1. GLAUCOMA MEDICATIONS Jill Autry, OD, RPh Eye Center of Texas, Houston
WHAT WE HAVE, WHERE WE’RE GOING…
Jill Autry, OD, RPh
Eye Center of Texas, Houston

2. THE HISTORY OF GLAUCOMA
The terms “glaucosis” and “hypochyma” were used synonymously
Vague terminology meaning “greenish/bluish” discoloration
Used indiscriminately in discussions of blindness until 1800s
“Hypochyma” linked later to cataract and considered treatable
“Glaucosis” was the incurable association

3. THE HISTORY OF GLUCOMA In 1622, linked to firmness of globe
“humour settled in hollow nerves…the eye grown more solid and hard than natural…”
Thought to be disorder of vitreous or choroid
In 1820, glaucoma and cataract were differentiated
In 1840, the term glaucoma was linked to increased IOP but only in regards to acute or absolute glaucoma
In 1857, the ophthalmoscope was invented allowing for view of optic nerve damage

4. THE HISTORY OF GLAUCOMA TREATMENT
In 1857, iridectomy was introduced for acute glaucoma
In 1875, the use of a miotic for acute glaucoma
In 1935, used medications for the treatment of a less acute form of increased IOP which can lead to same end result
In 1957, oral CAI for use in glaucoma treatment

5. DIAGNOSIS Gonioscopy Optic nerve examination Intraocular pressure
Pachymetry
Visual field
Nerve fiber layer analysis

6. AQUEOUS AND ANATOMY
Aqueous is continuously produced by the ciliary body
2-3 µl/minute produced on a diurnal curve
Turnover every hours
Aqueous flows from the posterior chamber through the pupil into the anterior chamber
Aqueous filters largely through the trabecular meshwork (90%)
Aqueous also exits to a smaller extent through the ocular venous system (10%)
Uveoscleral outflow (ciliary body, choroid, scleral vessels)

7. AUTONOMIC NERVOUS SYSTEM
Sympathetic regulation
Fight and flight
2 main classes of receptors
Beta receptors (ß1 and ß2)
Alpha receptors (α1 and α2)
Parasympathetic regulation
Lay down on the couch and go to sleep

8. AUTONOMIC NERVOUS SYSTEM
Pupil is controlled by both
Sympathetic system dilates the pupil by stimulating the contraction of dilator muscle
Parasympathetic system constricts the pupil by causing contraction of the sphincter muscle.
Ciliary body is controlled by both
Sympathetic system for aqueous production
Parasympathetic system causing ciliary body muscle movement

9. PILOCARPINE Cholinergic, parasympathomimetic agent
Mechanisms of action are completely mechanical
Causes miosis of pupil by contraction of iris sphincter muscle
Constricts the pupil pulling the peripheral iris away from the trabecular meshwork
Pulls scleral spur posteriorly and internally
Produces alterations in ciliary body mediated configuration of the outflow apparatus

10. PILOCARPINE Max of 10-20% IOP reduction
Available in 0.5%, 1%, 2%, 3%, 4%, 6%
Pilopine HS 4% gel
1% or 2% is most widely used
Chronic use limited by efficacy, compliance factors, and side effects

11. PILOCARPINE Adverse effects and limitations Pupil constriction
Permanent after long term use
Induced myopia
Headache
Accommodative spasm
Blurred vision
Retinal detachment
Frequency of use

12. WHEN TO USE PILO Acute angle closure Prophylaxis against angle closure
Verify with gonioscopy
Other eye should be narrow, too
Usually hyperopic, older patients with increasing lens size
Can be precipitated by certain medications
??? Wait until IOP is below 40mmHG????
Prophylaxis against angle closure

13. WHY NOT USE PILO MORE? Miosis Young patients Inflammatory conditions
Increased headache
Blurred vision secondary to fluctuating myopia
Inflammatory conditions
Increases flare in the anterior chamber
Myopic patients
More at risk for retinal detachment
Patients with cataracts
Pupil constriction limits vision
Small pupil can complicate cataract extraction

