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Pharmacology: Pharmacodynamics: Dorzolamide is carbonic anhydrase inhibitors for ophthalmic use. Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye. It catalyzes the reversible reaction involving the hydration of carbonic dioxide and the dehydration of carbonic acid. In human, CA exists as a number of isoenzymes, the most active being CA-II, found primary in red blood cells (RBCs), but also in other tissues. Inhibition of CA in the ciliary processes of the ye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular pressure (IOP), Dorzolamide reduce elevated IOP by inhibiting CA-II. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.
Pharmacokinetics: When topically applied, dorzolamide reach the systemic circulation and accumulate in RBCs during chronic dosing as a result of binding to CA-II. Extensive distribution into RBCs yields a long half-life, approximately 3.5 to 4 months. The parent drugs form a single N-desethyl metabolite that inhibit CA-II less potently than the parent drug, but also inhibits CA-I. The metabolite also accumulates in RBCs, where it binds primary to CA-I. Plasma protein binding is moderate (approximately 33%) for dorzolamide. This agent is primary excreted unchanged in the urine, and the metabolite also is excreted in urine.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day. Papillomas were not seen in rats given oral doses of 1 mg/kg/day. These doses represent estimated plasma Cmax levels in rats, 138 and 7 times higher than the lower limit of detection in human plasma following ocular administration, respectively.
No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day. This dose represents an estimated plasma Cmax level in mice, 582 times higher than the lower limit of detection in human plasma following ocular administration.
The increased incidence of urinary bladder papillomas seen in the high-dose males rats is a class-effect of carbonic anhydrase inhibitors in rats. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and divers sodium salts.
No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day or monkeys dosed topically to the eye for one year. An oral dose of 2 mg/kg/day in dogs represents an estimated plasma Cmax level, 137 times higher than the lower limit of detection in human plasma following ocular administration. The topical ophthalmic dose in monkeys was approximately equivalent to the human topical ophthalmic dose.
The following tests for mutagenic potential were negative: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test.
In reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at dose of 15 and 7.5 mg/kg/day, respectively. These doses represent estimated plasma C max levels in rats, 104 and 52 times higher than the lower limit of detection in human plasma following ocular administration, respectively.
