Timolol

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.

Toxicity

The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse.
Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment.

Originator

Blocadren,MSD,UK,1974

The Uses of Timolol

Timolol is a β-adrenergic blocker most commonly used to treat raised blood pressure; used to treat angina (pain from inadequate oxygen supply to the heart muscle); treatment of so me disturbances of heart rhythm; used to prevent migraine headaches; drops treat some types of glaucoma (raised pressure within the eye).

The Uses of Timolol

Betimol(Sanofi Winthrop).

The Uses of Timolol

Timolol is a nonselective β-adrenoblocker that prevents action of catecholamines. When used locally in the form of eye drops, intraocular pressure decreases. It is used for chronic open-angle glaucoma as well as closed-angle glaucoma.

Indications

Ophthalmic timolol is indicated for the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma. The oral form of this drug is used to treat high blood pressure. In certain cases, timolol is used in the prevention of migraine headaches.

Background

Timolol is a nonselective beta-adrenergic antagonist given in an eye drop solution to reduce intraocular pressure, or pressure in the eyes. It is also used in tablet form as a drug to treat hypertension. Timolol was first approved by the FDA in 1978. This drug is marketed by several manufacturers and is an effective agent for the management of conditions such as open-angle glaucoma and hypertension.

Definition

ChEBI: (S)-timolol (anhydrous) is the (S)-(-) (more active) enantiomer of timolol. A beta-adrenergic antagonist, both the hemihydrate and the maleate salt are used in the mangement of glaucoma, hypertension, angina pectoris and myocardial infarction, and for the prevention of migraine. It has a role as an antiglaucoma drug, an antihypertensive agent, an anti-arrhythmia drug and a beta-adrenergic antagonist. It is a conjugate base of a (S)-timolol(1+). It is an enantiomer of a (R)-timolol.

Manufacturing Process

Step A: Preparation of 3-tert-Butylamino-2-Oxopropanol - To an aqueous solution of tert-butylamine (1 mol) at ambient temperature, there is added slowly and with vigorous stirring 2 mols bromoacetol. The reaction mixture is allowed to stand at ambient temperature for about 5 hours whereupon it is made basic by the addition of sodium hydroxide.
The reaction mixture then is extracted with ether, the excess amine is removed from the ethereal solution under reduced pressure and the ether then removed by evaporation to give 3-tert-butylamino-2-oxopropanol. Step B: A solution of the 3-tert-butylamino-2-oxopropanol in a mixture of pyridine hydrochloride and pyridine is treated with p-toluenesulfonylchloride. The mixture is stirred for 1/2 hour at 25° to 30°C and then poured into cold water. The solution is treated with potassium carbonate and the pyridine evaporated in vacuo at a temperature between 55° and 60°C. The aqueous residue is treated with potassium carbonate and the mixture extracted with methylene chloride. Evaporation of the dried extract provides 1- toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane.
Step C: Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Oxopropoxy)- 1,2,5-Thiadiazole - The 1-toluenesulfonyloxy-2-oxo-3-tert-butylaminopropane, prepared as described in Step B, (11 mols) is added to 0.80 N methanolic sodium methoxide (15 ml) at 0°C. The mixture is stirred for 15 minutes at 0° to 5°C, treated with 3-morpholino-4-hydroxy-1,2,5-thiadiazole (4.29 grams) and then refluxed for 16 hours. The solvent is evaporated in vacuo and the residue is treated with excess potassium carbonate to provide 3-morpholino- 4-(3-butylamino-2-oxopropoxy)-1,2,5-thiadiazole.
Step D: Chemical Reduction Preparation of 3-Morpholino-4-(3-tert_x0002_Butylamino-2-Hydroxypropoxy)-1,2,5-Thiadiazole - The 3-morpholino-4-(3- tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole (0.01 mol) is dissolved in isopropanol (10 ml). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to crystallization. The solid material is removed by filtration and dried thus providing 3-morpholino-4-(3- tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 161° to 163°C (as hydrochloride).
Alternative Step D: Reduction with a Reductate - Sucrose (1 kg) is dissolved in water (9 liters) in a 20-liter bottle equipped with a gas trap. Baker's yeast (Saccharomyces cerevisiae, 1 kg) is made into a paste with water (1 liter) and added to the sucrose solution with stirring. After lively evolution of gas begins (within 1 to 3 hours), 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)- 1,2,5-thiadiazole hydrogen maleate [1.35 mols, prepared by reaction of the 3- morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole with an equimolar quantity of maleic acid in tetrahydrofuran]. The mixture is allowed to stand until fermentation subsides, after which the bottle is kept in a 32°C incubator until all fermentation has ended (in approximately 1 to 3 days). The yeast is filtered off with addition of diatomaceous earth and the filtrate is evaporated to dryness to give S-3-morpholino-4β-tert-butylamino-2- hydroxypropoxy)-1,2,5-thiadiazole, MP 195° to 198°C (as hydrogen maleate), according to US Patent 3,619,370.
Step E: The base may be converted to the maleate by maleic acid

Therapeutic Function

Antiarrhythmic, Antiglaucoma

Contact allergens

Timolol was implicated in allergic contact dermatitis due to beta-blocker agents in eyedrops.

Pharmacokinetics

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.

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.

Metabolism

Timolol (Timoptic) is almost completely absorbed from the gastrointestinal tract. Peak plasma levels occur 2 to 4 hours after oral administration; the plasma halflife of timolol is approximately 5.5 hours.The extensive tissue distribution of timolol into lung, liver, and kidney is similar to that of other -blockers. Approximately 70% of the drug is excreted in the urine within 24 hours, mostly as highly polar unconjugated metabolites. Only 6% of an administered dose is recovered in the feces. Although timolol is approved for the topical treatment of elevated intraocular pressure, there is limited information about its pharmacokinetics following administration by this route.The drug apparently can reach the systemic circulation after intraocular instillation, but plasma levels are only about 7% of those achieved in the aqueous humor.