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Home , Brimonidine

8/16/2018

Ocular Pharm: COPE Disclosures: A Conglomeration of New Ideas,

New Uses, Old Drugs, & Old Topics • I do not have any relevant financial relationships to disclose.

• The content and format of this course is presented without Chris Borgman, OD, FAAO commercial bias and does not claim superiority of any commercial product or service.

Ground Rules…

• References/sources available if you want them… Alphagan (Brimonidine) • I’m not perfect… & Pupillary ??? • Please email me with questions: • [email protected]

The Scotopic Miosis Brimonidine (Alphagan-P) • Speculated to be: • Due to a change in balance between the pupil sphincter and pupil dilator muscles. • A highly specific α-2 receptor agonist • Alpha-2 receptors at pre-synaptic nerve terminals • Binding sites for brimonidine localized on the iris

• Activation of Alpha-2 receptors inhibits the release of the neurotransmitter, • Tonus of the cholinergic driven sphincter remains intact/unaffected (PNS) • Therefore, norepinephrine is not available for receptor activation & adrenergic Pupil Dilation • Dilator (SNS controlled) is relaxed in the presence of the alpha-2 agonist  decreased by 1-2 mm • Therefore, the sphincter has increased control over pupil size • Onset 30 mins; up to 4-6 hrs McDonald et al, J Cataract Surg 2001, 27:560-564  the balance has shifted to PNS  Smaller pupil

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Why less effect on pupil size in bright illumination? When can we use this? • Complaints of glare/haloes/starbursts in dark/scotopic conditions • Brimonidine • Driving, movies, etc. • Has no effect the cholinergic driven sphincter muscle in photopic conditions (PNS) • There is a less obvious size difference with and without brimonidine • MOA: Pupil size is ≥ treatment zone diameter • General Tx Zone = 6.0 - 6.5 mm diameter • Ortho K Tx Zone = 6.0 – 6.5 mm diameter

• LASIK/PRK • OrthoK • Therefore, photopic pupil size is relatively normal • RGP’s

Scoptopic Pupil Size & Age Wouldn’t work too? Brimonidine Pilocarpine Ciliary spasm? No Yes Effective in Photopic? No Yes Effective in Scotopic? Yes Yes Systemic side effects? Limited SLUDGE Ocular side effects? RD

Bradley et al. Dark-adapted pupil diameter as a function of age measured with the NeurOptics pupilometer. J Refract Surg. Bottom Line  consider Brimonidine in patients with scotopic vision complaints 2011;27:202-7.

Brimonidine tartrate 0.025%

• Diluted brimonidine solution  vasoconstriction • Post-synaptic junction Alphagan (Brimonidine) • Phase 3 trials completed (Bausch & Lomb) • Lumify©  (over-the-counter) & Redness Reliever • No rebound hyperemia with discontinuation • No tachyphylaxis noted • Seems to work on smaller caliber conjunctival vessels without affecting larger vessels so blood flow is not affected • Venules > arterioles • α2 receptors predominantly in veins! • α1 receptors predominantly in arteries!

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Lumify now available! McLaurin E, et al. Optom Vis Sci. 2018 • Phase III Clinical Trial (B&L) • Brimonidine 0.025% QID x 30 days • n=60 • 40 brimonidine, 20 vehicle • Onset: 1-5 minutes! • Duration of action: 8 hours! • Largest effect within first 4 hrs • No tachyphylaxis! • Negligible rebound redness • Note: IOP did not decrease! • Only 4 subjects (10%) had SE’s from brimonidine

McLaurin E, et al. Brimonidine ophthalmic solution 0.025% for reduction of ocular redness: a randomized clinical trial. Optom Vis Sci. 2018;95:264-71.

