Ophthalmology in FocusOphthalmology in Focus

Empowering Pharmacists to Improve Glaucoma Outcomes and

Ocular Health

PresentersRandall Seifert, PharmDS i A i DSenior Associate DeanProfessorPharmacy Practice and Pharmaceutical SciencesUniversity of MinnesotaUniversity of MinnesotaCollege of PharmacyDuluth, Minnesota

Tim Cernohous, PharmD, RPhPhD Candidate, Social and Administrative PharmacyUniversity of MinnesotayCollege of PharmacySPC Therapeutics, LLCEssentia HealthDuluth, Minnesota

Disclosures

Dr. Cernohous and Dr. Seifert disclosed no relevant financial relationships with any p y

commercial interests.

Learning Objectives

After completing this activity, participants will be able to:

g j

• Outline the safety and efficacy of available glaucoma medications, including associated adverse events of treatment

• Describe the factors involved in ocular inflammation and dry eye disease, including comorbid conditions, modifiable risk factors, and appropriate pp ppharmacotherapy

• Take a more active role in screening, treating, and counseling patients with glaucoma and other ocular g p gdiseases

• Adhere to guideline-directed and evidence-based pharmacotherapy in the treatment of glaucomap py g

Audience Response Question

How often do you screen for or discuss ocular

p

How often do you screen for or discuss ocular conditions with your patients?

1. Always2. Often3. Rarely4. Never

Audience Response Question

How confident are you in your ability to consult and

p

How confident are you in your ability to consult and medically manage patients with glaucoma?

1. Very confident2. Confident3. Somewhat confident4. Not confident

US Prescription Ophthalmic Drug MarketDrug Market

$2,500 –

$3,000 –2007

2010

2015-2020

Mill

ions

$1,500 –

$2,000 –

$ in

M

$1,000 –

$500 –

$0 –Dry Eye, Allergy,

Inflammation

Infection Glaucoma Retinal and Vitreous

Disorders

Insight Pharma Reports/H.M. Pharma Consultancy.

Definition of Glaucoma

• Family of ocular diseases ycharacterized by progressive optic neuropathy and VF loss

Gradual optic disk cupping a structural– Gradual optic disk cupping—a structural change characteristic of glaucoma

– Associated VF deficitsP i ti l li ll l– Progressive retinal ganglion cell loss

• No longer defined alone by elevated IOP

VF = visual field; IOP = intraocular pressure.Quigley HA. Prog Retin Eye Res. 1999;18(1):39-57. David R. Expert Opin Investig Drugs. 1998;7(7):1063-1086.

Glaucoma

• Estimated 2.5 million people in the United States have POAG as of 2000

• 130,000 will be blind as a result of the disease• Half of those with POAG may not be aware they have the disease

S d l di f bli d ld id l di i• Second leading cause of blindness worldwide; leading cause in African Americans and Hispanics

• 10 million people have above normal IOP that may lead to glaucoma• 120 000 are presently blind from glaucoma• 120,000 are presently blind from glaucoma• 5500 become blind each year from the disease• Direct annual medical cost related to glaucoma was estimated to be

$2 9 billion$2.9 billion

POAG = primary open-angle glaucoma.Fleming C, et al. Ann Fam Med. 2005;3(2):167-170. Congdon N, et al. Arch Ophthalmol. 2004;122(4):477-485. Rein DB, et al. Arch Ophthalmol. 2006;124(12):1754-1760. Glaucoma Research Foundation. http://www.glaucoma.org/learn/glaucoma_facts.php. Accessed February 20, 2012. Quigley HA, et al. Br J Ophthalmol. 2006;90(3):262-267. Prevent Blindness America®. Vision problems in the U.S.: prevalence of adult vision impairment and age-related eye disease in America. http://www.preventblindness.org/vision-problems-us. Accessed February 10, 2012.

Major Types of Glaucoma

Primary glaucomas

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Primary glaucomas• POAG• NTG• NTG• OH

ACG• ACGSecondary glaucomas

NTG = normal- (low) tension glaucoma; OH = ocular hypertension; ACG = angle-closure glaucoma.

Progression of ON Damageg g

ON = optic nerve.

Aqueous Humor Dynamicsq y

In glaucoma,outflow isimpaired

Angle-Closure Glaucoma

• Characterized by sudden:

g

y– Onset of visual loss – Excruciating pain

Halos– Halos– Nausea and vomiting

• Patients are occasionally thought to have acute gastrointestinal disease

• Requires immediate• Requires immediate transfer from ED to ophthalmology for treatment

ED = emergency department.Salmon JF. Glaucoma. In: Riordan-Eva, P, et al. Vaughan & Asbury's General Ophthalmology. 18th ed. New York, NY: McGraw Hill; 2011.

