Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

Figure 27.7 Overview of factors (small ovals) to consider for assessing the efficacy of a glaucoma drug on “IOP response” (large center oval). (Modified fr om McLaren NC, Moroi SE. Clinical implications of pharmacogenetics for glaucoma therapeutics. Pharmacogenomics J. 2003;3:197-201.)

When to Quit and Move on to Surgery

Possibly the biggest mistake in treating patients with glaucoma is continuing to try various combinations of drugs when the target IOP is not being reached instead of moving on to laser or incisional surgical intervention. The indications for quitting medical therapy include an inability to maintain target IOP, progressive glaucomatous damage on maximum medical therapy, and the patient's inability to tolerate or adhere to the medical regimen.

PHARMACOGENETICS

The variations in the drug-mediated IOP response are due to a combination of factors, including adherence, biologic mechanisms related to aqueous humor dynamics (see Chapter 1), ocular and systemic conditions, and possibly environmental factors and genetics (Fig. 27.7). At present, certain environmental factors have been shown to contribute to variation in

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IOP response to medications. Specifically, the concurrent use of some systemic medications, such as systemic ß-blockers and calcium-channel blockers, m ay decrease the efficacy of topically applied ß- blockers (21, 62). The study of the impact of genetics on drug response is known as pharmacogenetics (63).

Pharmacogenetics attempts to determine whether differences in drug response, which may be related to either efficacy or toxicity, are attributable to the diversity in genes that are transmissible from one generation to the next. Most drugresponse variations are of the Gaussian type, which tend to be viewed as environmentally determined but usually have some definable hereditary elements (64, 65). The tails

of the Gaussian distribution curves are of clinical interest: Those at the lower limits are typically identified as “nonresponders” and those with values at the upper limits are classified as “super responders.” In the OHTS, patients who were randoml y assigned to medical treatment showed a Gaussian-type distribution of IOP response following treatment with topical ß-blockers (21) . Recently, a medical record, population-based study found that among the four candidate genes of the ß 1-, ß 2-, and

ß 3adrenergic receptor genes and the CYP2D6 gene, one gene variation in the ß 2-adrenergic receptor

gene was associated with a 20% or greater IOP decrease with use of topical timolol (66). This has not yet been repeated, but because this gene is not a primary open-angle glaucoma locus (67), this genetic marker needs to be validated as a potential research tool for predicting drug response to topical ß- blockers.

Informed expectations of glaucoma drug efficacy may be determined from clinical pharmacology trials. There is no clear definition of a “clinical respond er” in the context of glaucoma medical treatment, b ut the selection of 15% reduction from baseline IOP at peak drug effect appears to have been first used in evaluating the efficacy of latanoprost (68). In another study, “nonresponders” to drug treatment were defined as patients whose IOP did not decrease by 10% (69). Prior to 1996, most glaucoma pharmacology trials defined efficacy on the basis of the mean IOP, and the variation in the IOP response had to be inferred from the standard errors of the mean and standard deviations. Since that time, the IOP response to a drug has been reported in numerous formats, which include the following: mean pretreatment IOP, mean posttreatment IOP, change in IOP, target change in IOP, percentage change in IOP, effect on diurnal IOP, “clinical success,” and percentage of patients achieving a specified target IOP. Much of this shift in data reporting may be attributed to the defined treatment goals in the glaucoma clinical trials (discussed at the beginning of this chapter).

The challenge of genomics is to determine whether we can predict disease risk, disease progression, and treatment outcome despite the intricate biologic and physiologic interactions among expression of drug target genes, drugmetabolizing enzymes, and disease genes. Identification of genetic markers of “poo r IOP responders” has the potential to target those p atients with disease to more appropriate treatment, such as surgery, to lower IOP more effectively, thus minimizing progressive optic nerve damage and visual field loss. We imagine that a “genetic panel ” will be developed with robust markers for common diseases, such as diabetes mellitus, hypertension, some cancers, macular degeneration, glaucoma, and commonly prescribed medications. Such genetic markers will need to be tested in stratified patient populations for predictive value and then validated in separate cohorts. A cost-benefit analysis with economic modeling will also need to demonstrate the health benefits and long-term cost savings to improve treatment outcomes and thereby decrease disease morbidity. The coverage of genetic testing will be determined through the process of technology assessment by national insurance and private payors. The future application of such a genetic profile could lead to fewer return office visits for follow-up for changed medical therapy, thus improving treatment outcomes.

