Chapter 233 – Current Medical Management of Glaucoma
RONALD L. GROSS
The armamentarium for the medical treatment of glaucoma recently experienced an unprecedented expansion of available agents. Years ago, the choice was limited to miotics, epinephrine (adrenaline), and oral carbonic anhydrase inhibitors. The introduction of topical ß-blockers in the 1970s was a significant advance, and ß-blockers quickly became the most commonly prescribed class of agents to lower intraocular pressure (IOP). They generally were the most effective medication to do so and were well tolerated by most patients. However, with experience, it was recognized that side effects, both local and systemic, could occur, and it became important to identify those patients at risk for these problems. More recently, with the introduction of topical carbonic anhydrase inhibitors, a-adrenergic agonists, and prostaglandin analogs and prostamides, additional agents have become available that effectively lower IOP and have side-effect profiles that appear to be advantageous in many patients.
It is important to recognize that no single medication can be used in all patients in all circumstances. Each of the available drugs has its own unique advantages and disadvantages, and currently six separate classes of antiglaucoma drugs are available. It is necessary to individualize each patient’s treatment regimen to maximize the benefits and limit the undesirable effects. It is not realistic to anticipate using all the available types of drugs for any single patient. Rather, it is vital to select the best agent for each particular patient’s needs.
The first step in the accomplishment of this aim is to educate the patient about glaucoma in terms of his or her particular situation. This allows the patient to participate in an informed way in decision making about the care required. Besides improving drug selection, better understanding of the disease and its treatment by the patient should improve compliance with the medical regimen. Compliance in glaucoma patients is difficult to assess, but effective medical treatment of the disease is dependent on the delivery of therapy by the patient or caregiver—in many cases, several agents multiple times a day, every day. Selection of an appropriate agent results in maximization of lowered IOP, ocular tolerability, and safety, which not only treats the glaucoma effectively but also minimizes the impact of treatment on the patient’s quality of life.
Historically, the effectiveness of a medication in the treatment of glaucoma was measured by its ability to lower IOP. However, more recently, the impact of other factors (e.g., blood supply of the optic nerve, local mechanical factors that affect the optic nerve, neuroprotection of the optic nerve) on glaucoma and glaucomatous optic neuropathy has been recognized. Although the clinical importance of these variables is not yet understood, it is anticipated that improvement in the efficacy of glaucoma treatment may include assessment of these parameters.
Once the decision to begin medical treatment has been made, two specific techniques may enhance the therapeutic index of any topical ophthalmic agent. First, patients are encouraged to perform nasolacrimal occlusion or gentle eyelid closure after the instillation of all topical ophthalmic drops. Such maneuvers decrease the systemic absorption of drugs and increase their intraocular levels, thus improving the therapeutic index. In patients on multiple topical agents, these maneuvers also reinforce the need to allow sufficient time between the instillation of different agents to allow absorption of the first one before any dilution by instillation of a subsequent one.
Second, with the increased number of choices, it is important to prove to the patient and the doctor that the drug is effective and well tolerated. To prove that IOP is lowered with efficacy, a one-eye therapeutic trial is performed that involves the initial administration of a single agent in only one eye while the fellow eye remains on the previous regimen (to act as a control). Because no drug lowers IOP effectively in all patients, this procedure identifies an agent’s effectiveness for the individual patient and thus prevents exposure to potential side effects without therapeutic benefit. If the agent is ineffective or not tolerated, it is discontinued and an alternative drug is evaluated. The trial period varies, depending on the agent tested, side effects, and efficacy. A period of 2–4 weeks is generally adequate. This maneuver can also demonstrate the continued efficacy of a drug after its long-term use. In this case, a reverse one-eye therapeutic trial is performed in which the drug is discontinued in one eye, and the results are compared with those for the eye in which treatment is continued. Again, this reaffirms that the chosen medical regimen must provide maximal benefit.
Finally, it is important to instruct the patient how and when to instill medications. Discussion of the preferred technique of instilling drops in the inferior cul-de-sac, with subsequent nasolacrimal occlusion or gentle eyelid closure, is likely to be of benefit. To confirm correct use, it is often helpful to have the patient demonstrate the technique of drop instillation on a subsequent visit. As to the time of administration, studies suggest that compliance is reduced when the frequency of administration is more than twice daily, which may be an important factor in the design of the patient’s regimen. It is critical that the regimen be one that the patient can reasonably be expected to perform.
DRUGS THAT DECREASE AQUEOUS PRODUCTION
Since their introduction, ß-blockers have become the mainstay of medical glaucoma therapy. Over time, the importance of patient selection has become clear. The most important feature that differentiates the available topical ophthalmic ß-blockers is receptor selectivity; nonselective agents block both ß1 and ß2 receptors, and ß1 -selective agents are more selective for the ß1 receptors. Selectivity has implications for both efficacy and safety.
ß-Blockers decrease aqueous humor production by the ciliary body and hence reduce IOP. Some evidence suggests that this occurs only during the day and not during sleep.  This may be important in patients who experience some
of the systemic side effects (e.g., lower blood pressure and pulse rate) at night, with the potential for disease progression without other therapy to lower IOP. At present, the implications of this potential problem are unclear.
