Prostaglandins=20 in Glaucoma

Dr=20 Meena Nair

Consultant=20 Glaucoma Services

Chaithanya=20 Eye Hospital and

Research=20 Institute

Trivandrum.

Prostaglandins comprise the latest class = of drugs=20 added to the list of glaucoma medications. They are ubiquitous local = hormones=20 that produce ocular inflammation and hypertension in high levels but in = smaller=20 amounts reduce 10P^1-4. =91Ambache=92 ^5-6 made the = first=20 observation of prostaglandin effects in the eye by isolating a substance = which=20 was a mixture of PGE₂ and F₂_a^7-9=20 in iris extracts that could produce miosis in cats. Four agents are = included in=20 the category of prostaglandins also called hypotensive lipids. These=20 are

v =20 Latanoprost = (approved=20 by USFDA in 1996)

v =20 Travoprost (approved in=20 2001)

v =20 Unoprostone = (approved=20 in 2000)

v =20 Bimatoprost (approved in = 2001)

Pharmacology:

Prostaglandins are eicosanoids which are = metabolic=20 products of arachidonic acid, a 20C structure ¹⁰ (refer Fig = 3).=20

For the prostaglandins, the last letter = refers to=20 specific chemical modifications of the ring structure. The subscripted = number=20 refers to the number of double bonds in the molecule. The greek letter = subscript=20 refers to the orientation of the hydroxyl group in the relation to the = ring=20 structure e.g. PGF₂_a

Prostaglandins are fatty acids which = structurally=20 carry a negatively charged =96 COOH group while prostamides are fatty = acid amides=20 that do not carry the negative charge. Both classes are derived from = membrane=20 lipids and are formed by different biosynthetic = pathways.

&nbs= p; =20

&nbs= p; =20 Fig 1 &nbs= p; = ; = &= nbsp; &n= bsp; =20 Fig 2

Prostanoid Receptors=20

Endogenous = Prostaglandins=20 have 4 subtypes of receptors ¹¹ and prostaglandins have = affinity for=20 more than one receptor.

4=20 subtypes

v =20 EP receptor = --=E0=20 PGD₂

v =20 FP receptor = --=E0 PGE₂

v =20 IP receptor = --=E0 =20 =20 PGF₂_a

v =20 TP receptor = --=E0 =20 PGI₂/TxA₂

PGE₂ and=20 F₂_a binding sites are seen in the ciliary = muscle and=20 iris sphincter muscle. FP and EP₂ receptors are seen in human = trabecular meshwork, EP₄,IP and TP receptors to a lesser = amount in=20 the trabecular meshwork and EP₁, EP₂ and FP = receptors are=20 seen in human scleral fibroblasts.

Structure:

&nbs= p; = ; = =20 Fig 3

Chemical = modifications made to the lipid molecule - &nbs= p; = ; = =20

&nbs= p; = ; = &= nbsp; &n= bsp; =20 =

1. =20 To improve = the=20 molecule solubility , C₁ carboxyl group modified with -an = ethyl amide=20 - Bimatoprost

&n= bsp; =20 &n= bsp; &nb= sp; &nbs= p; = ; = &= nbsp; -an=20 isopropyl ester =96 Latanoprost

=20 &nbs= p; = ; = = &n= bsp; &nb= sp; Travopros= t

=20 Unoprostone

&n= bsp; &nb= sp; &nbs= p; = ; =20

&n= bsp; &nb= sp; &nbs= p; = ; = &= nbsp; =20

2. =20 Phenyl ring = addition=20 to the omega chain improves FP receptor selectivity and 10P reduction=20

(i.e latanoprost, travoprost and=20 bimatoprost)

3. =20 Saturation = of=20 C_13-14 double bond on omega chain reduces=20 hyperemia

Mechanism=20 of Action

Prostaglandins have an unusual effect on aqueous = humor=20 dynamics =96 it increases the non-conventional outflow through ciliary = body face=20 and iris root to suprachoroidal space.

