Ординатура / Офтальмология / Учебные материалы / Atlas of Glaucoma Second Edition Choplin Lundy 2007

TARGET INTRAOCULAR PRESSURE

AGIS, CIGTS, OHTS, and EMGTS have provided guidelines for establishing target IOP in glaucoma patients (Table 15.1). Each of these clinical trials evaluated patients with different stages of glaucoma. Patients in the AGIS study, who had a mean IOP of 12.3 mmHg and IOP of less than 18 mmHg at all visits, on average, had no progression in visual fields over 8 years of treatment. Higher IOP during the study was correlated with greater visual field progression. Patients with newly diagnosed early OAG in the treated arm of the EMGTS had IOP reduced by 25% from baseline, from 20.6 to 15.5 mmHg, and the rate of progression reduced from 62 to 45%. In the OHTS the rate of progression to glaucoma was 4.4% in the treated patients compared to 9.5% in the untreated group. The IOP of the treated group was reduced by 22.5% to a mean of 19.3 mmHg. The newly diagnosed glaucoma patients in the CIGTS trial had similar rates of progression, whether in the surgical treatment arm with IOP ranging from 14 to 15 mmHg, or in the medical treatment arm with IOP ranging from 17 to 18 mmHg.

Different rates of progression in these studies are explained by the various ways visual field progression was determined, patients at different stages of glaucoma and with different types of glaucoma, and possibly the variety of treatments used to lower the IOP. What we have gleaned from these studies is that the lower the IOP the slower the rate of progression of the disease. Currently, the accepted thinking is that the more advanced the disease, the lower the target IOP. As these studies represent a relatively short time period in the course of disease in a glaucoma patient, it may be that achieving lower IOP earlier in the disease will prove to be more beneficial. Fortunately for our patients, lower target IOP is more easily achievable due to the more effective and better tolerated ocular hypotensive medications that became available in the mid-1990s.

When initiating therapy for a newly diagnosed glaucoma patient, consideration must be given to starting with medical therapy or going straight to surgery. The CIGTS has suggested that at 5 years from initial treatment there is no real difference in progression rates between patients initially treated medically versus those treated surgically. Certainly, surgery carries more risk compared to medical therapy, but perhaps lower cost over the course of a patient’s lifetime. At present, the standard of care in the United States remains initial medical therapy in most cases of newly diagnosed open-angle glaucoma, with an individualized target in mind, periodically reassessing the patient for control and progression. The medical regimen is adjusted accordingly, with surgery remaining an option should it be necessary.

PRINCIPLES OF MEDICAL THERAPY FOR GLAUCOMA

Six different classes of topical ocular hypotensive medications (Table 15.2) are available for the treatment of glaucoma: prostaglandin analogs, selective and non-selective -adrenergic antagonists, selective 2-adrenergic agonists, carbonic anhydrase inhibitors, direct and indirect-acting cholinergic agonists, and non-selective and adrenergic agonists (Figure 15.1). The mechanism by which each class reduces IOP, either by decreasing aqueous inflow or increasing outflow is described in Table 15.2. Each class includes several different compounds and formulations, increasing the number of potential therapeutic options.

Various factors must be considered when determining initial treatment for an individual patient. These factors include medical history, history of prior adverse reactions to ocular medications, cost of therapy, frequency of dosing, and anticipated compliance with therapy. Ultimately, the physician must weigh which medication has the highest benefit/risk ratio and take into consideration which medication will result in the highest compliance.

COMPLIANCE

Since glaucoma is usually an asymptomatic disease, patients may have difficulty accepting the diagnosis and the need for life-long medication, particularly when vision is unaffected and they are asymptomatic. The lack of symptoms and preservation of central vision until late in the course of the disease hinders compliance since the patient does not realize the potential gravity of the situation. In addition, the medications may burn or sting and may be expensive, which poses additional barriers to compliance. It is important to take the time to explain the disease process, demonstrate the potential for (or the presence of) visual field loss, and emphasize the benefit of the prescribed treatment plan on reduction of visual field loss.

Even ‘convinced and committed’ patients have limits on what they can successfully manage, especially when multiple medications are prescribed. Compliance studies demonstrate reduced compliance with a higher number of medications and increased dosing of medications. Several other factors have been identified which lead to reduced compliance, and these are listed in Table 15.3.

