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
Anatomy Review
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
Glaucoma
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
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 uveoscleral 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
 Brands
• Latanaprost
(0.005% Sol.)
 Usage:
• Once daily at bedtime
• 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
• Brands
– Lumigan
(0.03% Sol.)
• Usage:
– Once daily at bedtime
– Should NOT be used under 18 yrs of age.
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
• 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 ??
 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 F2alpha 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 promelanosomeconcentrating hormone
 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
 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.
Thank
You
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