The Biology, Pathology and Therapeutic Use of Prostaglandins in the Eye

Carol B Toris; Vikas Gulati

Disclosures

Clin Lipidology. 2011;6(5):577-591. 

In This Article

Ocular Therapeutic Uses of PG Agonists & Antagonists

PG Agonists

Topical ocular PG agonists have been developed for two purposes: to treat elevated IOP and slow the progression of glaucoma and to increase eyelash growth for cosmetic effect.

Ocular Hypertension & Glaucoma Glaucoma is a multifactorial group of ocular disorders associated with progressive optic neuropathy and characteristic visual field loss. Glaucoma is the second leading cause of blindness in the world.[55] Several large multicenter randomized trials have demonstrated that lowering IOP prevents the development of glaucoma in some people and slows the rate of progression in others.[56–60] IOP is reduced clinically by surgical procedures, laser treatments, implantation of drainage devices and topical or systemic application of pharmacological drugs, among which are the PGF analogs. Drugs that reduce IOP work in several ways. They can slow the aqueous humor formation rate by the ciliary body, decrease the resistance to aqueous humor outflow across the trabecular meshwork, increase the drainage rate of aqueous humor through the ciliary muscle and choroid (uveoscleral outflow) or they can act by a combination of these effects.[61] Additionally, IOP can decrease if the pressure in the vessels that drain aqueous humor from Schlemm's canal (episcleral veins) decreases but this has not been found to be the primary mechanism of action of any IOP lowering drug.

PGF Analogs Three PGF analogs are approved for clinical use in the USA: travoprost (0.004%), latanoprost (0.005%) and bimatoprost (0.03 and 0.01%). Two additional analogs are prescribed in Europe and Asia, unoprostone and tafluprost. These drugs (Figure 3) work similarly, by improving the drainage of ocular aqueous humor from the anterior chamber angle. Latanoprost primarily increases uveoscleral outflow.[62] Bimatoprost 0.03% reduces IOP, by increasing tonographic outflow facility and uveoscleral outflow.[63,64] Travoprost 0.004% primarily increases outflow facility but also has a small effect on uveoscleral outflow.[65,66] Unoprostone increased outflow facility in one study,[67] but not in others.[68,69] There is no definitive study that has found an increase in uveoscleral outflow with unoprostone treatment. Discrepancies among the studies may be due to differences in study design, method of measurement and/or concentration of drug.

Figure 3.

Prostaglandin F and topical ocular prostaglandin analogs used to treat elevated intraocular pressure.
Modifications of PGF, the parent compound, were made to produce the five PGF analogs for treatment of glaucoma. Unoprostone was the first PGF analog to be approved for topical ocular use but it is not longer sold in the USA. Tafluprost is approved in Europe and Asia and is under review for approval in the USA. Bimatoprost, latanoprost and travoprost are widely prescribed throughout the world.
PG: Prostaglandin.

Latanoprost, travoprost and bimatoprost are PG analogs that retain the 15-position hydroxyl group of natural PGF, and have high pharmacological activity. The hydroxyl group at the 15-position was once thought to be necessary for the manifestation of the activity of PGs.[70] However, tafluprost has a substitution of two fluorine atoms for the 15-position hydroxyl group (Figure 3), thus preventing ketonization by 15-hydroxy-dehydrogenase (one of the major pathways involved in the metabolization of PGs). Consequently, metabolism of tafluprost occurs through β-oxidation of the α-chain of the PG skeleton.[71] In PG derivatives other than bimatoprost, the α-chain ending of the PG skeleton is isopropyl-esterified, and for this reason these derivatives are converted into an active form (carboxylic acid form) by corneal esterase, and penetrate rapidly into the anterior chamber of the eye. Tafluprost has a high affinity for the FP receptor and almost no potential to bind to the other PG receptors.[72] The affinity of travoprost for the FP receptor has been reported to be over twice that of latanoprost.[73] Both unoprostone and bimatoprost have a low affinity for the prostanoid FP receptor.[74,75]Ex vivo binding of bimatoprost to a complex receptor consisting of FP and splice-variant FP receptors (generated using reverse transcription techniques from RNA obtained from enucleated human eyes) has been reported.[76] However, the expression or presence of such a receptor in human tissue specimens has not been demonstrated to date. Lack of an IOP lowering response with PGs in FP receptor knockout mice supports a critical role for this receptor in the IOP effects of PGs.[77]