Brimonidine Gel Final thoughts on Brimonidine 0.025%... • Approved for rosacea redness/erythema • • Dose: one drop q6-8h in affected eye(s); max of QID Dosing: Apply to erythematous patches once daily • MOA: post-synaptic alpha agonist  sympathomimetic • Causes vasoconstriction of facial blood vessels • “In conclusion, the results from this trial suggest that brimonidine tartrate • Onset 30 minutes; Duration up to 12 hours ophthalmic solution, 0.025% is safe and well tolerated and is effective in • FDA category B

reducing ocular redness in adult subjects. Additionally, use of brimonidine • Main SE’s: 0.025% does not appear to be limited by side effects associated with • *Flushing /redness (8-10%)* currently marketed ocular redness relief .” • Worsening of rosacea (5%) • Torkildsen GL, et al. 2018. • 1 month study showed modest results only: • 28% saw reduction in redness with brimonidine • 10% saw reduction in redness with vehicle

Torkildsen GL, et al. Evaluation of efficacy and safety of brimonidine tartrate ophthalmic solution, 0.025% for treatment of ocular redness. • Other use: Immature scar redness reducer Curr Eye Res. 2018;43:43-51.d

Rosacea Erythema Improvement with Brimonidine

Time post-application Brimonidine gel Placebo 30 minutes 28% 7% 15 days 56% 21% 29 days 58% 32% Fowler J, et al. J Drugs Dermatol. 2013;12:650-6. Topiramate (Topamax)

Time post-application Brimonidine gel 1 day 6-14% 1 month 29-34% “Adverse events were mild, transient, and limited to the skin. Irritation, flushing, 1-3 months 42% worsened erythema, burning sensation, and 10-12 months 19.5% pruritus were the most commonly reported Fowler J, et al. J Drugs Dermatol. 2013;12:650-6. side effects.” Moore A, et al. J Drugs Dermatol. 2014;13:56-61.

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PTC /IIH Treatment Options… Topamax vs. Diamox? • = CAI inhibitor ; works on and choroid 1. Weight loss (5-10% is sometimes curative!) plexuses 2. Carbonic anhydrase inhibitors • Topiramate = novel anticonvulsant; epilepsy/migraines • Multiple MOA’s • Acetazolamide (Diamox) 1. Enhancement of GABA • No oral steroids  weight gain 2. Na channel blockade 3. Ventricoloperitoneal Shunt / Lumboperitoneal Shunt 3. Glutamate receptor blocker • Headaches only ; vision stable • Also has carbonic anhydrase inhibition component; and decreases appetite 4. Optic Nerve Fenestration • Weight loss of 5-10% alone may be curative in some cases of IIH • Vision/Visual Field worsening ; no headaches • Average weight loss of 7.3% was obtained in one year on topiramate • 11% weight loss in patients with BMI>30 in one year 5. Venous Sinus Stenting • drug….be careful of sulfa • In venous sinus stenosis • FDA Category D • Cleft palate risk Alore PL, Jay WM, Macken MP. Topiramate, pseudotumorcerebri, weight-loss and : an ophthalmologic perspective. Sem Ophthalmol. 2006;21:15-17.

Topiramate Ocular Side Effects • Angle closure glaucoma and myopic shift!!! Topiramate MOA: • 85% of this happens within first 2 weeks of therapy • MOA = lenticular/uveal effusion and ciliary edema causing forward • All sulfa derived drugs can induce myopic shift & acute angle closure displacement of the lens-iris diaphragm with resultant narrowing of the by increasing osmotic status of the tissues  H2O naturally follows anterior chamber. gradient • ***Ciliochoroidal effusion occurs • HCTZ • Aka: suprachoroidal effusion, supraciliary effusion, ciliochoroidal detachment • Trimethoprim • Abnormal collection of fluid that expands suprachoroidal space, producing internal • Acetazolamide elevation of choroid • Not related to dosage (86 reports): • Idiosyncratic response…no pattern • Ciliary body edema is final common pathway Dosage Incidence of Angle Closure/Myopia • Ciliary processes rotate forward, pushing iris/lens forward toward anterior <50 mg/day 47% of cases chamber angle 50-75 mg/day 33% of cases • Relaxation of the lens fibers causes lens thickening  increased myopia 100 mg/day 13% of cases >100 mg/day 7% of cases

Topiramate-induced angle closure glaucoma??? Check list… Topiramate and EtOH-ism??? • Search list! • When was medication started? Increased dosage recently? • Myopic Shift? • Narrow anterior chamber on SLE? • MOA: suppression of ethanol-induced nucleus accumbens • Elevated IOP ? release  inhibition of EtOH reinforcing effects • Detection of ciliochoroidal effusion? • Ant Seg Ultrasonography • “…there is now solid clinical evidence to support the efficacy of topiramate for the • B-scan for Post Seg treatment of alcohol dependence. Topiramate's therapeutic effects appear to be • Ant Seg OCT robust, with a medium effect size, thereby potentially ushering in a new era of a reliably • Stop med! efficacious medicine for the treatment of alcohol dependence.” • Consult with prescribing physician first… --- Johnson BA, et al. 2010 • Reduce IOP, cycloplege patient • Consider steroid

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Topiramate and other substance abuse???

