Carbonic anhydrase inhibitors brinzolamide

Local side effects include burning, stinging, itching, foreign body sensation, dry eyes, and conjunctivitis. Brinzolamide may have a lower incidence of these side effects since the drug is in a neutral pH solution. Dorzolamide has been reported to cause irreversible corneal decompensation. Taste abnormalities have been reported with each agent. Both topical carbonic anhydrase inhibitors are sulfonamides and are contraindicated in patients with history of sulfonamide hypersensitivity.10,13... 

Acetazolamide is a carbonic anhydrase inhibitor that is administered orally for the treatment of glaucoma. Topical carbonic anhydrase inhibitors include dorzolamide and brinzolamide. Carbonic anhydrase inhibitors reduce the production of aqueous humour, thereby reducing intraocular pressure. They can be used alone or in addition to beta-blocker therapy in glaucoma patients. 

Pharmacology Brinzolamide and dorzolamide are carbonic anhydrase inhibitors formulated for topical ophthalmic use. 

A variety of thiophene-fused 1,2-thiazines have been prepared as carbonic anhydrase inhibitors for the treatment of glaucoma <2002JME888, 2000BMC957>. The drug brinzolamide (under the trade name Azopt ) 24 has recently been approved by the FDA. 

Adverse effects associated with brinzolamide are similar to those of other carbonic anhydrase inhibitors. In clinical experience with topical ocular administration of brinzolamide, events including transient, momentary blurred vision, bitter, and sour or unusual taste were reported in approximately 5 % - 10% of patients. Ocular discomfort, discharge or other ocular signs, and headache were reported at an incidence of 1 -5% [15]. 

The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma, making it the most common indication for use of carbonic anhydrase inhibitors. Topically active carbonic anhydrase inhibitors (dorzolamide, brinzolamide) are available and reduce intraocular pressure without producing detectable plasma levels. Thus, diuretic and systemic metabolic effects are eliminated for the topical agents. 

Figure 10-15 Mean intraocular pressure (lOP) change (mm Hg) for the various treatment groups by visit and time of day for a 3-month treatment period. Each value represents the least-squares mean of the change from baseline diurnal lOP, and all were significant. (Adapted from Silver LH, Brinzolamide Primary Therapy Smdy Group. Clinical efficacy and safety of brinzolamide [Azopt], a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 1998 126 400-408.)...

Silver LH, Brinzolamide Primary Therapy Smdy Group. Clinical efficacy and safety of brinzolamide (Azopt), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 1998 126 400-408. 

The carbonic anhydrase inhibitors, of which acetazol-amide (rINN), a non-competitive inhibitor, is the prototype, are not suitable for normal diuretic use, because tolerance soon develops. However, they are well suited to brief intermittent use, particularly in the relief of glaucoma and in the prevention of acute mountain sickness. Acetazolamide and methazolamide (rINN) should be used with caution in the long-term control of glaucoma because of its serious systemic adverse effects. However, brinzolamide (rINN) and dorzolamide (rINN) are available for long-term topical administration. 

Carbonic anhydrase inhibitors Dorzolamide Brinzolamide Decrease aqueous inflow Ocular burning and stinging, transient blurry vision, itching, conjunctivitis, superficial punctate keratitis, tearing, photophobia... 

Brinzolamide is a carbonic anhydrase inhibitor that causes an inhibition of carbonic anhydrase in the cihary processes of the eye deaeases aqueous. It is indicated in the treatment of elevated lOP inpatients with ocular hypertension or open-angle glaucoma. The development of topical carbonic anhydrase inhibitor took many years but was an important event because of the poor side-effect profile of oral carbonic anhydrase inhibitors (CAIs). Dorzolamide (Trusopt) and brinzola-mide both work by inhibiting carbonic anhydrase (isoenzyme n), which is found in the ciliary body epithehum. This reduces the formation of bicarbonate ions, which reduces fluid transport and thus lOP. hi fact, the P-receptor antagonist timolol has been combined with the carbonic anhydrase inhibitor dorzolamide in a single medication (Cosopt). 

The development of a topical carbonic anhydrase inhibitor was prompted by the poor side-effect profile of oral CAIs. Dorzolamide (trusopt) and brinzolamide (azopt) both work by inhibiting carbonic anhydrase (isoenzyme II), which is found in the ciliary body epithelium. This reduces the formation of bicarbonate ions, which reduces fluid transport and thus lOP. 

C. Clinical Uses The major application of carbonic anhydrase inhibitors is in the treatment of glaucoma. Acetazolamide must be administered orally, but topical analogs are now available (dorzolamide, brinzolamide) for use in the eye. Carbonic anhydrase inhibitors are also used to prevent acute mountain (high-altitude) sickness. These agents are used for their diuretic effect only if edema is accompanied by significant metabolic alkalosis. 

Benzenesulfonamides, or more generally arylsulfonamides, are a class of carbonic anhydrase inhibitors that consist of a sulfonamide attached to an aromatic moiety, classically a benzyl ring [98-100]. The deprotonated sulfonamide coordinates the catalytically active Zn " in the substrate binding pocket of the enzyme (Figure 1.12). Many different additional substituents are tolerated on the aromatic system, as can be seen by the broad range of structures of carbonic anhydrase inhibitors in clinical use including dichlorophenamide, brinzolamide, and acetazolamide (Figure 1.13). 

Except for dorzolamide and brinzolamide, carbonic anhy-drase inhibitors are administered systemically. Carbonic anhydrase is an enzyme found in many tissues of the body, including the eye Inhibition of carbonic anhydrase in Hie eye decreases aqueous humor secretion, resulting in a decrease of IOE These drugs are used in the treatment of elevated IOP seen in open-angle glaucoma... 

CAIs reduce lOP by decreasing ciliary body aqueous humor secretion. CAIs appear to inhibit aqueous production by blocking active secretion of sodium and bicarbonate ions from the ciliary body to the aqueous humor. Topical CAIs such as dorzolamide and brin-zolamide are well tolerated and are indicated for monotherapy or adjunctive therapy of open-angle glaucoma and ocular hypertension. Relatively specific inhibitors of carbonic anhydrase enzyme II such as dorzolamide and brinzolamide reduce lOP by 15% to 26%. 

Carbonic anhydrase (CA) inhibitors acetazolamide, brinzolamide and dorzolamide (Fig. 20.15) act through... 

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