The medications currently available are extremely effective and, in many patients, when dosed as recommended, do stabilize glaucoma. It is anticipated that medications that will be developed in the future will be even more effective and may be able to be administered less frequently, thereby

potentially improving patient compliance. Currently, devices that may assist with instillation of the drops and act as dosing reminders are under evaluation. These devices include Xalease which is a delivery aid specifically for use with Xalatan, the Lumigan Compliance Aid for Lumigan which is a reminder device having a flashing light and optional alarm, and the Travatan dosing aid specifically for use with Travatan. The Travatan dosing aid has an audible alarm, a flashing light, and a one-drop dispenser mechanism, and it records when the drop is dispensed (Figure 15.2). These devices may be beneficial for some patients, but additional methods to enhance

compliance that are tailored to the individual patient may need to be developed. Additionally it is important to educate our patients as to what is meant by q.d., or b.i.d, or t.i.d. dosing. Preferable terminology is every 24 hours and every 12 hours for q.d. and b.i.d. dosing respectively. In order to devise a reasonable three-times-a-day dosing regimen, a discussion with the patient as to the typical times they awaken and retire is helpful. The waking hours can be evenly divided so that the medication administration will be every 5–6 hours. If a patient is taking two or more topical medications, they need to be instructed to wait at least 5 minutes between dosing.

(b)

(c)

Figure 15.2 Dosing and compliance aids. Several dosing aids and compliance aids (a–c) are under evaluation for enhancing compliance with topical therapy. Each aid can be used only with the compounds manufactured by one company, due to the differences in the design of the bottles.

prescribed (Table 15.2). Responses in an individual patient may be similar to what has been defined in the large populations enrolled in these studies or may range from no response to occasionally a greater reduction in IOP. Each class of medication has been

Topically applied medications leave the eye via the nasolacrimal drainage system and are systemically absorbed when they come into contact with the mucosa in the oral and nasal pharynx. Reducing the amount of drug exiting the eye through the nasolacrimal canal will increase ocular contact time and reduce the probability of systemic side-effects.

Two fairly simple techniques may be used to decrease passage of topically applied medication into the nasolacrimal duct. The first technique is simply to close the eyelids for one to two minutes after instillation of the eye drop. This inhibits action of the ‘lacrimal pump’ associated with blinking that is responsible for the movement of tears across the cornea from the temporal side (where the lacrimal gland is located) to the nasal side (where the drain is located).

The second technique is punctal occlusion, in which pressure is applied to the area of the puncta and nasolacrimal sac, for one to two minutes following drop instillation, as illustrated in Figure 15.3. Both techniques, especially in combination, prolong ocular contact time with the drug, enhancing absorption while minimizing systemic absorption via the nasolacrimal duct. Decreased serum levels of topically applied medications have been demonstrated following the use of these techniques.

AVAILABLE AGENTS

Introduction of the prostaglandin analogs in 1996, the topically active carbonic anhydrase inhibitors

Figure 15.3 Nasolacrimal occlusion and eyelid closure.

Nasolacrimal occlusion and eyelid closure should be performed for 1 to 2 minutes following instillation of topical medications to increase the amount of drug available for ocular absorption and decrease the amount of drug absorbed systemically through the nasolacrimal apparatus.

in 1994, and the chronic use of selective 2-adren- ergic agonists in 1993 has markedly changed the medical management of glaucoma. In addition to these three classes of compounds, -adrenergic antagonists have been in use since 1978, parasympathomimetics since 1877, and non-selective adrenergic agonists since the 1950s. The relative efficacy, side-effects, cost, additivity, and probable compliance with each of these agents allows the physician to determine which of these medications should be prescribed for first, second, third and, if necessary, fourth line use. There are several different agents available in each class of compounds. Agents in the same class of compounds act at the same receptor and usually have similar effects on IOP. Thus, using two agents from the same class or substituting agents from the same class will typically not cause greater reductions in IOP. Sideeffects of the agents in the same class may vary, due to different formulations, different preservatives and different receptor binding. Thus, medications in the same class may be substituted in an attempt to improve tolerability. A medical regimen should be designed to attain a target IOP, with the fewest associated side-effects, which the patient can administer on a regular basis.

Prostaglandin analogs

In recent years, a major shift has occurred in glaucoma management. Prostaglandin analogs have become the most common class of agents prescribed as first-line therapy in the treatment of glaucoma. This class of compounds is the most efficacious and is associated with the fewest systemic side-effects. Enhanced compliance is anticipated with the once-a-day dosing regimen.