• “There is now a growing body of literature examining the efficacy of topiramate in many different substance related disorders, including alcohol dependence and withdrawal, nicotine dependence, cocaine Iopidine () dependence, benzodiazepine dependence and withdrawal, and ecstasy abuse.” & Horner Syndrome • Shinn AK, et al. 2010

• We should be ready for more topiramate use in our patients!

Shinn AK, Greenfield SF. Topiramate in the treatment of substance related disorders: a review of the literature. J Clin Psychiatry. 2010;71:634-48.

HS Diagnosis…. • 1) Cocaine 5-10%------Is it a Horner’s? Diagnosis continued… • MOA: Indirect-acting sympathomimetic; increases norepinephrine (NE) availability • Horner’s pupil = no dilation • 3) Apraclonidine 0.5% or 1.0% • Normal pupil = dilation Assess after 30-60 minutes • Weak alpha-one receptor agonist affinity • Maintenance of anisocoria = Horner’s • Reversal of anisocoria after 30-60 minutes if denervation • Bilateral Dilation = physiologic anisocoria } hypersensitivity is present • Horner’s pupil will dilate • 2) Hydroxyamphetamine 1%------Where is the lesion causing the HS? • Lid ptosis can also improve • 5-8 • MOA: indirect sympathomimetric; forces NE out of presynaptic terminal Minimum days needed for denervation hypersensitivity • • No dilation = post-ganglionic (3rd order neurons) False negatives possible in early stages • Dilation = pre-ganglionic or central (1st or 2nd order neurons)

• Cocaine and Hydroxyamphetamine must be separated by 24-72 hours; cocaine interferes • Apraclonidine effectively replaces cocaine to determine presence of HS with hydroxyamphetamine • Still need imaging and/or hydroxyamphetamine to determine location

Reversal of anisocoria with apraclonidine 0.5%

Mineralcorticoid Receptor Antagonists & CSR

• Note the improved ptosis OD too

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Central Serous Chorioretinopathy OCT Evidence of MOA? • Circumscribed serous RD; usually macular region • Pathophysiology = unknown • New evidence: diffuse choroidal thickening in CSCR eyes (and • M>F (72-88% of time); 30-50 YO age range normally contralateral eyes) • Bilateral in 40% • Choroidal vascular hyperpermeability! • Most acute episodes resolve in 2-3 months on own • Recurrences common (up to 50%)  chronic CSCR in 5-10% of cases • How does this hyperpermeability occur? • Chronic CSR = >3-4 mo duration in most studies • Unknown still… • Historically, corticosteroids can aggravate CSCR; unknown • Corticosteroid related? MOA • Exogenous/endogenous cortisol, Cushing’s syndrome, psychological stress, Type A, pregnancy = risk factors • Males, HTN, collagen vascular diseases, H.Pylori infection • PDT, anti-VEGF, CAI’s , beta-blockers have been tried with varied success

Corticosteroids Eplerenone (Inspra) • Produced by adrenal cortex: 1. Mineralcorticoid = aldosterone • FDA-approved in 2002 for HTN; 2003 for CHF • Bind to both mineralcorticoid (MR) and glucocorticoid receptors (GR)! • Oral mineralcorticoid/aldosterone receptor antagonist 2. Glucocorticoid = cortisol • Competitive antagonist with high selectivity of MR; potassium sparing diuretic • Bind to both mineralcorticoid and glucocorticoid receptors too! • Reverses “endothelial vasodilatory potassium channel (KCa2.3)” activation in choroid • Stops/reverses choroidal thickening/leakage; down regulates KCa2.3 • Cross binding to each receptor! Equal affinity for both! • KCa2.3 only is expressed in choroid, not retina! • This is why MCR antagonists do not induce retinal vessel vasodilation! • MOA: Excess cortisol spills over to activate MR receptors as well • Side effects: hyperkalemia • Choroid has both MR and GR; retina does not! • Contraindications: or renal disease, pregnancy • Glucocorticoids & Mineralcorticoids both induce choroidal enlargement/thickening and cause vessel dilation and leakage which can overcome RPE’s defenses  • Standard dose for CSCR: 25 mg/day PO x 1 week, then 50 mg/day x 3 months neurosensory detachment

