Role of Prostaglandin Analogs in The Treatment of Glaucoma - PowerPoint PPT Presentation

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Role of Prostaglandin Analogs in The Treatment of Glaucoma

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Title: Role of Prostaglandin Analogs in The Treatment of Glaucoma


1
Role of Prostaglandin Analogs in The Treatment of
Glaucoma
  • Mahmood J Showail MD

2
Glaucoma
  • One of the most common cause of blindness in the
    world.

3
Glaucoma
  • Glaucoma is characterized by three factors
  • Elevated Intra Ocular Pressure (IOP)
  • Optic nerve damage
  • (cupping of the disc)
  • Progressive loss of
  • visual field

4
Glaucoma
Visual Field Loss
Optic Nerve Damage
Intraocular Pressure
5
GlaucomaMechanisms of aqueous humor
  • Aqueous is produced by the ciliary processes
  • It flows into the posterior chamber
  • Bathes the lens
  • Fills the anterior chamber

6
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

7
Aqueous Humor Outflow
  • There are two major component of aqueous outflow
  • Trabecular outflow pressure dependant
  • Uveoscleral outflow pressure independant

8
Trabecular 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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10
Anatomy Review
11
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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.

13
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.

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15
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.

16
Aqueous 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

17
Goldman 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

18
How would we decrease the pressure?
19
GlaucomaDecrease the IOP in Glaucoma
  • Decrease the inflow
  • Blocking the mechanism of production
  • Increase the outflow
  • Through the trabecular meshwork
  • Through the uveoscleral channels

20
Prostaglandin Analogs
21
Prostaglandins Analogs
  • Latanaprost (Xalathan)
  • Bimatoprost (Lumigan)
  • Travoprost (Travatan)

Side effects Iris pigmentation and
irritation/redness
22
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

23
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

24
So, 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

31
Latanoprost (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.

33
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

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35
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

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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.

39
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

40
Travoprost (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.

41
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42
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

43
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44
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

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.

47
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.

48
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.

49
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

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

51
Summary Common Side Effects Prostaglandin
Analogs
  • Ocular
  • Change in iris color
  • Burning
  • Stinging
  • Decreased VA
  • Sensitivity to light
  • Pain
  • Hyperemia
  • Systemic
  • Headaches

52
  • DRUG INTERACTIONS Bimatoprost The concomitant
    use of Latanoprost and Bimatoprost may result in
    increased intraocular pressure. Risk D Consider
    therapy modification

53
  • Thank You
  • ..
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