Intramol Mechanism of Action

Pharmacology: Pharmacodynamics: Ophthalmological beta-blocking agent.
Timolol is a non-selective β-adrenergic blocker, which does not possess significant intrinsic sympathomimetic or local anaesthetic (membrane-stabilising) activity. When applied topically in the eye, it reduces both elevated and normal intraocular pressure by inhibiting the production of aqueous humour. Unlike miotics, Timolol reduces intraocular pressure with little or no effect on pupil size or accommodation.
The onset of reduction in intraocular pressure following ocular administration of Timolol can be detected within 30 minutes after a single dose. The maximum effect usually occurs in one to three hours and significant lowering of intraocular pressure can be maintained for as long as 24 hours following a single dose.
If systemically absorbed, as is possible, Timolol maleate is capable of producing beta-blockade elsewhere in the body with consequent systemic effects (increased airway resistance, bradycardia, hypotension, etc.).
Pharmacokinetics: Topical instillation of 50 μl of a 0.5% solution of Timolol to the rabbit eye resulted in rapid appearance of Timolol in the aqueous humour and to a much lesser degree in the plasma. The concentration in the aqueous humour (mean of 2.47 μg/mL) peaked 30 minutes after instillation.
The plasma concentration (0.188 μg/mL) also packed at this time.
Following topical instillation in humans, the Timolol concentration in aqueous humour was 8-100 ng/mL within the first hour while the mean plasma concentration was approximately 1 ng/mL seen with therapeutic doses of oral Timolol.
Toxicology: Preclinical Safety Data: Acute Toxicity Studies: Data have been reported in a number of animal species. Oral LD50 in the mouse and rat are 1137 mg/kg and 1028 mg/kg respectively.
Chronic Toxicity Studies: No adverse effects were observed with ophthalmic topical administration of Timolol in rabbits and dogs in studies lasting one and two years respectively. In studies with oral administration in high dosed dogs and rats, bradycardia and weight increase in the heart, kidneys and liver were observed as adverse effects.
Carcinogenicity: In a life-time study in mice, Timolol increased the incidence of benign and malignant pulmonary tumours, benign uterine polyps and mammary adenocarcinomas in female mice when administered orally at doses of 500 mg/kg per day, but not at 5 to 50 mg/kg per day. In a 2-year study in rats, oral Timolol increased the incidence of adrenal phaeochromocytomas in male rats at 300 mg/kg per day but not at 25 or 100 mg/kg per day.
Mutagenicity: Timolol was not shown to be mutagenic when tested in vivo (mouse) in the micronucleus test and cytogenic assay (at doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 0.1 mg per 1 mL).
Reproduction and Fertility: Reproduction and fertility studies in rats have not shown that Timolol causes any adverse effects on male or female when administered orally at doses of up to 125 times the maximum recommended human oral dose of 30 mg. Studies in rats have shown that Timolol at doses up to 50 mg/kg/day (50 times the maximum recommended human oral dose) caused delayed foetal ossification; however, there were no adverse effects on post-natal development of offspring. Teratogenic studies in mice and rabbits have not shown that Timolol at doses up to 50 mg/kg/day causes foetal malformations. In mice, Timolol at doses of 1000 mg/kg/day (1000 times the maximum recommended human oral dose) was maternotoxic and resulted in an increased incidence of foetal resorptions.
In rabbits, Timolol at 100 mg/kg/day (100 times the maximum recommended human oral dose) increased incidence of foetal resorptions but not maternotoxicity.
Timolol maleate 0.25% eye drops have not been adequately studied in human pregnancy. Although timolol ophthalmic solution may be absorbed systematically, daily treatment with Timolol ophthalmic solution 0.25% (1 drop twice daily in both eyes) will not exceed 0.4 mg Timolol compared with the oral therapeutic dose of 20-60 mg/day. However, as a precautionary measure, it is recommended that Timolol should not be used in pregnancy unless the potential benefit to the pregnant woman exceeds the potential risk to the fetus.