Pratap Challa, MD, MS and David L. Epstein, MD, MMM
Carbonic anhydrase inhibitors (CAIs) can be useful in the treatment of all the glaucomas by virtue of their ability to reduce aqueous secretion and thus lower intraocular pressure (IOP)1 regardless of the nature or extent of obstruction to outflow. Their mechanism of action appears to be the inhibition of CA isoenzymes that result in decreased bicarbonate ion secretion into the posterior chamber by the nonpigmented ciliary epithelium.2 These enzymes are among the fastest known enzymes, and they catalyze the conversion of carbon dioxide and water into bicarbonate and hydrogen ions. Bicarbonate ions are actively secreted into the aqueous humor, resulting in a passive diffusion of water. Therefore, inhibition of bicarbonate formation decreases aqueous formation.
The first agents in this class that were effective in treating glaucoma were given systemically, but now topical agents are available and are frequently used to treat a wide variety of the glaucomas. Topical therapy will be discussed further in the next chapter; however, a brief mention of it in comparison to systemic medications is warranted. Although the site of action for glaucoma therapy is the non-pigmented ciliary epithelium (isoenzymes type II and IV), other ocular structures also express CA, and their inhibition can lead to unintended side effects. Isoenzyme types I and II are important for the corneal endothelial pump function,3 and the topical application of such drugs will continuously and progressively bathe the corneal endothelium with this enzyme inhibitor as the drug passes into the anterior chamber. Moreover, due to the high efficiency of this enzyme class, nearly total (99.9%) inhibition is needed to achieve pressure lowering. Hence, topical therapies need to cross the cornea and diffuse to the ciliary epithelium in sufficient drug concentrations for therapeutic effect. Topical delivery can thus result in direct exposure of the cornea and result in decreased endothelial pump function and increased corneal edema. Both reversible and irreversible corneal decompensation has been rarely reported with topical CAI use.4,5 Oral CAI agents have generally not been reported to have endothelial side effects as strong as topical agents.6 Because oral agents diffuse through the bloodstream to reach their site of action, avascular structures such as the corneal endothelium have relatively less drug exposure. Therefore, if no other alternative therapies exist, oral agents may be considered in patients at risk for corneal compromise.
Another issue is whether the topical CAI drugs produce maximal IOP lowering, equivalent to that of systemic agents. In general, the authors feel that one oral agent, acetazolamide (Diamox), results in a slightly better pressure-lowering effect than topical agents alone.7,8 This has been shown to be true in a small case series of patients that compared acetazolamide to topical dorzolamide. Acetazolamide reduces aqueous flow by 29% compared to dorzolamide’s 17%.9 This effect did not appear to be due to the metabolic acidosis induced by systemic CAIs,10 but rather to their nonselective action on both the CA II and IV isoenzymes of the ciliary epithelium. Of note, topical CAIs have a preferential affinity for the CA II isoenzyme,11 and thus concomitant topical and systemic CAI therapy is not justified. The readers should also keep in mind that a comparison of 2 different delivery routes is always problematic because equivalent drug levels may or may not reach the site of action. Therefore, bioavailability of a drug plays a major role in efficacy.
|Oral Carbonic Anydrase Inhibitor Added To
|Prostaglandin F2α analogs
|Topical carbonic anhydrase inhibitors
The following discussion relates to the oral use of CAI agents with which we have had broad experience and which likely will still continue to be used for the foreseeable future. In general, oral CAIs can be added to most classes of glaucoma medications (Table 14-1).