Eplerenone vs. … Mineralcorticoid Receptor • Both are mineralcorticoid receptor blockers! • MR agonists  upregulate KCa2.3 channels  choroidal vasodilation/leakage  • Both are potassium-sparing diuretics! SRF accumulation • Risk of hyperkalemia! = Biggest Risk! • Eplerenone = 1-3% risk @ 50-200 mg/day • Spironolactone = 3-6% risk @ 12.5-400 mg/day • MR antagonists  down-regulate KCa2.3 channels  choroidal vasoconstriction  SRF reduction • Standard Eplerenone dose for CSCR: 25 mg/day PO x 1 week, then 50 mg/day x 3 months • Eplenerone has 10-20x lower affinity for MR than spironolactone • However, Eplerenone has a much higher selectivity for MR without SE’s • Remember, MR is NOT found in retinal tissues, therefore retina is unaffected by both • Bottom Line: Eplenerone is best choice with the least probable SE’s at this time mineralcorticoids and glucocorticoids

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Resident’s Case: 47 Year old HF w/ chronic CSR (6+ mo) Eplenerone: 6 weeks later

How effective is Eplerenone on CSCR? Bottom Line..

• Consider Eplerenone in CSCR lasting >3-4 months • Reduced SRF within 1 month = 25-71% • Maybe in first line Tx??? • Reduced SRF within in 3 months = 93% • 25mg daily x 1 week then 50 mg PO daily for up to 3 months • Complete resolution within 3 months= 64-67% • Tx lasted until resolution of fluid or 3 months of treatment • Monitor serum potassium levels; co-manage with PCP • Measure serum potassium levels q1-3 months • “It’s relatively limited adverse effect profile and high selectivity and • Discontinue med if: specificity (to the mineralcorticoid & glucocorticoid receptors) make • Kalemia increase of >5 mmol/L eplerenone an ideal treatment modality for CSCR.” • Creatinine clearance rate decrease of <60 mL/minute • Salz DA, et al. 2015 Ophth Surg Lasers Imag • Ret. Likely best avoided in patients with renal problems • Monitor q4-6 weeks while on medication with OCT’s

Aripiprazole (Abilify)

• medication • Schizophrenia • Schizoaffective disorder • Resistant depression Abilify & Blurry Vision? • Bipolar disorder • OCD • MOA’s: • Dopamine receptors (D2 & D3)  partial agonist • Serotonin receptors (1A)  partial agonist • Serotonin receptor (2A)  antagonist

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Blurred Vision? Borgman’s Theoretical MOA??? • 3 of 926 subjects (0.32% cases) • Transient increase in myopia • Studies show: • How? • Increased levels of serotonin  increased sympathetic innervation  mydriasis! • The various mechanisms of drug-induced myopia reported in literature are: • SSRI’s and/or MAOI’s • accommodation spasm • ciliary spasm • Abilify () is a serotonin receptor blocker (5-HT2A receptor) • increase in thickness of the lens and peripheral uveal effusion • ciliary body rotation and edema resulting in forward movement of iris lens • Decreased levels of serotonin  decreased sympathetic innervation  miosis & accomm diaphragm • Increased myopia!  acute myopia

Sharif NA, et al. RT-PCR mapping of serotonin receptor subtype mRNAs in human ciliary body and trabecular meshwork. IOVS. 2005 May;46:3688.

Phenylephrine Review…

Phenylephrine & • Developed in 1933 from EPI • Potent vasoconstrictor  alpha-1 agonist Risk of Increased Blood Pressure • No beta receptor activity at all • Dilation of pupil without cycloplegia • Negligible effect on IOP • Maximum dilation = 15-90 minutes • Maximum duration of action = 6-7 hrs • Peripheral vasoconstriction can lead to rapidly elevated BP in some patients Is the fear justified??? • Systolic and diastolic are affected

Can PHE cause increased BP? Phenylephrine-Induced HTN How likely is this to happen if it does? • Widespread use; actual risk is  Sn/Sx: likely lower than reported • HA • Tachycardia • Likely idiosyncratic responses • Chest pain • First episodes of elevated BP from topical PHE were in 1956 • Majority of cases are within 10-30 • Palpitations • Some authors say: PHE has no effect on BP minutes of instillation • Perspiration • Some authors say: Mixed PHE-induced HTN responses • Nausea/vomiting • HTN effect is transient; 20-60 • SOB • Others yet say: definite increases in BP with topical PHE minutes duration • Reflex bradycardia/ • HTN effects coincide with peak  End-Organ Damage: tissue and plasma levels • SAH • Mass confusion across the board… • Aneurysm rupture • 2.5% PHE ≈ 10% PHE with dilation • *Papilledema • Pulmonary edema • MI • Orthostatic hypotension pts at • CVA highest risk?