ß-blockers are effective topical agents, with the mean peak IOP lowered by at least 25% and the mean trough lowered by 20% using nonselective agents.  In general, these nonselective agents lower IOP equally effectively; the data support timolol, levobunolol, metipranolol, and carteolol equivalence.   For the ß1 -selective agent betaxolol, IOP reduction is slightly less. When ß-blockers alone are not adequate to control the patient’s glaucoma, other classes of agents may be added. Although supporting data are not complete, it appears that other agents add to the effect of all ß-blockers; the exceptions are epinephrine-like drugs, which have a greater effect when added to the selective agent betaxolol than when added to nonselective agents. Given the small additive effect, the use of these agents along with ß-blockers is less common now because of the development of newer agents.
None of the ß-blockers should be used more than twice daily. Certain nonselective agents, including timolol maleate and levobunolol, may be used once daily in some patients. Timolol maleate 0.5% in a gel-forming solution (Timoptic-XE) once daily is essentially equivalent to timolol solution twice daily. With other agents, peak and trough levels of IOP are checked to confirm the duration of action. Once-daily instillation may be more convenient for the patient, which enhances compliance and reduces the amount of drug used. Also, many agents are available in more than one concentration. Lower concentrations are preferred and are as effective in the majority of patients. Unfortunately, no studies have proved that lower concentrations have a lower incidence of side effects or produce less severe side effects. It is possible that all available concentrations fall above the threshold on the dose–side effect curve.
Another aspect of efficacy is the use of generic agents. Unlike with oral agents, bioequivalence or equal effectiveness is not required to be proved when topical ophthalmic generics are introduced. Although these generic agents may be less expensive, whether these savings are sufficient to justify their use must be determined by the physician, the patient, and local health care policy. Unfortunately, no data are available on which to base this determination.
The successful treatment of glaucoma is based not only on efficacy but also on side effects and compliance. Therefore, it is vital to select out patients who will not benefit from or may be harmed by the drug. Contraindications to ß-blocker use include asthma, severe chronic obstructive pulmonary disease, bradycardia, second- or third-degree heart block, and congestive heart failure.
Clinically, it is prudent not to use this class of drugs (selective or nonselective) in any patient who requires respiratory medications, has a heart rate of less than 55 beats/minute, has or has had heart failure, or has a history of present or past use of antidepressant medications or impotence. A positive history of cardiac problems or symptoms is usually present in patients who have greater than first-degree heart block.
Although cardiac and pulmonary side effects are the most obvious, in a large review, central nervous system problems were the most frequent, ranging from hallucinations to depression to a general feeling of malaise. These side effects may be much more difficult to identify. In the majority of patients, if the drug used may be causing or exacerbating such problems, it is stopped to establish whether the symptoms improve. The elderly appear to be at the greatest risk for ß-blocker side effects. A conscious effort is required to identify susceptible patients (in line with the overall philosophy of individualization of therapy and specific assessment of drug effects). Other systemic side effects of topical ß-blockers are rare, although the dermatological problem alopecia has been described.
A difference exists between the nonselective and selective ß-blockers with regard to the incidence and severity of side effects. A ß1 -selective agent is much safer in appropriate patients, but not completely safe. The same complications, such as diminished pulmonary function or decreased exercise-induced tachycardia, may occur with its use, but they occur less frequently and may be less severe. The decision as to which class of ß-blocker is appropriate for a specific patient is reduced to a simple observation: for a particular patient, if efficacy is the main concern, a nonselective agent is appropriate (with some sacrifice of the safety profile), but if safety is the primary concern, the use of a ß1 -selective drug to limit potential side effects justifies the slight reduction in efficacy.
Other problems with these drugs are less common. Locally, they are well tolerated, although corneal hypesthesia and epithelial changes have been reported. Additionally, some investigators believe that their use should be avoided in diabetic patients, because the symptoms of hypoglycemia may be masked and those of myasthenia gravis may be exacerbated.  Also, it has been suggested that patients who are undergoing allergy tests or desensitization should not use ß-blockers of any kind, even topical agents, because ß-blockade may make resuscitation more difficult should anaphylaxis occur. The use of ß-blockers in neonates is avoided because apnea may develop. Less well understood is the implication that ß-blockers may have an undesirable effect on plasma lipids. Systemic ß-blockers are known to result in undesirable changes in plasma lipid profiles. However, systemically, they are actually protective when the clinical outcomes of elevated plasma lipids (i.e., heart attack and stroke) are considered, because of their positive effect on cardiovascular function. Topical timolol and, to a lesser extent, carteolol reduce high-density lipoproteins by 9% and 3%, respectively; however, no data indicate that this results in a higher risk of cardiovascular disease.  The difference between these two drugs may arise from the intrinsic sympathomimetic activity that carteolol possesses. The mechanism and significance of intrinsic sympathomimetic activity are not clear. Theoretically, the partial agonist activity should cause less vasoconstriction and cardiopulmonary effects, but clinically, it does not result in an appreciable difference in safety or efficacy compared with other nonselective agents.
Although it is true that topical ß-blockers are effective and well tolerated by the majority of patients, on rare occasions these agents have been linked with death. Therefore, it is our obligation to identify those patients who may benefit most from their use and those patients in whom their use should be avoided (and for whom other classes of agents may be used).
Recently, the more specific a-agonists have become available. The first one introduced was apraclonidine, a relatively selective a-adrenergic agonist derived from clonidine, but with an amide group at C4 of the benzoic ring, which makes the drug more polar and less permeable to the blood-brain barrier. As a result, it has fewer central nervous system effects and also produces fewer adverse systemic reactions, such as reduction of systemic blood pressure. Brimonidine is the most recently introduced a-adrenergic agonist; it is a 2-imidazoline derivative with a quinoxaline ring and bromine as side groups.
