Transcript Glaucoma

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
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 canalvenous 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 +
Timolol
(0.005% with 0.5% solution)
• Usage:
– Once daily in the morning
– 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 ??
 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
• Latanaprost
(0.005% Sol.)
 Usage:
• Once daily at bedtime
 Brands
• Xalatan
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
– Bimatoprost
• Brands
– 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
– Travoprost
(0.004% Sol.)
• Usage:
– Once daily at bedtime
Brands
Travatan –
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:
• Change in iris
color
• Burning
• Stinging
• Decreased VA
• Sensitivity to light
• Pain
• Hyperemia
 Systemic:
• Headaches
 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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