Role of Prostaglandin Analogs in The Treatment of Glaucoma

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Role of Prostaglandin Analogs in The Treatment of
Glaucoma

• Mahmood J Showail MD

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Glaucoma

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

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Glaucoma

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

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Glaucoma
Visual Field Loss
Optic Nerve Damage
Intraocular Pressure
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Anatomy Review
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GlaucomaMechanisms of aqueous humor

• Aqueous is produced by the ciliary processes
• It flows into the posterior chamber
• Bathes the lens
• Fills the anterior chamber

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GlaucomaAqueous 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

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Glaucoma
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Open Angle Glaucoma
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Open Angle Glaucoma

• Most common form of glaucoma
• Caused by blockage in the TM leading to decreased
  drainage of aqueous into the Schlemms canal

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Open Angle Glaucoma
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Angle closure Glaucoma
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ACGAngle closure Glaucoma

• Anatomically the angle is narrow
• Risk of angle closure occurs when the pupil is
  dilated

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ACGAcute Angle Closure Glaucoma
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ACGAcute Angle Closure Glaucoma
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How would we decrease the pressure?
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GlaucomaDecrease the IOP in Glaucoma

• Decrease the inflow
• Blocking the mechanism of production
• Increase the outflow
• Through the trabecular meshwork
• Through the uveoscleral channels

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OAGMedical 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.

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OAGTopical medications (cont.)

• Epinephrine drugs
• Dipivefrin (Propine)
• Alpha adrenergic agonists
• Apraclonidine (Iopidine)
• Brimonidine (Alphagan)
• Lower IOP by decreasing
• the aqueous production

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OAGmedications (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

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OAGGlaucoma medications (cont.)

• Prostaglandins
• Latanaprost (Xalathan)
• Travatan
• Increase the outflow through the uveo-scleral
  channels.

Side effects Iris pigmentation and
irritation/redness
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Glaucoma DrugsProstaglandin 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
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Glaucoma DrugsProstaglandin 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

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Glaucoma DrugsProstaglandin 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

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Glaucoma Drugs Side Effects Prostaglandin
Analogs

• Ocular
• Change in iris color
• Burning
• Stinging
• Decreased VA
• Sensitivity to light
• Pain
• Hyperemia

• Systemic
• Headaches
• Hypertension

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Glaucoma DrugsCombination 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

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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

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So, How would Prostaglandin analogs works ??
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• Latanoprost is a prostaglandin F2a analogue. Its
  chemical name is isopropyl - (Z) -7
  (1R,2R,3R,5S) 3,5-dihydroxy-2-(3R)-3-hydroxy-5-p
  henylpentyl cyclopentyl -5-heptenoate.
• Its molecular formula is C26 H40 O5 and its
  chemical structure is

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

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• 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.

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• 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

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• 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

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• 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.

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• 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

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

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• 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.

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• CLINICAL STUDIES
• Patients with mean baseline intraocular pressure
  of 24 25 mmHg who were treated for
• 6 months in multicenter, randomized, controlled
  trials demonstrated 68 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.

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• 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.

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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.

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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.

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ADVERSE REACTIONS SIGNIFICANT

• gt10 Ocular Blurred vision, burning and
  stinging, conjunctival hyperemia, foreign body
  sensation, itching, increased pigmentation of the
  iris, and punctate epithelial keratopathy

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• 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

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• 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.

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

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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

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• 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

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

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• 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.

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• 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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• Thank You
• ..