Apraclonidine decreases aqueous production but is also associated with an increase in outflow facility and a decrease in episcleral venous pressure. Brimonidine is 23 times more a2 selective than apraclonidine and 12 times more selective than clonidine. Its mechanism of action includes a reduction in aqueous formation as well as an increase in uveoscleral outflow.
The first clinical use of apraclonidine was in a 1% concentration to decrease IOP in short-term situations, such as the prevention of pressure spikes after anterior segment laser surgery. It was shown to be very effective for this purpose after argon laser trabeculoplasty,  argon laser iridotomy,
neodymium:yttrium-aluminum-garnet (Nd:YAG) laser iridotomy, Nd:YAG laser capsulotomy, and even cataract surgery and trabeculectomy. Also, it was used successfully in cases of acute angle-closure glaucoma and as prophylaxis against high IOP spikes after cycloplegia.
In addition to its use in acute situations, apraclonidine is used in the chronic treatment of glaucoma. Initially, apraclonidine 1% was administered; subsequently, apraclonidine 0.5% was introduced for use in addition to the maximum-tolerated medical therapy for the treatment of glaucoma. Both concentrations were shown to yield similar IOP reductions. Apraclonidine is also used successfully as an adjunct of ß-blockers, including timolol.
Brimonidine 0.5% prevented the rise in postoperative IOP after laser trabeculoplasty to a greater extent than did vehicle. Spikes greater than 10?mmHg (1.3?kPa) occurred in 1–2% of cases using brimonidine versus 23% using vehicle. In a 12-month comparison of twice-daily brimonidine 0.2% versus timolol 0.5%, both were equally effective at the 2-hour peak. No tachyphylaxis was seen with either drug over the 12 months of the study. At trough (12 hours), IOP was 3.7–5.0?mmHg (0.5–0.7?kPa) with brimonidine, compared with 5.8–6.6?mmHg (0.8–0.9?kPa) with timolol. There was no difference between the groups in terms of optic disc and visual field, which were unchanged in 94% of patients.  Brimonidine 0.2% was compared with betaxolol 0.25% twice daily in a 3-month study, which demonstrated that brimonidine at peak decreased IOP by 5.5–6.2?mmHg (0.7–0.8?kPa) compared with baseline; this was greater than the 3.5–4.1?mmHg (0.5–0.6?kPa) decrease in IOP with betaxolol (P<.001). No difference occurred between drugs at trough, and no tachyphylaxis was found with either drug. Brimonidine is approved for use three times a day but is commonly used twice daily, since at morning trough, there is no difference in IOP between the two regimens. 
Chronic use of apraclonidine is limited by the potential for allergic reaction ( Fig. 233-1 ), which may be severe, and also because the drug may lose effect over time. Previous studies using apraclonidine 1% reported a variable incidence of allergic reaction of up to 48%, although the rate using apraclonidine 0.5% was 15% initially. Systemically, this drug is well tolerated, with the primary systemic side effect being dry mouth—not unexpected with an a-agonist. Brimonidine shows no effect on mean heart rate, mean blood pressure, or pulmonary function. In the longer term (6- and 12-month studies of brimonidine compared with timolol), adverse effects included dry mouth in 30% of patients and fatigue-drowsiness in 15.8% (as a result of which 2.5% of patients exited the study), compared with 13.6% with fatigue (P = .342) in the timolol groups. Compared with betaxolol, no statistically significant differences occurred in
Figure 233-1 Follicular conjunctival reaction to apraclonidine.
the systemic parameters studied, and no suggestion of a reduction in exercise-induced tachycardia was found.
Ocular effects included conjunctival blanching in 11–17% (vehicle, 9%) of cases and burning-stinging in 24% (timolol, 41%). Within this class of agents, the allergy often limits the drug’s clinical usefulness and appears to be a response to haptens, which are oxidation products of the drug. Apraclonidine and epinephrine contain the hydroquinone subunit and are therefore oxidized more easily than are clonidine and brimonidine. Thus, the allergic response caused by brimonidine is less frequent and less severe, with a rate of approximately 5% at 3 months and 12% at 12 months.  A different formulation of brimonidine has been introduced that reduces the concentration to 0.15% and replaces benzalkonium chloride with a proprietary Purite preservative. The most significant clinical improvement with the new formulation is a reduced incidence of allergic reactions by more than 50% (7.1% vs. 17.1%). Use of the Purite preservative could be a great advantage to patients in whom benzalkonium chloride causes ocular surface disruption. This includes patients who are particularly sensitive to the preservative, as well as patients taking multiple drops in whom toxicity may be cumulative.
Carbonic Anhydrase Inhibitors
Carbonic anhydrase is an enzyme that catalyzes the reaction of H2 O and CO2 in equilibrium with H+ and HCO3 – . The enzyme is located in the cell membranes of the pigmented and nonpigmented ciliary epithelium. The net effect of the enzyme on aqueous production is to generate bicarbonate ions, which are transported actively across the ciliary epithelial membrane into the posterior chamber (sodium is the primary cation); an osmotic gradient is established. Water passively follows because of the presence of the gradient, which results in fluid production. Inhibition of this enzyme results in lower IOP because aqueous production is decreased approximately 50% or more ; aqueous outflow and episcleral venous pressure are affected little or not at all.
