Caution is recommended when either apraclonidine or brimonidine is used in patients on a monoamine oxidase inhibitor (MAOI) or tricyclic antidepressant therapy. Apraclonidine has a much greater affinity for α1-receptors than does brimonidine and is therefore more likely to produce vasoconstriction in the eye.

Robin AL. Argon laser trabeculoplasty medical therapy to prevent the intraocular pressure rise associated with argon laser trabeculoplasty. Ophthalmic Surg. 1991;22(1):31–37.

Schuman JS, Horwitz B, Choplin NT, David R, Albracht D, Chen K. A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension: a controlled, randomized, multicenter clinical trial. Arch Ophthalmol. 1997;115(7):847–852.

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) decrease aqueous humor formation by direct antagonist activity on ciliary epithelial carbonic anhydrase and perhaps, to a lesser extent only with systemic administration, by production of a generalized acidosis. The enzyme carbonic anhydrase is present in many other tissues, including corneal endothelium, iris, retinal pigment epithelium, red blood cells, brain, and kidney. More than 90% of the ciliary epithelial enzyme activity must be abolished to decrease aqueous production and lower IOP.

Topical CAI agents are available for long-term treatment of elevated IOP. Dorzolamide and brinzolamide are sulfonamide derivatives that reduce aqueous formation by direct inhibition of carbonic anhydrase in the ciliary body. They have fewer systemic side effects than the oral agents. Dorzolamide and brinzolamide are currently available for use 3 times daily, although the reduction in IOP is only slightly greater when compared to the IOP reduction with twice-daily therapy. For patients taking an oral CAI, there is no advantage to adding a topical CAI.

Common adverse effects of topical CAIs include bitter taste, blurred vision, and punctate keratopathy. Dorzolamide may cause transient burning because of its lower pH, whereas brinzolamide is a suspension, resulting in white deposits in the tear film. Eyes with compromised endothelial cell function may also be at risk of corneal decompensation.

The systemic agents can be given orally, intramuscularly, and intravenously. They are most useful in acute situations (eg, acute angle-closure glaucoma). Oral CAIs begin to act within 1 hour of administration, with maximal effect within 2–4 hours. Sustained-release acetazolamide can reach peak effect within 3–6 hours of administration. Because of the adverse effects of systemic CAIs, however, long-term therapy with these agents should be reserved for patients whose glaucoma is not controlled with topical therapy and who have refused surgery or in whom surgery would be inappropriate.

Systemic acetazolamide and methazolamide are the oral CAI agents most commonly used; another agent in this group is dichlorphenamide. Methazolamide has a longer duration of action and is less bound to serum protein than is acetazolamide; however, it is less effective than acetazolamide. Methazolamide and sustained-release acetazolamide are the best tolerated of the systemic CAIs. Methazolamide is metabolized by the liver, thereby decreasing some of the risk of systemic adverse effects. Acetazolamide is not metabolized and is excreted in urine.

Adverse effects of systemic CAI therapy are usually dose-related. Many patients develop paresthesias of the fingers or toes and complain of lassitude, loss of energy, and anorexia. Weight loss is common. Abdominal discomfort, diarrhea, loss of libido, impotence, and an unpleasant taste in the mouth, as well as severe mental depression, may also occur. There is an increased risk of the formation of calcium oxylate and calcium phosphate renal stones. Because methazolamide has greater hepatic metabolism and causes less acidosis, it may be less likely than acetazolamide to cause renal lithiasis.

CAIs are chemically derived from sulfa drugs; therefore, their use may cause an allergic reaction in individuals with a sulfa allergy. The level of cross-reactivity is low, however. Aplastic anemia is a

rare but potentially fatal idiosyncratic reaction to CAIs. Thrombocytopenia and agranulocytosis can also occur. Although routine complete blood counts have been suggested, they are not predictive of this idiosyncratic reaction and are not routinely recommended. Hypokalemia is a potentially serious complication that is especially likely to occur when an oral CAI is used concurrently with another drug that causes potassium loss (eg, a thiazide diuretic). Serum potassium should be monitored regularly in such patients.

Oral CAIs are potent medications with significant adverse effects. Therefore, the lowest dose that reduces the IOP to an acceptable range should be used. Methazolamide is often effective in doses as low as 25–50 mg given 2 to 3 times daily. Sustained-release formulations may have fewer side effects. A typical dosing regimen for acetazolamide is 250 mg 4 times daily; for sustained release, 250–500 mg twice daily.

Fraunfelder FT, Fraunfelder FW, eds. Drug-Induced Ocular Side Effects. Boston: Butterworth-Heinemann; 2001.

Strahlman E, Tipping R, Vogel R. A double-masked, randomized 1-year study comparing dorzolamide (Trusopt), timolol, and betaxolol. International Dorzolamide Study Group. Arch Ophthalmol. 1995;113(8):1009–1016.

Parasympathomimetic Agents

Parasympathomimetic agents, or miotics, have been used in the treatment of glaucoma for more than 100 years. Traditionally, they were divided into 2 groups, direct-acting and indirect-acting anticholinesterase agents. However, indirect-acting agents fell out of use because of ocular and systemic adverse effects, and they are no longer available for glaucoma therapy, including echothiophate iodide, the agent typically used in the past.

