GLAUCOMA MEDICATIONSWHAT WE HAVE, WHERE WE’RE GOING…

Jill Autry, OD, RPhEye Center of Texas, Houston

drjillautry@tropicalce.com

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

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

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

DIAGNOSIS

• Gonioscopy

• Optic nerve examination

• Intraocular pressure

• Pachymetry

• Visual field

• Nerve fiber layer analysis

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)

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

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

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

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

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

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

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

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

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

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

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

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

Comparison from Phase III Trials

NOTE * Lumigan Travatan XalatanIOP Reduction

> Timolol (mmHg)> 2.5 1.2 1.2

% Patients

< 17 mm Hg64% 56.3% 49.5%

Mean IOP-Blacks 17.1 17.2 18.6 IOP- Non-Blacks 16.9 18.5 18.6Hyperemia 45% 49.5% 15%Iris Pigmentation 1.5% 2.5% 16%

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

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

ALPHA-2 AGONISTS

2-adrenergic agonist

• Apraclonidine (Iopidine)

• Brimonidine (Alphagan)– Enhanced α2 selectivity due to double ring

structure

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

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

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

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

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

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

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

Beta BlockersTimoptic (timolol)

Timoptic XE (timolol gel)

Betimol (timolol)

Betagan (levobunolol)

OptiPranolol (metipranolol)

Ocupress (carteolol)

Betoptic S (betaxolol)

CONCERNS WITH TREATMENT

• Elderly

• Lung Disease– Contraindicated in asthma, COPD, etc.

• Heart disease– Contraindicated in CHF (heart failure)

• Diabetes

• Impotence

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

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

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

15.2 15.3

21.9

0

4

8

12

16

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0 1 2 3

COMBIGAN™ in Adjunctive Therapy With a PGA: Mean IOP

Mea

n I

OP

(m

m H

g)

Month

-6.9 mm Hg(29%)

Added to a PGA baseline

* *

*P < .0001 vs baseline

COMBIGAN™(brimonidine tartrate/timolol maleate

ophthalmic solution) 0.2%/0.5% + PGA (n = 37)

11Nixon and Hollander. Nixon and Hollander. 22AAO, 2007. Data on file, Allergan, Inc.AAO, 2007. Data on file, Allergan, Inc.

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

TOPICAL CAI

• Reduce aqueous humor production

• Max IOP reduction of 15-20%

• bid to tid dosing

• Dorzolamide (Trusopt®)

• Brinzolamide (Azopt®)

• Dorzolamide + Timolol – Cosopt®

ADVERSE EFFECTS/CONCERNS

• Bitter taste

• Stinging

• Conjunctival hyperemia

• Tachyphylaxis

• Concerns with history of sulfa allergies

• Corneal concerns

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

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.

INDIGENT PROGRAMS• Allergan (Lumigan, Alphagan P,

Combigan)– 1-800-553-6783

• Alcon (Azopt, Travatan Z, Betoptic S)– 1-800-222-8103

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

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

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

USE IN LOWERING IOP

• Treatment of acute angle closure glaucoma

• Treatment of less acute increased IOP

• Treatment of post-surgical IOP spikes

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”

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

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

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

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

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

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

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

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

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

Advances in Ocular Delivery

• Increased ocular contact time– Ointments– Gels– Liposome formulations– Nanoemulsions

• Colloidal systems– Disperse and encapsulate meds

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

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

DRUG RELEASING CONTACT LENS

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

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

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

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

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

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

IN CONCLUSION…

Jill Autry, OD, RPHdrjillautry@tropicalce.com