Carbonic anhydrase inhibitor topical

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. 

Viader MP, McKeever BM, Navia MA. Thienothiopyran-2-sulfonamides novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma. J Med Chem 1989 32 2510-13. 

Carbonic anhydrase inhibitors decrease aqueous humor production by inhibition of the carbonic anhydrase isoenzyme II located in the ciliary body. In the eye, carbonic anhydrase catalyzes the conversion of water and carbon dioxide to bicarbonate and hydrogen ion, which is a significant step in aqueous humor production. Carbonic anhydrase inhibitors are available in systemic and topical preparations.10,13,14... 

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... 

RA Lewis, RD Schoenwald, MG Eller, CF Barknecht, DC Phelps. (1984). Ethox-zolamide analogue gel, a topical carbonic anhydrase inhibitor. Arch Ophthalmol 102 1821-1824. 

Carbonic anhydrase inhibitors (low risk) Monoamine oxidase inhibitors (low risk) Topical cholinergics (low risk)... 

Acetazolamide is a carbonic anhydrase inhibitor, which reduces intraocular pressure by reducing aqueous humour production. It is used in the treatment of glaucoma. Acetazolamide is administered systemically. Recently newer carbonic anhydrase inhibitors have been developed, which are available as topical agents (for example, dorzolamide). 

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. 

X. de Leval, M. Hies, A. Casini, J.M. Dogne, A. Scozzafava, E. Masini, F. Mincione, M. Starnotti, C.T. Supuran, Carbonic anhydrase inhibitors Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity, J. Med. Chem. 47 (2004) 2796-2804. 

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]. 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

Metabolic acidosis has also been described with the topical carbonic anhydrase inhibitor dorzolamide. 

The thieno[2,3-Z ]furan-2-sulfonamides (346) (Scheme 28) have been prepared and evaluated as topical carbonic anhydrase inhibitors <91JMC1805>. 

The thieno[2,3-6]furan-2-sulfonamides (11), thieno[2,3-6]thiophene-2-sulfonamides, and thieno-[3,2-6]thiophene-2-sulfonamides were prepared and found to be a new class of topically active ocular hypotensive carbonic anhydrase inhibitors (91JMC1805,92JMC3027). 

This is well illustrated by efforts in developing topically effective carbonic anhydrase inhibitors such as dorzolamide through significant alternations in chemical structure. Other efforts have been based on simple chemical modifications, i.e. a prodrug approach. 

Maestrclli, E, Mura, R, Casini, A., Mincione, F., Scozzafava, A., and Supuran.C.T. (2002), Cyclodextrin complexes of sulfonamide carbonic anhydrase inhibitors as long-lasting topically acting antiglaucoma agents,/. Pharm. Sci., 91(10), 2211-2219. 

Figure 2.6 Dorzolamide 16, a topically active carbonic anhydrase inhibitor, resulted from a structure-based ligand design it is used for the treatment of glaucoma. Sulfaguanidine 17 inhibits thyroid hormone biosynthesis. A phenylog of sulfanilamide 11 (Figure 2.4), dapsone 18, is used for the treatment of leprosy.

Barboiu M, Supuran CT, Menabuoni L, Scozzafava A, Mincione F, Briganti F, Mincione G (1999) Carbonic anhydrase inhibitors, synthesis of topically effective intraocular pressure lowering agents derived from 5-(aminoalkyl-carboxamido)-l,3,4-thiadiazole-2-sulfonamide. J Enz Inhib 15 23 -6... 

Other Medical Conditions. Other systemic disorders can be affected by or contraindicate the use of topically applied medications. Examples include myasthenia gravis, which can be worsened with topical timolol, and erythema multiforme (Stevens-Johnson syndrome), which can be caused or exacerbated by topical ocular sulfonamides and related antiglaucoma drugs such as carbonic anhydrase inhibitors. 

Of the commonly used therapeutic drugs, the greatest risks are encountered when clinicians prescribe topical steroids (for extended periods), systemic steroids, P blockers, miotic antiglaucoma agents, and oral carbonic anhydrase inhibitors (CAIs). Optometrists should be aware of the adverse effects that attend the use of these drugs and should warn patients accordingly. Disclosures should be documented in the patient record. 

Given topically to individnals with elevated lOP, timolol induces a significant and long-lasting ocnlar hypotension. Mean decreases in lOP are approximately 25%, and the maximal efficacy of 0.25% and 0.5% timolol is similar. The ocular hypotensive activity of timolol is greater than that of pilocarpine and topical carbonic anhydrase inhibitors (CAIs). 

Adapted from HachAJ.Topical acetazolamide and other carbonic anhydrase inhibitors in the current medical therapy of the glaucomas. Glaucoma 1986 8 20-27.)... 

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.)...

Comoy CW, MarenTH. Fffect of pH on the ocular distribution of a topical carbonic anhydrase inhibitor. Exp Eye Res 1995 6l 213-222. 

Podos SM, Serle JB. Topically active carbonic anhydrase inhibitors for glaucoma.Arch Ophthalmol 1991 109 38-40. 

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. 

TaUuto DM, Wyse TB, Krupin T. Topical carbonic anhydrase inhibitors. Curr Opin Ophthalmol 1997 8 2-6. 

Patients with bullous keratopathy should have their lOP measured (even though corneal edema results in underestimated lOP) because angle-closure glaucoma can cause similar corneal edema. In addition, patients with Fuchs dystrophy have an increased risk of developing open-angle glaucoma in addition to the bullous keratopathy. Topical carbonic anhydrase inhibitors should be avoided in these patients because of the potential of worsening the corneal decompensation. 

The most efficient topical medications to reduce lOP in postoperative patients are those whose mechanism involves aqueous suppression. These agents would include topical carbonic anhydrase inhibitors, apracloni-dine, brimonidine, beta-blockers, and oral carbonic anhydrase inhibitors. Prostaglandin analogues and miotics are effective in lowering the lOP postoperatively however, they may cause increased inflammation and should not be considered a first-line treatment. 

The aqueous suppressants include the P-adrenergic antagonists, a-agonists, carbonic anhydrase inhibitors (CAIs topical and oral), and hyperosmotics (intravenous). The topical fiarms of this classification are used routinely in clinical practice. The oral and intravenous formulations are generally reserved fiar use under special circumstances. 

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. 

In a 3-month prospective study of the adverse effects and efficacy of topical dorzolamide in 39 patients intolerant of systemic carbonic anhydrase inhibitors, the effect on mean intraocular pressure was similar to that of acetazolamide, and health assessment scores improved significantly in seven of the eight categories of the SF-36 health assessment questionnaire used to evaluate changes in well-being and quahty of life (4). There were no adverse effects with the switch in medication. 

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