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GLAUCOMA MEDICATIONS Jill Autry, OD, RPh Eye Center of Texas, Houston

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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

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

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)

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

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

Primary Open Angle Glaucoma Ocular Hypertension Pigmentary Glaucoma Pseudoexfoliative glaucoma Angle recession glaucoma Not during acute episode if possible

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

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

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

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

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)

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®

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”

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

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

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

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

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

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

Advantages Increase compliance Increase contact time Decrease medication concentration Up to 50% absorption through cornea

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

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

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

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

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