GLAUCOMA MEDICATIONS

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

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 1.5-3 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 • Accommodative spasm • Retinal detachment • Frequency of use

12. WHEN TO USE PILO • Acute 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 • 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

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) *P < .0001 vs baseline Month 1Nixon and Hollander. 2AAO, 2007. 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. 2007 Oct;125(10):1345-50. • 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) • 1-800-553-6783 • Alcon (Azopt, Travatan Z, Betoptic S) • 1-800-222-8103

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

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