&nbs= p; = ; = =20 Fig 4 =

Topical PG = ester is=20 absorbed into cornea (ref Fig:4)

1. =20 Where it is = converted=20 to free PG. Free PG passes into aqueous

2. =20 and it is = carried=20 into ciliary muscle and binds to the FP receptor on the ciliary muscle = cell=20 surface

3. =20 binding = initiates a=20 single cascade inducing transcription =20 of MMP genes

4. =20 gene = products are=20 translated to proMMP=92s

5. =20 which are = secreted=20 into the extracellular space around ciliary muscle = fibers

6. =20 proteolytic = truncation induces activation of the MMP=92s

7. =20 which = initiate=20 collagen degradation in ECM

8. =20 this = decreases=20 hydraulic resistance and facilitates uveoscleral = outflow

To summarize, possible mechanisms by which = prostaglandins=20 improve uveoscleral outflow are by a

reduction of = ECM collagen=20 I, III, IV, V, VI laminins, fibronectins in the interstitial spaces of = the=20 ciliary muscle and induction of ciliary muscle to produce MMP 1,2,3 and=20 9.

Storage:

v =20 Unopened = bottles of=20 latanoprost to be refrigerated. =20 Once opened can be stored at room temperature = (25^oc or 77^oF) for six weeks. Other prostaglandin = analogues=20 stored at room temperature (15^oc to 25^oC/59^oF to 77^oF for bimatoprost , 2^oc to 25^oC/36^oF to 77^oF for travoprost and=20 unoprostone).

Drug=20 efficacy and interactions

Latanoprost (0.005%) applied once daily produces a = mean IOP=20 reduction of = 27%⁼²⁰compared to 20% with Timolol 0.5% twice daily¹⁴ and 21% = with=20 Brimonidine Tartartate 0.2% twice daily¹⁵. Combination of = Latanoprost=20 with Timolol twice daily produces an additional IOP reduction of = 13% - 37%^16-18, with = oral=20 Acetazolamide 250mg twice daily produces an additional 15% IOP=20 reduction¹⁹, with Dipivefrine 0.1% twice daily resulted in an = additional IOP reduction 16-19%²⁰. In clinical trials it was = apparent=20 that Pilocarpine did not impair the IOP lowering effect of=20 Latanoprost.

Bimatoprost (0.03%) applied once daily = produces IOP=20 reduction of 33-36%. Its successfully lowers IOP in patients = unresponsive to=20 Latanoprost²¹. Mean IOP reductions were 8mm Hg (32.4%) and = 5.5mm Hg=20 (22.7%) with Bimatoprost 0.03% and Timolol 0.5% twice daily=20 respectively^{22 =}.=20 Comparing Bimatoprost efficacy with Travoprost 0.004%, studies have = shown 7.4=20 -8.8mm Hg (34-36%), 4.6 -7.2mm Hg (19-29%²³), a three month=20 prospective study by Parrish Colleagues ²⁴ showed almost = similar IOP=20 lowering efficacy between Latanoprost, Bimatoprost and Travoprost but = the=20 Bimatoprost/Latanoprost study group compared the percentages of = treated patients achieving IOP = reduction after=20 six months of treatment²⁵ which showed that a = significantly fewer patients receiving = Latanoprost=20 achieved a 15% or 20% decrease in IOP at each time point. On patients=20 uncontrolled on topical Beta blockers alone, Bimatoprost lowered IOP = more than=20 combination with Dorzolamide²⁶. Bimatoprost and the = association of=20 Latanoprost plus Timolol were equally effected in lowering IOP in = glaucomatous=20 patients²⁷. There is no additive role in adding other = prostaglandin=20 analogues to patients who are on Latanoprost or = Bimatoprost.