Normal-Tension Glaucoma

– 25% to 50% of individuals with primary glaucomatous optic disc changes and visual field deficits have normal IOP measurements

– Glaucomatous optic disk or VF changes have an IOP consistently below 21 mm Hg

• May be caused by an abnormality in the optineurin gene on chromosome 10• May be caused by vascular or mechanical abnormalities at the optic nerve head• May be a purely vascular disease

– Before a diagnosis of normal tension glaucoma is made a differential diagnosis for many other factors must be ruled out

– Bottom line, approximately 60% have progressive VF loss– Increased IOP is no longer considered to be part of the definition of

POAG

Quigley HA. New Engl J Med. 1993;328(15):1097-1106. Salmon JF. Glaucoma. In: Riordan-Eva, P, et al. Vaughan & Asbury's General Ophthalmology. 18th ed. New York, NY: McGraw Hill; 2011.

Ocular Hypertension

• Elevated IOP without disk or field

yp

Elevated IOP without disk or field abnormalities and is more common than POAGthan POAG– Rate at which such individuals develop

glaucoma is approximately 1% to 2% per yearglaucoma is approximately 1% to 2% per year• Should undergo regular monitoring (once

or twice a year) of IOPs optic disks andor twice a year) of IOPs, optic disks, and VFs

Salmon JF. Glaucoma. In: Riordan-Eva, P, et al. Vaughan & Asbury's General Ophthalmology. 18th ed. New York, NY: McGraw Hill; 2011.

Primary Open-Angle Glaucoma

• Glaucomatous optic

y p g

Glaucomatous optic disk or field changes – Associated with

elevated IOPs– Normal-appearing open

anterior chamber angleanterior chamber angle– No other reason for IOP

elevation

Salmon JF. Glaucoma. In: Riordan-Eva, P, et al. Vaughan & Asbury's General Ophthalmology. 18th ed. New York, NY: McGraw Hill; 2011.

Risk Factors for POAG• Elevated IOP

– IOP >21 mm Hg• Diurnal fluctuation in IOP—higher in early morning• Patient susceptibility

– Cup/disc > 50– Cup/disc >.50– Advanced age ( >50 years)– Central corneal thickness <555 microns– Race (African descent 6 to 8 times more common than non-African descent)

A 40– Age >40 years• Family history of glaucoma• Concomitant conditions (eg, diabetes, hypertension)• Myopia• Myopia• Compromised ocular and systemic hemodynamics• History of migraine, Raynaud’s phenomenon, cardiogenic factors

American Academy of Ophthalmology. Preferred Practice Pattern® guidelines. http://one.aao.org/CE/PracticeGuidelines/PPP.aspx. Accessed February 20, 2012. Wolfs RC, et al. Arch Ophthalmol.1998;116(12):1640-1645.

Screening for POAG

• Either direct ophthalmoscopy of the dilated

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Either direct ophthalmoscopy of the dilated eye or slit lamp examination

• Direct ophthalmoscopyDirect ophthalmoscopy – Sensitivity of 59% and a specificity of 73% in

detecting and classifying optic disc changes• VF analyzers

– Sensitivity of 95% and a specificity of 93% for y p ydetecting moderate to severe glaucoma (n=137)

Quigley HA, et al. Ophthalmology. 1992;99(1):19-28. Coleman AL, et al. J Glaucoma. 1996;5(6):384-389. Patel SC, et al. Am J Ophthalmol. 2000;129(3):323-327.

VF Examination

http://webeye.ophth.uiowa.edu/eyeforum/images/glaucoma/fig-6-12.gif. Accessed February 17, 2012.

Relationship Between IOP and VF Deterioration POAG

12

Deterioration—POAG

8

10

ents

Visual Field LossStable Visual Field

4

6

mbe

r of P

atie

2

4

Num

012 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Mean IOP (mm Hg)

Mao LK, et al. Am J Ophthalmol. 1991;111(1):51-55. AGIS Investigators. Am J Ophthalmol. 2000;130(4):429-440. Shirakashi M, et al. Ophthalmologica. 1993;207(1):1-5. Stewart WC, et al. Am J Ophthalmol. 1993;116(2):176-181. Bojić L, et al. Acta Med Croatica. 1998;52(4-5):219-220.

Measuring IOPg

Treatment of POAG

• Most recent treatment is based on theMost recent treatment is based on the results of the OHTS

• Patient characteristics with greatest risk:• Patient characteristics with greatest risk:– IOP >25 mm Hg

V ti l t di k ti f th 0 5– Vertical cup-to-disk ratio of more than 0.5 – Central corneal thickness of less than 555 μm

• Patients may have glaucomatous changes without elevated IOP

OHTS = Ocular Hypertension Treatment Study.Kass MA, et al. Arch Ophthalmol. 2002;120(6):701-713.

