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