KEY POINTS

At the present time, we have solid evidence to inform patients with newly diagnosed glaucoma about the condition, its treatment, expected outcomes, and impact of this chronic disease and various treatments on their quality of life.

Patient-centered communication is essential to modify health behaviors to assess the impact of treatment on the physical and social functioning and other quality-of-life parameters (51, 70), including the cost of treating the disease.

Relative elevation of IOP is the major causative risk factor for the development and progression of glaucoma. A target IOP should be established with minimal fluctuation over a 24-hour period under glaucoma treatment. This initial target IOP may need to be reassessed if there is glaucoma progression.

Preventing progressive glaucomatous damage with the fewest medications in the lowest concentration needed to achieve the target IOP and considering the patient's quality of life should

be the goals of therapy.

Initiation or change of therapy with a uniocular trial can be helpful to assess side effects and efficacy.

Patient-centered communication on the disease, treatment, simplified medical regimen, possible drug side effects, and proper eyedrop administration are essential for proper adherence to treatment.

When medical treatment is ineffective, initially substitute (rather than add) medications. Stopping treatment periodically may help to assess its continuing efficacy.

When the glaucoma is not controlled medically, the physician should not hesitate to move on to surgical intervention.

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Shields > SECTION III - Management of Glaucoma >

28 - Prostaglandins and Hypotensive Lipids

Authors: Allingham, R. Rand

Title: Shields Textbook of Glaucoma, 6th Edition Copyright ©2011 Lippincott Williams & Wilkins

> Table of Contents > SECTION III - Management of Glaucoma > 28 - Prostaglandins and Hypotensive Lipids

28

Prostaglandins and Hypotensive Lipids

The prostaglandins, thromboxanes, and leukotrienes are eicosanoids, which are metabolic products of 20-carbon arachidonic acid (Fig. 28.1). After the prostaglandins are synthesized, they are released and transported out of cells by transporters (1). The prostaglandins that reach the systemic circulation are inactivated in the lung and liver (2). The earliest physiologic effect observed for prostaglandins was contraction of the human uterus after exposure to seminal fluid (3). The initial ocular observation of miosis in the cat was noted after exposure to iris extracts (4). In rabbits, the topical application of 25 to 200 µg of prostaglandins caused an initial rise in intraocular pressure (IOP), followed by pressure reduction for 15 to 20 hours, whereas a 5-µg dose p roduced ocular hypotension without an initial pressure rise (5). Early studies on relatively large doses of topical prostaglandins revealed inflammation with conjunctival hyperemia and breakdown of the bloodaqueous barrier (6). Subsequent studies indicated that smaller amounts of prostaglandins lowered IOP, which led to the development of this drug class for the medical management of glaucoma.

Several important chemical modifications were made to improve the bioavailability and to make it a more selective FPreceptor agonist (Fig. 28.2) (7). The addition of a phenyl ring to the omega chain (i.e., latanoprost, travoprost, and bimatoprost) improved the selectivity for the FP receptor. To improve solubility, the C-1 carboxyl group was modified with an ethyl amide in the case of bimatoprost or an isopropyl ester for latanoprost, travoprost, and unoprostone. This modification at the C-1 carboxyl group creates a lipophilic prodrug, which is hydrolyzed by the cornea into the free acid drug form (8).

Figure 28.1 Overview of the products derived from arachidonic acid metabolism. MECHANISMS OF ACTION

The prostaglandins have a mixed pharmacologic response because of the diversity of the receptors. The prostaglandin or prostanoid receptors include four subtypes (EP, FP, IP, and TP) of receptors for the endogenous prostaglandins, PGD2, PGE2, PGF2a, and PGI2 or TXA2, respectively (9). The prostanoid

receptors are in the family of the G protein-coupled receptors (10). The prostanoid FP receptor exists in two forms: type A for the full-length receptor and type B for the splice variant, which is truncated or shortened compared with the full-length form (11). Both FP receptor forms couple to phospholipase C, P.403

which triggers the release of the second messenger inositol phosphate production and subsequently activates a molecular transduction cascade that leads to IOP reduction.

group.