14. Prostaglandins Prostaglandin F2α analogues
Xalatan (latanoprost)
Lumigan (bimatoprost)
Travatan (travoprost); Travatan Z (BAK free)
Increase fluid outflow through ocular venous system (uveoscleral outflow)
Max IOP reduction of 33-40%
Once daily (qhs) meds
Twice daily yields less IOP reduction

15. Prostaglandins Systemic side effects are extremely rare
Allergy is extremely rare
Most side effects are local and cosmetic
Conjunctival hyperemia
Iris pigmentation
Periorbital darkening
Eyelash growth/thickening/darkening

16. WHEN PROSTAGLANDINS ARE YOUR FIRST CHOICE
Primary Open Angle Glaucoma
Ocular Hypertension
Pigmentary Glaucoma
Pseudoexfoliative glaucoma
Angle recession glaucoma
Not during acute episode if possible

17. WHEN PROSTAGLANDINS ARE YOUR LAST CHOICE
Elevated IOP secondary to trauma
Inflammatory glaucoma
Glacomatocyclitic iritis (aka Possner-Schlossman)
Fuch’s Heterochromic iridocyclitis
IOP increases due to herpetic disease
History of/concern of inducing macular edema
Diabetic with macular edema, epiretinal membrane
Steroid induced glaucoma
Post-surgical IOP spike
Neovascular glaucoma
Unilateral treatment

18. Comparison of Prostaglandins
Similar in ability to lower pressure
Lumigan 0.03% is lower across more time points
Xalatan has highest non-responder rate
All are associated with hyperemia
Structure mediated, not preservative mediated
Lumigan 0.03%=Travatan Z>Xalatan
Less severe hyperemia (66%) with new Lumigan 0.01% compared with Lumigan 0.03%
All may cause iris color and eyelash growth
Iris color changes permanent
Least with Lumigan; most with Xalatan
Eyelash changes impermanent; most with Lumigan

19. Comparison from Phase III Trials
NOTE *
Lumigan
Travatan
Xalatan
IOP Reduction
> Timolol (mmHg)
> 2.5
1.2
% Patients
< 17 mm Hg
64%
56.3%
49.5%
Mean IOP-Blacks
17.1
17.2
18.6
IOP- Non-Blacks
16.9
18.5
Hyperemia
45%
15%
Iris Pigmentation
1.5%
2.5%
16%

20. WHEN ADDING AGENTS Think mechanism of action
Best chance of additivity by combining medications with different mechanisms
PGAs lower IOP by increasing aqueous outflow (uveoscleral/trabecular)
Complement a PGA by adding a drug that inhibits aqueous production
Brimonidine (also has uveoscleral MOA)
CAI
Beta-blocker

21. CILIARY BODY AND AUTONOMIC NERVOUS SYSTEM
Sympathetic system increases aqueous production
Through stimulation of ß receptors
ß blockade decreases aqueous production
Sympathetic system decrease aqueous production
Through activation of α2 receptors
α2 agonists decrease aqueous production

22. ALPHA-2 AGONISTS 2-adrenergic agonist Apraclonidine (Iopidine)
Brimonidine (Alphagan)
Enhanced α2 selectivity due to double ring structure

23. BRIMONIDINE
Primary mechanism of action is decreased aqueous production
Great additive agent to PGA
Secondary mechanism of action is enhanced uveoscleral outflow
Great combination agent with timolol
Max IOP reduction of 20-30%
Bid to tid dosing

24. ALPHAGAN P 0.1% Purite preservative Higher pH
Neutral, nonionized form is better absorbed
Decreased drug concentration
50% decrease
Unaltered efficacy
Less chance for local allergy
Less chance for systemic side effects
Dry mouth, fatigue, hypotension

25. OCULAR ALLERGY Ocular allergies in up to 30% of patients
Original Alphagan 0.2% and generic brimonidine 0.2%
30% allergy rate
Alphagan P 0.15%
20% allergy
Alphagan P 0.1%
10% allergy

