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GLAUCOMA MEDICATIONSWHAT WE HAVE, WHERE WE’RE GOING…
Jill Autry, OD, RPhEye Center of Texas, Houston
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
20
24
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
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