2. Medical Therapy in Glaucoma M. GHASSAMI MD

3. Medical Therapy in Glaucoma The Ocular Hypertension Treatment Study demonstrated that topical ocular hypotensive medications can delay or prevent onset of glaucoma and progression of visual defects in people with elevated IOP but who have no evidence of glaucomatous damage.

4. 3 targets for glaucoma management LOWER IOP SAFE AND EASY TO USE NEUROPROTECTION/ VASOPROTECTION

5. Characteristics Effective(decrease in IOP) Patient compliance Medical Economy Circadian control of IOP

6. Prostaglandin Analogs Cholinergic Agents Beta Blockers Adrenergic Agents Carbonic anhydrase inhibitors Hyperosmotics Fixed combination of topical IOP-lowering drugs. Medical Therapy in Glaucoma

7. (HYPOTENSIVE LIPIDS) IN GLAUCOMA Prostaglandin Analogs

8. Prostaglandin Therapy A. Robin Johns Hopkins University Baltimore, USA The most desirable traits for first-line therapy for glaucoma are safety, efficacy and ease of use. On this basis, the first-line medication of choice should be latanoprost.

9. Research & Development Center, Santen Pharmaceutical Co. Ltd., Ikoma, Nara, Japan. ishidan@santen.co.jp Cardiovascular drug reviews 2006 PMID: 1 6939629 To date, three prostanoids (latanoprost, travoprost and bimatoprost) have been launched in many countries, Hence, prostanoids currently occupy center stage among glaucoma medications.latanoprosttravoprost bimatoprost It cannot be denied that in terms of efficacy, safety, patient compliance, and medical economy prostanoids are currently the first-line medicines among ocular antihypertensive drugs.

10. European journal of ophthalmology 2007 Jul-Aug changes in medical and surgical treatments of glaucoma between 1997 and 2003 in France. CONCLUSIONS: Between 1997 and 2003, new glaucoma drugs, primarily prostaglandins, improved intraocular pressure control and delayed surgery, reducing glaucoma surgery by 22%.

12. Latanoprost reduces the need for surgery in glaucoma patients Ref: 1) J of Glaucoma 2000; 9: 183-186 2) Drugs of future 1998; 23(8): 908-911

13. Four agents are in the category Latanoprost (approved in the United States in 1996) Unoprostone (approved in 2000), Travoprost (approved in 2001), Bimatoprost (approved in 2001) Prostaglandin Analogs

14. History and Name Prostaglandins are metabolic products of arachidonic acid, a 20-Carbon structurs. They are group of lipids that are derived enzymatically from fatty acids.

15. History and name The name prostaglandin derives from the prostate gland.prostate gland Many other tissues secrete prostaglandins for various functions, and have important functions in the body. In eye the nonconventional outflow (uveoscleral outflow) is improved with resulting decrease in IOP.

16. Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects. A crossover study.bimatoprostlatanoprost travoprost CONCLUSIONS: Bimatoprost, latanoprost, and travoprost have similar mechanisms of action. All 3 drugs reduce IOP without significantly affecting the aqueous production rate. All drugs increase aqueous humor outflow, either by enhancing the pressure- sensitive (presumed trabecular) outflow pathway or by increasing the pressure-insensitive (uveoscleral) outflow, but the assessment of the amount of flow through each pathway depends upon the measurement technique.Bimatoprostlatanoprost travoprostIOPaqueous humor Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA. Ophthalmology 2008 May PMID: 18452763

17. Two major routes aqueous outflow. Prostaglandin analogs act by increasing outflow, primarily through the uveoscleral pathway (blue arrows), with some contribution through the conventional trabecular outflow pathway (green arrows).

18. MECHANISM OF ACTION Studies of human autopsy eyes revealed high levels of specific binding sites for PGs. in areas of the ciliary muscles and iris sphincter muscle. PGs. decreased fibrillar collagen and increased matrix metalloproteinase (MMP)-1, -2, and -3 in the ciliary muscle and sclera.

19. MECHANISM OF ACTION MMPs causes cytoskeletal alteration. Collagen reduction in the sclera. Dilated spaces between ciliary muscle bundles. Relaxation of the ciliary muscle. Increased trans scleral permeability. And thereby facilitates uveoscleral outflow.

20. FLUCTUATIONS IN IOP Medications with a long-term circadian control of IOP are hypothesized to have better clinical effectiveness. When we use PGs. at 9 pm.reduction in IOP occurs within 3-4 hours, peaks within 8-12 hours. (and thats also the time when IOP is at its peak) Therefore 2 peaks meet i.e. the IOP at its peak and Latanoprost at its peak..and persists for up to 24 hours or longer after topical application Ref: 1. Drugs and Aging 1999; 14(5): 387-398 2. Drugs and Aging 2003; 20(8): 597-630 3. AHFS 2000; 2596-2600 4. Can. J. Ophthalmol; 33(5); 1998; 255-266

21. FLUCTUATIONS IN IOP PG analogs potentially can reduce IOP below episcleral venous pressure, (unlike medications that increase outflow facility.) Reducing glaucomatous damage during sleep. (when ocular perfusion pressure may be reduced secondary to decreased systemic blood pressure.)

