TARIQ ALASBALI
Jan 02, 2016
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
30
40
30
20
05
10152025303540
MildDamage
AdvanceDamage
NTG OHT
% r
educ
tion
from
bas
elin
e
Ref: Survey of Ophthalmology 2003; 48 (suppl 1); 53-57
Target IOP is based on over-all glaucomatous damage
Not only controlling peak IOP is important but the drug should also control fluctuations in IOP
REQUIREMENT OF AN AGENT
FOR PROVEN 24-HOUR CONTROL
In POAG what is your first line drug and why?
What are your next choices?
PG/PAPG/PA
Target Not AchievedTarget Not Achieved
EffectiveEffectiveNot at TargetNot at Target
Target Achieved:Target Achieved:Continue to FollowContinue to Follow
Beta-BlockerBeta-Blockeraa
BrimonidineBrimonidineaa
Topical CAITopical CAIaa
CholinergicCholinergicbb
Oral CAIOral CAIbb
a: Order depends a: Order depends on side effects & on side effects & contraindications contraindications
b: Secondary Drugs b: Secondary Drugs Consider other Consider other therapies alsotherapies also
Continue & Return to Top Continue & Return to Top with Additional Drugwith Additional Drug
Ineffective Or Side effectIneffective Or Side effect
Discontinue & Return to Top Discontinue & Return to Top with Different Drugwith Different Drug
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 classDrug classMedicationMedicationMean ↓IOP Mean ↓IOP % ↓IOP% ↓IOP
PGAPGALatanoprostLatanoprost
BimatoprostBimatoprost
TravoprostTravoprost
6-8 mm Hg6-8 mm Hg
7-8 mm Hg7-8 mm Hg
7-8 mm Hg7-8 mm Hg
~ 30%~ 30%
B-blocker, non B-blocker, non selectiveselective
TimololTimolol~6mm Hg~6mm Hg~25%~25%
A-2 adrenergicA-2 adrenergicBrimonidineBrimonidine2-6 mm Hg2-6 mm Hg20-25%20-25%
B-blocker, B-blocker, selectiveselective
BetaxololBetaxolol4-5 mm Hg4-5 mm Hg~20%~20%
CAICAIDorzolamideDorzolamide3-5 mm Hg3-5 mm Hg15-20%15-20%
Prostaglandin Analogues & Prostamides: Dosing & Preparations Latanoprost
Travoprost Bimatoprost
All QHS
Latanoprost: Instillation at 9 pm
0
Baseline
Latanoprost
27
25
23
21
19
17
15
15 18 2121 24 03 06 09 12
Time (hours)
IOP
)m
mH
g(
Latanoprost when instilled at 9 pm effective controlled IOP at 9 am Peak IOP
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):755-64.1-Clin Experiment Ophthalmol. 2006:34(8):755-64. 2-Adv Ther. 2004 Jul-Aug;21(4):247-62.2-Adv Ther. 2004 Jul-Aug;21(4):247-62. 3-Ophthalmology.2005:112(7):1177-11853-Ophthalmology.2005:112(7):1177-1185
PROSTAGLANDIN: Proven for 24 hour IOP Control
Ref: Invest Ophthalmol Vis Sci 2000; 41: 2566-2573
27
25
23
21
19
17
15
015 18 2121 24 03 06 09 12
Tim e (hou rs)
B ase line
Tim o lo l tw ice da ily
La tanop rost
D o rzolom ide th ree tim es dailyIO
P (
mm
Hg
)
Latanoprost, travoprost, and bimatoprost were effective in reducing the 24-h IOP in patients with XFS and OH
Eye (2007) 21, 453–458
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
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?
Alpha 2 Agonists:Dosing & Preparations
BRIMONIDINE :THE NEUROPROTECTIVE 2 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 Ophthalmology 2004;88:953-956
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.
OphthalmologyOphthalmology Volume 112, Issue 12Volume 112, Issue 12, December 2005, 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 CombinationCosopt
CombiganXalacom 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):70-62-Ophthalmology. 2004 Feb;111(2):276-8.
33--Acta Ophthalmol Scand. 2003 Jun;81(3):242-6Acta 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 once-daily evening administration of the LTFC. (1)
(1) Current Medical Research and Opinion, Volume 23, Number 5, May 2007 , pp. 1025-1032(8) (1) Current Medical Research and Opinion, Volume 23, Number 5, May 2007 , pp. 1025-1032(8)
EXAMPLE
Abstract conclusion:
Bimatoprost provided greater mean IOP reduction than travoprost.
Br J Ophthalmology 2006; 90:1370-1373Br J Ophthalmology 2006; 90:1370-1373..
Main outcome measureMain outcome measure To evaluate the efficacies of bimatoprost and travoprost for To evaluate the efficacies of bimatoprost and travoprost for lowering of IOP for the treatment of glaucoma and ocular HTN.lowering of IOP for the treatment of glaucoma and ocular HTN.
ResultResult:: The mean reduction in the bimatoprost group were The mean reduction in the bimatoprost group were
greater than the reduction in the travoprost group at greater than the reduction in the travoprost group at every study visit, but theseevery study visit, but these
differences were not significant (p >0.207)differences were not significant (p >0.207)..
COMPLIANCE: THE HIDDEN CHALLENGE OF GLAUCOMA
MANAGEMENT
Patient Compliance: GlaucomaPatient 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
Adv Ther. 2001 Sep-Oct;18(5):205-15.
BAK has demonstrated cytotoxic effects in cell culture, as well as in animal and human studies.
Physicians should consider treatment with new-generation preparations containing low-risk preservatives, especially in patients receiving multiple ophthalmic medications.
PreservativesPreservatives
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. Cornea. 2004 Jul;23(5):490-6.
British Journal of Ophthalmology423-418-86-2002:
Preservatives
Preservatives
Alphagan P Purite Alphagan 0,005% Lumigan 0,005% Combigan 0.005% Trusopt 0.0075% Cosopt 0.0075% Azopt 0.01% Timoptic 0.01% Betoptic 0.01% Travatan 0.015% Xalatan 0.02% Xalacom 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