1. Eye drops for glaucoma – past, present and future
Jonathan G Crowston MBBS, FRCOphth, FRANZCO, PhD
MD, Centre for Eye Research Australia

2. No financial interests in any of the commercial products mention.
Consultant/ Scientific Advisory Boards:
Alcon
Allergan
Annexon
AusBio
Pfizer
MSD
Polyactiva
Seagull Technologies
Santaris

3. Castor seeds (4000 – 2000 BC)
Georgi Markos

4. The Ebers Papyrus
Kohl, Antimony
1553 BC

5. Glaucoma drops
1950 Alexander and Connor

6. Glaucoma Therapeutic Timeline
Neuroprotection
Gene transfer
Immunotherapy
SiRNA’s
Betagan
Betoptic
Timoptic
Pilocarpine
Propine
But what has the clinician historically had available to address these concerns? Up until the 1970s, relatively little. And what was available was generally of only moderate efficacy by today’s standards, presented unacceptable side effects—if not toxicity—in a large percentage of patients, and required less convenient QID dosing.
The introduction of topical dipivefrin in the early 1970s was a significant step forward. Its twice-daily dosing was more convenient, and it proved more effective and better tolerated than the epinephrine from which it was derived.
Another significant advance was the ophthalmic beta-blockers, introduced in the late 1970s. Nonselective beta-blockers combined effective IOP management with convenient twice-daily dosing—though they still posed cardiopulmonary side effects in some patients. Selective beta-blockers proved safer, but were so at the expense of efficacy.
The 1990s was a decade of great change for glaucoma treatment. Topical carbonic anhydrase inhibitors were introduced that were safer and more effective than their systemic predecessors. Prostaglandins were introduced one of which proved highly effective at managing IOP in many—though not all—patients. And some established products released extended-action formulations that improved convenience. Finally, the 1990s was the decade in which one second-generation 2 agonist was proven exceptionally safe, highly effective at suppressing intraocular pressure, and perhaps most significantly, showed strong evidence of neuroprotection.
Since the 1870s, glaucoma therapy has made significant strides in IOP management, ocular and systemic safety, patient convenience, and now—in addressing the fundamental mechanism of visual loss from glaucoma—optic neuropathy.
1870s ‘80s ‘90s 1900s ‘10s ‘20s ‘30s ‘40s ‘50s ‘60s ‘70s ‘80s ‘90s
Alphagan
Azopt
Betoptic-S
Cosopt
Iopidine
Trusopt
Xalatan
Travatan
Lumigan
Diamox
Epinephrine
Combigan
Xalacom
DuoTrav
GanFort

9. An uncomfortable truth!
Persistence with topical glaucoma medication
50% discontinued all drops by 6 months
37% of pts refilled at 3 years
Only 10% had no gaps in refill rate
Nordstrom and Friedman AJO 2005

10. Fixed combinations Xalacom – Xalatan + Tim DuoTrav – Travatan + Tim
Ganfort – Lumigan + Tim
Cosopt – Trusopt Tim
Combigan – Alphagan + Tim
Azarga – Azopt Tim
Simbrinza – Alphagan and Azopt

11. RVEEH/ CERA
Melbourne prospective case-control study POAG vs controls (mean age 66yrs , 33% single med)
Significant increase in signs and symptoms in POAG vs controls
POAG
n=300
Controls
n=100
Symptoms
31%
24%
Signs
71%
33%
Validated 7pt questionnaire (Shihpai)
TBUT <5sSchirmer <5mmMGD testFluoresceine stain (CCLRU)
S. Ghosh et al.
CLEO 2012

12. Predictors of OSD signs in glaucoma
No. of MEDICATIONS
OR 2.31 ( )
DURATION of THERAPY 
OR 1.08 ( )
S. Ghosh
CLEO 2012

13. Benzalkonium Chloride (BAK)
Generic (Trade Name)
Preservative
Brimonidine (Alphagan1)
0.005% BAK
Brimonidine with Purite (Alphagan P1)
0.005% SOC
Brinzolamide (Azopt 1)
0.01% BAK
Levobunolol (Betagan1)
Betaxolol (Betoptic S Suspension1)
Dorzolamide/Timolol (Cosopt1)
0.0075% BAK
Bimatoprost (Lumigan2)
Timolol (Timoptol1)
Timolol (Timoptol-XE1)
0.012% BDD
Travoprost (Travatan3)
0.015% BAK
Dorzolamide (Trusopt1)
Latanoprost (Xalatan1)
0.02% BAK
For most glaucoma agents that we use there are 2 constituents. The active drug and the preservative to keep bottles free of microbes
Alkyldimethylbenzylammonium
chloride
BAK: Benzalkonium chloride; BDD: Benzododecinium bromide ; SOC: Stabilized Oxychloro Complex

14. BAK other uses

15. Preservative-free drops
Lumigan, Ganfort (PF)
Saflutan (PF)
BAK free

16. Glaucoma Australia

17. The washout effect % Loss of 1st Drug
Besides a decrease in the percentage of patients who are compliant, other potential problems can develop with patients on multiple medications. Although we ask patients to wait a minimum of 5 minutes between dosing different medications, how many actually do this? This slide demonstrates the issue of “washout effect”. If patients only wait 30 seconds between dosing medications, up to 45% of the first medication can be washed out by the second. If the patient waits two minutes, 17% of the first medication is washed out. Patients should wait at least 5 minutes, to eliminate the potential to washout the first medication. 1
1. Chrai SS, Makoid MC, Eriksen SP, Robinson JR. Drop size and initial dosing frequency problems of topically applied ophthalmic drugs. J Pharm Sci. 1974;63(3):
Chrai SS, Makoid MC, J Pharm Sci. 1974; 63(3):

18. Double Dot technique
Don’t Open eyes Technique and Digital Occlusion Tear duct
Ivan Goldberg

19. Eye drop aids

20. Glaucoma drug delivery

21. Future eye drops
Nerve protection

22. Thank you
Maggie McNeil
Val Scaf