Evidence suggests that topical treatment with FP receptor agonists increases uveoscleral outflow via activation of a molecular transduction cascade. FP receptor activation results in the induction of the nuclear transcription factors c-Fos and c-Jun.[78] The next step is the initiation of alterations in gene expression, followed by increases in the transcription of MMPs.[79] Translation of MMP mRNA produces proenzymes that initiate the degradation of the extracellular matrix[80,81] within the ciliary muscle, iris root and sclera.[82] Degradation in the extracellular matrix improves outflow of aqueous humor through the uveoscleral pathway.[62,83] PGF has been demonstrated to increase the MMP synthesis in the ciliary body of live monkeys[84] and in human ciliary muscle cell cultures exposed to latanoprost acid.[19,83]

In addition to activation of a molecular transduction cascade, PGs may increase the spaces between the muscle bundles by relaxing the ciliary muscle to a small extent,[85] reorganizing the cytoskeleton,[83,86] changing the shape of ciliary muscle cells, and/or compressing the extracellular matrix within the ciliary muscle.

Bimatoprost, latanoprost and travoprost have been shown clinically to lower IOP by 30–35% from baseline.[87–91] The ocular hypotensive effect of unoprostone has been shown to be lower than that of latanoprost.[92]

PG EP2/EP4 Analogs Prostaglandin EP2/EP4 analogs are currently under development for the treatment of glaucoma, but none is yet clinically approved. Early studies of topical PGE2 in cat and rhesus monkey eyes[93,94] demonstrated a decrease in IOP that was long-lasting and greater than PGF. However, PGE2 was less stable in aqueous solution[95] and caused more ocular side effects than PGF which made this compound less desirable. Recent advances in prostanoid receptor pharmacology have enabled the re-evaluation of PGE2 analogs for the treatment of glaucoma.

Although the EP2 receptor is structurally and functionally distinct from the FP receptor, the effects of EP2 and FP receptor stimulation on aqueous humor outflow are similar. They both increase uveoscleral outflow. Interestingly, the selective EP4 receptor agonist 3,7-dithia PGE1, when given topically to monkeys, increased outflow facility instead of uveoscleral outflow.[96] An explanation for the differences between EP4 and EP2 receptor agonists remains elusive.

Nitric Oxide-donating PG Analogs Another PG compound that has been evaluated as a potential treatment of elevated IOP is PF-3187207, a nitric oxide donating PG analog. It lowered IOP in several animal models of glaucoma.[97] This compound decreased IOP more than with latanoprost alone, presumably by additive contributions by the nitric oxide component in addition to the PG component of the compound. The IOP-lowering mechanism of action of PF-3187207 has not been elucidated to date.[98]

Eyelash Growth While undergoing Phase III clinical trials, the topical PGF analog, latanoprost, was noted to stimulate eyelash growth.[99] This occurred by prolonging the anagen phase of the hair cycle. This phenomenon is not unique to latanoprost but appears to be a side effect to some degree of all drugs of this class. Bimatoprost has been re-evaluated as an eyelash growth cosmetic product and has been remarketed for that purpose.

Functional PG Antagonists

NSAIDs (Inhibit COX) Nonsteroidal anti-inflammatory drugs are a diverse group of compounds that share in common an inhibition of the COX enzyme. They lack the steroid nucleus derived from cholesterol. NSAIDs can be subdivided into traditional NSAIDs (inhibiting both COX-1 and COX-2) or selective COX-2 inhibitors.

Most NSAIDs are organic acids and include derivatives of salicylic acid (e.g., aspirin), propionic acid (e.g., flurbiprofen), acetic acid (e.g., indomethacin, ketorolac and diclofenac), enolic acid (e.g., piroxicam), fenamic acid (e.g., mefenamic acid) among several others. When systemically administered, NSAIDs are tightly bound to plasma proteins, metabolized by liver enzymes and eliminated via glomerular filtration or tubular secretion. They have a propensity to accumulate at sites of inflammation due to the low pH at these sites.

