Title: Role of Prostaglandin Analogs in The Treatment of Glaucoma
1Role of Prostaglandin Analogs in The Treatment of
Glaucoma
2Glaucoma
- One of the most common cause of blindness in the
world.
3Glaucoma
- Glaucoma is characterized by three factors
- Elevated Intra Ocular Pressure (IOP)
- Optic nerve damage
- (cupping of the disc)
- Progressive loss of
- visual field
4Glaucoma
Visual Field Loss
Optic Nerve Damage
Intraocular Pressure
5GlaucomaMechanisms of aqueous humor
- Aqueous is produced by the ciliary processes
- It flows into the posterior chamber
- Bathes the lens
- Fills the anterior chamber
6GlaucomaAqueous 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
7Aqueous Humor Outflow
- There are two major component of aqueous outflow
- Trabecular outflow pressure dependant
- Uveoscleral outflow pressure independant
8Trabecular Outflow
- Most of the aqueous exits the eye through
trabecular meshwork- schlemms canal- venous
system - The TM can be devided into three zones
- Uveal
- Corneoscleral
- Juxtacanalicular
- The primary resistance occurs at the
juxtacanalicular tissue.
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10Anatomy Review
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12- The TM functions as a one way valve that permits
aqueous to leave the eye by bulk flow . - Once in schlemms canal, aqueous enter the
episcleral veinous plexus by way of scleral
collector channels.
13Uveoscleral Outflow
- The aqueous passages from the anterior chamber
into the cilliary muscle and then into the
supracilliary and suprachoroidal spaces. - The fluid then exits the eye through the intact
sclera or along the nerves and the vessels that
penetrate it.
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15Uveoscleral Outflow
- Uveoscleral outflow is pressure independent and
is believed to be influnced by age. - Recent researches suggest that it may be a more
important route of aqueous outflow than
previously thought . Possibly accounting for up
to 50 in normal eyes of young people.
16Aqueous Humor Outflow
- The facililty of outflow C in goldman
equationvaries widely in normal eyes - The mean value reported from 0.22 to
0.28 µl/min/mmHg - Outflow facililty decrease with age is affected
by surgery, trauma, medications and endocrine
factors - Patients with glaucoma and elevated IOP have
decreased outflow facililty
17Goldman equationPº (F/C) Pv
- Pº IOP in mmHg
- F rate of aqueous formation µl/min
- C facililty of outflow µl/min/mmHg
- Pv episcleral venous pressure mmHg
18How would we decrease the pressure?
19GlaucomaDecrease the IOP in Glaucoma
- Decrease the inflow
- Blocking the mechanism of production
- Increase the outflow
- Through the trabecular meshwork
- Through the uveoscleral channels
20Prostaglandin Analogs
21Prostaglandins Analogs
- Latanaprost (Xalathan)
- Bimatoprost (Lumigan)
- Travoprost (Travatan)
Side effects Iris pigmentation and
irritation/redness
22Glaucoma 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
23Xalacom
- Careful medical history is important
- Notify the doctor if the patient suffers from
- Asthma
- Heart disease
- Diabetes
- Hypoglycemia
- Overactive thyroid gland
- Hypotension
- Vascular disorders
24So, How would Prostaglandin analogs works ??
25- Prostaglandin analogues lower intraocular
pressure by increasing uveoscleral outflow. - Although the precise mechanism is not clearly
understood, there appears to be activation of a
molecular transduction cascade and increase in
the biosynthesis of metalloproteneases ( MMP-1,
MMP-2 MMP9). - This lead to reduction of extracellular matrix
components within the cilliary muscle, iris root
and sclera
26- Uveoscleral out flow is known to flow from the
anterior chamber into the extracellular spaces of
the ciliary muscle and then in large part pass
through sclera. - Hence, It is possible that reduction of ECM and
widening and decompressing the connective tissue
that is present within portions of the
uveoscleral pathway may contribute to the
mechanism of ?? outflow.
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28- Additional mechanisms that may contribute to PG
mediated increase of uveoscleral outflow include - Relaxation of ciliary muscle and widening of
intermuscular spaces. - Cell shape changes
- Cytoskeletal alteration
- Compaction of the ECM within the tissue of the
uveoscleral outflow pathway .
29- Many study have reported that PGF2a and its
analouges and prodrugs can increrase total
outflow facility in monkeys and human ( a
comination of trabecular, uveoscleral and pseudo-
facililty ) - less consistent finding is an increase in
trabecular outflow facility with a lot of
controversies.
30- Trabecular outflow facility is not always
increased following topical treatment with PG
analogs but evidence is building that the effect
is real and not unique to any one drug of this
class. - Latanoprost, travoprost, bimatoprost, and
unoprostone all have been found to significantly
increase trabecular outflow facility in at least
one clinical study
- Update on the Mechanism of Action of Topical
Prostaglandins for Intraocular Pressure Reduction
doi10.1016/j.survophthal.2008.08.010
31Latanoprost (Xalatan)
- 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
32- Latanoprost is a colorless to slightly yellow oil
Benzalkonium chloride, 0.02 is added as a
preservative.
33Glaucoma 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
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35Bimatoprost (LUMIGAN)
- Bimatoprost, an amide that is classified as a
prostamide, ( so it is not a prostaglandin but it
acts on FP prostanoid receptor) - The free acid of bimatoprost is identical to that
of latanoprost with exception of a double instead
of a single bond at the carbon13-14 position
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37- The free acid of bimatoprost is known to be a
very potent FP receptor agonist - The hydrolysis of bimatoprost have been
demonstrated in human corneal tissue in vitro. - Enzymes including amidases,peptidases and fatty
acid amide hydrolases capable of hydrolysing
bimatoprost to its free acid and activate FP
prostanoid receptor
38- Bimatoprost appears to reduce the IOP of patients
who are unresponsive to latanoprost. -
- suggesting that the prostamide bimatoprost and
the FP receptor agonist latanoprost stimulate
different receptor populations. - This is consistent with studies on isolated
iridial cells where bimatoprost stimulated an
entirely different cell population to those
sensitive to PGF2a and bimatoprost acid . - An equally plausible explanation is that some
eyes may be deficient in corneal esterase and
thus are not able to adequately convert the
prodrug latanoprost into its free acid active
form.
39Glaucoma 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.
40Travoprost (TRAVATAN)
- Travoprost is a PGF2a analog, is an isopropyl
ester of the enantiomer of fluprostenol. - It is structurally similar to other f2a anlogs.
- It is a selective FP prostanoid receptor agonist.
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42Glaucoma 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
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44Pharmacokinetics
- 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
45- 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 2 hours after topical administration.
46- Pediatric Use Safety and effectiveness in
pediatric patients have not been established.
47CONTRAINDICATIONS
- 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.
48WARNINGS / 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.
49ADVERSE REACTIONS SIGNIFICANT
- gt10 Ocular Blurred vision, burning and
stinging, conjunctival hyperemia, foreign body
sensation, itching, increased pigmentation of the
iris, and punctate epithelial keratopathy
50- 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
51Summary Common Side Effects Prostaglandin
Analogs
- Ocular
- Change in iris color
- Burning
- Stinging
- Decreased VA
- Sensitivity to light
- Pain
- Hyperemia
52- 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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