Goals of Therapy

• Dependent on clinical findings and extent of IOP

py

p g• Individualized to patient• Reduction in mean IOP to <18 mm Hg or

20% to 30% lowering• Those with normal IOP may be reduced to 10 to

12 mm Hg12 mm Hg• Control of diurnal IOP fluctuation throughout the

dayy• IOP lowering to <18 mm Hg with monotherapy if

possible

Kass MA, et al. Arch Ophthalmol. 2002;120(6):701-713.

Nonpharmacologic Therapies

Lifestyle factors potentially contributing to POAG

p g p

y p y g• Smoking • Alcohol• Physical activities

Nonpharmacologic treatment approaches• Exercise (isokinetic)

Mi i i ff i i t k• Minimize caffeine intake• Limited evidence for diet and supplementation

Klein BE, et al. Am J Ophthalmol. 2007;144(6):961-969. Rhee DJ, et al. Survey Ophthalmol. 2001;46(1):43-55.

Treatment Considerations

• Although high IOP is certainly not the only factor g g y ycontributing to ON damage, it is the only risk factor that can be clinically modified

• Medically lowering IOP in patients with OH may reduce• Medically lowering IOP in patients with OH may reduce the incidence of glaucoma

• In at least two-thirds of patients with high-tension f Oglaucoma, marked lowering of the IOP stops progression

of the disease• Even in NTG patients, the IOP level is a risk factor p ,

related to the degree of glaucomatous damageCartwright MJ, et al. Arch Ophthalmol. 1988;1067):898-900. Crichton A, et al. Ophthalmology. 1989;96(9):1312-1314. Kass MA, et al. Arch Ophthalmol. 1989;107(11):1590-1598. Kidd MN, et al. Br J Ophthalmol. 1985;69(11):827-1314. Kass MA, et al. Arch Ophthalmol. 1989;107(11):1590 1598. Kidd MN, et al. Br J Ophthalmol. 1985;69(11):827831. Odberg T. Acta Ophthalmol. 1987;65(suppl 182):27-29. Roth SM, et al. Ophthalmic Surg. 1991;22(12):724-729. Kolker AE. Trans Am Ophthalmol Soc. 1977;75:539-555. Leydhecker W, et al. Int Ophthalmol. 1989;13(1-2):113-117. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998;126(4):487-497. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998;126(4):498-505.

Audience Response Question

Which one of the following therapeutic categories

p

Which one of the following therapeutic categories is the most effective in lowering IOP?

1. Beta-blockers2. Carbonic anhydrase inhibitors3. Prostaglandins4. Cholinergics

Topical Medications for Glaucoma p

Drug Class IOP Lowering mm HG

Prostaglandin analogues 6 – 8

Combination—dorzolamide and timolol ophthalmic 4 – 6

Miotics 3 – 5

Beta-blockers 3 – 5

Carbonic anhydrase inhibitors 2 – 4

Alpha agonists 2 – 6

Single-Bottle Treatments

• Prostaglandin

g

g– Bimatoprost, latanoprost,* travoprost

• Beta-adrenergic antagonist– Timolol,* levobunolol,* betaxolol,* metipranolol*

• Selective alpha-adrenergic agonistApraclonidine * brimonidine*– Apraclonidine, brimonidine

• Topical CAI– Brinzolamide, dorzolamide*o a de, do o a de

• Fixed combinations– Timolol/dorzolamide, timolol/brimonidine

*Denotes generic available (generic availability varies by strength and dosage form). CAI = carbonic anhydrase inhibitor.Gheith ME, et al. Clin Ophthalmol. 2008;2(1):15-20.

High Responder Ratesto Desired Target IOPto Desired Target IOP

PGAs have higher responder rates than beta-blockers12-month US study; all patients; mean IOP at 4 PM; phase 3 clinical trial

9187

100(%)

54

8073

87

62

82

60708090

ing

at 4

AM

4536

20304050

s R

espo

ndi

010

<22 mm Hg <20 mm Hg <18 mm HgPatie

nts

PGAs = prostaglandin analogues.Netland PA, et al. Am J Ophthalmol. 2001;132(4):472-484.

Travoprost 0.004% (n=197) Latanoprost 0.005% (n=193) Timolol 0.5% (n=195)

Two-Bottle Treatment

Prostaglandin • Topical beta-blockerProstaglandin Topical beta blocker• Topical CAI• Selective alpha agonist

Timolol/dor olamide

++• Timolol/dorzolamide• Timolol/brimonidine

Topical beta-blocker• Prostaglandin• Topical CAI++ Topical CAI• Selective alpha agonist

Drug Treatments for Glaucomag

Drug Pharmacology Mechanism of Action Dosage FormUsual Dose

(drops)Drug Pharmacology Mechanism of Action Dosage Form (drops)