Currently, there are three prostaglandin F2 derivatives commercially available in the USA:

Figure 15.4 Prostaglandin F2 derivatives. Currently, there are three prostaglandin F2 derivatives commercially available in the USA: latanoprost (Xalatan 0.005%), bimatoprost (Lumigan 0.03%), and travoprost (Travatan 0.004%).

latanoprost (Xalatan 0.005%), bimatoprost (Lumigan 0.03%), and travoprost (Travatan 0.004%) (Figure 15.4). Lantanoprost, bimatoprost, and travoprost have been shown to be more effective than once or twice daily administration of timolol. Solo administration of these prostaglandins reduces intraocular pressure between 25% and 35%. The recommended dosing regimen is once-daily in the evening. Studies have concluded that dosing more frequently than once daily and that dosing in the morning rather than in the evening is less efficacious. There is no clear explanation for these findings regarding the optimal dosing regimen. These three FP receptor agonists reduce IOP primarily by increasing aqueous outflow through the uveoscleral pathways. They also secondarily increase traditional, pressure-dependent outflow, but do not reduce aqueous humor flow rates. The increase in outflow is due to the effect of the prostaglandins on the extracellular matrix in the uveoscleral pathway. Chronic administration of prostaglandins stimulates secretion of matrix metalloproteinases which initiate degradation of the extracellular matrix between bundles of the ciliary muscle, allowing for increased aqueous egress from the eye. The parent compounds of these three prostaglandins are prodrugs. They are cleaved by corneal esterases and enter the anterior chamber as free acids (Figure 15.5). The free acids have potent agonist activity at the FP receptor, while bimatoprost itself is also an FP receptor agonist.

These three prostaglandin analogs have been shown to be similarly efficacious in a number of studies. A few studies have suggested IOP reductions of 0.5–1.0 mmHg greater with bimatoprost compared to latanoprost. These IOP differences have occasionally been statistically significant and the clinical significance of these small differences remains to be determined. Data gathered from the

Figure 15.5 Prodrug metabolism. Prodrugs are designed to have enhanced penetration by varying the lipid and aqueous solubility characteristics, allowing for lower concentrations of active drug to be topically applied. The lower concentration of administered drug reduces ocular and systemic side-effects. Dipivalyl-epinephrine is a prodrug of epinephrine. In this case pivalyl acid is substituted for hydroxyl groups on the epinephrine molecule creating a more lipid-soluble compound that has 17 times greater penetration through the cornea. Esterases cleave the substituted pivalyl during transit through the cornea, producing pivalic acid and epinephrine. The three commercially available prostaglandins are also lipophilic prodrugs. Lantanoprost and travoprost are isopropyl esters, while bimatoprost is an ethyl amide. All three compounds are hydrolyzed within the eye to their corresponding free acids. The free acids are potent stimulators of the FPreceptor, which is responsible for the hypotensive effect of this class of drugs.

phase III clinical trials suggest that travoprost may be more effective in lowering intraocular pressure in black patients than in non-black patients. A rigorously designed study to address this question directly needs to be performed.

Ocular side-effects that may be annoying to patients include hyperemia and foreign-body sensation. The degree of conjunctival hyperemia associated with these three agents is generally mild and rarely a cause for discontinuation of therapy. Bimatoprost has been reported to cause the greatest degree of conjunctival hyperemia, and latanoprost the least degree of hyperemia. Individual patients may have enhanced responses or improved tolerability to one of these three compounds. Thus, in individual patients experiencing side-effects or in patients having less than expected IOP reductions, substitution of a different prostaglandin may occasionally lead to enhanced IOP control and/or to a reduction in side-effects such as hyperemia and foreign-body sensation.

