Medical Therapy Of Glaucoma

Medical treatment for glaucoma involves multiple medications (Table 2) [3, 5, 10]. The principal goal of medical treatment is lowering of intraocular pressure. Local administration of cholinergic agents, beta-adrenergic blockers, and alpha-

TABLE 1 Classification of Glaucoma

1. Congenital glaucoma

2. Primary glaucoma a. Open angle glaucoma b. Closed angle glaucoma

3. Secondary glaucoma

TABLE 2 Medical Therapy of Glaucoma

1. Cholinergic agents (pilocarpine)

2. Beta-adrenergic antagonist agents (timolol)

3. Alpha-adrenergic agents (epinephrine)

4. Diuretics a. Osmotic diuretics (mannitol)

b. Loop diuretics (ethacrynic acid)

5. Ocular (ciliary) carbonic anhydrase inhibitors a. Systemic (acetazolamide)

b. Topical (dorzolamide)

adrenergic agonists have been used to treat glaucoma. Cholinergic agents, with the prototype drug pilocarpine, lower intraocular pressure by stimulation of the ciliary muscle and by constriction of the pupil, with the resultant reduction of trabecular resistance to aqueous humor outflow. Beta-adrenergic antagonists, with the prototype drug timolol, lower intraocular pressure by blockade of the ciliary process production of aqueous humor. Alpha-adrenergic agonists, with the prototype drug epinephrine lower intraocular pressure by stimulation of receptors in the trabecular network with a marked increase in aqueous humor outflow.

Diuretics have been used to treat glaucoma for many years. The major mechanism involved is not an increase in renal salt and water excretion, but rather a decrease in local eye aqueous humor production, leading to a reduction of intraocular pressure. However, other mechanisms of diuretic action have been suggested as well.

The classic diuretic used in the treatment of glaucoma is the carbonic anhydrous inhibitor acetazolamide 16]. A similar agent, methazolamide, has also been used. Carbonic anhydrase inhibitors block the hydration reaction of carbon dioxide, with the subsequent formation of bicarbonate in many tissues including the ciliary body. The enzyme carbonic anhydrase is located in the ciliary body, but its specific role in aqueous humor production is not certain. Reduction of bicarbonate production with carbonic anhydrase inhibitors is directly correlated with a fall in aqueous humor production. There does not appear to be a role for these agents in direct fluid removal from the anterior chamber. The development of systemic metabolic acidosis has little effect on intraocular pressure or aqueous humor production. Use of carbonic anhydrous inhibitors clinically has resulted in a decrease in aqueous humor flow rate by approximately 40-60%. This results in a decrease in intraocular pressure of 2-10 Torr. It has long been held that carbonic anhydrase inhibitors are effective in the treatment of glaucoma only when given systemically. When administered by this route, they have many side-effects and are difficult to use clinically, as up to 50% of patients may need to stop these agents because of intolerable side-effects [3]. Frequent side-effects include fatigue, malaise, confusion, depression, paresthesia, and loss of appetite. All of these side-effects may be related to the systemic acidosis that develops with the use of these agents. Significant gastrointestinal side-effects include nausea, vomiting, and diarrhea. Hyperventilation in response to the metabolic acidosis may compromise patients with marginal pulmonary reserve. Hypokalemia, metabolic acidosis, and transient polyuria occur in virtually all patients who use these medications. Renal calculi can occur in part related to a decrease in urinary citrate excretion. Severe bone marrow toxicity has been described rarely with the development of aplastic anemia and agranulocytosis.

The recent development of topical carbonic anhydrase inhibitors of the sulfonamide family, such as Dorzolamide, that rapidly penetrate the cornea represents a significant advance in the treatment of glaucoma [7]. This route of administration precludes the undesirable side effects mentioned above as there is no detectable drug or metabolite in the blood. Such agents display high activity against corneal carbonic anhydrases II and IV, and their efficacy in reducing intraocular pressure is similar to that achieved by intravenous administration of potent carbonic anhydrase inhibitors [1, 7].

Intravenous administration of the osmotic diuretic mannitol by drawing fluid out of the eye into the hypertonic plasma has been used to acutely lower intraocular pressure. Mannitol, however, is rarely used in the routine treatment of glaucoma.

Conventional diuretics, including thiazides and loop diuretics have been tried in the treatment of glaucoma. There is very little effect, however, on either aqueous humor production or intraocular pressure. The traditional loop diuretic ethacrynic acid has recently been used in a nontraditional manner to treat glaucoma [ 1 ]. Ethacrynic acid when injected locally into glaucomatous eyes has resulted in a marked reduction in intraocular pressure. The effect is immediate and lasts for approximately 1 week. The absorption of the drug into the eye after oral and intravenous administration is suspect and may limit its clinical utility. The proposed mechanism of action for ethacrynic acid is a washout of debris from the trabecular network, thereby allowing an increase of aqueous fluid outflow from the anterior chamber.

The use of diuretics in the treatment of glaucoma has been sharply reduced, as it has been appreciated that glaucoma is primarily a disease of inadequate drainage of aqueous humor rather than an excess of fluid production. Therefore the major forms of therapy involve increasing aqueous humor drainage either medically or most often by surgical methods, rather than reducing aqueous humor production using systemic diuretics.

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