16

Prostaglandin Analogs

Angela Turalba, MD, MMS and Douglas J. Rhee, MD

Unoprostone was the first commercially available prostaglandin analog (PGA) and was introduced in the mid-1990s. Latanoprost, bimatoprost, and travoprost were released soon after. Because of their favorable balance of intraocular pressure (IOP)-lowering effect and systemic safety, PGAs are very popular agents for the medical management of glaucoma.

Prostaglandins and thromboxanes belong to a family of compounds called prostanoids, which are defined as cyclo-oxygenase products derived from C-20 unsaturated fatty acids (namely, arachidonic acid). In the 1930s, Euler isolated a highly active, lipid-soluble compound from sheep vesicular glands and named it prostaglandin.¹ Euler’s substance was later determined to represent a family of prostaglandins. Bergstrom et al were the first to characterize the prostaglandin family with the identification of PGE2 and PGF2α in the 1950s.² Ocular prostaglandins (initially called irin) were first extracted from a homogenate of iris in 1955.³ PGE2 and PGF2α were later identified as the active components of irin in 1966.⁴ The ocular hypotensive effect (preceded by an initial hypertensive phase in rabbits) of intracameral prostaglandins was noted in 1971.⁵ Camras et al⁶ showed a similar effect from topically applied prostaglandins in 1977. In rabbits, the initial hypertensive phase was related to the high doses, induced miosis, breakdown of the blood-aqueous barrier, and protein leakage.⁷ Further studies^8,9 in the early 1980s revealed that there is a sustained lowering of IOP without a significant hypertensive phase in other species.

MOLECULAR PHARMACOLOGY

PGAs increase aqueous drainage, primarily by enhancing uveoscleral outflow up to 60%.^7,10–12 Additionally, bimatoprost, latanoprost, and travoprost all have some effect on trabecular outflow.¹³ PGAs are chemical derivatives of prostaglandin F2 and agonists of the prostanoid FPA and FPB receptors. Latanoprost and travoprost are ester prodrugs, while bimatoprost is an amide prodrug. These prodrugs are hydrolyzed by esterases in the cornea into free acids that are the active compounds that bind the FP receptors. A study¹⁴ using knockout mice have shown that the IOP-lowering effect of PGAs is dependent on the presence of intact FP receptors. FP receptors have been detected in the iris, trabecular meshwork (TM), ciliary muscle, and sclera of the human eye.^15–17 Cloning and sequence analysis of prostaglandin receptors have indicated that prostaglandin receptors are G-protein coupled receptors, which, when activated, initiate a transduction cascade involving protein kinase C and the induction of nuclear transcription factors, specifically c-Fos and c-Jun.^18,19 In TM cells, stimulation with PGF2α causes an increase in intracellular calcium and inositol phosphate. In ciliary body smooth muscle (CBSM) cells, PGF2α does not change IP3 production, but does increase cyclic AMP (cAMP) levels.²⁰ The effect of PGAs may be mediated by cAMP production, but PGF2α has the least ability to do so in cultured CBSM cells.^20,21 PGF2α may also mediate its effects through stimulation of phospholipase A2 causing the release of arachidonic acid for PG synthesis and the endogenous release of PGE2, PGD2, and PGF2α.²² PGE2 and PGD2 are much more potent activators of the adenylate cyclase system.20,21 In vitro, TM cells produce PGE2, PGF2α, and 6KF1α.²³ The eventual induction of transcription factors resulting from these signaling pathways initiates alterations in gene expression, including the dose-dependent upregulation of matrix metalloproteinases (MMPs) in ocular tissues, including CBSM cells.^19,24,25

There are 22 unique MMPs, to date.²⁶ MMPs are zinc-dependent endopeptidases that are collectively capable of degrading all extracellular matrix (ECM) components.²⁷ As with any enzyme, MMPs can be regulated at transcription, activation, and kinetics. For most MMPs, with the notable exception of MMP-2, transcriptional regulation is more important. For MMP-2, activation and kinetic inhibition seem to be more important.^26,28,29 Many MMP promoters (MMP-1,-3,-7,-9,-10,-12,-13)²⁶ contain AP-1 (interacts with Fos and Jun transcription factors) and PEA-3 (interacts with ETS transcription factors) binding sites. MMPs-1 and -3 also contain an additional platelet-derived growth factor-responsive cis-acting element.^30,31 Other factors, such as growth factors, hormones, cytokines, and cell-cell and cell-ECM contact, can alter MMP gene expression.²⁷ Generally, TGFβ, retinoic acids, and glucocorticoids suppress MMP gene expression.³² Mitogen-activated protein kinases are important to transcription regulation in tumor cells.²⁷ Activation of pro-MMPs can be performed by soluble enzymes (eg, plasmin), membrane-bound enzymes (eg, MT1-MMP), and autocatalytic activity (eg, MMP-3).^32–34 Enzymatic activity can be inhibited by the tissue inhibitors of metalloproteinases (TIMPs) through direct competitive binding at the catalytic site of the MMP. To date, 4 human TIMPs (TIMPs-1 through -4) have been identified. MMPs with numeric designations higher than 9 and MT-MMPs are not well studied in the TM (with the exception of MT-MMP-1/MMP-14). Plasmin, an activator of MMP activity, is upregulated in response to latanoprost.³⁵

