Transcript GLAUCOMA MEDICATIONS - Nevada Optometric Association

GLAUCOMA MEDICATIONS
WHAT WE HAVE, WHERE WE’RE GOING…
Jill Autry, OD, RPh
Eye Center of Texas, Houston
[email protected]
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
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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
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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
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Conjunctival hyperemia
Iris pigmentation
Periorbital darkening
Eyelash growth/thickening/darkening
WHEN PROSTAGLANDINS
ARE YOUR FIRST CHOICE
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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
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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
Xalatan
IOP Reduction
> Timolol (mmHg)
> 2.5
1.2
1.2
% Patients
< 17 mm Hg
64%
56.3%
49.5%
17.1
16.9
45%
1.5%
17.2
18.5
49.5%
2.5%
18.6
18.6
15%
16%
Mean IOP-Blacks
IOP- Non-Blacks
Hyperemia
Iris Pigmentation
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
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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
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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 Blockers
Timoptic (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?
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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
COMBIGAN™ in Adjunctive Therapy
With a PGA: Mean IOP
Mean IOP (mm Hg)
24
21.9
Added to a PGA baseline
-6.9
mm Hg
(29%)
20
16
15.2
*
15.3
*
12
COMBIGAN™(brimonidine tartrate/timolol maleate
8
ophthalmic solution) 0.2%/0.5% + PGA (n = 37)
4
*P < .0001 vs baseline
0
0
1
2
3
Month
1Nixon
and Hollander. 2AAO, 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
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Reduce aqueous humor production
Max IOP reduction of 15-20%
bid to tid dosing
Dorzolamide (Trusopt®)
Brinzolamide (Azopt®)
Dorzolamide + Timolol
– Cosopt®
ADVERSE EFFECTS/CONCERNS
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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):104855.
– 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
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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
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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
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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
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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
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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
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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
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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, RPH
[email protected]