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.

RETINAL HEMORRHAGES: ARTICLE ON PUBMED

 

Retinal hemorrhages can occur in a variety of disorders, ranging from ocular conditions such as acute posterior vitreous detachment (PVD), optic disc drusen and vascular occlusive retinal disorders (e.g. Central Retinal Vein Occlusion) to systemic diseases such as diabetes, hypertension, leukemia and lupus. These hemorrhages can also present in non-glaucomatous optic atrophy. 

In glaucomatous individuals, these so-called DRANCE HEMORRHAGES, signify focal optic disc damage and visual field loss.

 

The Asia Pacific Glaucoma Guidelines mentions that compared to a single episode of disc hemorrhage, recurrent hemorrhages increase the risk of optic nerve damage by 3-4 times.

In individuals with ocular hypertension (OHT), the appearance of disc hemorrhages increases the risk of conversion to open angle glaucoma by 6 times (by univariate analysis) and by 4 times (by multivariate analysis). 

Recently, we have published an article on retinal hemorrhages. The article takes a broad view of such hemorrhages seen in clinical practice. 

The link to the article is available here: https://www.ncbi.nlm.nih.gov/books/NBK560777/

 

FREQUENCY DOUBLING TECHNOLOGY

 

 

INTRODUCTION:

• FDT is also known by the moniker FDP (Frequency Doubling Perimetry).

• FDT is a rapid method to analyze the visual field.

• The machine uses a large (10°x 10°), low-spatial-frequency sinusoidal grating (< 1 cycle/degree).

• The grating has black and white bars that undergo a rapid counter-phase flicker (>15 Hz), so that the black bars become white and the white bars become black.

• The use of low-spatial-frequency target undergoing rapid flicker leads to the frequency doubling illusion, so that at a certain level of contrast the number of visible lines appear to double.

• When this state is achieved the patient starts seeing twice as many bars as are actually present in the grating.

• The ability to perceive this optical illusion is the function of the Magnocellular pathway. This pathway is apparently damaged early in glaucoma.

• About 15% of the optic nerve fibers are made up of M cells and 15 to 25% of these M cells (called My cells) have non-linear properties capable of eliciting the frequency doubling illusion.

• Thus, only about 5% of all retinal ganglion cells are tested during FDT, allowing loss in any of these cells, to be more readily identified due to reduced redundancy.

• On the other hand, standard automated perimetry (SAP) assesses a larger number of visual cells, which has the disadvantage of overlapping during the testing procedure. Therefore, FDT is supposed to pick up glaucomatous field defects earlier than SAP.

• During FDT testing, the counter-phase flicker rate (25 times per second) and dimension of grating pattern are kept constant and contrast between black and white bars are modified in bracketing phenomena like perimetry till the patient starts seeing shimmering bars in his field of vision.

• This thresholding is done several times within 3 db and the threshold is obtained.

• An advantage of FDT is that refractive errors, even upto 6 Diopters, do not affect the procedure.

 

COMMON TESTING STRATEGIES:

1. Suprathreshold – (used as a screening test)

2. Threshold

 

TESTS AVAILABLE: (IN BOTH STRATEGIES)

1. C-20: 17 targets in central 20°, evaluating four 10° test locations per quadrant, in addition to a central circular target.

                                                               i.      C-20-1 suprathreshold test begins with stimuli with a contrast that 99% of normal population is able to see (1% probability level); best for screening large population; therefore 1% of normal population will miss it. Thus, the false +ve will be less but mild glaucoma field defect can be missed.

                                                             ii.      C-20-5: stimulus used is at a contrast level that 95% of the normal population can detect (5% probability level). Therefore, the rate of false +ve will be more but it will be more sensitive to shallow early field loss. It is useful for patients with risk factor/ symptoms.

    2.    N-30: It adds two test points out to 30 degrees, in the nasal field to improve sensitivity to nasal step defects. In the same way as C-20 suprathreshold testing, the N-30 suprathreshold testing also can be done at 1% and 5% probability level.

 

PARTS OF PRINTOUT:

1. General data- i.e. the program (Full threshold N-30) used, name of the patient, identity number, date and time of testing, which eye is tested, test duration.
2. Below that is the threshold map. (contrast level converted to threshold) in dB in all 19 squares of the right eye.
3. Total deviation probability map is below the threshold map and is given for all 19 squares.
4. Pattern deviation probability map is below the total deviation.
5. The legends of the symbols are given at the bottom, below the left eye, i.e. the second eye.

 

 Matrix FDT- Reliability indices

 

RELIABILITY INDICES:
                                                                 1. Fixation loss- Heijl-Krakau fixation loss method- two or more are significant.
                                                                 2. False +ve and
                                                                3. False –ve

INDICES:

                                                               i.      Mean deviation (MD): Average difference from expected value for patient’s eye +ve value is better than expected, however here it is –ve.

                                                             ii.      PSD (pattern standard deviation) measure for entire field of localized loss relative to expected hill of vision.

       +ve PSD means that it is more than expected. This indicates that localized glaucoma will have higher PSD and in diffuse or general VF loss, PSD will be closer to zero. However, in such cases the MD will be high. In glaucoma associated with cataract or cases of advanced glaucoma, the MD as well as the PSD will be abnormal. Significant abnormal MD or PSD is printed with a p-value besides it. The report of the other eye (i.e. left eye) is printed below the report of the right eye, in same manner. 

WHAT TO LOOK FOR:

                                                               i.      No. of points depressed

                                                             ii.      Location of point involved

                                                           iii.      Pattern of involved points

                                                           iv.      Depth of depression

                                                             v.      Comparison between two eyes

                                                           vi.      MD and PSD

                                                          vii.      In repeat test, the change from previous test should be noted

                                                        viii.      Correlation with ocular examination

ADDITIONAL POINTS:

1. Unlike SAP, even one depressed FDT area is significant because fewer and larger regions are tested and more weightage is given if consistent and repeated defects are seen in following test.
2. Total deviation map and pattern deviation map depict the expected location of physiological blind spot.
3. Diffuse field changes seen with an elevated PSD may suggest underlying glaucomatous loss.

 FURTHER READING: http://webeye.ophth.uiowa.edu/ips/PerimetryHistory/FDP/