Several NSAIDs have been used as topical formulations for the treatment of eye diseases. These include indomethacin 0.1% and 1%, flubiprofen 0.03%, suprofen 1%, ketorolac tromethamine 0.4% and 0.5%, diclofenac 0.1%, nepafenac 0.1% and bromfenac 0.09%. Nepafenac is a prodrug that is converted to its active form, amfenac, by intraocular hydrolases. These compounds are easily absorbed through the cornea after topical administration and reach therapeutic levels in the anterior segment of the eye. It is uncertain at this time whether topically administered NSAIDs reach sufficient concentrations in the posterior segment to suppress COX.[100,101] However, detectable levels of topical bromfenac and nepafenac were found in the posterior segment of rabbit eyes where suppression of PG synthesis was demonstrated.[102,103] Higher levels of NSAIDs in the posterior segment can be obtained by periocular[104,105] and intravitreal injection.[106,107]

The therapeutic effects of NSAIDs correlate with their ability to inhibit the enzyme COX (PGG/H synthase) and thereby reduce the production of PGs. In addition to IOP regulation, endogenous PGs have been demonstrated to be involved in ocular inflammation and allergies, iris smooth muscle contraction and disruption of the blood–aqueous barrier. Based on these functions of PGs, NSAIDs have been used for a variety of applications in ocular therapeutics.

Nonsteroidal anti-inflammatory drugs have multiple uses in clinical practice, not all of which are approved by the US FDA. One common use is in the control of postoperative inflammation after cataract surgery[108–110] which provides a visual benefit.[111,112] Off-label uses include the control of inflammation after other ocular surgical procedures, such as glaucoma, vitreoretinal and strabismus surgeries. NSAIDs are frequently used in addition to topical steroids in the postoperative period to control inflammation. In some studies NSAIDs were more effective than steroids in reversing the observed flare.[113,114] An additive effect of concomitant use of steroids and NSAIDs in the postoperative period also has been demonstrated.[115,116]

Inflammation is believed to play a significant role in the pathogenesis of cystoid macular edema (CME), the most common cause of vision loss after cataract surgery. The incidence of detectable CME has varied widely from 9 to 44% depending upon the method of detection.[117,118] A small percentage of these cases comprise 'visually significant CME'. Moreover the natural course of CME in a majority of cases is spontaneous resolution. These factors make it difficult to ascertain the therapeutic benefit of a treatment in the management of CME. However, a meta-analysis involving an extensive review of available literature has concluded that prevention and treatment of CME with NSAIDs is beneficial.[119] At the same time, a long-term visual benefit of prophylactic treatment for CME with NSAIDs has never been demonstrated.

Some NSAIDS are approved for control of pain and photophobia following refractive surgery.[120,121] A reduction in corneal sensitivity and thereby pain after corneal abrasions has been reported with the use of topical NSAIDs.[122] Endogenous PGs play a role in the intraoperative pupillary constriction in cataract surgery making the surgery more challenging. NSAIDs can prevent intraoperative miosis and FDA approval has been granted for some NSAIDs to be used for this purpose,[123] although the mydriatic properties seem to be a class effect and not specific to any one NSAID.[124]

Ketorolac is an NSAID that is FDA approved for the treatment of 'allergic conjunctivitis' encompassing several specific diagnoses. Even though PGD2 is the most likely PG produced by mast cells during type I hypersensitivity reactions, PGE1, PGE2 and PGF are also produced. NSAIDs relieve the symptoms of itching, discharge, swelling, foreign body sensation and injection associated with allergic conjunctivitis.[125,126]

Nonsteroidal anti-inflammatory drugs can provide an adjunctive benefit in the management of uveitis. Steroids remain the mainstay of treatment for this condition. Systemically administered NSAIDs are used for the treatment of idiopathic orbital inflammation or orbital pseudotumor. Topical and systemic NSAIDS are used in the treatment of scleritis and episcleritis, and other ocular surface inflammatory conditions.

Elevated levels of PGs in humans and animal models of diabetic retinopathy have been demonstrated.[127,128] NSAIDs have provided beneficial effects in the animal models.[129] In the Dipyridamole Aspirin Microangiopathy of Diabetes study, high doses of aspirin (990 mg) were found to slow the development of retinal microaneurysms.[130] Reports on benefit of NSAIDs in cases of diabetic macular edema are limited at this time. However, there is a potential role for NSAIDs, given the demonstration of involvement of inflammatory mediators in the pathogenesis of the process.