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Worst Cases Reported In Literature… 10% PHE Total Risk of Adverse Events Total (n) 10% PHE Severe 10% PHE Increased BP • Cotton pledget soaked in 10% PHE and left on surgical eye Adults 1864 7.56% (n=141/1864) 14.70% (n=274/1864) • More than one drop of 10% PHE Pediatrics 44 11.36% (n=5/44) 84.09% (n=37/44) • PHE used in conjunction with

• Multiple rounds of PHE in peds/children 2.5% PHE Total Risk of Adverse Events Total (n) 2.5% PHE Severe 2.5% PHE Increased BP Adults 2210 0.18% (n=4/2210) 0.70% (n=15/2155) Pediatrics 363 0.28% (n=1/363) 4.98% (n=12/241)

Note: numbers based on 80+ articles on HTN & PHE risk

What about # of drops and risk in ADULTS??? What about # of drops and risk in PEDS???

Total (n) Risk of causing increased blood pressure in Total (n) Risk of causing increased blood pressure in adult patients pediatric patients 10% PHE---1 gtt OU 460 2.17% (n=10/460) 10% PHE---1 gtt OU 4 100% (n=4/4) 10% PHE---2 gtts OU 181 11.05% (n=20/181) 10% PHE---2 gtts OU 20 100% (n=20/20) 10% PHE---3+ gtts OU 761 26.81% (n=204/761) 10% PHE---3+ gtts OU 20 65% (n=13/20)

Total (n) Risk of causing increased blood pressure in adult Total (n) Risk of causing increased blood pressure in pediatric patients patients 2.5% PHE---1 gtt OU 767 0.65% (n=5/767) 2.5% PHE---1 gtt OU 31 0% (n=0/31) 2.5% PHE---2+ gtts OU 414 1.93% (n=8/414) 2.5% PHE---2 gtts OU 0 Unable to quantify with available studies 2.5% PHE---3+gtts OU 211 7.11% (n=15/211)

PHE Guidelines • One drop of 2.5% PHE OU should be used without hesitation • <1% risk of elevated BP with one round of 2.5% • 5-10% PHE is best reserved for stubborn posterior synechiae cases JAMA Ophthalmol. 2015;133:647-52. • If used, no more than one drop in each eye, or two drops total in single eye • Conclusion: Phenylephrine, 2.5% leads to no clinically • Do NOT use 5-10% in infants relevant change in BP or HR and can be considered safe to • Only use one drop of 2.5% PHE OU in select cases in peds use in clinical routine. The changes in BP and HR seen with phenylephrine, 10% are short lived and of uncertain clinical • Borgman’s Rule: no more than 2 rounds of 2.5% PHE OU should be used relevance. at any one visit in adults regardless of BP

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Dx = Superior Oblique Myokymia

• First reported in 1906 by Duane “unilateral rotary nystagmus” Topical • In 1970, Hoyt coined term “superior oblique myokymia”

& Superior Oblique Myokymia • Defn: monocular quivering/firing of superior oblique • Sx: spontaneous monocular diplopia, quivering/jumping of vision, monocular oscillopsia, key is monocular nature • Sn: low amplitude, high frequency intorsion of affected eye, intermittent/cyclic frequency, worse when looking down and in towards nose • Most attacks last between 3-15 sec, rare cases of indefinite attacks

New Tx? SOM Tx Options Topical Beta-blockers??? • Observation • Bibby et al. (1994) showed one case report of a patient’s SOM Sx being • Medical relieved with glaucoma drops • Oral medications • Based off of case reports which used oral • Surgical • Weak membrane stabilizing abilities of beta blockers = MOA • EOM/Strab surgery • Microvascular decompression • MOA: hypothesized that enough drug was absorbed systemically through conjunctival blood vessels to elicit its effect (systemic theory)

30 YO WF with SOM x 10 yrs Story doesn’t end here…

• Given that numbers of SOM are low to begin with……cases reports of topical beta-blockers providing relief of Sx are even rarer • Started topical timolol 0.5% drops BID OD! • Patient reported 100% resolution of Sx after only 2 days of • Bibby et al……hypothesized “systemic theory” use!!!! • Phone call 4 months later, still 100% resolution of Sx but only • I developed my own theory…… using drops QAM OD • Chris Borgman’s “Localized Theory” • 12+ month later….still Sx-free on drops!