Oral CAIs are potent antiglaucoma agents that are generally drugs of last resort in most patients because of the potential for serious, even life- threatening, systemic side effects.12 Therefore, topical therapies and even strong miotics, in pseudophakic eyes, despite all their limitations and concerns, are usually preferred to the oral CAIs. In general, laser trabeculoplasty should be performed before use of oral CAIs when possible. Also, for unilateral uncontrolled glaucoma (assuming a good fellow eye), other options should be fully explored first. Yet, oral CAIs are responsible for the prevention of blindness in many patients with glaucoma. Due to the effects of the drug on the renal tubule, patients need to be informed that CAIs do at first cause an acute diuresis, but this is short lasting. Patients should also have their potassium levels monitored as this electrolyte can be lost through the gastrointestinal system.13
The CAIs are useful in certain secondary glaucomas to protect the eye from damage by the glaucoma until the underlying cause of the glaucoma is removed. Special considerations are involved in use of these drugs in angle-closure glaucoma, and this is further detailed in the chapter dealing with angle-closure glaucoma. In all cases of progressive adult open-angle glaucoma, we currently use topical (and frequently oral) CAI treatment in addition to standard maximal topical antiglaucoma drugs prior to considering surgery. What is written here concerns principally the use of CAI agents in the management of chronic glaucoma when various agents are to be considered. It does not include treatment of acute glaucoma, for which acetazolamide, in addition to topical beta-blockers and alpha-adrenergic agents, is often utilized because of its rapid action (within 30 minutes) and because the course of treatment is so brief that problems of side effects are relatively few.
Some glaucoma patients tolerate oral CAI therapy well and can be maintained on long-term therapy. However, 30% to 50% of patients are unable to take CAI medications for prolonged periods because of unpleasant and sometimes debilitating side effects. The most common side effect that results in discontinuation of long-term oral CAI therapy is a symptom-complex of malaise, fatigue, weight loss, anorexia, depression, and often loss of libido. Patients who have this malaise symptom complex often state that they feel “awful,” “do not care whether they live or die,” or that “they would rather go blind than continue with this type of drug.” We have seen such patients unnecessarily hospitalized for extensive evaluation for occult malignancy or other disease suspected because of severe loss of weight and appetite. The occurrence of such malaise-type symptoms is often associated with the development of systemic metabolic acidosis. All patients undergoing chronic oral CAI therapy develop systemic acidosis, but the patients with these symptoms are generally more acidotic than other patients.10 Sometimes, in stoic patients on long-term oral CAI therapy, the degree of metabolic acidosis is alarming and may lead to hospitalization in a medical ward.
Some patients on chronic CAI therapy develop symptoms of abdominal distress: cramping, epigastric burning, nausea, irritation, and diarrhea. These gastrointestinal side effects, unlike the malaise symptom-complex, seem to be unrelated to the degree of metabolic acidosis. These gastrointestinal disturbances seem to be local irritative phenomena and have often responded to a simple change in regimen, such as administering the CAI with food, changing to a slow-release oral CAI preparation, or adding alkaline antacid therapy. Patients with a history of gastrointestinal disease who are on CAI therapy sometimes develop symptoms that are refractory to all attempts at relief. It is curious that CAI therapy may be expected to reduce secretion of hydrochloric acid in patients with peptic ulcer, yet such patients may not tolerate CAI therapy because of aggravation of their abdominal symptoms.
The systemic administration of CAIs has also exhibited the rare but potentially lethal side effect of bone marrow suppression. Thrombocytopenia, aplastic anemia, agranulocytosis, and pancytopenia have been reported and can be either idiosyncratic or dose related.14,15 Of note, topical CAIs have also been reported to result in rare (but reversible) case reports of thrombocytopenia.16
Many conflicting statements have been made concerning potassium supplementation in patients on long-term oral CAI therapy. We have found that patients receiving CAI treatment tend to have only small decreases in serum potassium assuming that they consume a normal diet. Some have suggested that patents with the malaise-type side effects may have more potassium loss. However, we have found no correlation between malaise and potassium loss. However, patients who are concurrently taking oral CAI agents for glaucoma and a thiazide diuretic for systemic hypertension often develop a large decrease in serum potassium and frequently require potassium supplementation. Such patients should have their potassium levels monitored, because hypokalemia can become a life-threatening cardiac situation. In general, we have found that most patients who are taking only CAI and no thiazides do not have an appreciable benefit from potassium supplementation, and thus we just monitor their serum potassium levels.