Carbonic anhydrase inhibitors dorzolamide

These constants are similar to those reported for the structurally similar carbonic anhydrase inhibitor, dorzolamide hydrochloride, (6.4 and 8.2,... 

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. 

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

Nesher R, Ticho U. Switching from systemic to the topical carbonic anhydrase inhibitor dorzolamide effect on the quality of life of glaucoma patients with drug-related side effects. Isr Med Assoc J 2003 5(4) 260-3. 

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

The application of structure-based design has already contributed significantly to the discovery of marketed drugs. We would like emphasize this point by briefly summarizing some structural aspects in the discovery of the carbonic anhydrase inhibitor dorzolamide [14,15]. 

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). 

Any of these four dmg classes can be used as additive second- or third-line therapy. In fact, the p-receptor antagonist timolol has been combined with the carbonic anhydrase inhibitor dorzolamide in a single medication (Cosopt). 

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, 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. 

Dorzolamide (Trusopt) [Carbonic Anhydrase Inhibitor, Sul-fonamide/Glaucoma A9ent] Uses Glaucoma Action Carbonic anhydrase inhibitor Dose 1 gtt in eye(s) tid Caution [C, ] Contra Component sensitivity Disp Soln SE Irritation, bitter taste, punctate k atitis, ocular all gic Rxn EMS t Effects W/ oral carbonic anhydrase inhibitors, salicylates EMS Drug is absorbed systemicaUy OD May cause electrolyte disturbances (K) and acidosis monitor ECG... 

Dorzolamide Timolol (Cosopt) [Carbonic Anhydrase Inhibitor/Beta Adrener9ic Bloclcer] Uses Glaucoma Action Carbonic anhydrase inhibitor w/ i-adrenergic blocks Dose 1 gtt in eye(s) bid... 

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. 

Diuretics are most commonly available in pill form. In a hospital setting, they may be administered intravenously or injected. Carbonic anhydrase inhibitors may be administered in eye drop form [dorzolamide (Trusopt)] to glaucoma patients. 

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. 

It may be necessary to combine these or add another agent such as oral acetazolamide and/or dorzolamide eye drops, which are both carbonic anhydrase inhibitors that reduce aqueous humour production. 

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.

Maren TH, Conroy CW, Wynns GC, Levy NS. Ocular absorption, blood levels, and excretion of dorzolamide, a topicaUy active carbonic anhydrase inhibitor. J Ocul Pharmacol Ther 1997 13 23-30. 

Pfeiffer N. Dorzolamide development and chnical appUcation of a topical carbonic anhydrase inhibitor. Surv Ophthalmol 1997 42 137-151. 

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. 

The safety profile and efficacy of 2% dorzolamide hydrochloride (Trusopt) eye-drops have been evaluated. It was as effective as pilocarpine 2% and its ocular hypotensive efficacy was comparable with that of betaxolol 0.5%. The patients reported less interference with quahty of life with dorzolamide than pilocarpine, particularly in regard to limitations in their ability to drive, read, and perform moderate activities. Long-term use was not associated with important electrolyte disturbances or the systemic effects commonly observed with oral carbonic anhydrase inhibitors (1-3). 

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. 

In this case the allergic reaction was caused by dorzolamide hydrochloride and not the preservative, benzalkonium chloride, since therapy was uneventfully continued with timolol maleate, which also contains benzalkonium chloride as a preservative. This is the first report of this phenomenon with a carbonic anhydrase inhibitor. 

Carbonic anhydrase inhibitors reduce aqueous humor formation. Topical carbonic anhydrase inhibitors, such as 2% dorzolamide two to four times a day, appear to significantly reduce lOP in some glaucomatous eyes. However, this treatment has not been critically evaluated for efficacy or safety in the horse and cost militates against its long-term use. Carbonic anhydrase inhibitors, such as acetazolamide and dichlorphenamide, can be used orally in conjunction with topical therapy. 

Figure 28-1 Dorzolamide (Trusopt). the first FDA-approved drug to be designed by structure-based methods, is a carbonic anhydrase inhibitor that is used to lower ocular pressure in glaucoma patients.

Figure 28-28 Dorzolamide (Trusopt), 1. also a constituent of Cosopt, was the first drug designed with structure-based CAOO methods to become commercially available. MK-927. 21, IS a close structural analogue and was the first carbonic anhydrase inhibitor to lower intraocular pressure In glaucoma patients...

Inhibitors to the enzyme carbonic anhydrase. This enzyme is widely distributed in the body and has a fundamental role in the control of acid-base balance. In the 1920s it was noticed that the SULPHONAMIDE sulfanilamide had a weak diuretic action. Acetazolamide is a subsequent thiadiazole-sulphonamide derivative with potent carbonic anhydrase inhibitor activity. Clinically, it is used for antiglaucoma TREATMENT, is a weak diuretic and can be used to treat mountain sickness. Dichlorphenamide and dorzolamide are sulphonamide derivatives also used for antiglaucoma treatment. Methazolamide is used as a diuretic. Now that seven or more isoenzymes of carbonic anhydrase have been cloned. Isolated and mapped, some new initiatives are aimed at developing agents with more selective actions. 

Figure 15. Chemical structures of the carbonic anhydrase inhibitors 15-21. The small aromatic sulfonamides 15 and 16 bind with nanomolar affinity to carbonic anhydrase. Methazolamide 18 was used for a long time to treat glaucoma. 19 was the first topically active inhibitor. Structure-based drug design at Merck first led to 20 and then to the marketed drug, dorzolamide 21.

Acetazolamide, dorzolamide Carbonic anhydrase inhibitor 4- HCO availability leads to 4 aqueous humor formation... 

Dorzolamide is a carbonic anhydrase inhibitor that inhibits carbonic anhydrase enzyme, reducing the rate of aqueous humor formation and thus lowering intraocular pressure (lOP). It is indicated in the treatment of elevated lOP in patients with ocular hypertension or open-angle glaucoma. 

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