The prostanoid receptors are distributed widely in ocular tissues, which accounts for the diverse biologic effects of prostaglandins on the eye (12). The expression and distribution of the prostanoid receptors in the human eye have been determined with radioligand receptor binding studies and a variety of molecular methods (13, 14 and 15). In most animal and human studies, the ocular hypotensive effect of prostaglandins, or hypotensive lipids, was not explained by reducing aqueous production, reducing episcleral venous pressure, or increasing conventional aqueous outflow (16, 17, 18 and 19). After binding and activating the FP receptors in the ciliary smooth muscle, the precise mechanism by which prostaglandins improve uveoscleral outflow (see Chapter 2) is not fully understood. Two possible mechanisms that have been studied are relaxation of the ciliary muscle and remodeling the extracellular matrix of the ciliary muscle.

In monkey studies, pilocarpine, which causes contraction of the ciliary muscle (see Chapter 32) and is known to reduce uveoscleral outflow, antagonized the PGF2a-induced ocular hypotension (20). The in

vitro studies of ciliary muscle response to PGF2a have been conflicting. Prostaglandin F2a consistently

relaxed carbachol-precontracted fresh ciliary muscle strips from monkey eyes (21). Similarly, trabecular and ciliary muscle contraction induced by endothelin was blocked by unoprostone, a docosanoid, which is a metabolite of docosahexaenoic acid (22). Studies in monkeys suggest a dual action of PGF2a on the

ciliary muscle, involving a shortonset, long-lasting relaxation and narrowing of the muscle fiber bundles and a slowly developing, shorter-duration dissolution of the intermuscular connective tissue (23). It is apparent from these and other studies that the effects depend on the species studied and the effect of aging (24). The clinical use of pilocarpine and latanoprost is discussed in the section “Drug Interact ion.” There is greater evidence to support the mechanism of remodeling the extracellular matrix of the ciliary muscle. In cultured smooth muscle cells, PGF2a activates the FP receptors and initiates a signal

transduction cascade that leads to the induction of the nuclear transcription factor and c-FOS (25). The c-FOS transcription factor binds to a special AP-1 transcription regulatory element in the promoter of certain genes, which leads to transcription of those particular genes (26). One gene class that is regulated by the AP-1 transcription regulatory element is the matrix metalloproteinase family (27). Specific molecules of the matrix metalloproteinase family degrade extracellular matrix substrates, such as certain collagens, fibronectin, or laminin. In ciliary muscle cultures, certain prostaglandin-like agents increase matrix metalloproteinases (28, 29). Collagen types I, III, and IV, laminin, fibronectin, and hyalurons were reduced in cultured human ciliary muscle treated by the free acid of latanoprost and PGF2a (30).

This prostaglandin-mediated increase in certain matrix metalloproteinases and change in extracellular matrix molecules seen in vitro in the cultured cells were observed in vivo.

In monkeys, immunohistochemical methods have identified increased expression of certain matrix metalloproteinases in ciliary muscle, iris root, and sclera (31). Both collagen type IV and myocilin (MYOC), formerly known as trabecular meshwork-inducible glucocorticoid response gene (TIGR) (see Chapter 8), appear to be colocalized in ciliary muscle, and topical PGF2a-isopropyl ester treatment

decreases MYOC expression in monkey eyes (32). Prostaglandin-mediated changes in extracellular matrix metalloproteinases have been identified in ciliary muscle (33), which correlates with the reduction in collagen molecules within the uveoscleral outflow pathways (34). The collective evidence of data supports that the prostaglandins enhance uveoscleral outflow by remodeling the extracellular matrix in the uveoscleral outflow pathway, with possible contributions from some relaxation of the ciliary muscle and change in cell shape by cytoskeletal alteration.

