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Home , Brimonidine

Financial Disclosures

• Aerie Pharmaceutical • Alcon Laboratories • Allergan Mechanisms in the Autonomic Nervous • Carl Zeiss Meditec System and GLAUCOMA MEDICATIONS DANICA J. MARRELLI, O.D., F.A.A.O., AAO Diplomate (Glaucoma)

UNIVERSITY OF HOUSTON COLLEGE OF OPTOMETRY

Autonomic Nervous System Review Review of ANS Review of ANS Parasymathetic System (Cholinergic) Parasymathetic System (Cholinergic)

• Peripheral efferent nervous system provides • “Rest and Digest” system • Pre‐ganglionic fibers leave central nervous system at innervation to heart, blood vessels, visceral organs • Pre‐ganglionic fibers synapse with few post‐ganglionic fibers craniosacral levels – Generally beyond conscious control • Activation of parasympathetic system results in • Ganglia are located close to effector organ – 2 neuron system (pre‐ and post‐ ganglionic neurons) conservation of energy and maintenance of organ function • Neurotransmitter: Acetyl Choline both Pre and Post Synapse – Functions to control ongoing activity of involuntary during periods of rest – organs by eliciting excitatory or inhibitory responses ACh hydrolyzed by acetylcholinesterase – Decreased heart rate – Both direct and indirect drugs • Made of sympathetic and parasympathetic systems – Decreased blood pressure • Muscarinic and Nicotinic Receptors – Most organs receive dual innervation – Increased GI and bladder function – Muscarinic = M1 & M2 mostly CNS and End Organ • Blood vessels –only receive sympathetic innervation – Bronchiole constriction – Pupillary – Nicotinic = CNS and Skeletal Striated Muscle

Review of ANS Review of ANS Review of ANS Sympathetic System () Sympathetic System (Adrenergic) • “Fight or Flight” system • Pre‐ganglionic fibers leave the central nervous system at • Alpha 1 thoracic/lumbar level of spinal cord – agonist Epi>NE>Isoproterenol • Single pre‐ganglionic fiber synapses with MANY • Sympathic ganglia are located just outside of sc post‐ganglionic fibers • Neurotransmitters: Acetyl Choline at Pre‐, Norepinepherine at – Post synaptic found: BV, Dilator, GI, Spleen – Increased heart rate Post‐ Synapse • Alpha 2 – Increased blood pressure – Re‐uptake of NE – NE also hydrolyzed by COMT and MAO – Agonists Epi>NE>Isoproterenol – Increased blood flow to skeletal muscle • Both direct and indirect drugs – Pre & Post Synaptic – Increased blood glucose • Receptors: – Inhibit release of neurotransmitter – Bronchiole dilation – Alpha 1 & Alpha 2 – Pupillary dilation – Beta 1 & Beta 2

1 Review of ANS ANS Pre and Post Synaptic Receptors OUTLINE

• Beta 1 • DRUG CLASSES – agonist Isoproterenol>Epi & NE • MECHANISM OF ACTION / EXPECTED RESPONSE – Found in Heart and GI • ADDITIVITY TO OTHER AGENTS • Beta 2 • SIDE EFFECTS – Agonists Isoproterenol>Epi>>>NE • CONTRAINDICATIONS – Found in Bronchial and Vascular Smooth Muscle • SPECIFIC DRUGS AVAILABLE

BETA BLOCKERS BETA BLOCKERS BETA BLOCKERS

• LOCAL SIDE EFFECTS • MECHANISM OF ACTION: Decrease – LOCAL • SYSTEMIC SIDE EFFECTS: aqueous production () – SPK – CARDIOVASCULAR: bradycardia, – PULMONARY: bronchospasm, asthma, • RESPONSE: Very good (25‐30% reduction – DRY EYE in IOP with non‐selective B‐Blocker) dyspnea – NEUROLOGICAL: depression, headache, insomnia, sexual dysfunction – OTHER: mask symptoms of hypoglycemia, change in lipid profile