26. WHEN TO USE BRIMONIDINE
Additive agent to a PGA
First or second line addition
Monotherapy with PGA is contraindicated
Post-op IOP spikes
Concerns for preservative toxicity
Only category B glaucoma drop for pregnancy

27. WHEN NOT TO USE BRIMONIDINE
History of allergy to brimonidine in any concentration
Eyelid swelling, tenderness, itching, follicular reaction
Can develop within weeks/months of initiation or even years later
Patients prone to hypotension
Patients with complaints of somnolence

28. CILIARY BODY AND AUTONOMIC NERVOUS SYSTEM
Sympathetic system increases aqueous production
Through stimulation of ß receptors
Beta blockade decreases aqueous production
Sympathetic system decrease aqueous production
Through activation of α2 receptors
α2 agonists decrease aqueous production

29. BETA BLOCKERS Decrease aqueous production No effect on outflow
Max IOP reduction of 20-30%
Once to twice daily (qd to bid) dosing
qd dosing equivalent to bid dosing
May be less effective if on oral beta blocker

30. Beta Blockers Timoptic (timolol) Timoptic XE (timolol gel)
Betimol (timolol)
Betagan (levobunolol)
OptiPranolol (metipranolol)
Ocupress (carteolol)
Betoptic S (betaxolol)

31. CONCERNS WITH TREATMENT
Elderly
Lung Disease
Contraindicated in asthma, COPD, etc.
Heart disease
Contraindicated in CHF (heart failure)
Diabetes
Impotence

32. Selective Beta Blocker
May cause less side effects
Still use cautiously
Betoptic S (betaxolol suspension)
Fewer side effects on the lung
Decreased efficacy vs. other beta blockers

33. LONG TERM EFFICACY Effect diminishes with time
First few weeks is “short-term” escape
Up-regulation of beta receptor numbers
Long-term drift
A receptor or intracellular tolerance develops

34. WHAT ABOUT COMBIGAN? Alphagan 0.2% with timolol 0.5%
Complementary mechanism of actions
Dosed BID
Less allergy than any of the other Alphagan products (5% vs 20% allergy rate)
50% less than 0.2 brimonidine
Advantages of combination therapy

35. COMBIGAN™ in Adjunctive Therapy With a PGA: Mean IOP
Added to a PGA baseline
-6.9 mm Hg (29%)
Mean IOP (mm Hg) * *
COMBIGAN™(brimonidine tartrate/timolol maleate
ophthalmic solution) 0.2%/0.5% + PGA (n = 37)
When used as an adjunct to prostaglandin analogue (PGA) therapy, COMBIGAN™ ophthalmic solution significantly reduced IOP from the PGA-treated baseline at both month 1 and month 3 (P < .0001).
At month 3, adjunctive COMBIGAN™ therapy provided an additional mean change from baseline IOP of 6.9 mm Hg (29%).
Mean IOP was 21.9 mm Hg in the COMBIGAN™ group at PGA-treated baseline and 15.3 mm Hg after 3 months of adjunctive COMBIGAN™ therapy.
Note to presenter: Results presented represent observed values in the worse eye. Baseline data were available for all 37 patients in the COMBIGAN™ group who used the fixed combination as adjunctive therapy with a PGA. Data were missing for 5 patients in the COMBIGAN™ group at month 1 and for 6 patients in the COMBIGAN™ group at month 3.
References
1. Nixon DR, Hollander DA. Comparison of the efficacy and tolerability of twice-daily COMBIGAN™ vs. Cosopt® fixed-combination therapies. Poster presented at: 111th Annual Meeting of the American Academy of Ophthalmology; November 10-13, 2007; New Orleans, LA.
2. Data on file, Allergan, Inc.
*P < vs baseline
Month
1Nixon and Hollander. 2AAO, Data on file, Allergan, Inc.