Other possible effects of this class of drugs have also been studied. The evidence on the potential effect of the prostaglandin agents on ocular blood flow in the various vascular beds of the anterior segment, retinal, choroidal, and retrobulbar hemodynamics is not well understood (35). The interaction between prostaglandin agents and adrenergic pathways has been suggested based on the observation that adrenergic antagonists blocked the PGE2-induced increase in total outflow facility (36). It appears that

the PGE class of prostaglandins has an additive effect in combination with latanoprost in lowering IOP

in glaucomatous monkey eyes by enhancing trabecular outflow (37, 38). SPECIFIC AGENTS

Latanoprost

Approved for use in 1996, latanoprost was the first clinically practical prostaglandin for the treatment of glaucoma. Latanoprost, 0.005%, given once daily, has been compared with timolol, 0.5%, used twice daily in 6-month trials enrolling ocular hypertensive and glaucoma patients. Three studies included a total of 829 volunteers. In one of these trials, the diurnal IOP reduction at 6 months was 27% with timolol, 31% with latanoprost applied in the morning, and 35% with latanoprost used in the evening (39). In the other two comparative trials, latanoprost was given in the evening, with one study reporting 6-month diurnal IOP reductions of 32.7% and 33.7% for timolol and latanoprost, respectively, and the other reporting 6-month IOP re ductions of 4.9 ± 2.9 mm Hg and 6.7 ± 3.4 mm Hg for timolol and latanoprost, respectively (40, 41). Unlike timolol, latanoprost lowers the IOP at night and during the day, providing uniform, around-the-clock IOP reduction when administered once daily, alone or in combination with timolol (42).

The effect of latanoprost after 2 years of treatment was evaluated in 532 patients (496 and 113 were treated for 6 and 24 months, respectively) (43), who continued latanoprost monotherapy treatment as part of an open-label trial from the initial 6-month phase III study in Scandinavia and the United Kingdom (39). Over all, there was a similar mean IOP reduction at 2 years, with a decrease of 8.9 mm Hg (34%), compared

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with 6 months, with a decrease of 8.2 mm Hg (32%). Of the 532 total patients, 20% were withdrawn from treatment because of adverse events based on increased iris color, ocular adverse events, nonocular adverse events, high risk for increased iris color, or IOP treatment failure. For the patients with IOP treatment failure, insufficient IOP control was more common in persons with open-angle glaucoma than in those with ocular hypertension. Patients who initially started with higher baseline IOPs had a higher risk of IOP treatment failure with latanoprost monotherapy.

In addition to its effectiveness to treat ocular hypertension and open-angle glaucoma, latanoprost has also been examined in pediatric glaucoma. In general, latanoprost appears to be safe but tends to be less effective in lowering IOP in children, who have diverse forms of glaucoma treated with concomitant medical antiglaucoma therapies, compared with adults (44). Among the various forms of glaucoma in the pediatric population, it appeared that the older children and those with juvenile-onset open-angle glaucoma showed a better response to this drug (45).

Several prospective studies have examined the efficacy of latanoprost in lowering IOP in patients with chronic angleclosure glaucoma. A meta-analysis was conducted to evaluate the efficacy of prostaglandin analogs in 1090 patients from nine randomized clinical trials with chronic angle-closure glaucoma treated with latanoprost, bimatoprost, or travoprost monotherapy (46). The difference in absolute IOP reduction between the prostaglandin analogs and timolol varied from 0.4 to 1.6 mm Hg during the diurnal curve, 0.9 to 2.3 mm Hg at peak, and 1.3 to 2.4 mm Hg at trough. For latanoprost, the relative IOP reduction was 31% during the diurnal curve, 34% at peak effect, and 31% at trough effect. For timolol, the relative IOP reduction was 23% during the diurnal curve, 24% at peak, and 21% at trough. Based on this meta-analysis, latanoprost is at least as effective as timolol at reducing the IOP efficacy in eyes with chronic angle-closure glaucoma.

Another prospective observational case series of 137 Asian patients with chronic angle-closure glaucoma, which was defined as trabecular meshwork not visible for at least 180 degrees on gonioscopy, were treated with latanoprost (47). After 12 weeks of treatment, latanoprost reduced IOP from 25.0 ± 5.5 to 17.5 ± 5.0 mm Hg. The percentage change in IOP was not affected by the degree of angle narrowing or extent of synechial angle closure.

Three smaller studies also reported on the IOP-lowering effect of latanoprost in patients with chronic angle-closure glaucoma. In a study of 14 Korean patients with 360 degrees of peripheral anterior synechiae on gonioscopy, latanoprost, 0.005%, once daily reduced the IOP from 30.3 ± 4.5 mm Hg at