1. Role of Prostaglandin Analogs in The Treatment of Glaucoma
Mahmood J Showail MD

2. Glaucoma
One of the most common cause of blindness in the world.

3. Glaucoma Glaucoma is characterized by three factors:
Elevated Intra Ocular Pressure (IOP)
Optic nerve damage
(cupping of the disc)
Progressive loss of
visual field

4. Glaucoma
Visual Field Loss
Optic Nerve Damage
Intraocular Pressure

6. Anatomy Review
20% of the aqueous humor is drained out through uveal-scleral channels

7. Glaucoma Mechanisms of aqueous humor
Aqueous is produced by the ciliary processes
It flows into the posterior chamber
Bathes the lens
Fills the anterior chamber
Aqueous exit the eye through
the trabecular meshwork
the canal of Schlemm
Released through the bloodstream

8. Glaucoma Aqueous Flow Dynamics
Inflow should be equal to the outflow
Normal IOP is between 10 – 20 mmHg
Normally the IOP is highest in the morning and lowest in the evening
Diurnal curve
Abnormal balance results in increased IOP causing glaucoma.

9. Glaucoma
Trauma

11. Open Angle Glaucoma

12. Open Angle Glaucoma Most common form of glaucoma
Caused by blockage in the TM leading to decreased drainage of aqueous into the Schlemm’s canal

13. Open Angle Glaucoma

14. Angle closure Glaucoma

15. ACG Angle closure Glaucoma
Anatomically the angle is narrow
Risk of angle closure occurs when the pupil is dilated

16. ACG Acute Angle Closure Glaucoma

17. ACG Acute Angle Closure Glaucoma

18. How would we decrease the pressure?

19. Glaucoma Decrease the IOP in Glaucoma
Decrease the inflow
Blocking the mechanism of production
Increase the outflow
Through the trabecular meshwork
Through the uveoscleral channels

20. Drugs to decrease the aqueous production: Betablockers
OAG Medical Treatment
Drugs to decrease the aqueous production:
Betablockers
Timolol (Cusimol)
Nyolol gel
Betoptic, Betagan
Side effects :
Decreased in heart rate
Respiratory difficulty.
Not for asthmatic patients.

21. OAG Topical medications (cont.)
Epinephrine drugs
Dipivefrin (Propine)
Alpha adrenergic agonists
Apraclonidine (Iopidine)
Brimonidine (Alphagan)
Lower IOP by decreasing
the aqueous production

22. OAG medications (cont.)
Carbonic Anhydrase Inhibitors (CAI)
Trusopt 2%, Azopt (solution)
Diamox tablet/capsules
Combination CAI and Betablockers
Cosopt, Xolamol
Topical CAI is preferred as they have less side effects

23. OAG Glaucoma medications (cont.)
Prostaglandins
Latanaprost (Xalathan)
Travatan
Increase the outflow through the uveo-scleral channels.
Side effects:
Iris pigmentation and irritation/redness

25. Glaucoma Drugs Prostaglandin Analogs
Action:
Reduce IOP by increasing the outflow through uveoscleral channels
Lowers IOP in 3- 4 hrs after instillation
Generics
Latanaprost
(0.005% Sol.)
Usage:
Once daily at bedtime
Brands
Xalatan
Contraindicated in asthmatic patients

27. Glaucoma Drugs Prostaglandin Analogs
Action:
Reduce IOP by increasing the outflow through uveoscleral channels
Lowers IOP in hrs after instillation
Generics
Travoprost
(0.004% Sol.)
Usage:
Once daily at bedtime
Brands
Travatan

29. Glaucoma Drugs Prostaglandin Analogs
Action:
Reduce IOP by increasing the outflow through uveoscleral channels
Generics
Bimatoprost
(0.03% Sol.)
Usage:
Once daily at bedtime
Should NOT be used under 18 yrs of age.
Brands
Lumigan

30. Glaucoma Drugs – Side Effects Prostaglandin Analogs
Ocular:
Change in iris color
Burning
Stinging
Decreased VA
Sensitivity to light
Pain
Hyperemia
Systemic:
Headaches
Hypertension

31. Glaucoma Drugs Combination Drugs
Prostaglandin + Betablockers
Decrease production of aqueous humor
(double effectiveness)
Generics
Latanoprost +
Timolol
(0.005% with 0.5% solution)
Usage:
Once daily in the morning
Brands
Xalacom

32. Xalacom Careful medical history is important
Notify the doctor if the patient suffers from:
Asthma
Heart disease
Diabetes
Hypoglycemia
Overactive thyroid gland
Hypotension
Vascular disorders

34. So, How would Prostaglandin analogs works ??

35. Latanoprost is a prostaglandin F2α analogue
Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl - (Z) -7 [(1R,2R,3R,5S) 3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl] cyclopentyl] -5-heptenoate.
Its molecular formula is C26 H40 O5 and its chemical structure is:

36. Latanoprost is a colorless to slightly yellow oil & Benzalkonium chloride, 0.02% is added as a preservative.

37. Mechanism of Action
Latanoprost is a prostanoid selective F2-alpha prostaglandin receptor agonist which is believed to reduce the intraocular pressure by increasing the outflow of aqueous humor.
Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow.

