PROSTAGLANDIN ANALOGS: MECHANISM OF ACTION

 

INTRODUCTION:

Anti-glaucoma medications reduce intra-ocular pressure (IOP) by their effects on aqueous humor dynamics.

These agents act by:

• Slowing the production rate of aqueous humor
  
• Decreasing the resistance to flow through the trabecular meshwork
  
• Increasing drainage through the uveoscleral outflow pathway
  
• Or by a combination of these mechanisms

Prostaglandin (PG) F2α analogs reduce IOP by stimulation of aqueous humor drainage primarily through the uveoscleral outflow (non-conventional) pathway. Minor effects on trabecular (conventional) pathway have been reported. Based on most studies, the PG effect on episcleral venous pressure is minimal.

EFFECT ON CONVENTIONAL AQUEOUS OUTFLOW PATHWAY:

Effects on trabecular outflow (Conventional pathway) facility also have been reported. Most studies have found a small (10–15%) increase that may or may not be statistically significant and is not clinically important. Histological analysis of latanoprost-treated anterior segments showed focal loss of Schlemm's canal endothelial cells, separation of inner wall cells from the basal lamina, cell disconnection from the extracellular matrix, and focal loss of extracellular matrix in the juxtacanalicular region.

Studies on EP receptor stimulation has shown that EP2 and EP4 activation results in increased cell contractility of the trabecular meshwork, and decreased cell contractility of the inner wall of Schlemm's canal, mediating IOP through the conventional pathway.

Outflow through the conventional pathway probably does not contribute to any reduction in IOP but an increase in aqueous flow could be considered a healthy side-effect of topical PG analogs because aqueous humor carries essential nutrients and removes waste products, crucial for keeping the avascular tissues of the anterior segment healthy.

EFFECT ON NON-CONVENTIONAL AQUEOUS OUTFLOW PATHWAY:

• Bimatoprost and Latanoprost increase uveoscleral outflow in ocular normotensive and hypertensive subjects. 
• Travoprost increased uveoscleral outflow in monkeys and marginally increased it in ocular hypertensive patients as well.
• Unoprostone, the weakest of the four prescribed PG analogs, is the only one that did not affect uveoscleral outflow in humans despite 5 days of twice-daily dosing.

(For more information on Unoprostone please follow this link:  https://ourgsc.blogspot.com/search?q=unoprostone )

A significant increase in aqueous flow was found at night in young healthy Japanese volunteers treated with Latanoprost, and during the day and at night in healthy predominantly Caucasian volunteers treated with bimatoprost.

 

Prostaglandin analogues elicit their effect by binding to specific receptors localized in the cell membrane and nuclear envelope.

There are 9 prostaglandin receptors: PGE receptor 1–4 (EP1–4), PGD receptor 1–2 (DP1–2), PGIP receptor, PGFP receptor, and thromboxane A2 receptor (TP), their designation based mainly on the prostaglandin for which binding is most specific.

PGF2α binds the FP, EP1, and EP3 receptors with significant affinity, while travoprost binds the FP receptor with highest affinity among the prostaglandin analogues, with minimal affinity for DP, EP1, EP3, EP4, and TP receptors. Pharmacologic and pharmacokinetic data suggest the existence of a unique bimatoprost receptor, distinct from the known FP receptors; however, this receptor is yet to be cloned.

Studies in mice suggest that FP and EP3 are the primary receptors that trigger downstream signaling pathways and the eventual physiologic response following treatment with latanoprost, bimatoprost, and travoprost.

However, in primates, EP2 receptor stimulation has been shown to increase uveoscleral outflow, and EP4 receptor activation reduces IOP by increasing outflow facility without effecting uveoscleral outflow. These results in mice and primates suggest that species-specific mechanisms may exist.

In the ciliary muscle, binding of prostaglandins and prostaglandin analogues to ciliary muscle FP receptors disrupts extracellular matrix turnover. PGF2α and prostaglandin analogues bind to EP and FP receptors in the ciliary muscle, resulting in ciliary muscle relaxation and increased aqueous humor outflow.

Matrix metalloproteinases (MMPs) degrade and remodel the extracellular matrix in the ciliary muscle, iris root, and sclera, reducing outflow resistance to fluid flow. The rate of turnover of the extracellular matrix is dependent on the balance between the molecules that degrade and remodel the extracellular matrix i.e. the MMPs, and their inhibitors [tissue inhibitor of metalloproteinase (TIMPs)].

Treatment with PGF2α and prostaglandin analogues increases the amount of MMPs, while maintaining TIMP expression. This shifts the balance in favor of degradation and remodeling of the extracellular matrix to enhance outflow facility.

Increase in uveoscleral outflow occurs through various mechanisms:

• Remodeling of the extracellular matrix of the ciliary muscle, and sclera causing changes in the permeability of these tissues;
• Widening of the connective tissue-filled spaces among the ciliary muscle bundles, which may be caused in part by relaxation of the ciliary muscle;
• Changes in the shape of ciliary muscle cells as a result of alterations in actin and vinculin localization within the cells.

Remodeling of the extracellular matrix within the ciliary muscle and sclera is the most thoroughly understood effect of PG treatment. Dissolution of collagen types I and III within the connective tissue-filled spaces between the outer longitudinally oriented muscle bundles results from PG-stimulated induction of enzymes MMP1, 2, and 3 in the ciliary muscle and surrounding sclera.

PGF2α- and latanoprost-induced secretion and activation of MMP-2 in ciliary muscle cells were shown to occur via protein kinase C and extracellular signal regulated protein kinase 1/2-dependent pathways.

Inhibition of the latanoprost-induced reduction of IOP in rats by thalidomide suggested that the IOP-lowering response is mediated, in part, through tumor necrosis factor-α-dependent signaling pathways.

PGF2α-isopropyl ester treatment was found to increase MMP-1, -2, and -3 in the sclera, which contributes to outflow.

Studies in FP receptor-deficient mice have shown that the FP receptor is essential for the early IOP lowering response to topical latanoprost, travoprost, bimatoprost, and unoprostone. The involvement of the FP receptor in the IOP reduction with long-term dosing is unknown.

Prostaglandins also alter the production of MMPs in human primary trabecular meshwork cells.

Prostaglandin analogues lower IOP through tissue impedance changes and long-term remodeling of the extracellular matrix within the conventional and unconventional outflow pathways. However, this does not explain the early effects of prostaglandin analogue treatment in cell culture models. IOP was found to be lowered within 2 h of treatment in mice and human anterior segment culture.

SOURCES:

1. Carol B. Toris, B’Ann T. Gabelt, and Paul L. Kaufman. Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction. Surv Ophthalmol. 2008; 53(SUPPL1): S107–S120. doi:10.1016/j.survophthal.2008.08.010.
2. Winkler NS, Fautsch MP. Effects of prostaglandin analogues on aqueous humor outflow pathways. J Ocul Pharmacol Ther. 2014;30(2-3):102-109. doi:10.1089/jop.2013.0179.