An important property of carbonic anhydrase is that it is necessary to inhibit nearly 100% of the enzyme at all times. Thus, topical carbonic anhydrase inhibitors may result in a lower IOP because of decreased aqueous production but not affect total body carbonic anhydrase; as a result, systemic effects are minimized.
Dorzolamide, a topical carbonic anhydrase inhibitor, is different in structure from the oral agents. It has a free sulfonamide group, which is essential for activity, but it also has a second amine moiety, which gives the compound increased aqueous solubility and results in suitable lipid-water solubility for corneal penetration; this allows effective topical application. When aqueous humor flow was measured fluorophotometrically, a 38% reduction was found with dorzolamide 2% in ocular normotensive cynomolgus monkeys, with no effect on outflow as measured by tonography; this confirmed the mechanism of action of this carbonic anhydrase inhibitor. Brinzolamide 1% was introduced as a suspension with a more physiological pH than dorzolamide solution. This resulted in a reduced occurrence of stinging with brinzolamide, but this medication is associated with transient blurring of vision following administration as a suspension.
In a 2% dorzolamide thrice-daily regimen, the peak effect was a 22% reduction of IOP, with a trough reduction of 18%. At all times after the administration of dorzolamide 2%, the effect was statistically significant (P =.01) compared with placebo.
In a 12-month study, dorzolamide three times a day was compared with timolol 0.5% twice a day or betaxolol 0.5% twice a day. At peak IOP, measured 2 hours after instillation, no statistically significant difference was found among the three medication regimens (21%, 23%, and 25%, respectively). However, at
troughs, 5 hours (18%, 19%, and 22%) and 8 hours (17%, 15%, and 20%) after instillation, timolol was more effective than dorzolamide or betaxolol. No statistically significant difference was found between dorzolamide and betaxolol at 12 months. As a treatment arm in this study, if dorzolamide three times a day did not control IOP adequately, timolol 0.5% twice daily was added. In this subset of 95 patients, IOP was reduced using dorzolamide alone from a mean of 29.3?mmHg (3.9?kPa) at baseline to 25.2?mmHg (3.4?kPa), or a 14% reduction. When timolol 0.5% was added, IOP was reduced from a mean of 25.2?mmHg (3.4?kPa) to 18.9?mmHg (2.5?kPa), an overall 34% reduction with the combination of the two medications, which indicates an additive effect. A pilot study was performed in which dorzolamide 2% was added to timolol 0.5% and administered to patients who had elevated IOP. The addition of the topical carbonic anhydrase inhibitor decreased IOP by an additional 13–21%. In another study, the additive effect of dorzolamide 2% twice daily was compared with pilocarpine 2% four times daily in a prospective manner in 261 patients over 6 months. Additional mean IOP reductions at the morning trough were 13% and 10% for dorzolamide 2% and pilocarpine 2%, respectively. Patients who received pilocarpine had the highest rate of discontinuation as a result of adverse clinical experience. Therefore, it appears that dorzolamide 2% is a reasonable choice for concomitant therapy.
The efficacy of brinzolamide l% was shown to be essentially equivalent to that of dorzolamide 2% when used either two or three times daily as a single agent or twice daily in addition to timolol 0.5%.
Carbonic anhydrase inhibitors lower IOP very effectively; however, their use in the chronic treatment of glaucoma is limited by the frequency and severity of side effects. The most common problem is a constellation of symptoms that include malaise, fatigue, anorexia, and depression. Gastrointestinal discomfort, which includes nausea, a metallic taste, and diarrhea, is also common. The more severe complications that limit the use of these agents are less common. Metabolic acidosis may occur in association with high-dose acetazolamide and must be avoided in patients who have severe hepatic or renal disease. Sickle cell crisis may be exacerbated by the acidosis as well, so patients at risk for sickle cell disease must be tested before the use of oral carbonic anhydrase inhibitors. Clinically, this often results in a delay in treating a patient who has acute glaucoma and very high IOP until the patient’s hemoglobin status is known. Some investigators suggest that the acidosis lowers IOP further, which may explain the general observation that acetazolamide lowers IOP more effectively than methazolamide or ethoxyzolamide, since the latter two agents do not induce a systemic acidosis. Morbidity is associated with the 11–15-fold increase in the incidence of renal calculi, which most commonly occur within the first 6 months of treatment and may arise from decreased excretion of urinary citrate or magnesium. Once renal stones occur in patients on these agents, the likelihood is high that they will occur again.
The greatest concern surrounding the use of oral carbonic anhydrase inhibitors is the potential mortality from blood dyscrasias. All blood components—red cells, white cells, and platelets—may be affected. In 1989, 139 cases of adverse hematological effects possibly related to carbonic anhydrase inhibitors were reported, with some fatalities attributed to their use. Aplastic anemia, which is frequently fatal, usually occurs within the first 6 months and appears to be an idiosyncratic reaction that is neither dose nor time dependent.  As a result, few investigators believe that periodic screening blood tests are justified. In fact, a strong case could be made that with the availability of topical carbonic anhydrase inhibitors, the use of oral agents should be limited to acute situations. In acute situations, when IOP must be lowered maximally, 500?mg of acetazolamide given orally as tablets (250?mg tablet × 2, not sustained release) has the most rapid onset. Often, oral administration is not possible because of nausea and vomiting, in which case the intravenous route is preferred; the peak effect by this route occurs in 10–15 minutes.