Numerous ocular side-effects that are primarily of cosmetic significance have been reported. These include darkening of the iris, hypertrichosis, hyperpigmentation and occasional poliosis of eyelashes, increased pigmentation of the periocular tissues, and increased hair growth on the periocular tissues (Figure 15.6). The iris hyperpigmentation is most commonly observed in eyes that are not uniform in color, such as green-brown, yellowbrown and blue/gray-brown. The percentage of patients exhibiting iris hyperpigmentation varies depending upon the methodology used to measure pigment, the retrospective or prospective nature of the study, and possibly the ethnicity of the patients studied. Typically iris hyperpigmentation has been reported in 10–30% of patients, although one study in Japanese patients with homogeneous brown eyes reported an increase in iris pigmentation in 52% of patients at 12 months. Another study reported that up to 90% of patients with iris colors susceptible to color change had increased pigmentation after 2 years of close follow-up. Increased iris pigmentation is usually observed after a minimum of 3 months of treatment, and there is little information available about the reversibility of iris pigmentation following discontinuation of these agents. Periocular hyperpigmentation has been reported in Caucasian patients and in African-American patients, and reverses within weeks to months of discontinuing the prostaglandin analog. Hyperpigmentation of the iris and periocular tissues is due to an increase in the quantity of pigment within the melanocytes, and is not due to a proliferation of these pigmented cells.

Other ocular side-effects which have been associated with the use of topical prostaglandins include cystoid macular edema (CME), uveitis, and herpetic keratitis. CME has been observed in both pseudophakic and phakic patients with predisposing factors, such as a compromised blood–aqueous barrier or prior episodes of CME. Anterior uveitis has been observed in patients with prior episodes of inflammation or intraocular surgery, but very rarely in patients without these predisposing factors. Recurrences of herpes simplex keratitis have been observed during treatment with prostaglandins, and in some cases have not resolved until the prostaglandins have been discontinued. Prostaglandins should be used cautiously in patients potentially predisposed to or having a history of these adverse ocular effects. In contrast to ocular side-effects, the incidence of systemic side-effects is rare and includes upper respiratory tract infections, flu-like syndrome and headaches.

Distribution of a fourth prostaglandin analog, unoprostone isopropyl (Rescula), was discontinued in the United States in 2004. This drug was developed and initially marketed in Japan. It is a less potent prostaglandin analog and has less of an

Figure 15.7 Allergic reaction to Timoptic XE. This patient used Timoptic solution without ocular side-effects for years, but developed an allergy to Timoptic XE following the initial instillation. Presumably the allergic response to Timoptic XE was due to the different preservative and vehicle. Recommended dosing of Timoptic XE is once daily, and is comparable in efficacy to onceor twicedaily dosing of solutions of non-selective -adrenergic antagonists. Once-daily dosing of Timoptic XE may be associated with fewer systemic side-effects than onceor twice-daily dosing with solutions of non-selective-adrenergic antagonists due to prolonged ocular contact and less passage of the drug through the nasolacrimal system.

Carteolol (Ocupress; no longer available as a branded product), 1.0% solution is comparable in efficacy to 0.5% timolol maleate. Carteolol possesses a quality known as intrinsic sympathomimetic activity (ISA). Carteolol, while acting as a-adrenergic competitive antagonist, also causes mild stimulation of the receptors. Thus, it may have less of an effect on the cardiovascular and respiratory systems. Although studies have shown that carteolol causes a smaller reduction of serum highdensity lipoprotein-cholesterol (HDL-C) compared to timolol, topical -adrenoreceptor antagonist

therapy has not been associated with an increased risk of myocardial infarction, despite the association of reduced serum HDL-C with an increased risk of myocardial infarction.

Metipranolol (Optipranolol) 0.3% solution is also comparable in efficacy to timolol 0.5% solution. Initial formulations outside the USA caused granulomatous uveitis. The drug was reformulated and this side-effect has not subsequently been reported.

Betaxolol (Figure 15.8) is the only commercially available topical 1 selective intraocular pressure-lowering medication. It is available as a 0.25% suspension (Betoptic-S) and a 0.5% solution. The suspension is more comfortable than the solution for most patients, but the two are equally efficacious. Both formulations lower intraocular pressure between 20% and 25% from baseline. This agent can be considered in patients with mild to moderate pulmonary disease without other contraindications to this class of compounds. All-adrenoreceptor antagonists must be used with caution in any patient with a history of reactive airway disease. It is advisable to consult with a patient’s internist or pulmonologist prior to prescribing these agents in patients with pulmonary disease. Betaxolol has intrinsic calcium channel blocking activity, which may increase ocular blood flow. Additional investigations of this property and the potential clinical benefit need to be conducted.

Ocular side-effects with topical beta blocker therapy rarely are a cause for discontinuation and include transient blurring of vision, punctate keratopathy, and ocular dryness. Topical beta blockers are extremely well tolerated, although numerous systemic side-effects have been reported to be