GLAUCOMA

Jonathan Penm

Clinical Pharmacist

Sydney Eye Hospital

OVERVIEW - GLAUCOMA

Eye anatomy Epidemiology Aetiology Clinical signs and symptoms Diagnosis Treatments

Pharmacological Surgical

Future directions

GLAUCOMA

“Glaucoma describes a group of eye diseases in which there is a progressive damage to the optic

nerve characterised by specific structural abnormalities of optic nerve head and associated

patterns of visual field loss”

Note: It is not defined as having increased intra-ocular pressure, but it is often accompanied by it.

NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucomahttp://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/cp113_glaucoma_nov_2010.pdf

EPIDEMIOLOGY - GLAUCOMA

Globally 1

Second leading cause of global blindness Leading cause of blindness is cataracts

Glaucoma is leading cause of irreversible blindness In 2010, ≈ 60.5 million people in the world affected

In Australia2

Affects 3% of those aged over 50 years ≈ 50% of cases are undiagnosed

1. World Health Organisation - http://www.who.int/bulletin/volumes/82/11/feature1104/en/2. Rochtchina E, Mitchell P. Projected number of Australians with glaucoma in 2000 and 2030. Clin Experiment Ophthalmol 2000; 28: 146-148.

THE EYE

Three Chambers Anterior Chamber

In front of iris

Posterior Chamber B/w iris and vitreous

Vitreous cavity B/w lens and retina

Image from: http://www.biographixmedia.com/human/eye-anatomy.html

THE EYE Three Layers

External Sclera and Cornea Conjunctiva

Middle Iris Ciliary body Uvea Choroid Lens

Inner Retina – contains photoreceptor cells Macula – central retina (central vision, fine detail) Fovea – centre of Macula

Image from: http://www.numarkpharmacists.com/health-advice/encyclopaedia/conjunctivitis-_-infective

AQUEUOS HUMOR

Produced by ciliary bodies1

Two modes of drainage1

C Trabecular outflow (90%) E Uveoscleral outflow (10%)

Diurnal variations2 Production ↓ 50-60% at night ↑ IOP at night

Partly due to positional changes

1. Olver, J. and Cassidy, L. Ophthalmology at a glance. Blackwell Science inc. Massachusetts 20052. Grehn, F. and Stamper, R. Essentials in ophthalmology: Glaucoma Springer –Verlag, Berlin, Heidelberg 2009Image from: Lang, G. Ophthalmology: A short textbook. Thieme Stuttgart. New York 2000

TYPES OF GLAUCOMA

Primary open angle glaucoma (POAG) Most common type (≈ 70%) Decreased aqueous drainage

Primary angle closure glaucoma Chronic

Gradual closure ofanterior chamber

Acute (Emergency) Sudden closure Can cause blindness

if not referredImages from: http://www.aafp.org/afp/990401ap/1871.html

TYPES OF GLAUCOMA

Secondary glaucoma Numerous causes

Uveitis, rubeolis, trauma, steroids, pseudoexfoliation, pigment dispersion etc…

Normal tension glaucoma Same clinical findings as POAG but IOP never

>21mmHg Still benefit from lowering IOP Slowest progression out of all glaucoma types

Congenital glaucoma Occurs in infancy Improper development of eye’s drainage channel

AETIOLOGY – RISK FACTORS FOR GLAUCOMA

Strength of risk From Patient History From Ocular examination

EXTREMELY HIGH(12 x or more)

Age over 80 IOP > 21 mmHg

HIGH(3x or more)

Age over 50Family HistoryAfrican-American – open angleAsian – closed angle

Cup:disc ratio

Cup:disc ratio asymmetry

MODERATE(1.5x or more)

Diabetes MyopiaRural location

Optic disc rim haemorrhage

LOW (Over 1x) Smoking

Unknown statistic Steroid useMigraine and peripheral vasospasmEye InjuryHigh blood pressure