In controlled clinical trials, only 5% of patients discontinued the drug because of drug-related adverse events, the majority of which were ocular.  As part of the controlled clinical trials, plasma and urine were tested, but no evidence of any hematological or urinary disturbances, which included acid-base or electrolyte changes, was found. Dorzolamide binds to the carbonic anhydrase in red blood cells with a half-life of several months; however, the significance of this as a risk factor for blood dyscrasias is not known. Dorzolamide did not appear to inhibit carbonic anhydrase enzyme elsewhere sufficiently to result in systemic effects, and the effects on blood pressure or heart rate were minimal or zero. The only frequent systemic side effect was a bitter taste, reported in approximately 25% of patients. Clinically, this effect can often be reduced if the importance of nasolacrimal occlusion or gentle eyelid closure for a few minutes after the instillation of all ophthalmic drops is emphasized.
With regard to adverse ocular events, approximately one third of patients treated with dorzolamide 2% experienced some level of ocular burn, sting, or discomfort. Superficial punctate keratitis was found in 12% of patients; interestingly, the rate in the placebo group was 10.5%, which suggests that this keratitis may be a response to the vehicle or preservative. This burning was less frequent with brinzolamide 1%.   As with the oral agents, inhibition of carbonic anhydrase within these cells, which could result in a negative effect on the corneal endothelium, has not been found clinically thus far. The overall allergic rate was approximately 10%. In general, dorzolamide and brinzolamide are well tolerated. 
As to the potential for sulfonamide allergy, the portion of the sulfonamide molecule that is most responsible for the allergic response is not present in dorzolamide. However, further work is required on this question, so caution must be used when sulfonamide allergy is a possible problem.
The use of dorzolamide in children was reviewed retrospectively in one study; no significant health problems were identified with acute or chronic use of this drug.
DRUGS THAT INCREASE AQUEOUS OUTFLOW
Nonspecific Adrenergic Agents
Adrenergic agents comprise two forms of drug—epinephrine (one of the earliest topical agents used to treat glaucoma) and the pro-drug dipivalvyl epinephrine, which was introduced subsequently. A much lower concentration of dipivinyl epinephrine is administered twice daily and metabolized into the active agent. A 10–20-fold dose reduction is obtained as a result of the better ocular penetration of the pro-drug.
The pharmacology of these drugs shows that they increase uveoscleral outflow but have little net effect on aqueous production. The a2 -specific adrenergic agonist brimonidine (discussed previously) has also been demonstrated to increase uveoscleral outflow, providing it with a dual mechanism of action.
Adrenergic agents have been widely used, and some investigators believe that dipivalvyl epinephrine should be considered a first-line agent instead of ß-blockers, because of its safety profile. However, because of its reduced efficacy, it is generally used as a first-line drug only when ß-blockers are contraindicated. It is still a reasonable choice for this purpose, with a cost advantage over many of the other available drugs. Use of adrenergic agents as adjunctive therapy is limited by their minimal additive effect in association with nonselective ß-blockers in most patients. However, they are slightly more additive to the selective ß-blockers. Overall, they lower pressure by an additional 10%.
Usually, adrenergic agents are well tolerated systemically; problems such as hypertension and headaches are
rare. Locally, they can cause stinging and irritation, and they have an allergic toxic rate of at least 15% (which includes conjunctival and periocular effects).
Miotic agents have long been an important class of drugs in the treatment of glaucoma. Their use has declined because of the availability of alternative agents with more desirable side-effect profiles. However, these drugs remain useful, particularly in patients for whom cost is an overriding concern and in patients whose eyes are not phakic.
Many different miotic agents are available, all of which have a similar mechanism of action. Miotics are parasympathomimetic agents whose action increases the contractile force of the longitudinal muscle of the ciliary body on its insertion into the scleral spur. This results in an increased facility of outflow of aqueous through the effects on the trabecular meshwork. The miotics either mimic the effect of acetylcholine (e.g., pilocarpine) or prevent the breakdown of endogenous acetylcholine by inhibition of the pseudocholinesterase enzyme.
Miotics were the earliest drugs used for glaucoma, and they lower IOP by 20–30%. They were used widely as first- or second-line agents, until the advent of a-adrenergic agonists, and as prostaglandin medications. They are additive to ß-blockers, adrenergic agents, and carbonic anhydrase inhibitors.
Although miotics lower IOP effectively, the clinical use of these drugs is often limited by their local ocular tolerance. From a systemic standpoint, they are quite safe. Although cholinergic effects, such as increased gastrointestinal motility and increased salivation, have been reported, these are quite rare. The use of irreversible cholinesterase inhibitors in patients under general anesthesia causes concern, since these agents inhibit total body cholinesterase; if an agent such as succinylcholine is used during anesthesia, insufficient endogenous enzyme is present to inactive it until more enzyme is synthesized, which results in a markedly prolonged effect.
The local undesirable effects associated with these drugs include pupillary miosis as a result of stimulation of the iris sphincter, burning on instillation of the drops, brow ache and headache after the initial use of the drops, myopic shift of refractive error because of contraction of the circulation muscle of the ciliary body and the resultant increase in power of the crystalline lens, and exacerbation of symptoms of crystalline lens opacity from the pupillary constriction. Such effects are often dose related. Pseudocholinesterase inhibitors are cataractogenic in adults and cause iris pigment epithelial cysts in children, although the latter may be prevented with the concomitant use of topical phenylephrine. The use of miotics has rarely been associated with the development of retinal detachments and cicatricial pemphigoid. 