BETA BLOCKERS BETA BLOCKERS Beta‐1 Selective B‐Blockers

• NON‐SELECTIVE BETA BLOCKERS • (generic 0.5%; Betoptic‐S ® 0.25%) • CONTRAINDICATIONS: – maleate • Timoptic ® • Much less potent IOP‐lowering effect – asthma (may use B1‐selective?) • Timoptic PF ® • May be used in patients with pulmonary disease – Chronic Obstructive Pulmonary Disease • Timoptic XE ® ‐ once daily • Istalol ® ‐ once daily (caution) – bradycardia • generic timolol maleate (and gfs) – cardiac failure (stage 4 cv disease) – timolol hemihydrate (Betimol ®) • LOOK AT PATIENT’S EXISTING – (Betagan ® and generic) MEDICATIONS!!!! – (Optipranolol ® and generic) – (Ocupress ® and generic)

2 BETA BLOCKERS ANALOGS PROSTAGLANDIN ANALOGS • SIDE EFFECTS • MISCELLANEOUS – SYSTEMIC • MECHANISM OF ACTION: Increase – LOCAL – Once a day v. twice daily dosing uveoscleral outflow • “4 Hs”: hyperemia, heterochromia, – Dosing guidelines hyperpigmentation, hypertrichiasis – Concurrent use of systemic B‐Blocker • RESPONSE: Very good (25‐36% + reduction – Redness in IOP) – Iris color change – Baseline vitals – Skin pigment changes – Monocular trial – Eyelash changes • Cystoid Macular Edema – Short term escape and long term “drift” • Exacerbation of Ocular Inflammation (??) • Prostaglandin‐induced orbitopathy

Prostaglandin Analogs PROSTAGLANDIN ANALOGS

• CONTRAINDICATIONS • Post‐marketing side effect: – CYSTOID MACULAR EDEMA following cataract surgery – “Prostaglandin‐related orbitopathy” – LIGHT COLORED/MIXED COLOR IRIDES • AVAILABLE DRUGS • Deepening of the upper eyelid sulcus – 0.005% (Xalatan ® and generic) • aka “sunken eye” – • More difficult to detect in bilateral therapy • Travatan Z ®– NO BAK preservative (Sof‐Zia) • Generic travoprost (BAK) • May be reversible with discontinuation of therapy – (Lumigan ® 0.01%) • NO generic substitutions available of 0.01% • Generic available in 0.03% (redness ) – (Zioptan ®) • Unpreserved, single unit dose packaging

PROSTAGLANDIN ANALOGS ADRENERGIC AGONISTS ADRENERGIC AGONISTS

• MISCELLANEOUS • EPINEPHRINE COMPOUNDS (aka “non‐ • ALPHA‐ADRENERGIC AGONISTS – No long term drift specific adrenergic agonists”) – MECHANISM OF ACTION: decrease aqueous – additive to other glaucoma meds – MECHANISM OF ACTION: Increase aqueous production AND increase uveoscleral outflow – dosing outflow – RESPONSE: good (20‐25% reduction in IOP) – packaging – RESPONSE: Moderate (not additive with non‐ – monocular use selective B‐Blockers) – cost – NO LONGER AVAILABLE (epinephrine, propine)

3 ADRENERGIC AGONISTS ADRENERGIC AGONISTS ADRENERGIC AGONISTS

• ALPHA‐ADRENERGIC AGONISTS • ALPHA‐ADRENERGIC AGONISTS – AVAILABLE DRUGS – SIDE EFFECTS: • (Iopidine ®) • ALPHA‐ADRENERGIC AGONISTS • SYSTEMIC: fatigue, dry mouth, minimal effects on • brimonidine ‐ more alpha‐2 selective – MISCELLANEOUS cardiovascular system – brimonidine 0.2% generic (BAK) • • LOCAL: allergy, mydriasis, lid retraction – brimonidine 0.15% “generic” (Polyquad ®) IOPIDINE V. ALPHAGAN – CONTRAINDICATIONS: – Alphagan‐P ®0.1% (non‐BAK, Purite ®) • Possible first‐line drug • Brimonidine/timolol fixed combination (Combigan ®) • appear to be relatively safe systemically • Dosing – Brimonidine 0.2% with 0.5% timolol maleate, preserved • Neuroprotection ??? • ABSOLUTELY CONTRAINDICATED IN CHILDREN with BAK • MAO inhibitors • Brimonidine/ fixed combination (Simbrinza®)

LoGTS LoGTS

• Randomized, double‐masked clinical trial to • Results: compare brimonidine 0.2% vs timolol 0.5% in – No significant difference in IOP preserving visual function in normal tension – Significant dropout in brimonidine group (allergy) glaucoma patients – Significant/dramatic difference in visual field – brimonidine 0.2% bid progression – timolol maleate 0.5% bid • 9% for brimonidine group – Followed with VF every 4 months for minimum of 4 • 39% for timolol group years • Question: what does this mean?

