Of Glaucoma Pharmacologic Therapy

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Transcript Of Glaucoma Pharmacologic Therapy

PHARMACOLOGY OF GLAUCOMA
TARIQ ALASBALI
Glaucoma: Treatment Goal
“The goal of glaucoma treatment is to preserve
the visual field of patients and prevent the loss
of visual function associated with the disease.”
Ref: Survey of Ophthalmology; 2003 Vol. 48(1): S1-S3
What is a target IOP?
“The IOP at which the rate of retinal
ganglion cell loss is no greater than the age
related loss.”Brubaker
AAO Guidelines: Target IOP
% reduction from baseline
40
40
35
30
25
20
15
10
5
0
30
30
20
Mild
Damage
Advance
Damage
NTG
OHT
Ref: Survey of Ophthalmology 2003; 48 (suppl 1); 53-57
Target IOP is based on over-all glaucomatous
damage
Optic
Nerve
Damage
IOP
Target
IOP
VF
Risk
Factors
FLUCTUATIONS IN IOP
REQUIREMENT OF AN AGENT
FOR PROVEN
24-HOUR CONTROL
Not only controlling peak IOP is important but the drug
should also control fluctuations in IOP
 In POAG what is your first line drug and why?
 What are your next choices?
PG/PA
Target Achieved:
Continue to Follow
Target Not Achieved
Ineffective Or Side effect
Effective
Not at Target
Continue & Return to Top
with Additional Drug
Discontinue & Return to Top
with Different Drug
Beta-Blockera
Brimonidinea
Topical CAIa
Cholinergicb
Oral CAIb
a: Order depends
on side effects &
contraindications
b: Secondary Drugs
Consider other
therapies also
Primary Drug Classes
 Prostaglandin Analogues / Prostamides
 Beta Adrenergic Antagonists
 ‘Beta blockers’
 Alpha 2 Adrenergic Agonists
 Carbonic Anhydrase Inhibitors
Primary Drug Classes

A meta-analysis of 27 articles suggests that
bimatoprost, travoprost, latanoprost, and
timolol are the most effective intraocular
pressure-reducing agents in POAG and OH
patients.
Ophthalmology. 2005 Jul;112(7):1177-85 .
Prostaglandin Analogues is approved by (FDA), as a
first line treatment for elevated (IOP) associated with
open angle glaucoma or ocular hypertension
http://www. medscape.com assessed on 18/11/03
Secondary Drug Classes
 Parasympathomimetics
 Cholinergic (Muscarinic) Agonists
 Acetylcholinesterase inhibitors
 Non-selective Adrenergic Agonists
 Rarely used
Drug class
Medication
Mean ↓IOP
% ↓IOP
PGA
Latanoprost
Bimatoprost
Travoprost
6-8 mm Hg
7-8 mm Hg
7-8 mm Hg
~ 30%
B-blocker, non
selective
Timolol
~6mm Hg
~25%
A-2 adrenergic
Brimonidine
2-6 mm Hg
20-25%
B-blocker,
selective
Betaxolol
4-5 mm Hg
~20%
CAI
Dorzolamide
3-5 mm Hg
15-20%
Prostaglandin Analogues &
Prostamides: Dosing & Preparations
 Latanoprost
 Travoprost
 Bimatoprost
 All QHS
Latanoprost:
Instillation at 9 pm
27
25
IOP (mmHg)
23
Latanoprost when
instilled at 9 pm effective controlled IOP at 9 am
Peak IOP
21
Baseline
19
Latanoprost
17
15
0
15
18
21
24
03
Time (hours)
06
09
12
Prostaglandin Analogues &
Prostamides: Mechanism of Action
 Increase uveoscleral outflow
 At least 8 PG receptor subtypes
 Latanoprost and Travoprost
 analogues of PGF2α bind known PG receptors
 Whether Bimatoprost works in the same way seems to depend on
whether you work for Allergan or Pfizer
Prostaglandin Analogues &
Prostamides: Mechanism of Action
 Free acid is active component at PG receptors
 Requires enzymatic cleavage
 Latanoprost and Travoprost are esters
 Esterases present in cornea and a.c.
 Bimatoprost is an amide.
Prostaglandin Analogues &
Prostamides: IOP Response
 Expected IOP lowering:
 ~30%
 Latan = Trav=Bim (1)
 Another finding difference, generally < 1mmHg (2)
 Recent Meta-Analysis (3)
 Latan: 31% peak, 28% trough
 Trav: 31 % peak, 29% trough
 Bim: 33 % peak, 28% trough
 Onset of IOP lowering
 2-4 hours
 Peak Effect
 8-12 hours
 Wash Out
 4-6 weeks
1-Clin Experiment Ophthalmol. 2006:34(8):755-64.
2-Adv Ther. 2004 Jul-Aug;21(4):247-62.