Direct-acting agents affect the motor end plates in the same way as acetylcholine, which is transmitted at postganglionic parasympathetic junctions, as well as at other autonomic, somatic, and central synapses. Indirect-acting agents inhibit the enzyme acetylcholinesterase, thereby prolonging and enhancing the action of naturally secreted acetylcholine. Pilocarpine is the only direct-acting agent still used in the treatment of glaucoma.

Parasympathomimetics reduce IOP by causing contraction of the longitudinal ciliary muscle, which pulls the scleral spur to tighten the trabecular meshwork, increasing the outflow of aqueous humor. Pilocarpine can reduce IOP by 15%–25%. The currently accepted indications for miotic therapy include long-term treatment of elevated IOP in patients whose drainage angles are persistently occludable despite laser iridotomy, and prophylaxis for angle-closure glaucoma prior to iridectomy.

Miotic agents have been associated with numerous ocular side effects. Induced myopia resulting from ciliary muscle contraction is a side effect common to all cholinergic agents. Brow ache may accompany the ciliary spasm, and the miosis interferes with vision in dim light and in patients with lens opacities. Miotic agents have also been associated with retinal detachment; thus, a peripheral retinal evaluation is suggested before the initiation of therapy. Miotics may be cataractogenic, particularly the indirect-acting agents. In children, they may also induce formation of iris pigment epithelial cysts. In pediatric and adult patients, these agents may cause epiphora by both direct lacrimal stimulation and punctal stenosis. These agents may also cause ocular surface changes resulting in drug-induced pseudopemphigoid.

Other potential ocular side effects include increased bleeding during surgery and increased inflammation and severe fibrinous iridocyclitis postoperatively. Because miotics can break down the blood–aqueous barrier, they should be avoided if possible in patients with uveitic glaucoma. Use of miotics occasionally induces a paradoxical angle closure, particularly in eyes with phacomorphic narrow angles, because contraction of the ciliary muscle leads to forward movement of the lens–iris interface and an increase in the anteroposterior diameter of the lens, which may cause or exacerbate

pupillary block in an eye with a large lens.

Systemic adverse effects, seen mainly with indirect-acting medications, include diarrhea, abdominal cramps, increased salivation, bronchospasm, and even enuresis. Depolarizing muscle relaxants such as succinylcholine cannot be used for up to 6 weeks after stopping indirect-acting agents.

Although miotic agents effectively lower IOP, they are poorly tolerated and have been associated with poor compliance because of the 2–4-times-daily regimen required. This class of agents is now rarely used in the treatment of POAG.

Pilocarpine absorbed to a polymer gel (pilocarpine gel) is administered once daily at bedtime. Although nocturnal dosing reduces problems from induced myopia and miosis, the gel is marketed at 4% concentration, which is still relatively poorly tolerated, especially in younger patients. On the other hand, pilocarpine is among the most affordable of agents, and miotics are much better tolerated in aphakic than in phakic eyes.

Hoskins HD Jr, Kass MA. Cholinergic drugs. In: Hoskins HD Jr, Kass MA, eds. Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas. 6th ed. St Louis: Mosby; 1989:420–434.

Combined Medications

Medications that are combined in a single bottle have the potential benefit of improved convenience and compliance, as well as reduced cost. Fixed combinations consisting of timolol and another agent —a CAI (dorzolamide, brinzolamide), an α2-adrenergic agonist (brimonidine), or a prostaglandin analogue (latanoprost, travoprost, bimatoprost)—are available in many countries (see Table 7-1). In general, the efficacy of fixed combinations of timolol and a topical CAI is similar to that of these components given separately. However, the main outcome of twice-daily dosing may be to increase the risk of systemic β-blocker side effects, because nearly the full effect of a β-blocker can be achieved with once-daily dosing. The ocular side effects are the same as for both drugs individually. In general, except in emergent situations, fixed combinations such as those with topical CAIs should not be used until the clinician has established that timolol alone does not sufficiently lower the IOP.

Strohmaier K, Snyder E, DuBiner H, Adamsons I. Dorzolamide-Timolol Study Group. The efficacy and safety of the dorzolamidetimolol combination versus the concomitant administration of its components. Ophthalmology. 1998;105(10):1936–1944.

Hyperosmotic Agents

Hyperosmotic agents are used to control acute episodes of elevated IOP. Common hyperosmotic agents include oral glycerol and intravenous mannitol.

When given systemically, hyperosmotic agents lower the IOP by increasing the blood osmolality, which creates an osmotic gradient between the blood and the vitreous humor, drawing water from the vitreous cavity and reducing the IOP. Because of the increased gradient, the larger the dose administered and the more rapid the administration, the greater the subsequent IOP reduction. A substance distributed only in extracellular water, such as mannitol, is more effective than a drug distributed in total body water (eg, urea). When the blood–aqueous barrier is disrupted, the osmotic agent enters the eye faster than when the barrier is intact, thus reducing the effectiveness of the drug and its duration of action.

Hyperosmotic agents are rarely administered for longer than a few hours because their effects are transient as a result of the rapid reequilibration of the osmotic gradient. They become less effective over time, and a rebound elevation in IOP may occur if the agent penetrates the eye and reverses the osmotic gradient.