CARBONIC ANHYDRASE INHIBITORS CARBONIC ANHYDRASE INHIBITORS CARBONIC ANHYDRASE INHIBITORS

• LOCAL SIDE EFFECTS (TOPICAL USE) • SYSTEMIC SIDE EFFECTS (Oral Use): – LOCAL IRRITATION • MECHANISM OF ACTION: Decrease – paresthesia – SPK aqueous production – metallic taste – • RESPONSE: – symptom complex CORNEAL EDEMA/DECOMPENSATION**** – – Oral: Very Good GI upset – metabolic acidosis – Topical: Variable – hypokalemia – renal calculi – transient myopia/angle closure (similar to topiramate)

4 CARBONIC ANHYDRASE INHIBITORS CARBONIC ANHYDRASE INHIBITORS Glaucoma ‐

• AVAILABLE DRUGS • Typically used in emergency/acute situations rather than long term due to systemic side effects: – • CONTRAINDICATIONS: ORAL – Paresthesia • acetazolamide (Diamox ®) – Kidney stones – disease – tabs (250mg) – generic only – Metabolic acidosis – time‐released capsules 500mg=SEQUELS ®and generic – Blood dyscrasia – COPD • (Neptazane ® and generic) • Typical use: – renal disease (Diamox ®) – TOPICAL – Post‐surgical IOP elevation – 500mg (two 250mg tabs) – Acute angle closure (NON‐PUPILLARY BLOCK ONLY –DO NOT USE IN TOPAMAX – • (Trusopt ® and generic) ANGLE CLOSURE!!!!!!) • brinzolamide (Azopt ®) – Extremely elevated IOP – Corneal endothelial dysfunction • dorzolamide with timolol maleate (Cosopt ® and • Dosing for chronic use: – sulfa allergy (???) generic) – 250 mg tablets qid – Also available – COSOPT PF ® – 500 mg time‐released capsules (Sequels ® or generic) bid • Brinzolamide/brimonidine (Simbrinza ®)

CARBONIC ANHYDRASE INHIBITORS MIOTICS (Topical) FIXED COMBINATIONS

• Dorzolamide 2%/timolol 0.5% • MECHANISM OF ACTION: Increase • MISCELLANEOUS – Cosopt ® and generic trabecular outflow – dorzolamide • Preserved with BAK • RESPONSE: Good to very good • tid v. bid dosing • Available in PF formulation (Cosopt PF ® brand only) • bitter taste • Dosing: BID • Rarely used for long term management due • allergy • Brimonidine 0.2% /brinzolamide 0.1% to high incidence of ocular side effects • stinging – Simbrinza ® brand only – brinzolamide • Preserved with BAK • less stinging • DOSING: TID

MIOTICS MIOTICS MIOTICS

• CONTRAINDICATIONS • SIDE EFFECTS – PSC • AVAILABLE DRUGS – LOCAL – young patient – • • miosis – neovascular or uveitic glaucoma Solution (1%, 2%, 4%) • browache • gel – retinal detachment • accommodative spasm/pseudomyopia • Ocusert – • retinal break (??) high myopia – – SYSTEMIC – asthma – • bronchospasm

5 MIOTICS HYPEROSMOTICS HYPEROSMOTICS

• MISCELLANEOUS • MECHANISM OF ACTION: dehydrate (& shrink) • AVAILABLE DRUGS – dosing vitreous – mannitol (IV) – cost • RESPONSE: very good in acute primary angle – secondary – glycerin (Osmoglyn) closure glaucoma • Pigmentary – isosorbide (ismotic) Variable Availability • Angle recession • SIDE EFFECTS: nausea/vomiting; • MISCELLANEOUS – acute angle closure – PUPILLARY BLOCK MECHANISM hyperglycemia/glycosurea (glycerin only) ONLY (Not for topiramate‐induced angle closure!!!) – isosorbide v. glycerin • CONTRAINDICATIONS: diabetes (glycerin only) – percentage – nausea prevention – break‐in dosing – concomitant use with oral CAI

Anything In the Pipeline? Anything In the Pipeline? Anything In the Pipeline?