36. CARBONIC ANHYDRASE
Carbonic anhydrase is an enzyme present in the biochemical production of aqueous
Causes bicarbonate and hydrogen movement
Inhibition of carbonic anhydrase
Blocks active transport needed for aqueous production
End result is reduction of aqueous humor formation
Subsequent decrease in intraocular pressure

37. TOPICAL CAI Reduce aqueous humor production
Max IOP reduction of 15-20%
bid to tid dosing
Dorzolamide (Trusopt®)
Brinzolamide (Azopt®)
Dorzolamide + Timolol
Cosopt®

38. ADVERSE EFFECTS/CONCERNS
Bitter taste
Stinging
Conjunctival hyperemia
Tachyphylaxis
Concerns with history of sulfa allergies
Corneal concerns

39. SULFA ALLERGY Sulfa allergy not sulfur allergy
Rash is common sign; usually seen in the antibiotic class of sulfonamides (like Septra or sulfacetamide ointment)
Less likely to see in non-antibiotic meds
Diamox, Neptazane, Azopt, Trusopt, Cosopt
Even less likely to see with topical medications
Sulfites and sulfates are chemically different-no cross reactivity with sulfa allergies

40. CORNEA AND CAI Invest Ophthalmol Vis Sci, 2008 Mar;49(3):1048-55.
Role of carbonic anhydrase in corneal endothelial HCO3-transport.
Arch Ophthalmol Oct;125(10):
Effect of dorzolamide on central corneal thickness in humans with cornea guttata.
Arch Ophthalmol. 204 Jul;122(7):1089.
Short-term effect of dorzolamide on central corneal thickness in humans with cornea guttata.

41. INDIGENT PROGRAMS Allergan (Lumigan, Alphagan P, Combigan)
Alcon (Azopt, Travatan Z, Betoptic S)

42. DIAMOX (Acetazolamide)
Nonbacteriostatic sulfonamide
Decreases carbonic anhydrase
Decreases hydrogen and bicarbonate formation
Results in decreased aqueous production in the ciliary body by producing a systemic acidosis
Results in alkaline diuresis in the kidney but tolerance develops quickly
Contraindicated in renal, hepatic, or respiratory disease

43. DIAMOX (Acetazolamide)
Decreases carbonic anhydrase in the ciliary body which decreases aqueous humor formation
Decreases IOP by 40-60%
Starts to work in 1 hour, peak effect at 4 hours
Comes in 125mg, 250mg, 500mg sequels
Angle closure dose: (2) 250mg tablets initially—needs PI

44. ADVERSE EFFECTS Metallic taste Paresthesias (“pins and needles”)
Used mostly in emergencies because of side effects with chronic use
Kidney stones
Acute respiratory failure
Acid-base imbalances
Blood dyscrasias (aplastic anemia)
Induced myopia

45. USE IN LOWERING IOP Treatment of acute angle closure glaucoma
Treatment of less acute increased IOP
Treatment of post-surgical IOP spikes

46. ORAL CAI USES Treatment of pseudotumor cerebri
Treatment of other causes of increased intracranial pressure
Controversial treatment of serous retinal detachments
Treatment/prevention of “altitude sickness”

47. OTHER USES FOR GLAUCOMA DROPS
May be helpful with Fuch’s patients
Avoid CAIs
Stabilizing visual acuity/Rx in RK patients
Especially prostaglandins given duration of action
Brimonidine can
Decrease pupil size to eliminate glare
Decrease hyperemia
Lacks side effects of pilocarpine

48. OTHER USES FOR GLAUCOMA DROPS
Iopidine® to diagnose Horner’s?
Has been demonstrated to have same sensitivity as cocaine test for diagnosis of Horner’s
Alphagan less likely to give reliable results secondary to increased alpha-2 selectivity
Pilocarpine for diagnosis of Adie’s pupil
1% dilute 1:10 to make 0.1% solution
2% dilute 1:20 to make 0.1% solution

49. ADIE’S TONIC PUPIL Usually young female Poor reaction to light
Slow constriction to near
Slow redilation following near constriction
Vermiform movement
Constricts to 0.125% pilocarpine
May not constrict in initial stage
Long standing can result in small pupil 49

50. Oral Pilocarpine Salagen® (oral pilocarpine)
5 mg qid for dry mouth
Approved for dry mouth with Sjogren’s patients
Approved for dry mouth associated with head/neck radiation
Also used Evoxac®
30 mg tid