COX-2 has been proposed as a mediator of angiogenesis with elevated levels demonstrated in neovascular membranes.[105,131] Recent genetic studies[132,133] report that complement factor H is involved in the pathogenesis of age-related macular degeneration (AMD) providing evidence that NSAIDs, due to their anti-inflammatory properties, could demonstrate benefits in the management of AMD. Reduction in the prevalence of AMD by NSAIDs has been suggested, but the evidence to support such use is limited at this time.[134,135] In a prospective cohort of rheumatoid arthritis patients on anti-inflammatory therapy, the prevalence of AMD was found to be lower than expected.[134] Another study reported lower incidences of choroidal neovascular membranes in AMD patients taking aspirin when compared with AMD patients not taking aspirin.[135]

Data from colon cancer studies have suggested a primary preventive role for NSAIDs.[136,137] Increased COX-2 expression in uveal melanoma and retinoblastoma has been found and a beneficial effect of amfenac in the inhibition of proliferation and progression of malignant cells has been reported.[138,139] This supports the possible use of NSAIDs in the management of ocular tumors.

A discussion of the side effects of systemically administered NSAIDs is beyond the scope of this article. However systemic side effects, consequent to systemic absorption of topical NSAIDs, have been reported.[140] Transient redness, burning and stinging have been described with all available topical NSAIDs. These vary somewhat with the specific NSAID, but no differences in patient acceptance have been found.[141] Corneal surface toxicity, sometimes severe, has been reported with all topical NSAIDs. Even though severe corneal complications including corneal melting have been reported in the past, systematic analysis has not established a clear correlation.[142,143] Several confounding factors including concomitant steroid use and inadequate follow up may have been contributory to these severe complications. A large percentage of these cases were associated with generic diclofenac that was subsequently withdrawn from the US market. The package insert for Ocufen® (Allergan, CA, USA) listed atonic mydriasis as a possible side effect. Delayed wound healing after corneal surface ablation also has been described with topical NSAID use.[144]

Topical Corticosteroids Corticosteroids modulate gene expression in a variety of cells by binding to specific receptors. This mechanism is responsible for a variable amount of delay observed between the administration and therapeutic effect of steroids in most tissues. The anti-inflammatory effects of steroids are mediated through the suppression of vasoactive and chemoattractive factors, enzyme suppression and reduced leukocyte migration. A variety of inflammatory, neural, chemical and mechanical stimuli can release arachidonic acid from plasma membrane phospholipids. This release is mediated by the enzyme phospholipase A2, which can be inhibited by corticosteroids, thereby reducing the production of both PGs and leukotrienes. Glucocorticoids inhibit the liberation of lysosomal enzymes and negatively regulate the gene expression for COX-2, inducible nitric oxide synthase and inflammatory cytokines.

Steroids are used topically, systemically or as periocular or intraocular injections for the management of a variety of ocular inflammatory conditions like blepharitis, allergic conjunctivitis, episcleritis, scleritis, keratitis, uveitis and vitritis among others. Steroids are used routinely for the control of postoperative inflammation after most ocular surgical procedures. Currently available topical steroids include prednisolone, dexamethasone, rimexolone, loteprednol and difluprednate. Triamcinolone, which also is available in a preservative free formulation, is administered by peri-ocular and intravitreal injection. Fluocinolone acetonide, available as a sustained release ophthalmic intravitreal implant is used for management of chronic noninfectious uveitis.

All steroids, despite how they are administered have demonstrated some degree of ocular toxicity. The common vision-threatening side effects of steroids include elevated IOP, posterior subcapsular cataracts and and increased predisposition to infections. Glaucoma patients and their first degree relatives are more likely to demonstrate an IOP rise in response to steroids when compared with healthy, unrelated people of similar age.[145,146] The Glc1A gene has been implicated in the IOP rise in steroid responders.[147] The elevated IOP in response to steroids may involve a direct action mediated by the steroid receptors found in the trabecular meshwork and anterior uveal tissue, leading to increased resistance to aqueous outflow from the eye.[148–150] The opposing effects of steroids and PGs on IOP can be explained by their opposing actions on MMPs in the ciliary body. Administration of latanoprost to organ and cell cultures has shown an upregulation of both MMP-3 and MMP-9 and a mild induction of MMP-2 in the ciliary body, but not the trabecular meshwork. On the other hand, corticosteroids, downregulate expression of these MMPs in both tissues. This inhibitory effect of corticosteroids on MMP production could be reversed by latanoprost.[151] Persistently elevated IOP can lead to optic nerve damage and permanent vision loss. IOP elevation correlates well with the anti-inflammatory efficacy and concentration of the steroid and the frequency and duration of therapy. The elevated IOP from steroid use is usually reversible after cessation of treatment. However, long-term use of steroids can lead to irreversible elevation of IOP. Cataracts induced by long-term steroid use are usually not reversible and may continue to progress even after the cessation of therapy.[152]

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