Prostaglandin analogues

Increases aqueous uveoscleral outflow and to a lesser extent

trabecular outflow

T t S l ti 1 Q HSTravoprost Solution 1 Q HS

Latanoprost Prostaglandin F2α Solution 1 Q HS

Bimatoprost Prostaminde analog Solution 1 Q HS

β-adrenergic Decreases aqueous production blocking agents of ciliary body

Betaxolol Relative β1 selective Solution 1 BID

Relative β1 selective Suspension 1 BID

Cartelol Nonselective Solution 1 BIDCartelol Nonselective Solution 1 BID

Levobunolol Nonselective Solution 1 BID

Metipranolol Nonselective Solution 1 BID

Timolol Nonselective Solution/gelling solution 1 QD to 1-2 QDsolution

HS = bedtime; BID = twice daily; QD = once daily.

Drug Treatments for GlaucomaDrug Pharmacology Mechanism of Action Dosage Form Usual Dose (drops)

Nonspecific agonists Increases aqueous humor outflow

Dipivefrin Prodrug Solution 1 BID

α2 adrenergic agonists

Both decrease aqueous production; brimonidine increases uveoscleral

outflow

Apraclonidine α2 agonist Solution 1 BID to TID

Brimonidine α2 agonist Solution 1 BID to TID

Carbonic anhydrase inhibitors

Decreases aqueous production of ciliary body

TopicalTopical

Brinzolamide Carbonic anhydrase II inhibition Suspension 1 BID to TID

Dorzolamide Carbonic anhydrase II inhibition Solution 1 BID to TID

Systemic

Acetazolamide Carbonic anhydrase II inhibition Capsuleceta o a de Ca bo c a yd ase b t o Capsu e

Methazolamide Carbonic anhydrase II inhibition Tablet

Combinations

Timolol-dorzolamide Solution 1 BID

Timolol-brimonidine Solution 1 BID

TID = three times daily.

Summary of Class-Specific ADRsy p

D Cl Sid Eff tDrug Class Side Effects

Prostaglandin agonistsHyperemia (25% to 45%), pigmentation of the iris, eye lids, and lashes (2% to 6%) and hypertrichosis (15% to 45%

ith bi t t) d (2% t 6%)with bimatoprost), dry eye (2% to 6%)

Beta-adrenergic blockers Localized stinging (5% to 15%), hyperemia, somnolence, decreases in HR and BP, bronchospasm

Alpha-adrenergic agonistsHyperemia (10% to 20%), itching (pruritus 10% to 20%), foreign object sensation (5% to 9%), decrease BP and/or HR, dizziness, allergic reactions

CAIs Burning and stinging, blurred vision, punctate keratitis

Nonspecific (dipivefrin) Headache, tearing, burning, stinging, hyperemia (1% to 10%) photophobia10%), photophobia

ADRs = adverse drug reactions; HR = heart rate; BP = blood pressure. American Hospital Formulary Service (AHFS) Drug Information 2012. Bethesda, MD: American Society of Health System Pharmacists; 2011.

Hyperemiay

Hyperpigmentationyp p g

Generic Ophthalmic Medications

• Testing of innovator and generic ophthalmic

p

g g pproducts– Prior to 1992, the FDA used to permit changes in

inactive ingredients for ophthalmic genericinactive ingredients for ophthalmic generic products without testing

– After 1992, generic ophthalmic solutions must have the same active and inactive ingredientshave the same active and inactive ingredients

– For products other than a solution, the generic has to demonstrate bioequivalence

• Stability, concentration, color coding

FDA = US Food and Drug Administration.American Glaucoma Society. Generic ophthalmic medications position statement. http://one.aao.org/ce/practiceguidelines/clinicalstatements_content.aspx?cid=e90121fe-1a9d-4030-a991-782f54cf23f5. Accessed February 20, 2012.

Adherence to Topical Ophthalmic MedicationsMedications

100 100

90

80

70inin

g on

90

80

70

60

50

40

Patie

nts

Rem

aM

edic

atio

n 60

50

40

Prostaglandins

Alpha-agonists

40

30

20Perc

enta

ge o

f M 40

30

20

Prostaglandins

CAIsCAIs

Beta-blockers10

0 |

0|

6|

12|

18|

24|

30|

36Months After Treatment Initiation

10

0 |

0|

6|

12|

18|

24|

30|

36

Alpha-agonistsBeta-blockers

Months After Treatment Initiation

Nordstrom BL, et al. Am J Ophthalmol. 2005;140(4):598-606.