• Rhopressa ® ( 0.02%) (Aerie • Roclatan® (netarsudil 0.02% and latanoprost • Vesneo® (latanoprostene bunod) (Bausch & Lomb) Pharmaceuticals) 0.005%) • “Nitric oxide‐donating prostaglandin analog” – Inhibits Rho kinase (ROCK) and – Aerie Pharmaceuticals, Inc transporter (NET) – Increased trabecular outflow and powerful vasodilating – 4 mechanisms (3 mechanisms of netarsudil plus effect – Three mechanisms of action: increased uveoscleral outflow from latanoprost) • Increased TRABECULAR outflow – Once daily latanoprostene bunod has been shown to be • Decreased aqueous production – Currently in Phase 3 trials non‐inferior AND superior to twice daily timolol 0.5% • Decreased episcleral venous pressure (NOVEL) – Lowers IOP more than latanoprost – Once daily dosing – FDA review – Currently in Phase 3 trials

FACTORS CONTRIBUTING TO NON‐ HOW DO WE START? Initial Drug Selection COMPLIANCE 1. Which drug will be BEST for my patient in terms of • MULTIPLE MEDS / FREQUENT DRUG INSTILLATION • Used to be “easier” with fewer drugs mechanism of action/contraindication profile • EXPENSE • Newer drugs allow for more tailor‐made drug 2. Do I need to worry about preservative? regimen • SIDE EFFECTS • Must consider safety, efficacy, compliance, 3. Will cost be a problem (should I consider generics)? • PATIENT’S UNDERSTANDING OF DISEASE and (yes) cost when deciding which drugs to • ASYMPTOMATIC DISEASE use • Generics and formulary coverage add an • CHRONIC DISEASE entire layer of complexity to the decision‐ making

6 BAK‐free Options Preservative‐free Options Generic Options

• Timoptic PF ® • Beta‐adrenergic antagonists: • Timoptic PF ® – timolol (solution or gel‐forming solution) • Travatan‐Z ® (BRAND ONLY)‐ or ‐Zioptan ® – levobunolol • Zioptan ® – carteolol • brimonidine 0.15% (polyquad) ‐or‐ Alphagan‐P ® 0.1% – metipranolol (purite) • Cosopt PF ® – betaxolol • PGAs • MMT (Generic: Cosopt PF® – latanoprost • PGA (3 to choose) – travoprost (not “Z”) • Preservative‐free MMT – bimatoprost (0.03%) • brimonidine • BAK‐free MMT: • Topical CAI • dorzolamide/timolol – Cosopt PF – Dorzolamide – Travatan Z (Brand) or Zioptan • brimonidine 0.15% and 0.2% – Brimonidine 0.15% or 0.2% – Zioptan • pilocarpine – Cosopt PF • Fixed combination: – dorzolamide/timolol

Contemporary Therapeutic Approach to Therapeutic Questions (at each visit) THERAPEUTIC APPROACH TO POAG POAG 1. Is patient using the drug? • Begin with prostaglandin • Consider additive nature of drugs 2. Is patient tolerating the drug? • If good response but still need lower IOP – Most glaucoma meds are additive to one another – Continue prostaglandin and ADD 3. Is there a therapeutic effect? • CAI – Exceptions: • • Non‐selective B‐B with epinephrine compounds • Alphagan 4. Am I reaching the target IOP? • • EASY switch to combo with any of these Miotics with (?) • If response to PGA is poor: • Oral with topical CAI’s – Consider non‐adherence (try longer) – Consider switching to brand if generic – Consider switching within class (???) – Consider switching class

