate, supraventricular conduction and cardiac output. Adults: Only one case of acute poisoning with timolol has been reported; this patient showed moderately severe symptoms. Children: An 18 month old girl developed bradycardia, respiratory depression and cyanosis 30 minutes after the administration of timolol eye drops. Teratogenicity: No epidemiological studies of congenital abnormalities among infants born to women treated with timolol during pregnancy have been reported. Interactions: Sinus bradycardia has been reported after concomitant treatment with timolol eye drops and quinidine. Clinical effects: Acute poisoning: Eye contact: Adverse systemic effects have been reported after treatment with ophthalmic solutions of timolol. Chronic poisoning: Eye contact: Dryness of the eye has been reported in a man treated with timolol 75 mg daily. Corneal anesthesia was observed in a patient treated with timolol eye drops. Systematic description of clinical effects: Cardiovascular: Acute: First-degree atrioventricular block has been reported after ingestion of blood pressure was 120/80 mmHg and the heart rate was 58/min. Bradycardia, hypotension, atrioventricular block and congestive cardiac failure may occur after administration of timolol. Respiratory: Acute: Reversible respiratory arrest was observed in a 62-year-old woman after instillation of timolol eye drops and may occur after oral administration. Bronchospasm may occur in susceptible patients after administration of timolol. Neurological: CNS: Acute: Drowsiness, vertigo, headache have been reported in one case. Fatigue, confusion, depression, hallucinations have been reported after administration of timolol. Peripheral nervous system: Acute: Worsening of myasthenia gravis may occur after administration of timolol. Autonomic nervous system: Acute: Effects of beta-blockade. Gastrointestinal: Acute: abdominal pain, nausea, vomiting and diarrhea may occur after administration of timolol orally or as eye drops. Dermatological: Acute: Urticaria may be observed. Eye, ear, nose, throat: local effects: Acute: Eyelid erythema and edema has been reported following ocular administration. Metabolic: Acid-base disturbances. Fluid and electrolyte disturbances: Hyperkalemia has been reported. Other clinical effects: Sexual dysfunction following usual doses of topical ocular timolol has been reported and may also occur after oral administration. Special risks: Timolol is eliminated in breast milk. No epidemiological studies of congenital anomalies among infants born to women treated with timolol during pregnancy have been reported.

Signs and Symptoms of Overdose

The Koc of timolol is estimated as 240(SRC), using a log Kow of 1.83(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that timolol is expected to have moderate mobility in soil.

/HUMAN EXPOSURE STUDIES/ This study was undertaken to see whether long-term locally applied ocular medications produced any alterations in the ocular surface, and, in particular, whether it caused damage to the mucus layer of the tear film. The ocular surface of 40 control subjects (group 1), 21 patients (group 2) chronically treated with a commercial preparation of 0.5% timolol maleate, and 20 previously untreated glaucomatous patients (group 3) in need of treatment with the same drug was studied. Parameters studied were Schirmer's test, lacrimal meniscus height, break-up time, fluorescein and rose Bengal stains, conjunctival impression cytology, mucus staining, and the ferning test. Patients in groups 2 and 3 showed a significant decrease (P < 0.001) in the number of normal Schirmer's and break-up time tests. All had positive vital stains. Results showed a significant decrease (P < 0.001) in goblet-cell density, mucus granules, and reticular sheets, and an increase (P < 0.001) in pathologic crystallization patterns. These results demonstrate that chronic application of a commercial preparation of timolol maleate damaged the ocular surface, especially the mucus layer of the tear film. /Timolol maleate/

/HUMAN EXPOSURE STUDIES/ Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolo and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation.