Diagnosed Glaucoma Glaucoma Suspect

Strategies to Improve Adherence

• Actively address at-risk patients • Review drug administration with h fill

g p

• Simplify and optimize treatment regimen when possible

• Reduce drug costs when ibl

each refill• Suggest that patients keep a

medication diaryU t l h il i dpossible

• Understand the patient’s health beliefs about glaucoma

• Provide patient disease

• Use telephone or mail reminders when possible

• Suggest the patient incorporate drops into daily activities• Provide patient-disease

education– Reinforce regularly– Use verbal and written delivery

drops into daily activities• Involve a helpful

caregiver/family member• Use open communicationUse verbal and written delivery

– Adapt information to those with poor vision or low literacy

Use open communication– Ask-tell-ask dialogue– Motivational interviewing– Stages of readiness for change

Budenz DL. Ophthalmology. 2009;116(11 suppl):S43-S47.

Glaucoma SurgeryLaser Trabeculoplasty

g y

Laser trabeculoplasty can be considered as initial therapy in selected patients [A:I]* or an alternative for patients who cannot or will not use medications reliably due to cost, memory problems, difficulty with instillation, or intolerance to the medication.

Incisional Glaucoma SurgeryTrabeculectomyFiltering surgery is effective in lowering IOP It is generally indicated whenFiltering surgery is effective in lowering IOP. It is generally indicated when medicine or laser therapy is insufficient to control disease and can be considered in selected cases as initial therapy.

Aqueous ShuntsAqueous ShuntsAqueous shunts have traditionally been used to manage medically uncontrolled glaucoma when trabeculectomy has failed to control IOP or is deemed unlikely to succeed.

*Level of importance A. Level of evidence I.National Guideline Clearinghouse. Primary open-angle glaucoma. http://www.guideline.gov/content.aspx?id=24810. Accessed March 14, 2012.

Figure 1: Incisional Glaucoma Surgery: Trabeculectomy

Figure 2: Laser Trabeculoplasty

http://ohioeyecareconsultants.com/eyeinfo/glaucomasurgery2.jpg. Accessed April 28, 2011. http://www.uwhealth.org/images/ewebeditpro2/upload/4588_Figure_1.jpg. Accessed April 28, 2011.

g p y

Audience Response Question

Dry eye incidence and severity of symptoms

p

Dry eye incidence and severity of symptoms is correlated with the number of ocular medications in usemedications in use.

1. True2 False2. False

Ocular Surface Anatomyy

Meibomian glands

Dry Eye Syndrome, Dry Eye Disease, or Dysfunctional Tear Syndrome

A multifactorial disease of the tears and

or Dysfunctional Tear Syndrome

A multifactorial disease of the tears and ocular surface that is characterized by:

Increased osmolarity of the tear film– Increased osmolarity of the tear film– Tear film instability

Inflammation of the ocular surface– Inflammation of the ocular surface

Ocul Surf. 2007;5(2):75-92. Perry HD, et al. Curr Opin Ophthalmol. 2004;15(4):299-304.

Symptoms of Dry Eye Syndrome

Patients usually present with the following

y p y y y

y p gcomplaints:

• Painful or sore eyesB i / ti i d (h i )• Burning/stinging, redness (hyperemia)

• Foreign body sensation• Blurred or poor visionBlurred or poor vision• Photophobia• Tired eyes• Paradoxical tearing• Dryness worse later in the day• Contact lens intolerance• Contact lens intolerance

Pictures of Dry Eye Syndromey y y

Prevalence and Risk Factors for Dry Eye

• Dry eye is a significant public health problem

for Dry Eyey y g p p

• US statistics– 7 million Americans over 40 years of age

5 7% of women over 50 years of age– 5.7% of women over 50 years of age– 9.8% of women over 75 years of age– 3.9% of men 50 to 54 years of age– 97.6% men over 80 years of age

• Prevalence increases with:– AgeAge– Menopause– Glaucoma

Schaumberg DA, et al. Am J Ophthalmol. 2003;136(2):318-326. Moss SE. Arch Ophthalmol. 2000;118(9): 1264-1268. Schaumberg DA, et al. Arch Ophthalmol. 2009;127(6):763-768.

OSD Prevalence Study: Conclusions

• OSD is a significant problem for many glaucoma

ConclusionsOSD is a significant problem for many glaucoma patients (48.4%)

• Prevalence is much higher than previously g p yreported in a population-based study of elderly patients (approximately 15%)

• OSD severity increases with the number of medications used

OSD = ocular surface disease.Fechtner R, et al. Presented at: Annual Meeting of the American Glaucoma Society; March 8, 2008; Washington, DC. Schein OD, et al. Am J Ophthalmol. 1997;124(6):723-728.

