Adverse effects of these drugs include headache, mental confusion, backache, acute congestive heart failure, and myocardial infarction. The rapid increase in extracellular volume and cardiac preload caused by hyperosmotic agents may precipitate or aggravate congestive heart failure. Intravenous administration is more likely than oral administration to cause this problem. In addition, subdural and subarachnoid hemorrhages have been reported after treatment with hyperosmotic agents. Glycerol can precipitate hyperglycemia or even ketoacidosis in patients with diabetes, because it is metabolized into sugar and ketone bodies. Hyperosmotics, as well as oral CAIs, are contraindicated in patients in renal failure or on dialysis.

General Approach to Medical Treatment

Open-Angle Glaucoma

The ophthalmologist should tailor therapy for open-angle glaucoma to the individual needs of the patient. As noted previously, a target IOP range is established as a goal. However, the effectiveness of therapy can be established only by careful repeated scrutiny of the patient’s optic nerve and visual field status.

Characteristics of the medical agents available for the treatment of glaucoma are summarized in Table 7-1. When making management decisions, the ophthalmologist should keep drug efficacy and patient compliance in mind. Treatment is usually initiated with a single topical medication, unless the starting IOP is extremely high, in which case 2 or more medications may be indicated. The selection of the agent for initial medical therapy should be individualized based on the efficacy, safety, and tolerability of the drug and the patient’s status and needs. A brief discussion with the patient regarding treatment options can be effective for determining the optimal choice. Prostaglandin analogues, β- blockers, α2-agonists, and topical CAIs are all reasonable choices for first-line therapy. The oncedaily prostaglandin analogues are the most effective agents to lower IOP, and they have the best systemic safety profile. Thus, they are commonly the first class of medications used in most patients. Although β-blockers are the best tolerated locally, they have significant systemic side effects. Because of the variability of IOP, it may be helpful (unless the IOP is extremely high) to test the medication in 1 eye until the effectiveness of therapy has been established. At that point, both eyes can be treated.

If 1 drug is not adequate to reduce IOP to the desired range, the initial agent may be discontinued and another tried. If no single agent controls the pressure, a combination of topical agents should be used. Again, individualizing the choice of agent is helpful for selection of the second-line medication. These choices include miotic therapy for nonphakic patients and, in rare instances, systemic CAIs for short periods when the clinical situation warrants the risk of adverse effects associated with their use. Clearly, when the patient requires 3 or more medications, compliance becomes more difficult and the potential for local ocular and systemic side effects increases.

Patients may not be able to tolerate multiple topical agents because of preservative toxicity. Benzalkonium chloride (BAK) is the agent most commonly used as a preservative and is present in most currently available topical ophthalmic eyedrops. If a reaction is suspected, an alternative can be used, including preservative-free timolol maleate (unit dose), brimonidine 0.1% preserved with Purite, timolol in gel-forming solution preserved with benzododecinium bromide, preservative-free tafluprost, preservative-free dorzolamide, preservative-free timolol/dorzolamide fixed combination, and BAK-free travoprost, which is preserved in the bottle with an ionic buffered system. If the level of glaucoma damage permits, it may be beneficial, for rehabilitation of the ocular surface, to stop all topical medications and to have the patient use unpreserved artificial tears frequently. The temporary

use of oral CAIs may be useful to lower IOP during this period, if clinically warranted.

Patients rarely associate systemic side effects with topical drugs and, consequently, seldom volunteer symptoms. The ophthalmologist must inquire about these symptoms. Communication with the primary care physician is important not only to provide information about the potential side effects of glaucoma medication but also to discuss the possible effects of other currently prescribed systemic medications on the glaucomatous process. Modification of systemic β-blocker therapy for hypertension, for example, may affect glaucoma control. Physicians should be aware that patient compliance may decline as the complexity and expense of the medical regimen increase.

Patients with open-angle glaucoma require careful monitoring. IOP, though important, is only one of several factors to monitor. Optic nerve photographs or drawings and visual fields must be compared periodically to ensure that the disease is stable (see Chapter 3). The condition of the patient and the severity of the disease determine how often each of these parameters must be checked. If the cupping or visual field damage shows evidence of progression despite apparent control of acceptable IOP, the ophthalmologist should consider other diseases (see the discussion of normal-tension glaucoma in Chapter 4). Other possible explanations include an IOP level that is too high for the particular patient’s optic nerve, IOP that may be spiking at times when the patient is not in the physician’s office, low central corneal thickness, sleep apnea, concomitant angle closure, and poor patient compliance.

Angle-Closure Glaucoma

The aim of medical treatment of acute angle closure​ is usually to lower the IOP in preparation for laser iridotomy. Rapid IOP reduction is required in order to prevent further damage to the optic nerve, to clear the cornea of edema, to reduce intraocular inflammation, to allow pupillary constriction, and to prevent formation of posterior and peripheral anterior synechiae (see Chapter 5). Medical therapy for chronic angle closure is the same as that for POAG, although miotics play a greater role. However, the use of miotics may induce a paradoxical increase in IOP if the angle is closed and the trabecular meshwork is nonfunctional.

