Glaucoma, drugs used carbonic anhydrase inhibitors

Acetazolamide is a carbonic anhydrase inhibitor that reduces aqueous humour production and is therefore indicated in glaucoma to reduce the intraocular pressure. Salbutamol is a selective, short-acting beta2-agonist used as a bronchodilator in asthma. Tolbutamide is a short-acting sulphonylurea used in type 2 (non-insulin dependent) diabetes mellitus. Chlorpromazine is an aliphatic neuroleptic antipsychotic drug used in schizophrenia. Zafirlukast is a leukotriene-receptor antagonist that is indicated in the prophylaxis of asthma but should not be used to relieve acute severe asthma. 

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... 

Along the same lines, several groups of chemists at Merck successfully produced substantial quantities of various important pharmaceutical intermediates used in the preparation of drugs under development. Among these we can mention MK-0417 (7), a soluble carbonic anhydrase inhibitor useful to treat glaucoma,41 the LTD4 antagonist L-699392 (8),42 and the antiarrhythmic MK-499... 

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 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.

This topically active carbonic anhydrase inhibitor is a powerful controller of the elevated intraocular pressure associated with glaucoma, and has been prepared by Merck in > 32% yield in a multistep synthesis starting from (R)-3-hydroxybutyrate [49]. Although the key ketone reduction step has been recently improved by researchers at Zeneca by replacing a chemical process with a biological one [50], the Merck synthesis well illustrates the potentialities of the approach to enantiomerically pure drugs based on the use of chiral non-racemic substrates. 

This drug is a weak diuretic. In addition, it is useful in the therapy of glaucoma, as it reduces the formation of water in the ocular fluid. It is also useful in the therapy of metabolic alkalosis. Additionally, carbonic anhydrase inhibitors may also be useful in the therapy of hypooxygena-tion ( mountain sickness ), because they decrease alkalinization of the blood by increased excretion of bicarbonate, and in some types of seizures. 

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... 

Carbonic anhydrase has also been discovered in the eye and the CNS. Consequently, its inhibitors have found use in the treatment of glaucoma, in reducing the high intraocular pressure which can lead to blindness in this disease. They are also effective, in combination with anticonvulsant drugs, in controlling certain forms of epilepsy. 

For topical therapy of open-angle glaucoma, the following groups of drugs can be used for reducing production of aqueous humor, p-blockers (e. g., timolol), a2-agonists (clonidine, brimonidine), and inhibitors of carbonic anhydrase (dorzolamide, brinzola-mide). 

Multihetero atom heterocycles are comparatively rare in nature, dendrodoine, a cytotoxic substance from a marine tunicate, is an example, however in medicinal chemistry they are of considerable significance Alprazolam is a major drug for the treatment of anxiety, Acetazolamide is an inhibitor of the enzyme carbonic anhydrase and is used principally for the treatment of glaucoma, and Fluconazole, is an antifungal agent. 

---