Major Categories of Dry Eye Syndromej g y y y

Both categories are characterized by increased tear filmBoth categories are characterized by increased tear film osmolarity and ocular surface inflammation

Aqueous Deficient-State Lack of tear production

Evaporative State Rapid tear evaporationEvaporative State p p(Intrinsic or Extrinsic)

Dry Eye Cascade: Causes and Contributing Factors of Abnormal Tear FilmContributing Factors of Abnormal Tear Film

Healthy Ocular SurfaceSurface

Abnormal or

Tears

Abnormal or Insufficient

Tears

ObservablePathophysiologies

A i

Increased Ocular

Reduced Tear Clearance

Aqueous Deficiency

TBUT LessTBUT Less

• Aging• Smoking• Dry environment• Hormonal changes• Contact lens• Blepharitis Osmolarity Irritation

Increased

Rate

TBUT Less Than Blink

Rate

Mucin

Blepharitis• LASIK• Auto-immune disease• Alcohol use• Pollution• Computer use

Cytokines

I fl ti

Mucin Abnormalities • Antidepressants

• Specific preservatives in topical medications

TBUT = tear film breakup time; LASIK = laser-assisted in situ keratomileusis. Gayton JL. Clin Ophthalmol. 2009;3:405-412.

Inflammation

Healthy Tear Film With Lipid, Aqueous, and Mucin Layers and Healthy Ocular Surface With Intact MicrovilliLayers and Healthy Ocular Surface With Intact Microvilli

Gayton JL. Clin Ophthalmol. 2009;3:405-412.

Progressive Damage of Corneal Surface Cells (Lost Microvilli) Due to Unhealthy Tear Film(Lost Microvilli) Due to Unhealthy Tear Film

Gayton JL. Clin Ophthalmol. 2009;3:405-412.

Commonly Used Drugs Associated With Dry EyeCommonly Used Drugs Associated With Dry Eye

Antihistamines

Antidepressants especially tricyclic antidepressants

Anticholinergics

Diuretics

Angiotensin-converting enzyme inhibitors

Oral contraceptives

Opioid narcotics

Antiparkinsonism agents

B t bl kBeta-blockers

Antipsychotics

Anxiolytics—benzodiazepinesAnxiolytics benzodiazepines

Mild/Moderate Patient

• 63-year-old female with POAG63 year old female with POAG• Postmenopausal • Controlled IOP• Mild field loss• Seasonal allergies• Contact lenses• Latanoprost• Red and gritty eyes• Comes to pharmacy asking for artificial tears

When May BAK Use Be Most Problematic?

• High BAK concentration: cell death is dose-dependent

Problematic?High BAK concentration: cell death is dose dependent– High concentration in a single drop or due to the accumulation of

dose with multiple drops

Growth arrest NecrosisApoptosis0.0001% BAK 0.05% – 0.1% BAK0.01% BAK

• Treatment of chronic ophthalmic diseases, such as glaucoma, with BAK-containing medications– Longer duration of BAK exposure increased corneal

epithelial cell lysis

BAK = benzalkonium chloride. De Saint Jean M, et al. Eye Res. 2000;20(2):85-94. Cha SH, et al. Clin Experiment Ophthalmol.2004;32(2):180-184.

Therapeutic Approaches

Remember that dry eye is a chronic condition and

p pp

Remember that dry eye is a chronic condition and our treatment is targeted to reducing symptoms and improving quality of life.

• Remove/avoid offending agent• Tear replacement• Increase tear production• Decrease inflammation

Tear conservation• Tear conservation

Nonpharmacologic Options• Remove/avoid offending agent or condition

p g p

• First identify environmental changes– Wear glasses—decrease evaporation of tears– Adjust vents

Adj t ili f id i t– Adjust ceiling fans—avoid air currents– Control humidity and a humidifier– Take frequent breaks from looking at a computer screen or other

visually demanding tasksvisually demanding tasks• Discontinue or avoid smoking• Pharmacists should review potential offending prescription

and non-prescription medicationsa d o p esc p o ed ca o s• Dietary changes

– Reduce alcohol– Add omega-3, fish oils, and/or flaxseedg , ,

Therapeutic Options

Artificial Tears Goal is to improve symptoms (but these t d t h l i th lagents do not heal or repair the ocular

surface)

Lipid-containing artificial tears Useful in patients with meibomian gland dysfunction as they tend to stabilize tear film by increasing the existing tear film layer

Preservative-free artificial tears Useful in moderate to severe dry eye patients who require artificial tears more than 4 timeswho require artificial tears more than 4 times a day. They avoid ocular surface damage from preservatives

Artificial tears with solutes Beneficial for patients with excessive tear film evaporationevaporation

Hypotonic artificial tears Decrease the osmolarity of the tear film

Ophthalmic gels and ointments Useful in severe cases and in patients with incomplete eyelid closureincomplete eyelid closure

Korb DR, et al. Optom Vis Sci. 2005;82(7):594-601. Noecker R. Adv Ther. 2001;18(5):205-215. Garrett Q, et al. Invest Ophthalmol Vis Sci. 2007;48(4):1559-1567. Troiano P, et al. Cornea. 2008;27(10):1126-1130.