To minimize the undesirable effects of miotics and improve compliance, several therapeutic modifications may be attempted. Because many symptoms are dose related, it is important to begin with as low a dose as possible and gradually increase the dose until the desired therapeutic effect is obtained or the IOP is lowered no further. Miotics are melanin bound, so higher doses may be necessary in patients who have more darkly pigmented irides. Typically, the peak of the dose-response curve is pilocarpine 4% in dark irides and 2% in blue irides. However, it is important to use the lowest dose possible to minimize side effects. Additionally, the frequency of instillation is important in terms of patient compliance. Pilocarpine is often prescribed four times daily. Many patients do as well with twice-daily dosing in association with nasolacrimal occlusion or forced eyelid closure as they do with four-times-daily dosing without these maneuvers. Use of alternative miotic agents also may decrease the frequency of administration. Carbachol is used three times daily in all patients, but often twice-daily administration is adequate. Because penetration of the corneal epithelium by this agent is variable, it is helpful (as with all miotics, which are almost always used as adjunctive agents) to instill it after other agents to facilitate absorption.
The pseudocholinesterase inhibitors also are advantageous because of twice-daily dosing. Pilocarpine gel was introduced to provide convenient daily dosing at bedtime, with the expectation that the majority of the undesirable effects would wear off by morning but the therapeutic effect would be maintained throughout the day. A gel delivery vehicle is a much more convenient dosing form for patients who use the higher doses of miotics; however, it is important to check that a lower IOP is maintained throughout the entire 24-hour period. Some patients require supplemental drops in the late afternoon or evening. A useful suggestion for patients is to wash off any excess gel upon awakening so that the eye is not redosed. Sustained-release pilocarpine in the form of Ocuserts theoretically is the most desirable delivery system. The semipermeable membrane delivers a very low dose of drug continuously, with replacement needed approximately every 7 days. The therapeutic effect is maintained and tolerability is improved; however, the usefulness of this method is limited by the manual dexterity necessary for replacement. Many elderly patients cannot insert sustained-release devices, which are better suited for younger patients.
Patients whose eyes have undergone cataract surgery tend to better tolerate miotics, since the miosis is less severe, no induced myopia occurs, and the patients tend to be older and suffer less brow ache and headache with use.
Unoprostone isopropyl 0.15% has been available in Japan for many years and was recently introduced into the United States. Structurally, it is a decosanoid derived from docosahexanoic acid with a 22-carbon backbone that poorly binds the FP receptor compared with prostaglandin F2a analogs that have a 20-carbon structure. The receptor at which unoprostone acts has not been identified; however, increased outflow is the mechanism of action. In 571 patients treated twice daily over 6 months, there was a 14% decrease in IOP (3?mmHg). This agent appears to be safe and well tolerated, with rare changes in iris color and an approximately 10% risk of conjunctival hyperemia; however, its clinical utility is often limited by its modest efficacy in lowering IOP. When twice-daily unoprostone was compared with once-daily latanoprost in 108 patients, unoprostone was found to be less effective in reducing IOP, with a 3.3?mmHg (14%) reduction from baseline compared with 6.7?mmHg (28%) with latanoprost. The difference of 3.4?mmHg was statistically significant (P <.001). A 30% reduction in IOP was achieved in only 8% of eyes treated with unoprostone, compared with 44% of those treated with latanoprost. It has been suggested that unoprostone may further reduce IOP when added to latanoprost. However, this additive effect was shown only in those patients (n = 14) with an IOP of 22?mmHg or greater on latanoprost alone; these patients had an additional 2.1?mmHg reduction in mean diurnal IOP and a further flattening of the diurnal curve.
Prostaglandins (PGs) are a relatively recent class of drugs added to the armamentarium of glaucoma medications. Latanoprost and more recently travoprost have been approved for use in glaucoma or ocular hypertension in patients who are intolerant of or insufficiently responsive to other agents that lower IOP.
Prostaglandins are derived from arachidonic acid and display a wide range of biological functions. Initially, interest in their ocular effects arose from the observation that prostaglandins can mediate inflammation. At that time, high doses of prostaglandins were found to increase IOP. After further tests, the 17-phenyl-substituted PGF2a ester analog latanoprost was found to provide the best combination of efficacy and side-effect profile. Another PGF2a ester analog, travoprost, has also been introduced.
Animal studies suggested that prostaglandins reduce IOP by increasing uveoscleral outflow, since no effect was found on fluorophotometrically measured aqueous flow or on tonographical ouflow. Further studies suggested that uveoscleral outflow increases because of relaxation of the ciliary body muscle and dilated spaces between ciliary muscle bundles, in addition to the altered metabolism of the extracellular matrix that surrounds the ciliary muscle cells. The exact mechanism by which this occurs is unclear, but available data in humans support uveoscleral outflow as the primary mechanism. Clinical implications arise because of the concern that drugs that focus on decreased aqueous production to lower the IOP may result in undesirable effects on the anterior segment. Additionally, because uveoscleral outflow does not end in the episcleral venous circulation, it is possible to obtain an IOP that is less than episcleral venous pressure (9–11?mmHg [1.2–1.5?kPa]), which may be very desirable, particularly in normal-tension glaucomas (see Chapter 221 ).