Comparison of = prostaglandin=20 analogues

Latonoprost

Bimatoprost

Travoprost

Unoprostone

Mean %=20 10P

27%

33%

28%

15%

Hyperemia=20 %

5-15%

15-45%

35% -50%

10-25%

Iris = pigmentation (6=20 months)

6.7%

1.2%

3.1%

<1%

Iris = pigmentation=20 (12 months)

16.1%

1.5%

Uses

v =20 Prostaglandins are=20 potent ocular hypotensives as first line therapy for ocular hypertension = and=20 POAG. In addition, Latanoprost has been found to be useful in

Juvenile OAG, Primary Angle closure = glaucoma=20 following yag PI if 10P elevation persists ²⁸.Prostaglandins = are=20 however a relative contraindication in inflammatory glaucoma=92s and = Posner=20 Schlossman syndrome due to their association with CME and uveitis. The = role of=20 prostaglandin analogues in glaucoma associated with penetrating = keratoplasty is=20 uncertain. In chemical burns, they have to be cautiously used.=20

Summary

Prostglandin analogues are highly = efficient ocular=20 hypotensives, well tolerated and systemically safe and have a promising = future=20 as first line drugs, adjunctive drugs and as substitutes in the medical=20 management of glaucoma.

References

1. =20 Bito LZ.=20 Prostaglandins and other eicosanoids : their ocular transport, = pharmacokinetics=20 and therapeutic effects (Review)

Transophthel Soc UK=20 1986;105(P+2):162

2. =20 Prostaglandins : old=20 concepts and new perspectives.

Arch ophthalmol 1987;=20 105:1036

3. =20 Villumsen = J. Alm A.=20 Prostaglandin F₂ alpha =96 isopropyl ester eye drops : = effects in=20 normal human eyes. Br J ophthalmol 1989;73:419

4. =20 Linden C. = Alm A.=20 Prostaglandin analogues in the treatment of glaucoma. Drugs Aging 1999 ; = 14;=20 387

5. =20 Ambache N. = Irin , a=20 smooth muscle contracting substance present in rabbit iris. J = Physiol(Lond)=20 1955;129: 65P-6

6. =20 Ambache = N.properties=20 of irin , a physiological constituent of rabbit iris. J. Physiol (Lond)=20 1957;135:114-32

7. =20 Anggard E, = Samuelson=20 B. Smooth muscle stimulating lipids in sheep iris: the identification of = prostaglandin F₂_a

: prostaglandins and related factors. = Biochem=20 pharmacol 1964;13:281-3

8. =20 Ambache = N;Kavanagh L,=20 whiting J. Some differences in cweal reactions between cats and rabbits. = Jphysiol (London) 1966;182:110-30

9. =20 Ambache N. = Brummer=20 Hc. A simple chemical procedure for distinguishing E and F = prostaglandins with=20 application to tissue extracts. Br J Pharmacol=20 1968;33:162-70

10. =20 Morrow JD, = Roberts LJ=20 II. Lipid- derived antacoids: eicosanoids and patelet =96 activating = factor. H:=20 Hardman J.G, Limbird LE, eds. Goodman and Gilman=92s the pharmacological = basis of=20 therapeutics, 10^th ed. New York: McGraw Hill,=20 2001

11. =20 Coleman RA, = Smith WL,=20 Narumiya S. International union of Pharmacology classification of = prosanoid=20 receptors: properties, distribution and structure of the receptors and = subtypes.=20 Phasrmcol Rev 1994;46:205

12. =20 Weinreb RN, Toris = CB, Gabett=20 BT, et al. Effects of = prostaglandins=20 on the aqueous humor outflow pathways. Surv Opthalmol 2002;47 (Suppl 1): = 55

13. =20 Dubiner H, = Cooke D et=20 al. Efficacy and safety of bimatoprost in patients with elevated = intra-ocular=20 pressure : 1 30 day comparison with latanoprost . Sun Opthalmol=20 2001;45:353-360

14. =20 Hedman A

&nbs= p; = ; = =20 Fig 3

Chemical = modifications made to the lipid molecule - &nbs= p; = ; = =20

&nbs= p; = ; = &= nbsp; &n= bsp; =20 =

Proved side effects

Comparison of = prostaglandin=20 analogues