Commercial Artificial Tear Products

Product Ingredients Brand NameCMCCMC 0.5%, glycerin, erythritol, levocarnitine, Purite preservative

Optive

CMC 0.5%, Purite preservative Refresh TearsCMC 1%, Purite preservative Refresh LiquigelCMC 0.25%, hypotonic, preservative free Thera TearsPEGPEG 400 0.4%, propylene glycol 0.3%, hyproxypropyl guar gelforming matrix and polyquaternium preservative

Systane

PEG 400 0.4%, propylene glycol 0.3%, hyproxypropyl guar gelforming matrix with sorbitol* and polyquaternium preservative

Systane Ultra

PEG 400 0.25%, hyaluronic acid, sodium chlorite preservative Blink Tears

*Addition of sorbitol is promoted to produce less blurred vision.CMC = carboxyl methylcellulose; PEG = polyethylene glycol.

Commercial Artificial Tear Products

Product Ingredients Brand NameHPMCHPMC 0.3%, Dextran 70 0.1%, bicarbonate, zinc Bion Tears

HPMC 0 3% Dextran 70 0 1% glycerin 0 2% polyquad Tears Naturale ForteHPMC 0.3%, Dextran 70 0.1%, glycerin 0.2%, polyquad 0.001% preservative

Tears Naturale Forte

HPMC 0.3%, Dextran 70 0.1%, polyquad 0.001% preservative

Tears Natural II

HPMC 0.3%, Dextran 70 0.1%, preservative free Tears Natural Free

HPMC 0.3%, sodium perborate preservative Genteal*

HPMC 0 2% di b t ti G t l MildHPMC 0.2%, sodium perborate preservative Genteal Mild

HPMC 0.2%, glycerin 0.2%, PEG 1%, BAK 0.01% as preservative

Visine Tears†

*Also available as a single-use, preservative-free vial. †Contains BAK.HPMC = hydroxypropyl methylcellulose.

Anti-inflammatory Agentsy g

Anti-inflammatory Medications Reserved for patients with moreAnti-inflammatory Medications Reserved for patients with more severe dry eye syndrome who have failed treatment with artificial tears

Topical steroids Used in pulse dosing to decrease p p gocular surface inflammation and symptoms

Oral tetracyclines Used for patients with ocular rosaceaand blepharitis

Topical cyclosporine 0.05% Used in aqueous-deficient states

O l 3 f tt id l t M ib i l d d f ti dOral omega-3 fatty acid supplements Meibomian gland dysfunction and evaporative states

Marsh P, et al. Ophthalmology. 1999;106(14);811-816. Frucht-Pery J, et al. Am J Ophthalmol. 1993;116(1): 88-92. Sall K, et al. Ophthalmology. 2000;107(4):631-639. Macsai MS. Trans Am Ophthalmol Soc. 2008;106:336-356.

Role of Topical Corticosteroids in Dry Eye

• All patients with dry eye have ocular inflammation

in Dry Eyep y y

• Not indicated for patients with mild dry eye responsive to artificial tears

• If patients do not respond to artificial tears with continued• If patients do not respond to artificial tears with continued signs of conjunctival redness, a course of topical steroids should be addedAd t t t i l ti t id i id t• Advantage to topical corticosteroids is rapid onset of action

• Short-term therapy is most appropriate because of the yrisk of elevating IOP and cataracts

• May be used in combination with cyclosporine– Why?Why?

Cyclosporine

• Therapeutic issues for the pharmacist

y p

p p– Comes as an emulsion. So remind patients to NOT SHAKE but

to GENTLY ROLL the container in their hands prior to administration

– Long onset of action—patience required so use of topical corticosteroids in combination is reasonable

– Used BID and should be used with artificial tears but wait 15 minutes between instillation of artificial tears and cyclosporineminutes between instillation of artificial tears and cyclosporine

– Side effects• Burning and stinging are the most common and can be troublesome• Blurred vision; clear or yellow fluid from eye; difficulty reading; eye pain;Blurred vision; clear or yellow fluid from eye; difficulty reading; eye pain;

feeling of having something in the eye; halos around lights; itching skin; redness of the white part of eye or inside of eyelid; sticky or matted eyelashes; watery eye

Dry Eye Treatment Guidelines

Severity Level* Signs and Symptoms Recommended Treatment

y y

1 Mild to moderate symptoms and no signsMild to moderate conjunctival signs

Patient counseling, preserved tears, environmental management, allergy eye drops, water intake, hypoallergenic productsIf i t t 2If no improvement go to 2

2 Moderate to severe symptomsTear film signsMild corneal punctate stainingConjunctival staining

Unpreserved tears, gels, ointments, topical steroids, topical cyclosporine, nutritional supportIf no improvement go to 3Conjunctival staining

Visual signsIf no improvement go to 3

3 Severe symptomsMarked corneal stainingCentral corneal staining

Tetracycline, punctal plugsIf no improvement go to 4

Central corneal stainingFilamentary keratitis

4 Severe symptomsSevere corneal staining, erosionsConjunctival scarring

Systemic anti-inflammatory therapy, oral cyclosporine, moisture goggles, punctal cautery surgertConjunctival scarring cautery, surgert

*At least one sign and one symptom of each category should be present to qualify for the corresponding level assignment.Ocul Surf. 2007;5(2):163-178.