22. FLUCTUATIONS IN IOP PGs are as effective at night as during the day. Latanoprost compared agents a fairly uniform circadian reduction in IOP. Ref: Invest ophthalmol Vis Sci 2000; 41: 2566-2573 Not only controlling peak IOP is important but the drug should also control fluctuations in IOP

23. Prostaglandin Analogs MECHANISM OF ACTION: uveoscleral outflow Pharmacodynamic: control fluctuations in IOP

24. TREATMENT REGIMEN The recommended treatment regimen is one drop. Maximum effect achieved with a concentration of 5mcg/ml given. More frequent dosing of these agents resulted in decreased efficacy of the drug (related to development of receptor subsensitivity) Ref: 1. Drugs and Aging 1999; 14(5): 387-398 2. Drugs and Aging 2003; 20(8): 597-6303.

25. one drop at 9 pm Prime time for instillation of Latanoprost:

26. Administration Latanoprost (0.005%), Travoprost (0.004%), and Bimatoprost (0.03%) are administered similarly as one drop daily to the eye. In contrast, 0.15% Unoprostone is administered as one drop two times daily to the eye.

27. INDICATIONS Clinical studies have also demonstrated that PGs lower IOP in patients with: Ocular hypertention POAG NTG Exfoliation syndrome, Pigment dispersion syndrome, Chronic angle-closure glaucoma. Stroid induced glaucoma may be less effective in pediatric patients.

28. LATANOPROST Latanoprost, was the first clinically practical prostaglandin for the treatment of glaucoma, Latanoprost has Undergone extensive clinical trials for efficacy, drug interactions, and side effects. In a pooled analysis of 1,389 patients, who were of four ethnic origins, from eight countries, after 3 to 6 months of treatment. Latanoprost resulted in an average7.9 mm Hg Decrease in mean diurnal IOP. monotherapy with latanoprost reduced IOP levels by 29-32% over 1-12 mounths.

29. Latanoprost Storage latanoprost exhibits thermal and ultraviolet instability. Protect from light. Store unopened bottle(s) under refrigeration and 2 o to 8 o C (36 o to 46 o F). Once a bottle is opened for use, it may be stored at room temperature up to 25 o C (77 o F) for 6 weeks. The other agents are recommended to be stored at room temperature.

30. ( Travoprost ( Travatan. Travoprost is a prodrug and has little, if any, pharmacologic activity until hydrolyzed in vivo to travoprost free acid. Travoprost 0.004% lowered IOP more than timolol, The decrease from baseline was 30% to 33% for travoprost compared with a 22% to 29% decrease for timolol.

31. ( Lumigan ) Bimatoprost latanoprost and bimatoprost caused similar IOP reductions (p<0.001). Bimatoprost-treated eyes had significantly higher grades of hyperemia than travoprost-.treated eyes,and latanoprost group.

32. UNOPROSTONE Unlike the 20-carbon molecular skeleton of arachidonic acid, unoprostone a, 22-carbon molecule. Unoprostone administered two times daily lowered lOP by 11 % to 23%. less effective than the other three analogs in clinical trials.

33. XALACOM Xalacom (Latanoprost 50 µg/mL & Timolol 5mg/ml). both of which lower the pressure within the eye in different ways. (prostaglandin drug works by increasing the outflow. The beta-blocking drug works by decreasing the fluid production). Before first opened, keep Xalacom in a fridge (between 2°C and 8°C), out of direct light. Once the bottle has been opened, Xalacom can be kept at normal room temperature up to 25°C, out of direct light. Xalacom must be used within 10 weeks after opening the bottle.

34. Possible side effects of prostaglandin analogs May cause reddening of the eyes (hyperemia)hyperemia May cause blurred vision; May cause eyelid redness; May permanently darken eyelashes; May cause eye discomfort; May eventually cause permanent darkening of the iris to brown (heterochromia);irisheterochromia May cause a temporary burning sensation during use. May cause thickening of the eyelashes. Rarely, herpes simplex keratitis.

35. Iris pigmentation Occurs in up to 1/6 patients with latanoprost. Mixed-color irises (i.e., brown-gray or brown-green) are most at risk. Is the result of increased melanin production. (melanocyte division is not stimulated, no risk for melanoma.) The color change is stable and not be reversible.

36. (A) Eye before treatment. Note the brown ring of pigmentation around the pupil and light pigmentation in the periphery. This baseline iris color is most likely to exhibit darkening during treatment. (B) Same eye following latanoprost treatment. Iris pigmentation

37. Increased eyelid pigmentation The mechanism of increased skin pigmentation appears to be related to enhancing tyrosinase activity, and altering the chemistry of the melanin.

38. numerous. Treated lashes are longer, thicker, darker, and more only cosmetic significance. Higher incidence of these changes with bimatoprost and travoprost.than with latanoprost

39. CME

40. WHAT CAUSES CME? The level of topical medications in the retina and choroid is potentially high enough to affect retinal physiology. Breakdown of the blood-aqueous barrier and ultimately the blood-retina barrier. Retinal vasodilation and vascular leakage. One study on the subject revealed that it was not the prostaglandin but rather the drug’s preservative that was linked to postoperative CME.

41. WHO IS AT HIGH RISK? 1-Preexisting CME or risk factors. 2-Individuals with other macular Diseases. 3-History of ocular inflammatory disease 4-History of retinal vein occlusion, diabetes, vitreous loss, uveitis, vitreomacular traction, an epiretinal membrane, aphakia, and an absent posterior capsule (post capsulotomy or via an intraoperative complication.)

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