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CB’s “Localized Theory” Proof of Localized Theory

• In SOM, when successfully treated with topical beta-blockers, the • After successful Tx for 2+ months… effect occurs locally at the trochlear nerve endings themselves • Patient instructed to stop all drops and/or on the trochlear muscle itself, not systemically absorbed • Sx returned to pre-treatment severity in 2-3 days via the conjunctival blood vessels. • Patient instructed to instill drops in contralateral eye • No effect, Sx still remained • • Patient told to re-start drops in original/affected eye I would argue AGAINST Bibby’s systemic absorption theory. • Sx disappeared in 1-2 days of use again • No recurrences since

Interesting Potential Off-Label Uses of β-Blockers??? What does this mean?

• Keep in mind…..this is only 1 case. 1. Superior Oblique Myokymia 

• Beta-blockers work locally on the ocular tissues themselves Borgman CJ. Topical timolol in the treatment of monocular oscillopsia secondary to superior oblique myokymia: a • Likely on superior oblique muscle itself or the trochlear nerve endings review. J Optom. 2014;7:68-74. • Perhaps not on a systemic level like Bibby et al. hypothesized… • “Localized theory” holds water! • However, still unproven…needs more research 2. Eyelid Myokymia 

MOA: stabilization of membrane excitability/resting state of action potential (phase 4) 

Ethambutol • Antituberculosis medication; predominantly bacteriostatic • Treatment: minimum of 6 months in most cases • Drug most often implicated in toxic optic neuropathy Ethambutol Ocular Toxicity Risk • D-isomer = therapeutic form Calculations • L-isomer = toxic form • Loading dose initially 25 mg/kg/day x 2 mo • Maintenance dose = 15-20 mg/kg/day • Ideal dose = 15 mg/kg/day • >25 mg/kg/day = High doses • No safe dose of EMB has been reported!

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Retrobulbar Optic Neuritis EMB Toxicity

• EMB causes demyelinating effect • VA = normal to NLP • EMB toxicity: • Onset = 2-12 months, average 6-7 months • after 36 months has been reported 1. Central • Acuity, contrast sensitivity, reading difficulty, color vision defects, VF defects within central 10° • Visual Recovery: 40-50% after 2-8 months of discontinuation • Most devastating • Unpredictable though… 2. Peripheral • Age: >60 YO = lower rate of recovery • VF defects outside central 10° • Daily dose >> duration of treatment • Temporal optic nerve atrophy! • Highest metabolic demand here (papillo-macular bundle) • Bottom line  mitochondrial dysfunction 2’ EMB toxicity

Table 1: Percentage risk range and mean risk of developing ocular toxicity based on daily dosing of Ethambutol in regards to milligrams per kilogram per Mean Risk of Ethambutol Optic Nerve Toxicity day (mg/kg/day) based on available literature1,2,4,6-8,12-14,22,24-26,28-30,38-46

Mean Risk of Ethambutol Optic Nerve Toxicity 50

Daily 15 17.85 20 25 30-35 40-50 60-100 45 Dose mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/ mg/kg/da 40 day y 35 30

25

Risk 0.62-2% 1.5% 3-6.3% 2.2-9.4% 15-18.6% 15- 40-50% 20

Range 33.3% Mean Toxicity ofRisk (%) 15

10

Mean 1.31% 1.5% 4.65% 5.8% 16.8% 24.15% 45% 5 Risk 0 0 10 20 30 40 50 60 70 80 90 Mean Daily Dose of Ethambutol (mg/kg/day)