Nutritional Supplements in Dry Eye

• Essential fatty acids—flaxseed oil and omega-3

pp y y

Essential fatty acids flaxseed oil and omega 3 fatty acids– May reduce inflammation in meibomian gland

dysfunction, rheumatoid arthritis, and tear gland inflammationMay improve the oily layer of tear film– May improve the oily layer of tear film

• In a pilot-prospective, randomized, double-masked, placebo-controlled trial of omega-3 fatty acid p g ysupplementation:– 70% of patients became asymptomatic and 30% experienced

improvement in symptoms from moderate to mildimprovement in symptoms from moderate to mild

Wojtowicz JC, et al. Cornea. 2011;30(3):308-314.

Dry Eye Treatment Pipeliney y p

Product Name Active Principle Clinical Trial Phase

Rebamipide 2(1H)quinolone derivative 3 (ongoing)

Ecabet sodium 12-sulfodehdroabietic acid(natural phenantrene-type

d)

2b (concluded)

compound)Idestrin (NP50301) 17beta-estradiol ester 2b (concluded)

Prolacria Diquafosol (P2Y2 receptor agonist)

3 (concluded in US; ongoing inJapan)agonist) Japan)

Vekacia Cyclosporin A 3 (ongoing)

Civamide Cis-capsaicin (zucapsaicin) TRPV-1 receptor modulator neuronal

3 (nasal formulation in cluster headache)1 receptor modulator, neuronal

calcium channel blockerheadache)

ST-603 Cyclosporin 3 (commenced April 2007)

ALTY-0501 Doxycycline 3 (concluded)ALTY 0501 Doxycycline 3 (concluded)

AL-2178 (FID 109980)

Rimexolone 3 (ongoing since July 2006)

Pharmacist Counseling Pearls About Lifestyle and Ocular Disease

POAG

Lifestyle and Ocular Disease

• Smoking cessation, alcohol avoidance, antioxidants and vitamins do not seem to be risk modifiers

• MarijuanaBilb d i k bil b d t h i ifi t i t• Bilberry and ginko biloba do not have significant impact on IOP

Dry EyeSmoking cessation is a risk modifier and ma help impro e• Smoking cessation is a risk modifier and may help improve symptoms

• Coffee drinking and moderate alcohol may be beneficial but data are mixeddata are mixed

• Essential fatty-acids: omega-3• Vitamins and antioxidants are not helpful

Kang JH, et al. Am J Epidemiol. 2003;158(4):337-346.

Pharmacist Counseling Pearls About Lifestyle and Ocular Disease (cont)

ARMD

Lifestyle and Ocular Disease (cont)

• Smoking cessation• Sunglasses—UV protection• Vitamins C E zinc and beta carotene*• Vitamins C, E, zinc, and beta-carotene*

– Some reduced progression in AREDS – Used AREDS formulation in late-stage ARMD in one eye and moderate to severe

disease in the other eyey

• Yellowish color of macula – dietary xanthophylls – lutein and zeaxanthin – absorb blue light and minimize oxidative damage

• AREDS-2 lutein, zeaxanthin, and omega-3 fatty acids—ongoingAREDS 2 lutein, zeaxanthin, and omega 3 fatty acids ongoing enrollment ended 2008 and patients followed for 5 and 6 years

*Vitamin C 500 mg, vitamin E 400 IU, beta carotene 15 mg, zinc oxide 80 mg, and copper 2 mg to preventcopper deficiency anemia from high-dose zinc.ARMD = age-related macular degeneration; AREDS = Age-related Eye Disease Study.

Color Code for Topical Ocular Medications

• Tan: Indicates anti-infectives or antimicrobials

MedicationsTan: Indicates anti infectives or antimicrobials

• Pink: Indicates anti-inflammatories or steroids• Gray: Indicates non-steroidal anti-inflammatories• Red: Indicates mydriatics and cycloplegics • Dark Green: Indicates miotics• Yellow: Indicates beta blockers• Yellow: Indicates beta-blockers• Dark Blue: Indicates beta-blocker combinations• Purple: Indicates adrenergic agonists• Orange: Indicates carbonic anhydrase inhibitors • Turquoise: Indicates prostaglandin analogues

American Academy of Ophthalmology. Policy statement color code for topical ocular medications. http://www.aao.org/about/policy/upload/Color-Codes-for-Topical-Ocular-Medications-2010.pdf. Accessed March 15, 2012.