3-Ophthalmology.2005:112(7):1177-1185
PROSTAGLANDIN:
Proven for 24 hour IOP Control
Baseline
Dorzolomide three times daily
27
Timolol twice daily
 Latanoprost, travoprost, and bimatoprost
were effective in reducing the 24-h IOP
in patients with XFS and OH
Latanoprost
25
IOP (mmHg)
23
21
19
17
15
Eye (2007) 21, 453–458
0
15
18
21
24
03
Time (hours)
Ref: Invest Ophthalmol Vis Sci 2000; 41: 2566-2573
06
09
12
Prostaglandin Analogues &
Prostamides: Interactions with
Other IOP drugs
 Theoretically expected to have poor
additivity with parasympathomimetics
 Clinically, this has not been proven
 Good additivity to others
Prostaglandin Analogues &
Prostamides: Side Effects
 Lash Changes
 Pigmentation
 Iris
 Periocular skin
 Pro-Inflammatory
 Hyperemia of Conjunctiva
 Uveitis
 CME
 Reactiviation of HSV keratitis
Beta-Blocker Preparations
 Non-selective
 Timolol 0.25%, 0.5%
 Gel-vehicle (Timoptic XE 0.25%, 0.5%)
 Levobunolol 0.25%, 0.5%
 Befunolol
 Metipranolol
 Beta 1 Selective
 Betaxolol 0.25%, 0.5%
Beta-Blocker Preparations
 With ISA
 Cartelol 0.5% - 2%
 Pindolol 2%
Beta Blockers: Mechanism of
Action
 Mediated through beta 2 adrenergic
receptors
 Decreases aqueous production
Beta Blockers: Dosing
 BID dosing except gel-vehicle
 Increasing beyond BID of no help
 Timoptic XE once daily in a.m.
Beta Blockers:
IOP Response
 Expected IOP lowering:
 ~25%
 Peak effect
 Two hours
 Wash out
 2-5 weeks
Beta Blockers
Use w/ systemic β-blocker:
• No additional effect on pulse or BP
• ↓ IOP lowering with ↑ oral dose
• Use of systemic β-blocker can mask prior IOP
elevation and cause pseudo-NTG picture
Beta-Blockers
 Carteolol 1%
 Intrinsic sympathomimetic activity
• Theoretically causes less bronchoconstriction,
bradycardia, vasoconstriction
• Less ocular irritation
• Better tolerated in dry eye patients
Beta-Blockers
 Betagan ® Levobunolol 0.25%, 0.5%
• Slightly longer half-life than timolol; ? qd dosage
 Betoptic-S® (betaxolol 0.25% ): β1-selective
•
Less pulmonary and CNS side effects
• Less systemic absorption than timolol
Beta Blockers: Side Effects
 Bronchospasm
 Bradycardia, arrhythmia
 CHF
 Syncope
 Hypotension
 Depression
 Sexual dysfunction
Beta-Blockers:
Contraindications
 Asthma (Reactive Airway Disease)
 Bradycardia
 Heart block
 Acute CHF
Alpha 2 Agonists:Dosing & Preparations
 Iopidine® (apraclonidine 0.5%, 1%)
 BID-TID
- α1, α2
Decreases aqueous production
May lose efficacy after 4-6 months
 Alphagan-P® (brimonidine 0.1%, 0.15%), generic brimonidine 0.2%
 BID-TID
- α2-selective
↓aqueous production; ↑uveoscleral outflow
May lose efficacy after 1 year
Neuroprotection?
BRIMONIDINE :
THE NEUROPROTECTIVE a2 AGONIST
 Brimonidine neuroprotection may be mediated through
up-regulation of Brain-derived neurotrophic factor BDNF
in the retinal ganglion cells RGCs.
 Brimonidine may be (potentially) used clinically as a
neuroprotective agent.
Arch Ophthalmol. 2002;120:797-803.
Alpha 2 Agonists: IOP
Response
 Expected IOP lowering:
 20-25%
 Peak Effect
 2 hours
 Wash Out
 1-3 weeks
Alpha 2 Agonists: IOP Response
A recent study conclude that Brimonidine
0.2% has a higher potency of lowering IOP
than brimonidine Purite 0.15% at trough
when used twice-daily.
However, ocular allergic reaction was more
frequent and severe with brimonidine 0.2%
than with brimonidine Purite 0.15%.
Journal of Ocular Pharmacology and Therapeutics. 2007, 23(5): 481-486.
Alpha 2 Agonists: IOP Response
 One study suggests:
brimonidine purite BID= dorzolamide BID
???
British Journal of Ophthalmology956-88:953;2004
Alpha 2 Agonists: Side Effects
 Follicular conjunctivitis
 50% apraclonidine
 15% (at least) brimonidine
 Less with Alphagan P
 Need more non-pharmaceutical company data
 Fatigue, drowsiness
 Eye lid retraction
 Dry mouth
 Hypotension
Alpha 2 Agonists: Side Effects
 Apnea in infants and young children
weight > 20 Kg
age > 6 Years
Alternative glaucoma therapy should be
considered .
Ophthalmology Volume 112, Issue 12, December 2005
CAIs : Dosing & Preparations
 Topical
 Trusopt® Dorzolamide 2%: BID – TID
 Azopt® Brinzolamide 1%: BID – TID
 Oral
 Diamox® Acetazolamide: 250mg QID, SR 500 BID
 Neptazane® Methazolamide: 50-100mg
Once/Day-TID
CAIs: Mechanism of Action
 Inhibit CA enzyme in ciliary body epithelium
 Decrease aqueous production
 Improve ocular blood flow?
