Timo-COMOD Mechanism of Action

ATC Code: SOTED01.
Pharmacology: Pharmacodynamics: Timolol is a non-selective beta-receptor blocker without intrinsic sympathomimetic activity or local anesthetic (membrane-stabilising) properties. It inhibits β₁-receptors, which are localised above all in the heart muscle as well as β₂-receptors.
The stimulating effect of catecholamines on the heart is reduced by timolol. In consequence, the neural transmission in the A-V node is decelerated and the systolic discharge is downcasted. The inhibition of β-receptors in the bronchioles leads to an increase of the airway resistance because of a preponderence of the parasympathicus.
Effect on the eye: Timolol eye drops reduce both elevated and normal intraocular pressure. The accurate mechanism of action of timolol by decreasing the intraocular pressure is not known by now. A fluorometric study and tonographic investigations suggest that its effect is based on the decrease in production of aqueous humor. In some studies a better outflow of aqueous humor could be observed.
The onset of pharmacologic effect is rapid, beginning about 20 minutes after local application to the eye. The maximal reduction of intraocular pressure is reached after one to two hours in a significant decrease in intraocular pressure lasts up to 24 hours under the influence of 0.25% or 0.5% timolol eye drops.
As in other agents which lower intraocular pressure, long-term use of timolol leads to tachyphylaxis in some patients. However, in a long-term clinical trial in which 164 patients treated with timolol were studied over 3 years, after intraocular pressures remained stable at their lowered levels.
In contrast to miotics, timolol reduces the intraocular pressure without affecting accommodation or pupil size. This is especially advantageous for cataract patients. If the patients' therapeutic regimen is changed from miotics to timolol, a correction of refraction may be necessary after the miotic activity subsides.
Pharmacokinetics: Aqueous humor levels: In rabbits aqueous humor levels of 461 ng/100 mg at maximum rate were measured 60 min after the application of 1 drop of timolol 1.0% in men aqueous humor levels of timolol 1 and 2 hours after application of 2 drops of timolol 0.5% amounted 150 ng/l00 mg. After 7 hours the level decreased down to 10 ng/100 mg.
Ocular tissue levels: One drop of a 0.25% solution of 14C-marked timolol was applied to a rabbit eye. The maximum radioactivity was detected after 15-60 minutes in various ocular tissues. In cornea nictilating membrane, iris and ciliary body, radioactivities corresponding to between 1 mg and 10 mg timolol per 100 mg of tissue were measured.
Systemic resorption: Experiments show that timolol is absorbed systematically after local application to the eye. In a clinical trial, timolol which is secreted mainly by the kidneys along with its metabolites, was detected in the urine in every patient.
Plasma concentrations: Plasma concentrations of timolol after local application of the recommended clinical dosages are frequently not detectable (<2 ng/mL) after either one-time usage or continuous use for 2 weeks. The maximal plasma concentration measured from a dosage of 2 drops twice daily was 9.6 ng/mL. It occurred 30 to 90 hours after the onset of usage.
In some cases, the use of timolol-containing eye drops in newborns and small children leads to a higher plasma concentration than in adults. A three week old infant, who was treated with a 0.25% timolol-containing eye drop solution at a dosage of one drop twice daily was found to have a timolol plasma concentration of 34 ng/mL.
Toxicology: Preclinical safety data: Acute toxicity: See Overdosage.
Chronic toxicity/Subchronic toxicity: In studies on rabbits for one year and dogs for two years, topically administered timolol maleate caused no side effects on the eye. Even the long term oral administration of high doses of timolol maleate to dogs and rats did not result in side effects except for bradycardia and an increase in the weight of several organs in particular, the heart, kidney and liver.
Mutagenic and carcinogenic properties: Detailed data on mutagenicity are not available; all currently available studies are negative.
During a two year study on rats in which timolol maleate was orally administered at very high doses (300 times higher than the maximal recommended dosage of 1 mg/kg/day for humans), a statistically significant (p<0.05). Increase in the rate of pheochromocytoma of the adrenal gland occurred in male rats. In rats administered with 25 to 100 times the maximal recommended dose for humans these types of changes did not occur. In a study on mice in which timolol was orally administered over their entire lifespan, a statistically significant (p<0.05). Increase in the rate of benign and malignant lung tumors as well as benign uterine polyps (in female mice) occurred with dosage of 500 mg/kg/day. The increases did not occur however with dosages of 5 or 50 mg/kg/day.
Mammary adenocarcinoma rates also increased in the mice receiving very high doses of timolol maleate (500 mg/kg/day). This may be related to an increase in the serum prolactin concentration, which was observed to be increased in the mice receiving 500 mg/kg/day but not in those receiving 5 or 50 mg/kg/day. An increase in the rate of mammary adenocarcinoma in rodents is seen after administration of several substances known to raise serum prolactin concentrations. In adult woman, the oral ingestion of timolol maleate 60 mg which is the maximum recommended oral dose for humans does not raise serum prolactin levels in a clinically significant manner.
Female mice receiving 500 mg/kg/day showed a statistically significant increase in neoplasms.
Toxicity on fertility and pregnancy: Studies on rats showed that the fertility of male and female rats was not adversely affected by doses of timolol up to 150 times greater than the maximum recommended dosage for humans. Experiments investigating the teratogenicity of orally ingested timolol maleate in mice and rabbits showed no evidence of fetal malformations at dosages of up to 50 mg/kg/day. Ossification was sometimes delayed, but this had no observable effect on postnatal development. Dosages of 1000 mg/kg/day in mice (1000 times the maximal recommended dose for humans) resulted in maternal toxicity as well as in increased rates of fetal resorption. Rabbits receiving 100 mg/kg/day showed similar increased resorption rates but no signs of maternal toxicity.