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

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

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

Glaucoma Visual Field Loss Optic Nerve Damage Intraocular Pressure

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

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

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.

Glaucoma Trauma

Open Angle Glaucoma

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

Open Angle Glaucoma

Angle closure Glaucoma

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

ACG Acute Angle Closure Glaucoma

ACG Acute Angle Closure Glaucoma

How would we decrease the pressure?

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

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.

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

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

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

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

Glaucoma Drugs Prostaglandin Analogs Action: Reduce IOP by increasing the outflow through uveoscleral channels Lowers IOP in 2 - 3 hrs after instillation Generics Travoprost (0.004% Sol.) Usage: Once daily at bedtime Brands Travatan

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

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

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

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

So, How would Prostaglandin analogs works ??

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:

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

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.

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

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

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.

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

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

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.

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.

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.

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.

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.

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

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

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.

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

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

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

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

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.

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.

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