Topical CAIs : IOP Response
 Expected IOP lowering:
 15-20%
 Wash Out
 Topical: 1 week
 Oral: 3 days
Topical CAIs : Side Effects
 Ocular surface irritation
 Contact allergy
 Contraindication:
 Sulfonamide allergy
Oral CAIs: Side Effects
 Paresthesias
 Tinnitus
 Depression
 Loss of appetite
 GI symptoms
 Kidney stones
 Metabolic acidosis
 Electrolyte imbalance
Oral CAIs: Side Effects
 Anaphylaxis
 Stevens-Johnson Syndrome
 Bone marrow dysfunction
 Idiosyncratic
 Can be any cell line
 aplastic anemia most described
 Some reversible some not
 Potentially lethal
CAIs
 Oral is additive to topical (1-2mmHg)
 Topical not additive to oral
 Methazolamide 75% liver metabolized
 Safer in renal disease
 Eg. Diabetic with CRF and NVG
Parasympathomimetics: Dosing &
Preparations
 Pilocarpine 0.5% - 4% BID-QID
 4% gel once daily (QHS)
 Carbachol 0.75% - 3% BID-TID
Parasympathomimetics: Mechanism
of Action
 Increase TM outflow
 Believed secondary to contraction of smooth
muscle fibers inserting into scleral spur
Parasympathomimetics: IOP
Response
 Expected IOP lowering:
 10-20 %
 Lowers IOP by 1 hour post instillation
 Wash Out:
 3 days
Parasympathomimetics: Side
Effects
 Pro-inflammatory
 Break down blood ocular barrier
 Miosis
 Brow ache (<~40 y.o.)
 P.S.
 Shallowing of A.C.
 Possible worsening of pupil block
 RD
 Cataract
Fixed Combination
 Cosopt
 Combigan
 Xalacom
 DuoTrav
 Ganfort
Fixed Combination
 XALACOM QD = TIMOLOL BID +
XALATAN QHS (1)
 XALACOM QD >
COSOPT BID (2)
 XALACOM QD > BRIMONIDINE BID +
TIMOLO BID (3)
1-Ophthalmology. 2006 Jan;113(1):70-6
2-Ophthalmology 2004 .Feb;111(2):276-8 .
3-Acta Ophthalmol Scand. 2003 Jun;81(3):242-6
Fixed Combination
 Martinez et all study showed a
significantly higher IOP-lowering
effect of a once-daily evening dose of
the BTFC compared to that of a oncedaily evening administration of the
LTFC.
(1)
(1) Current Medical Research and Opinion, Volume 23, Number 5, May 2007 , pp. 1025-1032(8)
EXAMPLE
Main outcome measure
To evaluate the efficacies of bimatoprost and travoprost for
lowering of IOP for the treatment of glaucoma and ocular HTN.
Result:
The mean reduction in the bimatoprost group were
greater than the reduction in the travoprost group at
every study visit, but these
differences were not significant (p >0.207).
Abstract conclusion:
Bimatoprost provided greater mean IOP reduction than travoprost.
Br J Ophthalmology 2006; 90:1370-1373.
COMPLIANCE: THE HIDDEN
CHALLENGE OF GLAUCOMA
MANAGEMENT
Patient Compliance: Glaucoma
Patient compliance is a particularly important issue
in glaucoma because:
 Asymptomatic
 Long term therapy
 Benefit of treatment not apparent
 Several medications
 Expense of treatment
 Inconvenience of treatment
 Side effects of treatment
Ref: J of Glaucoma 1992; 1: 134-136
Patient Non-compliance:
Glaucoma
 Available literature suggests that between 28%
and 58% of glaucoma patients do not use their
medications as prescribed
 Non compliance is probably 30%-40%
Ref: http://www.escrs.org/April 2003 assessed on 27/03/04
Preservatives
 BAK has demonstrated cytotoxic effects in cell
culture, as well as in animal and human studies.
 Physicians should consider treatment with newgeneration preparations containing low-risk
preservatives, especially in patients receiving
multiple ophthalmic medications .
Adv Ther. 2001 Sep-Oct;18(5):20515.
Preservatives
 A study on rats corneas suggest that
glaucoma medications with low levels of
BAK, alternative preservatives such as
Purite®, or preservative-free formulations are
more benign to the ocular surfaces.
Cornea. 2004 Jul;23(5):490-6.
Preservatives
British Journal of Ophthalmology:2002-86-418-423
Preservatives












Alphagan P
Alphagan
Lumigan
Combigan
Trusopt
Cosopt
Azopt
Timoptic
Betoptic
Travatan
Xalatan
Xalacom
Purite
0,005%
0,005%
0.005%
0.0075%
0.0075%
0.01%
0.01%
0.01%
0.015%
0.02%
0.02 %
A Little Perspective…
“The risk and cost, including side effects
of treatment to lower pressure, must be
weighed against the risk of pressure
itself.”Hodapp
If you light a lamp for somebody ,
It will also brighten your path