Administration of Ocular Medications

Patients should be shown how to instill eyedrops properly and should be given instructions on nasolacrimal occlusion. Nasolacrimal occlusion can be used to reduce the systemic absorption of topical ocular medications and to prolong their ocular contact time. Teaching the patient to close the eyes for 1–3 minutes after instillation of the eyedrop will also promote corneal penetration and reduce systemic absorption of the drug. These procedures are especially important with the use of β- blockers. In addition, they ensure that there is a sufficient amount of time between the instillation of different medications. Eyedrops to be administered at the same time should be separated by at least 5 minutes to prevent washout of the first drug by the second. Patients should be taught how to space their medications, and instructional charts should be given. It may be useful to coordinate the administration of medication with a part of the daily routine, such as meals. A dosing aid device may also be considered, especially for patients who live alone or who are unable to successfully instill eyedrops.

Use of Glaucoma Medications During Pregnancy or by Nursing Mothers

Unfortunately, there is little definitive information concerning the use of glaucoma medications in pregnant women or nursing mothers. In 1979, the US Food and Drug Administration (FDA) introduced a classification system to indicate the potential teratogenicity of approved medications.

Drugs are rated A, B, C, D, or X, with the X category being the most teratogenic. For example, brimonidine has a Pregnancy Category B rating, and all other glaucoma agents have a Pregnancy Category C rating. The rating Pregnancy Category B indicates that animal studies of the drug have revealed no harm to the fetus, but no adequate and well-controlled studies have been done in pregnant women; or, animal studies of this drug have shown an adverse effect, but adequate and wellcontrolled studies in pregnant woman have failed to demonstrate a risk to the fetus. The Pregnancy Category C rating indicates that no animal studies have been conducted and that it is not known whether the drug can cause harm when given to a pregnant woman. The drug should be used during pregnancy only if clearly indicated. This category also includes drugs that have shown an adverse effect in animal studies, but there are no adequate and well-controlled studies of these drugs in pregnant women.

Timolol, despite its Pregnancy Category C rating, tends to be used during pregnancy, because of its long track record. However, β-adrenergic antagonists, which are concentrated fivefold in breast milk, should be avoided in nursing mothers because of their potential adverse effects on infants. Brimonidine has been reported to cause respiratory arrest in infants and young children and should not be used in these patients. The CAIs have been shown to be teratogenic in rodents. Although human information is lacking, oral CAIs should not be used by women in their childbearing years or by those who are pregnant. Because prostaglandins increase uterine contractility and may induce labor, they should not be used during pregnancy. In general, it is prudent to minimize the use of medications in pregnant women whenever possible, and the clinician may want to consider laser trabeculoplasty or surgical intervention in cases where vision loss is a concern.

Brauner SC, Chen TC, Hutchinson BT, Chang MA, Pasquale LR, Grosskreutz CL. The course of glaucoma during pregnancy: a retrospective case series. Arch Ophthalmol. 2006;124(8):1089–1094.

Sheth BP. Drugs and pregnancy. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2007, module 7.

Use of Glaucoma Medications in Elderly Patients

There are specific considerations with regard to the use of glaucoma medications in elderly patients. First, elderly patients generally have greater difficulty instilling their medications than do younger patients; consequently, compliance may be affected. This may be due to tremor, poor coordination, or a comorbidity such as arthritis. Compliance will also be affected in an elderly patient with reduced mental capacity or poor memory and a complicated drug regimen, especially since this individual is most likely already taking multiple systemic medications for other ailments. Second, elderly persons have a greater susceptibility to the systemic adverse effects of glaucoma medications, as for example, α2-agonists, the systemic side effects of which are often symptomatic in these patients. This is especially important to remember with the use of β-adrenergic antagonists. It has been shown that a significant proportion of asymptomatic elderly patients suffer a significant, but reversible, reduction in pulmonary function.

Diggory P, Cassels-Brown A, Vail A, Abbey LM, Hillman JS. Avoiding unsuspected respiratory side-effects of topical timolol with cardioselective or sympathomimetic agents. Lancet. 1995;345(8965):1604–1606.

Generic Medications

Many of the β-blockers and, increasingly, other classes of glaucoma medications are available as generic agents. Although the generic agents may be less expensive, in most cases little data are available to prove or disprove equivalent efficacy and safety between brand-name and generic medications.

Compliance

Glaucoma medications are effective only if patients use them. Patient education is usually the first step in improving compliance. Understanding the disease and the nature and benefits of treatment enhances compliance. Education should also include a discussion of treatment alternatives. When patients are aware of the possible side effects of a medication, compliance is also enhanced.

In addition, it is vital to teach patients how to properly instill medications. The ophthalmologist should confirm that the patient or someone else will be successful in instilling eyedrops. Compliance is further enhanced by a drug regimen that is designed to be as simple as possible. The fewest number of medications, instilled with the least frequency, is optimal. When the patient requires multiple drugs and doses, it may be helpful to coordinate administration with daily events. The ophthalmologist must make sure that the patient understands the regimen. A written schedule is very helpful.