Pharmacological profiles of the potent carbonic anhydrase inhibitor dorzolamide hydrochloride, a topical antiglaucoma agent.

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  • KOBAYASHI Masahiko
    Tsukuba Research Institute, Pharmacology, Banyu Pharmaceutical Co., Ltd.
  • NAITO Kyozo
    Medical Information Section, Banyu Pharmaceutical Co., Ltd.

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  • 塩酸ドルゾラミド（トルソプト点眼液）点眼用炭酸脱水酵素阻害薬の薬理作用と臨床効果
  • シンヤク ショウカイ ソウセツ エンサン ドルゾラミド トルソプト テンガンエキ テンガンヨウ タンサン ダッスイ コウソ ソガイヤク ノ ヤクリ サヨウ ト リンショウ コウカ

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Carbonic anhydrase (CA) plays an important role in the secretion of aqueous humor. The orally administered CA inhibitor acetazolamide lowers the intraocular pressure (IOP) of patients with glaucoma. However, approximately 50% of patients stop treatment with acetazolamide as a consequence of intolerable side effects due to the extraocular inhibition of the enzyme. This prompted attempts to develop a topically active CA inhibitor. Merck Research Laboratories focused on developing a water- and solvent-soluble compound to penetrate the cornea. Dorzolamide hydrochloride is a potent inhibitor of human CA isoenzyme II, with an IC50 value of 0.18 nM in vitro. In contrast, its inhibitory activity against human CA isozyme I is much weaker (IC50 value of 600 nM). Topically administered dorzolamide penetrated the ciliary body, inhibited its CA activity and had a hypotensive effect in rabbits; in contrast, topical administration of acetazolamide or methazolamide did not decrease IOP. In clinical trials, dorzolamide administered 3 times daily was effective in lowering IOP in patients with open-angle glaucoma or ocular hypertension. The hypotensive effect of dorzolamide 0.5% was similar to that of oral CA inhibitors or timolol (0.25%) twice daily. Dorzolamide did not induce the severe systemic adverse events associated with oral CA inhibitors. Dorzolamide was as effective as pilocarpine or dipivefrine as an adjunctive therapy in patients receiving β-adrenergic antagonists. Dorzolamide also reduced IOP and accelerated retinal arteriovenous passage time in addition to improving visual function in patients with normal-tension glaucoma.

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