Pharmacology: Pharmacodynamics: Latanoprost: Latanoprost is a prostanoid selective FP receptor agonist which is believed to reduce the intraocular pressure by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.
Timolol: Timolol is a nonselective β-adrenergic blocking agent. Timolol does not have substantial intrinsic sympathomimetic, parasympathomimetic, or local anesthetic activity. Following topical application to the eye, timolol reduces both elevated and normal intraocular pressure (IOP) in patients with or without open-angle (chronic simple, noncongestive) glaucoma or ocular hypertension. Timolol reduces IOP with little or no effect on accommodation or pupillary size. In patients with elevated IOP, timolol reduces mean IOP by about 25-33%. The drug appears to be equally effective in light- and dark-colored eyes.
The exact mechanism by which β-blockers, including timolol, reduce IOP has not been clearly defined. Fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect. β-adrenergic blocking agents may block endogenous catecholamine-stimulated increases in cyclic adenosine monophosphate (AMP) concentrations within the ciliary processes and subsequent formation of aqueous humor. Timolol appears to cause little or no change in aqueous humor outflow facility.
Pharmacokinetics: Latanoprost: Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Studies in man indicate that the peak concentration in the aqueous humor is reached about 2 hours after topical administration.
Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost could be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration.
Metabolism: Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterase in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
Excretion: The elimination of the acid of latanoprost from human plasma was rapid (t1/2 = 17 minutes) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose is recovered in the urine after topical and intravenous dosing, respectively.
Timolol: 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 administration 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. Following topical application to the eye of 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.
Toxicology: Preclinical Safety Data: Latanoprost: Mutagenicity and carcinogenicity: Latanoprost was not mutagenic in microbial (Ames), mouse lymphoma, or in mouse micronucleus tests; however, chromosome aberrations were observed in vitro with human lymphocytes.
No evidence of carcinogenic potential was observed in mice or rats given latanoprost by oral gavage in dosage up to 170 mcg/kg daily (approximately 2800 times the recommended maximum human dose) for 20 or 24 months, respectively. In vitro and in vivo studies evaluating unscheduled DNA synthesis in rats receiving latanoprost were negative.