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

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Intraocular Pressure
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
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
Aqueous Humor Outflow

 There are two major component of

aqueous outflow :

• Trabecular outflow “pressure dependant”

• Uveoscleral outflow “pressure independant”
 Trabecular Outflow
 Most of the aqueous exits the eye through trabecular
meshwork- schlemm’s canal- venous system

 The TM can be devided into three zones

• Uveal
• Corneoscleral
• Juxtacanalicular
 The primary resistance occurs at the juxtacanalicular
tissue.
Anatomy Review
 The TM functions as a one way valve that
permits aqueous to leave the eye by bulk
flow .

 Once in schlemm’s canal, aqueous enter

the episcleral veinous plexus by way of
scleral collector channels.
 Uveoscleral 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.
 Uveoscleral 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.
Aqueous Humor Outflow

 The facililty of outflow “C in goldman

equation”varies 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
 Goldman equation
Pº = (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”
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
Prostaglandin Analogs
Prostaglandins Analogs

• Latanaprost (Xalathan)
• Bimatoprost (Lumigan)
• Travoprost (Travatan)

Side effects:
Iris pigmentation and
irritation/redness
 Glaucoma Drugs

Combination Drugs
• Prostaglandin + Betablockers
– Decrease production of aqueous humor
• (double effectiveness)
• Generics • Brands
– Latanoprost + – Xalacom
Timolol
(0.005% with 0.5% solution)

• Usage:
– Once daily in the morning
 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
 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
 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.
 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 .
 Many study have reported that PGF2α
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”.
 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
doi:10.1016/j.survophthal.2008.08.010
 Latanoprost (Xalatan)
 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.
 Glaucoma Drugs

Prostaglandin Analogs

 Action:
• Reduce IOP by increasing the outflow through
uveoscleral channels
• Lowers IOP in 3- 4 hrs after instillation

 Generics  Brands
• Latanaprost • Xalatan
(0.005% Sol.)

 Usage:
• Once daily at bedtime
 Bimatoprost (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
 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
 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 PGF2α 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.
 Glaucoma Drugs

Prostaglandin Analogs
• Action:
– Reduce IOP by increasing the outflow through
uveoscleral channels

• Generics • Brands
– Bimatoprost – Lumigan
(0.03% Sol.)

• Usage:
– Once daily at bedtime
– Should NOT be used under 18 yrs of age.
 Travoprost (TRAVATAN)
 Travoprost is a PGF2α analog, is an
isopropyl ester of the enantiomer of
fluprostenol.

 It is structurally similar to other f2α anlogs.

 It is a selective FP prostanoid receptor

agonist.
 Glaucoma Drugs

Prostaglandin Analogs

• Action:
– Reduce IOP by increasing the outflow through
uveoscleral channels
– Lowers IOP in 2 - 3 hrs after instillation
Generics Brands
– Travoprost Travatan –
(0.004% Sol.)

• Usage:
– Once daily at bedtime
 Pharmacokinetics
 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
 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.
 Pediatric Use:
Safety and
effectiveness in
pediatric patients
have not been
established.
 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
 Summary – Common Side Effects

Prostaglandin Analogs
 Ocular:  Systemic:
• Change in iris • Headaches
color
• Burning
• Stinging
• Decreased VA
• Sensitivity to light
• Pain
• Hyperemia
 DRUG INTERACTIONS
Bimatoprost: The concomitant use of
Latanoprost and Bimatoprost may result
in increased intraocular pressure. Risk
D: Consider therapy modification
Thank
You
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