38. This drug decreases IOP by increasing aqueous outflow through the uveoscleral outflow system.2 3 Compounds related to prostaglandins called prostamides are also used to reduce IOP.4 These drugs, which have structures similar to those of prostaglandins, are thought to enhance outflow through both the uveoscleral outflow pathway and the traditional outflow system, but the actual mechanisms of their action are still unknown. Trabecular meshwork and ciliary muscle are two major tissues of the outflow systems, but little is known about the biological changes in these two tissues during long-term use of prostaglandin analogues

39. Outflow of aqueous humor may be increased by the prostaglandin analogues by alterations in the extracellular matrix. Other changes may influence cellular metabolism, such as the increases in IGF1, tumor necrosis factor superfamily-10 and promelanosome-concentrating hormone

40. The recommended dosage is one drop (1
The recommended dosage is one drop (1.5 µg) in the affected eye(s) once daily in the evening. If one dose is missed, treatment should continue with the next dose as normal.
The dosage of XALATAN Sterile Ophthalmic Solution should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including XALATAN Sterile Ophthalmic Solution is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the intraocular pressure lowering effect or cause paradoxical elevations in IOP.

41. Reduction of the intraocular pressure starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours.
XALATAN may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart

42. Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

43. Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug
is hydrolyzed to the acid form to become biologically active. Studies in man indicate
that the peak concentration in the aqueous humor is reached about two hours after
topical administration.

44. CLINICAL STUDIES
Patients with mean baseline intraocular pressure of 24 – 25 mmHg who were treated for
6 months in multicenter, randomized, controlled trials demonstrated 6–8 mmHg reductions
in intraocular pressure. This IOP reduction with XALATAN Sterile Ophthalmic Solution
0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily.

45. PHARMACODYNAMICS / KINETICS Onset of action: 3-4 hours   Peak effect: Maximum: 8-12 hours
Absorption: Through the cornea where the isopropyl ester prodrug is hydrolyzed by esterases to the biologically active acid. Peak concentration is reached in 2 hours after topical administration in the aqueous humor.

46. CONTRAINDICATIONS
XALATAN has been reported to cause changes to pigmented tissues. The most
frequently reported changes have been increased pigmentation of the iris and
periorbital tissue (eyelid) and increased pigmentation and growth of eyelashes.
These changes may be permanent.

47. WARNINGS / PRECAUTIONS
Concerns related to adverse effects:
Bacterial keratitis: Inadvertent contamination of multiple-dose ophthalmic solutions, has caused bacterial keratitis.
Ocular effects: May permanently change/increase brown pigmentation of the iris, the eyelid skin, and eyelashes. In addition, may increase the length and/or number of eyelashes (may vary between eyes); changes occur slowly and may not be noticeable for months or years. Long-term consequences and potential injury to eye are not known.

48. ADVERSE REACTIONS SIGNIFICANT
>10%: Ocular: Blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, and punctate epithelial keratopathy

49. 1% to 10%:   Cardiovascular: Chest pain, angina pectoris   Dermatologic: Rash, allergic skin reaction   Neuromuscular & skeletal: Myalgia, arthralgia, back pain   Ocular: Dry eye, excessive tearing, eye pain, lid crusting, lid edema, lid erythema, lid discomfort/pain, photophobia   Respiratory: Upper respiratory tract infection, cold, flu

50. Special populations:
Contact lens wearers: Contains benzalkonium chloride which may be adsorbed by contact lenses; remove contacts prior to administration and wait 15 minutes before reinserting.

51. DRUG INTERACTIONS Bimatoprost: The concomitant use of Latanoprost and Bimatoprost may result in increased intraocular pressure. Risk D: Consider therapy modification

52. Mechanism of Action of Bimatoprost, Latanoprost, and Travoprost in Healthy Subjects: A Crossover Study
American Academy of Ophthalmology
K. Sheng Lim, MD12, Cherie B. Nau, BS1, Megan M. O'Byrne, MS3, David O. Hodge, MS3, Carol B. Toris, PhD4, Jay W. McLaren, PhD1, Douglas H. Johnson, MD1

53. Purpose
To study the effects of 3 prostaglandin analogs, bimatoprost, latanoprost, and travoprost, on aqueous dynamics in the same subjects and to compare techniques of assessing outflow facility

54. Design
Experimental study (double-masked, placebo-controlled, randomized paired comparison, 4-period crossover).
Participants
Thirty healthy adult subjects

55. Methods
Bimatoprost, latanoprost, travoprost, or a placebo was administered to the left eye once a day in the evening for 7 days, after a minimum 4-week washout period between each session. Tonographic outflow facility was measured by Schiøtz tonography and pneumatonography on day 7. On day 8, the aqueous humor flow rate and fluorophotometric outflow facility were measured by fluorophotometry. Uveoscleral outflow was calculated from the aqueous humor flow rate and outflow facility using the Goldmann equation.

56. 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.

57. Thank You ..