Trusopt Mechanism of Action

DORZOLAMIDE HCl (TRUSOPT) Ophthalmic Solution is a novel carbonic anhydrase inhibitor formulated for topical ophthalmic use. Unlike oral carbonic anhydrase inhibitors, DORZOLAMIDE HCl (TRUSOPT), which is administered topically, exerts its effects directly in the eye.
Pharmacology: Pharmacodynamics: Mechanism of Action: DORZOLAMIDE HCL (TRUSOPT) is a potent inhibitor of human carbonic anhydrase II. Following topical ocular administration, DORZOLAMIDE HCL (TRUSOPT) reduces elevated intra-ocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and visual field loss. DORZOLAMIDE HCL (TRUSOPT) does not cause pupillary constriction and reduces intra-ocular pressure without side effects such as night blindness, accommodative spasm. DORZOLAMIDE HCL (TRUSOPT) has minimal or no effect on pulse rate or blood pressure.
In patients with glaucoma or ocular hypertension, the efficacy of dorzolamide given t.i.d. as monotherapy (baseline IOP ≥23 mmHg) or given b.i.d. as adjunctive therapy while receiving ophthalmic beta-blockers (baseline IOP ≥22 mmHg) was demonstrated in large-scale clinical studies of up to one-year duration. The IOP-lowering effect of dorzolamide as monotherapy and as adjunctive therapy was demonstrated throughout the day and this effect was maintained during long-term administration. Efficacy during long-term monotherapy was similar to betaxolol and slightly less than timolol. When used as adjunctive therapy to ophthalmic beta-blockers, dorzolamide demonstrated additional IOP lowering similar to pilocarpine 2% q.i.d.
In addition, a clinical study was undertaken in 184 (122 for dorzolamide) paediatric patients from 1 week of age to <6 years of age with glaucoma or elevated intraocular pressure (baseline IOP > 22 mmHg) to assess the safety of DORZOLAMIDE HCl (TRUSOPT) when administered topically t.i.d (three times a day). Efficacy results in paediatric patients suggest that the mean IOP decrease observed in the dorzolamide group was comparable to the mean IOP decrease observed in the timolol group even if a slight numeric advantage was observed for timolol.
Longer-term efficacy studies (>12 weeks) are not available.
Pharmacokinetics: When topically applied, dorzolamide reaches the systemic circulation.
To assess the potential for systemic carbonic anhydrase inhibition following topical administration, active substance and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free active substance in plasma are maintained. The parent active substance forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent active substance but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs slower elimination phase with a half-life of about four months.