THERAPEUTIC APPROACH TO POAG THERAPEUTIC APPROACH TO POAG THERAPEUTIC APPROACH TO POAG

• TREATMENT “PEARLS” • Where do these fit in? • Consider laser trabeculoplasty OR – Check IOP at different times of day pre‐treatment (establish a true – Epinephrine/Propine trabeculectomy once two or three pre‐treatment IOP) medications are failing to control the – Once patient on therapy, CHECK IOP ON THERAPY – Pilocarpine – Proper instructions to patients: dosing and lid – Oral CAI’s (controversy exists). closure/nasolacrimal occlusion – Iopidine – Don’t add multiple meds at once – Monocular trial concept – Ask patients about side effects on follow‐up – If a med doesn’t work, STOP IT

7 THERAPEUTIC APPROACH TO MANAGEMENT OF SECONDARY OAG ACUTE ANGLE CLOSURE THERAPEUTIC APPROACH TO ACUTE WITH PUPILLARY BLOCK ANGLE CLOSURE WITH PUPILLARY • PIGMENTARY GLAUCOMA • Diamox 500 mg (2 250‐mg tabs) BLOCK • EXFOLIATION GLAUCOMA • Beta‐blocker if no contraindications x 2‐3 • Role of isosorbide/glycerin • ANGLE RECESSION GLAUCOMA doses (every 5‐10 minutes) • Topical prednisolone acetate • UVEITIC GLAUCOMA • Alpha agonist every 5‐10 minutes x 2‐3 doses • Pilocarpine 2% (or 1%) ‐ ???wait until IOP • Ultimately: Dismiss with pilo Rx (OU) and <50; fellow eye gets dose, too steroid until can get laser iridotomy

THERAPEUTIC APPROACH TO ACUTE ANGLE Topiramate‐induced Angle Closure Topiramate‐Induced Angle Closure CLOSURE WITHOUT PUPILLARY BLOCK • May cause myopic shift and acute angle closure – occurs in 3/100,000 • Mechanism of angle closure without pupillary block • Usually occurs within the first two weeks –one case was after only two doses at 25mg/day • Pathophysiology: – Plateau Iris ‐ Unknown what triggers reaction: ‐ Possible blood‐eye barrier disruption? – Post‐lenticular ‐ Hypersensitivity reaction? • “Aqueous Misdirection” / “Malignant Glaucoma” ‐ Change in membrane potential? TOPIRAMATE (TOPAMAX®, TROKENDI XR®) • Drug‐induced (Topamax, Diamox) 1) Choroidal effusion • FDA approved for: 2) Anterior displacement of Iris/CB/Lens diaphragm 3) Zonules relax • Various Epileptic Disorders • Therapeutic Approach 4) Lens thickens • Migraines 5) Induced Myopia – Plateau Iris: similar to AAC with pupillary block in acute 6) Acute angle closure • Pain • Weight loss phase; LPI not helpful • IOP: usually below 40 ‐ Some degree of CB shutdown with detachment • phentermine with topiramate (Qsymia®) – Drug‐induced: COMPLETELY DIFFERENT APPROACH! ‐ Carbonic Anhydrase inhibition • Sulfa-based with carbonic anhydrase inhibition

Drug‐Induced Angle Closure EXAMPLE 1 EXAMPLE 1

• Choroidal/ciliary effusion causes forward movement • 55yo healthy AAM with moderate/severe POAG • First choice branded PGA of ciliary body/lens/iris – Highest IOP 28mmHg – Returns 1 month – Miotics will make this WORSE – Target 40% reduction (<17mmhg) • Using medication consistently – Cycloplegics will improve this (counter‐intuitive!) – Excellent insurance coverage, not concerned about cost • C/O moderate redness, tolerable – Carbonic anhydrase inhibitors will make this worse! • IOP 14mmHg – First choice? Yes: No: – Aqueous Suppressants ‐Pilo – What now? – Cycloplegics ‐CAI – Steroids