The Calculation Example #1

퐵표푑푦 푊푒𝑖푔ℎ푡(푙푏푠) • A 150 lbs male who is taking 1000 mg Ethambutol daily for her Mycobacterium = 푤푒𝑖푔ℎ푡 𝑖푛 푘𝑖푙표푔푟푎푚푠 avium complex infection. What is the total dose per day that the patient is getting 2.2 푙푏푠 and respectively what would be his risk of developing ocular toxicity based on this dose? 1 150 푙푏푠 푇표푡푎푙 푑푎𝑖푙푦 푑표푠푒 (푚푔) 푥 = 푑표푠푒 표푓 푚푔/푘푔/푑푎푦 • = 68.18 푘푔 표푓 푏표푑푦 푤푒𝑖푔ℎ푡 푏표푑푦 푤푒𝑖푔ℎ푡 푘푔 2.2 푘푔 1 • 1000 푚푔 푥 = 15 푚푔/푘푔/푑푎푦 68.18 푘푔 • ~1.31% risk

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Table 1: Percentage risk range and mean risk of developing ocular toxicity based on daily dosing of Ethambutol in regards to milligrams per kilogram per Example #2: day (mg/kg/day) based on available literature1,2,4,6-8,12-14,22,24-26,28-30,38-46 • Example #2: A 100 lbs female who is taking 1600 mg Ethambutol daily for her Mycobacterium tuberculosis infection. What is the total dose per day that the Daily 15 17.85 20 25 30-35 40-50 60-100 patient is getting and respectively what would be her risk of developing ocular Dose mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/ mg/kg/d toxicity at this dose? day ay 100 푙푏푠 • = 45.45 푘푔 2.2 푘푔 1 Risk 0.62-2% 1.5% 3-6.3% 2.2-9.4% 15-18.6% 15- 40-50% • 1600 푚푔 푥 = 35 푚푔/푘푔/푑푎푦 Range 33.3% 45.45 푘푔 • ~16.8% risk Mean 1.31% 1.5% 4.65% 5.8% 16.8% 24.15% 45% Risk

Table 1: Percentage risk range and mean risk of developing ocular toxicity Recommendations… based on daily dosing of Ethambutol in regards to milligrams per kilogram per day (mg/kg/day) based on available literature1,2,4,6-8,12-14,22,24-26,28-30,38-46 1. Prior to starting EMB  Baseline exam 2. 1 month later 3. q3-6 months while on EMB Daily 15 17.85 20 25 30-35 40-50 60-100 4. D/c with any signs of toxicity Dose mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/ mg/kg/d day ay • Acuity, Pupils, DFE, HVF, Fundus photos, OCT, color vision at every visit Risk 0.62-2% 1.5% 3-6.3% 2.2-9.4% 15-18.6% 15- 40-50% • Consider both 10-2 & 24/30-2 protocols Range 33.3%

Mean 1.31% 1.5% 4.65% 5.8% 16.8% 24.15% 45% • Communicate findings (and risk) to prescribing PCP! Risk

Oxybutynin

• Parental drug for overactive bladder syndrome • 10-17% of the adult population has OBS

Oral Anticholinergics & • Moderately potent anticholinergic, antispasmodic, and local Ocular Side Effects anesthetic properties • 10% as potent as atropine in antispasmodic actions • 4% as potent as atropine in mydriasis

• Blurred vision occurs in 3.8% of patients taking medication

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Parasympathetic Nervous System Review Oxybutynin • Of all oral anticholinergics, oxybutynin has highest risk of • Parasympathetic innervation controls: • Accommodation systemic/ocular SE’s • Lacrimation Anticholinergic Medicaion Highest Risk of Causing Side Effects • Pupil miosis • Convergence oxybutynin Highest • Urination • MOA: muscarinic receptor agonism with propiverine High • M1, M2, M3, M4, and M5 receptors identified fesoterodine Intermediate • M3  pupil miosis, convergence, accommodation, lacrimation, & urination • Oxybutynin blocks M1 & M3 solifenacin Intermediate • Mydriasis • Cycloplegia tolterodine Intermediate/Low • Ocular surface dryness darifenacin Intermediate/Low • Binocular vision dysfunction • Reduces bladder contraction trospium Low

