Aqueous humor formation

Pharmacology These agents are nonbacteriostatic sulfonamides that inhibit the enzyme carbonic anhydrase. This action reduces the rate of aqueous humor formation, resulting in decreased lOP. 

Mechanism of Action A carbonic anhydrase inhibitor that reduces formation of hydrogen and bicarbonate ions from carbon dioxide and water by inhibiting, in proximal renal tubule, the enzyme carbonic anhydrase, thereby promoting renal excretion of sodium, potassium, bicarbonate, and water. Ocular Reduces rate of aqueous humor formation, lowers intraocular pressure. Therapeutic Effect Produces anticonvulsant activity. 

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. 

There are several types of -class CAs i.e., a-CA I-VII, reported in the literature, out of which the human carbonic anhydrase II (HCA II), the most extensively studied carbonic anhydrase, has an exceptionally high CO2 hydration rate and a wide tissue distribution 107). The HCA II comprises a single polypeptide chain with a molecular mass of 29.3 kDa and contains one catalytic zinc ion, coordinated to three histidine residues, His 94, His 96, and His 119. A tetrahedral coordination geometry around the metal center is completed with a water molecule, which forms a hydroxide ion with a pK value of 7.0 108). Quigley and co-workers 109,110) reported that the inhibition of the synthesis of HCO3 from CO2 and OH- reduces aqueous humor formation and lowers intra-ocular pressure, which is a major risk factor for primary open-angle glaucoma. 

Fluid movement from the stroma of the ciliary processes into the posterior chamber requires the transepithelial movement of several ions. Assuming that Na, HCO3, and CT are the major ions involved in secretion, Figure 1014 illustrates how these ions may function in fluid movement across the nonpigmented ciliary epithelium and into the posterior chamber. Inhibition of carbonic anhydrase in the ciliary processes decreases bicarbonate, sodium, and fluid movement into the posterior chamber, with the net result being decreased aqueous humor formation. 

Most tissues contain carbonic anhydrase in quantities that exceed physiologic requirements. Because of this excess, at least 99% of carbonic anhydtase activity must be inhibited to depress aqueous production significantly. Drug levels sufficient to reduce aqueous humor formation are readily achieved after systemic and topical administration of CAIs. However, systemic use has the disadvantage of significantly inhibiting the activity of carbonic anhydrase throughout the body. 

Topical CAls offer distinct advantages over other inhibitors of aqueous humor formation. Compared with P-blockers, CAls reduce the nocturnal aqueous flow rate by 25%. P-Blockers lack the ability to suppress aqueous formation below the already reduced flow rate that occurs during sleep. In contrast to systemic CAls, topical CAls lack most of the systemic side effects while producing a comparable ocular hypotensive effect. None of the topical CAls, however, has the ability to reduce lOP to the level achieved by 500 mg of oral acetazolamide.Topical agents are used in place of systemic CAls for chronic treatment of primary and secondary open-angle glaucomas. Other recently developed medications have probably relegated the position of topical CAls to second- or third-line therapy. Cosopt may simplify therapy and improve compliance for patients who require treatment with both timolol and dorzolamide. 

Rosenberg LF, Krupin T, Tang L, et al. Combination of systemic acetazolamide and topical dorzolamide in reducing intraocular pressure and aqueous humor formation. Ophthalmology 1998 105 88-93. 

When administered systemically cardiac glycosides reduce lOP in humans. Systemic digoxin therapy has been shown to reduce lOP by 14% in the glaucomatous human eye, and aqueous humor formation can be reduced by as much as 45% after several days of digoxin therapy. 

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. 

Topical non-selective B adrenoceptor antagonists, such as 0.5% timolol maleate, used two to four times a day, reduce lOP in horses by reducing aqueous humor formation and can be used in conjunction with topical or oral carbonic anhydrase inhibitors. 

Ocular Reduces the rate of aqueous humor formation, lowers intraocular pressure. Diamox only Increases C02 tension, retards neuronal conduction, producing anticonvulsant activity. 

Aqueous humor is formed in the ciliary body and its epithelium (Figs. 92-1 and 92-2) through both filtration and secretion. Because ultrafiltration depends on pressure gradients, blood pressure and lOP changes influence aqueous humor formation. Osmotic gradients produced by active secretion of sodium and bicarbonate, and possibly other solutes such as ascorbate from the ciliary body epithelial cells into the aqueous humor, result in movement of water from the pool... 

Apraclonidine epinephrine Sympathomimetic a2 agonist effects (prejunctional) cause 4- NE release — 4. aqueous humor formation E causes T outflow... 

Betaxolol, timolol Beta blockers Block actions of NE at ciliary epithelium 4- aqueous humor formation... 

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. 

With prolonged use of the carbonic anhydrase Inhibitor diuretics, the urine becomes more alkaline, and the blood becomes more acidic. When acidosis occurs, the carbonic anhydrase Inhibitors lose their effectiveness as diuretics. They remain Ineffective until normal acid-base balance In the body has been regained. For this reason, this class of compounds Is limited In Its diuretic use. Today, they are most commonly used In the treatment of glaucoma. In which they reduce the rate of aqueous humor formation and, subsequently, reduce the Intraocular pressure. These compounds also have found some limited use In the treatment of absence seizures, to alkallnize the urine, to treat familial periodic paralysis, to reduce metabolic alkalosis, and prophylactically, to reduce acute mountain sickness. 

Acetazolamide was the first of the carbonic anhydrase Inhibitors to be Introduced as an orally effective diuretic, with a diuretic effect that lasts approximately 8 to 12 hours (see Table 27.2 for Its pharmacokinetic properties). As mentioned earlier. Its diuretic action Is limited because of the systemic acidosis it produces. Acetazolamide reduces the rate of aqueous humor formation and is used primarily for reducing intraocular pressure in the treatment of glaucoma. The dose is 250 mg to 1 g per day. 

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