In three large, multicenter trials that compared latanoprost 0.005% once daily with timolol 0.5% twice daily for 6 months, latanoprost reduced IOP by 25–34% and was statistically more effective than timolol in two of the three studies.   Also, it was shown that evening administration of latanoprost was significantly more effective than morning administration; the peak effect occurs approximately 12 hours after instillation. In addition, latanoprost reduced IOP in patients equally, day or night, and there was no suggestion of loss of effect during the 12 months of treatment. Travoprost 0.004% is a synthetic analog of prostaglandin F2a , as is latanoprost. In many respects, travoprost and latanoprost are similar. Mechanistically, both bind the FP receptor—in fact, travoprost appears to bind with higher affinity than latanoprost—and both lower IOP by increasing uveoscleral outflow. Both are administered once daily. Their efficacy appears to be similar as well. In phase III studies involving 605 patients, travoprost 0.004% once daily demonstrated about a 1.0–1.3?mmHg greater reduction in IOP
Figure 233-2 Mean intraocular pressure change.
compared with timolol 0.5% twice daily. This magnitude of efficacy is similar to that shown by latanoprost.
A 12-month study directly comparing travoprost 0.004% and latanoprost 0.005% showed essentially no difference in mean IOP reduction (6.6–8.1 versus 6.2–8.1?mmHg, respectively) and showed a statistical advantage favoring travoprost at only a single point of the diurnal curve ( Fig. 233-2 ).
Travoprost 0.004% was shown to lower IOP by up to 3.2?mmHg more than timolol in black patients and to produce a lower mean IOP than latanoprost in black patients (17.2 versus 18.6?mmHg). This may reflect an increased efficacy of travoprost in blacks. Analysis of the pooled travoprost data shows that travoprost is more effective in black patients than in nonblack patients, but additional studies will be necessary to determine whether travoprost is superior to other agents in black patients.
Latanoprost 0.005% once daily was shown to be additive to twice-daily timolol 0.5%. It reduced IOP an additional 13% in one study and an additional 30–35% in another.  Animal experiments suggested that prostaglandins and pilocarpine would not be additive. However, in one human study, it was shown that a 14–18% further reduction in IOP could be obtained by the addition of latanoprost to pilocarpine 2% three times daily. There are some data available concerning the additive effect of travoprost to timolol.  Adding travoprost 0.004% once daily to timolol 0.5% twice daily resulted in an additional 5.7–7.2?mmHg reduction in IOP compared with placebo, which provided an additional 1.3–2.8?mmHg reduction in IOP.
Figure 233-3 Iris color changes after latanoprost treatment. A, Before treatment in a patient with a green-brown iris. B, After 6 months of latanoprost treatment, the iris has increased pigmentation.
Reported side effects in controlled trials of latanoprost 0.005% once daily included conjunctival hyperemia (generally mild, 36%), burning and stinging (25%), blurred vision (17%), itching (15%), foreign body sensation (33%), tearing (6%), and eye pain (13%).
Latanoprost resulted in increased iris pigmentation in 11–23% of patients   ( Fig. 233-3 ). In most cases, the eyes in which the iris color changed had a characteristic concentric heterochromia before treatment, with greater pigmentation around the pupil than in the periphery. In patients who have pure blue, gray, green, or brown eyes, the risk of increased iris pigmentation is estimated to be 4%. In patients who have mixed blue and gray-brown eyes, the estimated risk is 20% at 2 years, and for patients who have green-brown or yellow-brown irides, the estimated risk is 50% at 1 year. This increased pigmentation occurs slowly but may be noticeable at 3 months, with a 6.8–11.6% increase in pigmentation seen at 6 months and a 15.5–22.9% increase at 12 months; sometimes 18 months or longer is required for the increased pigmentation to become manifest. Iris nevi do not appear to be affected. This change in pigmentation does not increase or decrease after cessation of latanoprost. Animal data suggest that the increased pigmentation may arise from increased production of melanin within the iris melanocytes rather than from cellular proliferation. The long-term consequences are not known.
The side effects with travoprost and latanoprost are similar to those with travoprost alone, but with a greater occurrence of hyperemia (49.5 versus 27.6%) and a slightly lower chance of increased iris pigmentation (2.8 versus 5.2%).
Latanoprost 0.005% has a plasma half-life of only 17 minutes. Therefore, with the very low concentration delivered, minimal systemic side effects are anticipated. No effect was found on resting heart rate, blood pressure, or blood
Figure 233-4 Graph shows the 10 a.m. pooled 6-month results from the phase III bimatoprost trials.
and urine laboratory values. The most frequently reported potential systemic effects include upper respiratory tract syndrome (24%), headache (9%), and back, muscle, or joint pain (6%).   The use of latanoprost in young patients has not been evaluated.
There is substantial evidence supporting the assertion that bimatoprost is a prostamide, an apparently different class of drugs from the prostaglandin analogs latanoprost and travoprost.   Like prostaglandins, prostamides are derived from membrane lipids, but unlike prostaglandins, the biosynthetic precursor of prostamides is anandamide, not arachidonic acid. Prostamides, including bimatoprost, do not bind to the prostaglandin FP receptor, and further reinforcing their uniqueness, they do not bind to any other known receptors.
Bimatoprost is the active drug, not a pro-drug requiring activation by corneal enzymes, as is the case with latanoprost and travoprost. Mechanistically, Brubaker et al. have shown that bimatoprost works by increasing outflow, producing both a 35% increase in trabecular outflow facility and a calculated 50% increase in uveoscleral outflow. This apparent dual mechanism of action is in contrast to the prostaglandin analogs, which appear to work primarily through an increase in uveoscleral outflow.