8 EXAMPLE 1 EXAMPLE 2 EXAMPLE 2

• First choice branded PGA • 55yo healthy AAM with mild POAG • Returns for 1 month progress – Returns 1 month – Highest IOP 28mmHg – Using consistently • Using medication consistently • C/O moderate redness, tolerable – Target 30% reduction (<20mmHg) – C/O red eyes, tolerable • IOP 22mmHg – Excellent insurance coverage, not concerned about cost – IOP: 21mmHg – First choice? SAME: Branded PGA – What now? • Getting a therapeutic effect (20% reduction = 23) – What now? • Not at target • Would SWITCHING to a beta blocker get us to target? Unlikely • ADD something; be prepared to SWITCH that to fixed combo

EXAMPLE 2 EXAMPLE 2 EXAMPLE 3

• Returns for 1 month progress • Returns for 1 month progress • 55yo hypertensive AAM with moderate/severe – Using medication consistently – Using medication consistently POAG – C/O red eyes, tolerable – C/O red eyes, tolerable – Uses for HTN – IOP: 21mmHg – IOP: 21mmHg – Highest IOP 28mmHg – Target 40% reduction (<17mmhg) – What now? TWO CHOICES: – – Excellent insurance coverage, not concerned about cost What now? • ADD BB, brimonidine, or topical CAI ‐‐‐OR‐‐‐ • THERAPEUTIC EFFECT? YES • SWITCH to BB – First choice? • REACHING TARGET IOP? NO (CLOSE) – May hit target with BB alone; if not, can easily switch to combo with one bottle meds

Barriers to EXAMPLE 3 Glaucoma Adherence –The Problem Compliance • 55yo hypertensive AAM with moderate/severe POAG • Social / environmental – Uses atenolol for HTN • Non‐adherence is a problem with all disease factors – Highest IOP 28mmHg management, especially chronic illnesses – Change in daily routine – Travel – Target 40% reduction (<17mmhg) • Poor adherence in glaucoma therapy is well • Problems with – Excellent insurance coverage, not concerned about cost medications documented – Side effects – First choice? – Cost – Associated with progression and blindness – Complexity* • Problems with Self – SAME AS CASE 1 except no topical BB • Average glaucoma adherence in glaucoma is ~60% – Memory • If need to add to PGA, add brimonidine or CAI, and switch to with “cycling” – Difficulty with instillation Simbrinza® if not adequate • Problems with Doctor – Inadequate education – Dissatisfaction with doctor

9 GAPS –Factors Associated With Non‐Adherence GAPS What Helps?

1. Not believing that vision loss is a possible result of • Better adherence based on self‐report than • Health Belief Model: Predicts that health behavior not using medications medication refill data will occur if 2. Traveling/ time away from home • Physicians showed very poor ability to detect – Patient believes a disease will affect them 3. Hearing all of what you know about glaucoma from your doctor adherence – Patient believes that it will have important consequences 4. Cost – Patient believes that the treatment will help mitigate the 5. Not receiving phone call reminders of follow‐up risk visits – There are not too many barriers to overcome 6. Non‐white implementing the therapy – Patient has sufficient self‐efficacy to carry out the plan

What Helps? Dosing Reminders FIRST ‐ IDENTIFY

• Systematic reviews of intervention studies are • Non‐adherent patients • Ask open‐ended questions difficult to interpret were randomized to – “Tell me how you use your drops.” • Possible helpful interventions: automated phone – “What is your understanding of glaucoma?” – Simple regimen intervention vs control • Reverse the judgmental environment – Instruction/counseling • Adherence improved – “It’s hard to use the drops exactly as prescribed.” – – Dosing reminders from 54‐73% in “No one is perfect.” – More frequent follow‐up intervention group • Explain the importance of accurate self‐report – “Adding more medication is not a good idea unless I know exactly how often you are using the current medication”

Next – Implement Intervention When Non‐adherence Continues SUMMARY

• Simple and affordable regimen • Consider laser and/or surgical intervention earlier in • Imperative to know mechanism of action, • Get family members on board patients whose poor adherence is recognized and contraindications, and side effects • Connect drop use with daily routine chronic • Imperative to ask about side effects at follow up • Teach/observe administration in office visits • • Personal phone call reminders/follow‐up Imperative to determine the effect of a drug before changing/adding meds • Utilize technology • Imperative to determine the TYPE/Mechanism of acute angle closure before beginning treatment

10 Thank you for your attention!

Questions? Email me: [email protected]

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