Why Oxybutynin with highest SE profile? Ocular Side Effects

• ***Ocular Surface Dryness • In order to cause CNS effects, any anticholinergic drug must first pass through the blood- brain barrier, which is formed by the endothelial cells that line cerebral capillaries and to their • M3 receptor antagonism on lacrimal gland continuous tight junctions • ***Decreased Accommodation Oxybutynin Other OBS medications • >1.00 D in 3-7% of patients Small molecular size Larger molecular size • Within first 4 weeks of initiating therapy High lipophilicity Low lipophilicity • Binocular Vision Dysfunction Neutral polarity Moderate polarity • Pupil mydriasis • Usually <1 mm • Oxybutynin’s properties allows it to pass through the blood-brain barrier much more easily than any of the other related molecules of this same family of drugs

• If M1 receptor antagonism is too severe  Alzheimer’s-like complications possible

Antimuscarinic Inhalers

• Combivent (ipratropium/albuterol) • Atrovent (ipratropium) • Spiriva (tiotropium) Betadine/Dexamethasone for EKC?

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EKC Tx Historically Betadine (Povidone-Iodine)

• Note: Contagious for 10-12 days from onset; can last 2-4 weeks • Povidone iodine is a broad spectrum microbiocide that • Treatment Options: destroys microbial protein and DNA; “antiseptic” • Nothing • Anecdotal reports of use in acute viral conjunctivitis • Artificial Tears • Dilute concentrations effective against: • Antibiotics?...Why? • HIV • Topical steroids • Fungi • Parasites • Prolong viral shedding phase… • Bacteria • Betadine?

FST-100 (Betadine & Dexamethasone) Pinto et al. Curr Eye Res. 2015. • Betadine 0.4% and Dexamethasone 0.1% --- dosed QID OU x 30 days Combination Med • 109 patients with proven EKC (56 = B/D, 53 = AT’s) • Same frequency of SEI’s in both groups • Betadine 0.4% and Dexamethasone 0.1% suspension • IOP’s were same in both groups • Commercial concentration = 5% and 10% • Duration of disease = 9.5 days in FST-100, 12 days in AT’s • Dosing: QID x 5+ days • Patient reported: • 3-5 days cure rate? Betadine/Dexamethasone Artificial Tears Tx did not help = 21% Tx did not help = 22.5% • Why? Tx did help = 79% Tx did help = 77.5% • “…to effectively treat both the inflammatory and infectious components of acute adenoviral conjunctivitis by decreasing the symptomatic period Discomfort with drops = 22.5% Discomfort with drops = 2% following infection, shortening the duration of viral shedding, and • “It is also important to note that although statistically significant, the reducing the potential for infectious transmission.” --- Pelletier JS, et al. dexamethasone 0.1%/povidone-iodine 0.4% formulation decreased the (2009) duration of conjunctivitis by only 2.4 d. Given the socio-economic impact of viral conjunctivitis, 2.4 d may be considered important.” --- Pinto et al. (2015)

Pinto RDP, et al. Dexamethasone/povidone eye drops versus artificial tears for treatment of presumed viral conjunctivitis: a randomized clinical trial. Curr Eye Res. 2015;40:870-7.

Latest study: Kovalyuk et al. Acta Ophthalmol. 2017 • PVI 1.0%/Dex 0.1% vs. Dex 0.1% alone vs. Artifical Tears alone Time for mainstream??? • N= 78 total (26 per group) • Dose: QID x 7 days • “A big pharmaceutical company we are all familiar with is currently • Compared: itching, redness, tearing, discharge, SPK, pseudomembranes, & SEI’s attempting to bring an EKC combination drop (PVI/Dexamethasone • PVI/Dex combo >Dex alone > AT’s in all comparison points! combination) to market and are currently in at least phase II trials…” • Adenoviral PCR elimination rates:

Days PVI 1.0% / Dex 0.1% Combo Dex 0.1% only Artificial Tears Day 3 56% 21% 26% • Stay tuned… Day 5 92% 38% 46% Day 7 99% 65% 77% • “…our results indicate that the combination of PVI 1.0%/dexamethasone 0.1% is effective in treating adenoviral keratoconjunctivitis. This combination improved the patient’s ailment and clinical signs to almost complete recovery in 5-7 days, which correlated with the eradication of the virus by PCR.”

Kovalyuk N, et al. Treatment of adenoviral keratoconjunctivitis with a combination of povidone-iodine 1.0% and dexamethasone 0.1% drops: a clinical perspective controlled randomized study. Acta Ophthalmologica. 2017;95:e686-92.

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Questions???

• Thank you!

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