Central corneal thickness

Adapted from NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma

AETIOLOGY

Additional risk factors for Angle Closure Glaucoma Hypermetropia (long-sighted) Family history of angle closure Advancing age Female Asian/Inuit descent Shallow anterior chamber

less than 2 mm deep centrally

CLINICAL SIGNS AND SYMPTOMS

Open angle glaucoma AND Chronic angle closure Both generally asymptomatic at early stage

Visual loss at later stage (need to lose > 30% axons) “Tunnel Vision” – initially lose peripheral vision

RNFL – Retinal nerve Fibre layerVF – Visual Field

Images from: http://www.moondragon.org/health/disorders/glaucoma.htmlTunnel Vision : The Economic Impact of Primary Open Angle Glaucoma. Centre for Eye Research Australia. Melbourne. 2008

CLINICAL SIGNS AND SYMPTOMS

Acute angle closure Symptoms may be present or occur episodically

Sudden onset of severely painful red eye Blurred Vision Coloured rings around lights Frontal headache Palpitations and abdominal pains Nausea and vomiting IOP: usually ~ 50-80mmHg

Severe, permanent damage can occur within several hours.

Total visual loss can occur within 24-36 hours.

DIAGNOSIS

1. Patient History (risk factors)1

2. Eye Structure1

Thinning of retinal nerve fiber layer - Numerous methods

Angle of anterior chamber assessment – Gonioscopy Optic Disc - Ophthalmoscopy or Optic disc

photography Identify size of optic disc Vertical cup: disc ratio Pattern of neuroretinal rim Presence of disc rim hemorrhage

1. Adapted from NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of GlaucomaImage from: Olver, J and Cassidy, L. Ophthalmology at a Glance. Blackwell Science. London. 2005

OPTIC DISC – VERTICAL CUP:DISC RATIO

Image from: Lang, G. Ophthalmology: A short textbook. Thieme Stuttgart. New York 2000

DIAGNOSIS

3. Eye Function1

Visual field assessment

4. Intraocular pressure (IOP)1

Tonometry can measure IOP and central corneal thickness (CCT)

CCT needed to interpret IOP Thick CCT will under-estimate IOP measurements Thin CCT will over-estimate IOP measurements

Normal IOP is usually < 21mmHg Ocular hypertension - patients with no signs of ocular

disease but IOP > 21mmHg

IOP should be measured at different times of the day

Adapted from NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma

TREATMENT INITIATION

Based on POAG damage and risk-assessment 5 year predicted risk of POAG - <5% (Low)

- 5-15% (Moderate)- >15% (High)

*Specified level is still unclear

POAG stage Risk status ↓ IOP Spcified level

Suspect Low No treatment

Moderate 20%

High 20% ≤24mmHg

Early Unspecified ≤19mmHg

Established Moderate 20% ≤16mmHg

High 30% ≈ episcleral venous pressure

Advanced Unspecified 30-50%

≤14 - 18mmHg*

Adapted from NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma

MEDICATION CHOICE

NB: First choice refers to medications that a treating health care provider prefers to use as the initial intervention. First line refers to a medication that has been approved by an official controlling body for initial intervention (Therapeutic Guidelines Limited)

Adapted from NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma

Often start medicationin one eye only Use other eye as control

Accounts for diurnal changes

If IOP not controlled, substitute med insteadof adding another med(tolerance to meds)

MEDICATION CONSIDERATIONS

Do not assume eye drops have no side-effects

Topical eye drops mimic intravenous drugs By-pass hepatic metabolism by:

Trans-conjunctival absorption Naso-lacrimal duct drainage with trans-nasal mucosal

absorption

Never use two drugs from the same class Increased risk of side-effects Sometimes can be counter productive

Use of 2 prostaglandin analogues increases IOP

MEDICATIONS – MODE OF ACTION↑ trabecular outflow

•Miotics

↓ aqueous humour production•β- blockers•Carbonic anhydrase inhibitors

↑ uveoscleral outflow

•Prostaglandin analogues

•Prostamide analogue

•α2 agonists

Image from: http://www.aafp.org/afp/990401ap/1871.html

?