51. Novel Pharmaceuticals
Adenosine A1 receptor antagonist
TGF-beta2 growth factor inhibition
Wnt antagonist sFRP1
Decreasing neuronal toxicity
Glutamate inhibition
Nitrous oxide inhibition
Capsase enzyme antagonists
Decrease matrix metalloproteinases

52. TOPICAL APPLICATION AND GLAUCOMA
Corneal permeability
Less than 5% of drop is absorbed through cornea
Conjunctival vasculature loss of drug
Tear wash out
Drug solution drainage through nasolacrimal system
Spillover out of the eye
High concentrations inducing local reactions
Preservative toxicity 52

53. SYSTEMIC TREATMENT AND GLAUCOMA
Blood-Aqueous Barrier
prevents systemically administered substances from entering into the aqueous humor
Blood-Retinal Barrier
severely limits drug entry into the extravascular space of the retina and into the vitreous
Need high systemic doses to overcome
Results in higher side effects/toxicity 53

54. Current Ocular Drug Delivery
Drops
Less than 5% of drop is absorbed into cornea or anterior chamber
Ocular toxicity of preservatives
Subconjunctival injections
Periocular injections
Intravitreal injections
Risk of infection/IOP spikes/RD
Sustained release implants
Systemic-oral and intravenous
Exposes whole body to potential toxicity 54

55. Advances in Ocular Drug Delivery
Formulation factors
Surfactants-dispersion of solutes
Viscolyzers-retention and bioavailability
Instilled volume
Reduced with thicker agents
Administration technique
Non-preserved buffering techniques
Minimizes toxicity
More natural pH 55

56. Advances in Ocular Delivery
Increased ocular contact time
Ointments
Gels
Liposome formulations
Nanoemulsions
Colloidal systems
Disperse and encapsulate meds 56

57. GLAUCOMA AND DRUG DELIVERY
Controlled release
Sustained pharmaceutical levels
Sustained IOP control
Decreased frequency of dosing
Compliance
Reduced drug concentration
Decreased local side effects
Avoid systemic side effects 57

58. DRUG RELEASING CONTACT LENS
Concerns
Ability to load total drug mass onto contact lens
Ability to release drug at therapeutic doses
Avoid creating ocular toxicity
Maintaining optical clarity
Maintaining refractive properties
Amenability to storage
Biocompatibility

59. DRUG RELEASING CONTACT LENS
Advantages
Increase compliance
Increase contact time
Decrease medication concentration
Up to 50% absorption through cornea

60. DRUG RELEASING CONTACT LENS
Hydrogel contact lens trial
Timolol and Brimonidine
Maximum uptake of drug and release was limited
Silicon-hydrogels were similar
Molecularly imprinted hydrogel CL
Better retention of drug and slower release
Smaller molecules load better

61. DRUG RELEASING CONTACT LENS
Liposomal coated hydrogel contact lenses
Lidocaine and levofloxacin trials
Drug entrapped contact lenses
Polymer technology
Drug containing surfactants
Drug polymer film coated in a hydrogel lens
Proven linear release kinetics

62. PLUG BASED DELIVERY SYSTEM
Drug core inside punctal plug
Sustained drug release over time
Phase II clinical trial
Latanoprost was used
L-PPDS
Latanoprost punctal plug delivery system

63. Subconjunctival Route
Safer and less invasive than the intravitreal route
Systemic absorption is low
Lower systemic side effects while providing a localized drug effect
Substantial evidence indicating that drugs administered subconjunctivally can reach the vitreous effectively
Injectable microspheres have already been tested
Timolol with continual release up to 107 days

64. INTRAVITREAL DELIVERY
Vitrasert
Ganciclovir implant for AIDS associated CMV
Retisert
Fluocinolone implant for posterior uveitis
Ozurdex
Dexamethasone injectable, biodegradable pellets for RVO
Medidur
Fluocinolone injectable implant for diabetic macular edema

65. Jill Autry, OD, RPH drjillautry@tropicalce.com
IN CONCLUSION…
Jill Autry, OD, RPH