On the molecular level, PGAs cause a change in the balance of MMPs and their kinetic inhibitors, TIMPs in both TM and CBSM cells.^36–38 Although this alteration of MMPs and TIMPs occurs in both cell types, the balance of MMPs and TIMPs is shifted to a larger degree in the ciliary body.³⁸ Furthermore, PGAs affect the downstream tissues in the uveoscleral pathway, increasing scleral permeability by altering the balance of MMPs and TIMPs in scleral fibroblasts.^39–41

On a cellular level, the PGA-induced shift in MMPs and TIMPs causes a decrease in ECM around CBSM cells after 4 to 8 days of treatment.^42,43 This finding corresponds to the clinical observation that a larger IOP reduction is observed after 4 to 5 days of daily dosing.^44,45 Chronic PGA use causes a decrease in ECM and alterations of cellular attachments in the juxtacanalicular region of TM. In the ciliary body, latanoprost has been found to decrease collagen types I, II, III, IV, and VI, as well as fibronectin, laminin, and hyaluronan.^35,46–48

From indirect evidence demonstrating the blunting of the PGF2α-induced hypotension by pilocarpine, there is some suggestion that CBSM tone may also be partially responsible for the hypotensive effects.^7,49 In vitro experiments with cultured CBSM cells show that there is a dose-dependent increase of calcium efflux (which would cause smooth muscle cell contraction) at high concentrations of PGF2α (10-8 to 10-6 mol/L). With concentrations lower than 10-8 mol/L, there was little change in calcium.⁵⁰ Physiologic measurements of contractile forces of bovine TM and ciliary muscle cells do not show any significant effect from PGF2α agonists.⁵¹

CLINICAL EFFICACY

There are several prospective clinical trials that demonstrate the efficacy of PGAs to lower IOP in patients with ocular hypertension and open-angle glaucoma. Latanoprost, travoprost, and bimatoprost dosed once daily are at least equally or more effective than timolol in lowering mean diurnal IOP when used as monotherapy.^52–54 Pooled data showed that latanoprost reduces mean diurnal IOP on average by approximately 30%, with a similar degree of IOP lowering seen with bimatoprost and travoprost.^52,55,56

PGAs are also equally or more effective in lowering IOP compared to pilocarpine, brimonidine, dorzolamide, and combination timolol-dorzolamide.^52,57–59 The IOP-lowering effect of PGAs has been demonstrated in various ethnic groups including White, Asian, African, and Hispanic populations.⁵⁵ PGAs are not as effective in children compared with adults, though they can significantly reduce IOP in select cases including juvenile open-angle glaucoma and older children.^60–62 Young animals and people have a higher proportion of their outflow through the uveoscleral pathway.^63,64 It is possible that this reduced effectiveness of PGAs in children may be related to a maximal amount of outflow through the uveoscleral pathway.

Except for unoprostone, which is dosed twice daily, the recommended dosage for latanoprost, travoprost, and bimatoprost is once daily in the evening. The evening dosing is thought to block the early morning diurnal IOP spike seen in some patients.⁶⁵ Dosage is an important factor that influences the effect of PGAs, and more frequent dosing has been shown to decrease the IOP-lowering effect.^6,54,66 Studies on long-term treatment with PGAs have shown no loss of effect over 1 to 5 years.^53,67,68

PGAs can produce a substantial additional reduction in IOP when added to other ocular hypotensive agents presumably because they act on different pathways compared to other glaucoma medications. When used with timolol, latanoprost and travoprost produce further reductions in IOP.^69–71 The addition of dorzolamide or brimonidine to a patient taking latanoprost results in additional IOP reduction.⁷¹ Initially, based on data from primate experimental models, pilocarpine was believed to inhibit prostaglandin-induced enhancement of uveoscleral outflow.^49–72 However, in humans, fluorophotometry data suggest that pilocarpine does not inhibit the uveoscleral outflow enhancement of prostaglandins.73–75 Although more effective combinations exist, prostaglandins and pilocarpine may be effective in lowering IOP when used together.⁷⁵ The use of 2 different PGAs in combination has not been demonstrated to have increased efficacy in IOP lowering when compared to the use of a single PGA.^76,77 Latanoprostene bunod is a novel nitric oxide–donating PGA that demonstrated non-inferiority compared to timolol 0.5% in phase 3 trials.^78,79 Latanoprostene bunod is rapidly metabolized in the eye into latanoprost acid and butanediol mononitrate, a nitric oxide–donating moiety. Nitric oxide donors reduce IOP by causing relaxation of the TM and Schlemm’s canal, enhancing aqueous outflow through the conventional pathway.

Stay updated, free articles. Join our Telegram channel

Join