In comparisons of bimatoprost once daily and timolol 0.5% twice daily, bimatoprost demonstrated statistical superiority in all measures of effectiveness in lowering IOP. Beginning at similar baselines, at month 6, bimatoprost 0.03% once daily lowered IOP at 10:00 a.m. (timolol peak) an average of 8.1?mmHg (33%), compared with 5.6?mmHg (23%) with timolol 0.5% twice daily. The difference between the two agents was consistently maintained at 2–3?mmHg throughout the day and throughout the study  ( Fig. 233-4 ).
Of more relevance in treating individual patients was a comparison of the two drugs’ success in allowing patients to reach a specific target pressure or obtain a desired percentage drop in IOP. At all IOPs from 13–18?mmHg at peak measurements for both drugs, bimatoprost patients were 50–120% more likely than timolol patients to reach the target. This is clinically important, because this range represents the target pressures for the majority of glaucoma patients ( Fig. 233-5 ).
Similarly, when effectiveness in lowering IOP was evaluated using percentage drop in IOP, bimatoprost was significantly more effective than timolol. Generally, a 20% reduction in IOP is the minimum acceptable efficacy for a single agent. A 20% drop in IOP was achieved in 87% of patients treated with bimatoprost, compared with only 60% of those treated with
Figure 233-5 Patients achieving target intraocular pressure levels in the phase III bimatoprost trials. Results shown are from the month 6 visit at 10 a.m.
timolol. Greater reductions in IOP are often desirable, and again, bimatoprost was significantly better than timolol at achieving substantial IOP reductions, with nearly two thirds of patients demonstrating a 30% reduction and nearly one third of patients obtaining a 40% reduction. When 12-hour diurnal IOP measurements were performed, bimatoprost was superior at all time points ( Fig. 233-6 ).
In a 3-month comparison of latanoprost and bimatoprost, with both medications given once daily, bimatoprost (n = 119) was about 0.5?mmHg more effective than latanoprost (n = 113) in lowering IOP at 8:00 a.m., although the differences between the groups were not statistically significant. Both medications
Figure 233-6 Twelve-hour diurnal intraocular pressure measurements.
were well tolerated, with no more than 5% of patients from either group discontinuing treatment because of adverse effects.
Hyperemia was found to be more common with bimatoprost than with latanoprost. The hyperemia appears to be conjunctival injection that is unrelated to either an allergic follicular conjunctival response or actual tissue inflammation. Overall, hyperemia occurred in about 45% of patients using bimatoprost; the severity of the hyperemia was trace to mild, with less than 4% of patients discontinuing bimatoprost due to tolerability issues. Clinically, in some patients the hyperemia is slightly greater and may be associated with mild burning. This appears to be most severe when beginning the medication and usually rapidly improves.
Bimatoprost demonstrated no effect on blood pressure, pulse, hematology, urinalysis, or any other parameter of systemic safety. Ocular evaluation showed no increase in aqueous flare. Ocular effects identified included eyelash growth, rare increase in iris color, and conjunctival hyperemia. At 12 months, increased iris pigmentation with bimatoprost, evaluated by the treating physicians using photographs of patients’ eyes, was only 1.5%. The experience with the prostaglandin analogs has reassured us that this change in iris color is primarily a cosmetic concern and is often not recognized by the patient. Although the change is irreversible, it is common to treat patients until iris pigmentation changes occur and then make a decision whether to continue the drug, based on the efficacy and the patient’s input.
THE MEDICAL ARMAMENTARIUM OF GLAUCOMA TREATMENT
As more experience with any drug is gained, its place in the decision-making process becomes more clear. Historically, the ß-blockers were the most common first-line agents used in the
TABLE 233-1 — DRUGS USED TO MANAGE GLAUCOMA
Mechanism of Action
Decreased aqueous production (?Daytime only)
Exacerbation of CCF
External eye—toxic reaction
Decreased aqueous production
External eye—toxic reaction
Uveoscleral outflow increase with brimonidine
Increased tonographic outflow
Carbonic anhydrase inhibitors
Decreased aqueous production
Risk of rare aplastic anemia—never reported
Lipids (prostaglandin analogs, prostamides decosanoids)
Iris color change
Periocular skin pigmentation
medical treatment of glaucoma. However, as our experience with newer agents, particularly those facilitating outflow, increased, they were recognized as being more efficacious in lowering IOP and systemically safer than ß-blockers. As a result, they are becoming the first-line agents in glaucoma treatment. When these agents are not appropriate, we still have other excellent choices, including the ß-blockers, a-agonists, and topical carbonic anhydrase inhibitors. In general, these agents are well tolerated by most patients, with a low rate of discontinuation attributable to the drugs. We must maintain vigilance to identify patients who should not receive these drugs because of the potential for ocular, pulmonary, cardiovascular, or central nervous system side effects. The current spectrum of glaucoma drugs is summarized in Table 233-1 .
Because about 50% of glaucoma patients take more than one class of agents, an understanding of the characteristics of these agents is necessary to make the best choices for our patients. With the recent introduction of many new agents, the availability of pertinent studies on which to base additive therapy is sometimes limited. Therefore, when using medications to treat glaucoma, it is imperative that the individual needs of the particular patient be considered. It is important to include the patient in the decision-making process, through education about the disease as well as discussion of the specific positives and negatives of the treatment options. The best regimen for an individual patient can be selected and tried using the one-eye therapeutic trial and correct instillation techniques. In this way, maximal compliance, which is often difficult to achieve and a limiting factor in effective medical therapy for glaucoma, may be obtained.
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