/HUMAN EXPOSURE STUDIES/ To determine the effect on serum lipid levels of carteolol hydrochloride 1.0% or timolol maleate 0.5% given twice a day to women age 60 years and older with primary open-angle glaucoma or ocular hypertension. We included 112 patients in this double-masked, randomized, multicenter trial. Fasting clinical laboratory studies were evaluated at baseline and at 12 weeks. Patients were instructed not to change their dietary, alcohol consumption, or exercise habits during the study. For the carteolol group, the high-density lipoprotein (HDL) and total cholesterol/high-density lipoprotein (TC/HDL) ratio at baseline of 50.1 +/- 1.5 mg/dl and 4.7 +/- 0.2 changed by the 12-week visit to 51.3 +/- 1.9 mg/dl (P = .25) and 4.6 +/- .02 (P = .47), respectively. For the timolol maleate group, the baseline HDL and TC/HDL ratio of 53.6 +/- 2.2 mg/dl and 4.4 +/- 0.2 changed to 50.2 +/- 1.9 mg/dl (P < .001) and 4.7 +/- 0.2 (P = .001), respectively, at the 12-week visit. Carteolol patients showed no significant change from baseline, whereas the HDL (P < .001) and TC/HDL ratio decreased (P = .001) significantly in the timolol maleate group. There also was a significant difference in the change from baseline at 12 weeks between carteolol and timolol maleate groups for the HDL and TC/HDL ratio (P = .01 and .012, respectively). No differences in TC, low-density lipoprotein (LDL), or triglycerides (TG) or in changes from baseline were observed between groups at 12 weeks (P > .05). At 12 weeks, no differences were observed between carteolol and timolol maleate groups in intraocular pressure or safety (P > .05), except that patients given carteolol demonstrated fewer solicited ocular symptoms (P = .007). Carteolol appears to be neutral in its effect on serum lipid levels, whereas timolol maleate adversely affects the HDL and TC/HDL ratio in women age 60 years and older with ocular hypertension or primary open-angle glaucoma. /Timolol maleate/

/SIGNS AND SYMPTOMS/ A 30 year old woman who ingested 650 mg of the drug experienced second- and third-degree heart block, which initially resolved without treatment. However, approximately 2 months later, she developed an irregular heartbeat, hypertension, dizziness, tinnitus, increased pulse rate and borderline first-degree heart block.

/SIGNS AND SYMPTOMS/ As with other beta-adrenergic blocking agents, symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure may occur with timolol overdosage.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

timolol

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl timolol and timolol maleate, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Timolol and timolol maleate/

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

S01ED01

C - Cardiovascular system

S - Sensory organs

QC - Cardiovascular system

QS - Sensory organs

S01ED01

Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases 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. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, 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.

beta-Adrenergic blocker

Following topical application to the eye, timolol maleate reduces both elevated and normal intraocular pressure in patients with or without open angle (chronic simple, noncongestive) glaucoma or ocular hypertension. Timolol reduces intraocular pressure with little or no effect on accommodation or pupillary size. In patients with elevated intraocular pressure, timolol reduces mean intraocular pressure by about 25-33%. The drug appears to be equally effective in light and dark colored eyes. ... The exact mechanism by which beta-blockers, including timolol, reduce intraocular pressure has not been clearly defined. Fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect. beta-Adrenergic blocking agents may block endogenous catecholamine stimulated increases in cyclic adenosine monophosphate concentrations within the ciliary processes and subsequent formation of aqueous humor. Timolol appears to cause little or no change in aqueous humor outflow facility. ... In some studies, timolol maleate applied topically to one eye reduced intraocular pressure in both eyes; the mechanism of this effect has not been elucidated. ... A slight decrease in the intraocular hypotensive effect may occur during the first 3 wk of timolol therapy, and tolerance may develop with prolonged use; however, the intraocular pressure lowering effect has been maintained for at least 3 yr with continuous use of the drug in some patients. /Timolol maleate/

Timolol maleate has pharmacologic actions similar to those of other beta-adrenergic blocking agents. The principal physiologic action of timolol is to competitively block beta-adrenergic receptors within the myocardium (beta1-receptors) and within bronchial and vascular smooth muscle (beta2-receptors). Unlike atenolol and metoprolol, timolol is not a beta1-selective adrenergic blocking agent; timolol is a nonselective beta-adrenergic blocking agent, inhibiting both beta1- and beta2-adrenergic receptors. Timolol also does not exhibit the intrinsic sympathomimetic activity seen with pindolol or the membrane stabilizing activity possessed by propranolol or pindolol. ... By inhibiting myocardial beta1-adrenergic receptors, timolol produces negative chronotropic and inotropic activity. The negative chronotropic action of timolol on the sinoatrial node results in a decrease in the rate of sinoatrial node discharge and an increase in recovery time, thereby decreasing resting and exercise stimulated heart rate and reflex orthostatic tachycardia by as much as 30%. High doses of the drug may produce sinus arrest, especially in patients with SA node disease (eg, sick sinus syndrome). Timolol also slows conduction in the atrioventricular node. Timolol usually produces a slight reduction in cardiac output, probably secondary to its effect on heart rate. The decrease in myocardial contractility and heart rate produced by timolol leads to a reduction in myocardial oxygen consumption which accounts for the effectiveness of the drug in chronic stable angina pectoris. ... Timolol suppresses plasma renin activity and suppresses the renin aldosterone-angiotensin system. The renin lowering effect of beta-adrenergic blocking agents may lead to a minimal reduction in glomerular filtration rate and occasionally may reduce renal blood flow; however, other mechanisms (eg, decreased cardiac output, unopposed alpha-mediated renal vasoconstriction) also probably contribute to these effects. Because of the suppression of aldosterone production, beta-adrenergic blocking agents usually produce no measurable increases in plasma volume or sodium and water retention. ... The precise mechanism of timolol's hypotensive effect has not been determined. Timolol may transiently increase peripheral vascular resistance at rest and with exercise, but peripheral vascular resistance usually returns to baseline with continued administration of the drug. It has been postulated that beta-adrenergic blocking agents reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release. /Timolol maleate/

Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of healthy volunteers.

Plasma half-life 3-5 hr

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.

It is metabolized extensively by the liver, and only a small amount of unchanged drug appears in the urine.

The metabolism of timolol maleate to its ring cleavage ethanolamine and glycine products was studied in 108 patients with essential hypertension who received 10 mg oftimolol maleate, administered as a single oral dose. The metabolism of timolol maleate was determined to be partly under monogenic control of the debrisoquine-type. The mean plasmatimolol maleate concentration in poor metabolizers of debrisoquine were double that of extensiv metabolizers. /Timolol maleate/

Timolol has known human metabolites that include 4-[4-[3-(tert-butylamino)-2-hydroxypropoxy]-1,2,5-thiadiazol-3-yl]morpholin-2-ol.

5JKY92S7BR

TIMOLOL ANHYDROUS

Mechanisms of Action [MoA] - Adrenergic beta-Antagonists

Established Pharmacologic Class [EPC] - beta-Adrenergic Blocker

Timolol anhydrous is a beta-Adrenergic Blocker. The mechanism of action of timolol anhydrous is as an Adrenergic beta-Antagonist.

TIMOLOL

Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

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.

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

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

One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers.

The degree of systemic absorption of timolol after topical application to the eye has not been fully elucidated; however, some absorption can apparently occur, since adverse systemic effects have occurred following ophthalmic instillation of the drug. Following topical adminstration of timolol 0.5% solution twice daily to the eye in a limited number of individuals, mean peak plasma concentrations were 0.46 or 0.35 ng/ml following the morning or afternoon dose, respectively. In individuals receiving topical timolol 0.5% as the gel-forming ophthalmic solution once daily in the morning, mean peak plasma concentrations following the dose were 0.28 ng/ml. Following topical application to the eye of a 0.25 or 0.5% solution of the drug, reduction in IOP usually occurs within 15-30 minutes, reaches a maximum within 1-5 hours, and persists about 24 hours.

Approximately 90% of an oral dose of timolol maleate is rapidly absorbed from the GI tract. Absorption of the drug is not reduced by food. Only about 50% of an oral dose reaches systemic circulation as unchanged drug since timolol undergoes extensive metabolism on first pass through the liver. Peak plasma concentrations of the drug usually are reached within 1-2 hr after oral administration. Considerable interindividual variation in plasma concentrations attained have been reported with a specific oral dose of timolol.

MEDICATION

Use (kg; approx.) in Germany (2009): >250

Tablets, 5, 10, and 20 mg. Ophthalmic solution, 0.25% and 0.5%. /Timolol maleate/

Ophthalmic Solution, 0.25% (of timolol), Timoptic (with benzalkonium chloride), Merck; Timoptic in Ocudose (preservative-free), Merck; 0.5% (of timolol), Timoptic (with benzalkonium chloride), Merck; Timoptic in Ocudose (preservative- free), Merck. /Timolol maleate/

Oral Tablets, 5 mg Biocardren, Merck; 10 mg, Biocardren (scored), Merck; 20 mg, Biocardren (scored), Merck. /Timolol maleate/

Oral Tablets, 10 mg with Hydrochlorothiazide 25, Timolide, Merck. /Timolol maleate combinations/

For more Formulations/Preparations (Complete) data for TIMOLOL (6 total), please visit the HSDB record page.