PROSTAGLANDIN ANALOGUES

Travoprost (TravatanTM)

Latanoprost (XalatanTM) - ↓ 25-30% IOPBimatoprost (LumiganTM) – Prostamide? PGF2α agonists

↑ Matrix Metalloproteinases 1 → degrade collagen and ciliary muscle extracelluar matrix

→ ↓ hydraulic resistance to uveoscleral outflow

Only need to use once a day Optimal effect at night Uveoscleral outflow independent of IOP

Due to bulk flow not diffusion. But poorer adherence at night2

Can use in morning if adherence is a problemImages from: http://www.ophmanagement.com/article.aspx?article=86747, http://www.alcon.com/en/alcon-products/pharmaceutical.asp , http://www.rxpharmacy.md/images/drugs/Xalatan.jpg1. Wang, N. Lu, Q. Li, J. and Wang L. (2008) Prostaglandin induces the expression of matrix metalloproteinase-1 in ciliary melanocytes. Chinese Medical Journal 121:1173-76 2. Kahook, M. and Noecker, R. (2007) Evaluation of adherence to morning versus evening glaucoma medication dosing regimens. Clinical ophthalmology. 1(1):79-83

PROSTAGLANDIN ANALOGUES – COMMON ADRS

Hyperemia (usually 2-6 months) Use at night

Irreversible ↑ iris pigmentation ~6 months to occur (Uniocular trial safe) Occurs more in those with mixed colour

Blue-brown Green-brown Yellow-brown

Reversible lengthening and thickening of eyelashes “Luscious Lashes” Marketed overseas: LatisseTM

Images from: http://archopht.ama-assn.org/cgi/content/full/119/2/191/FIGECS90151F1http://www.allaboutvision.com/conditions/glaucoma_news-archive.htm

PROSTAGLANDIN ANALOGUES

Infrequent ADRs Reversible macular oedema Iristis/uveitis

Monitor in those with a history of iritis/uveitis Contra-indicated in those with active iritis/uveitis

Darkening of eyelid skin

Pregnancy: Cat B3 (Avoid use)

If poor response, can switch to another PG analogue Drugs are structurally different

Images from: http://archopht.ama-assn.org/cgi/content/full/119/4/614

BETA-BLOCKERS

Timolol – Non-selective β-blocker – ↓ 25% IOP

TenoptTM, TimoptolTM 0.25, 0.5% eye drops – 1 drop daily - bd Timoptol – XETM 0.25, 0.5% eye drop – 1 drop daily

Gellan Gum Store bottle upside down to ↓ bubble formation when applied

NyogelTM 0.1% eye ointment – Apply once a day

Betaxolol – β1-selective – ↓ 20% IOP

BetopicTM, BetoquinTM (Solutions) and Betoptic STM (Suspension) 1 drop bd

Suspension may ↓ local stinging. Images from: http://www.inhousedrugstore.com/eyes/timoptolxe.htmlhttp://www.drug3k.com/drug/Betoptic-11746.htmhttp://www.33drugs.org/product/betoptic-0-25.html

BETA-BLOCKERS

Morning dosing is preferred (more important than night time dosing) ↓ 50-60% of aqueous production at night

Mane dosing (↓ 20% IOP)1

bd dosing. (↓ 25% IOP)1

But ↑ ADRs XE has similar effect as bd conventional

May cause nocturnal hypotension at night2 ↓ Ocular perfusion → damaging optic nerve

Washout period of 2-4 weeks Tolerance may occur after 1 year treatment

1. Soll D. (1980) Evaluation of timolol in primary open glaucoma: once-a-day vs twice-a-day. Achieves of Ophthalmology 98:2178-21812. Franks W. fixed-combination latanoprost-timolol for treatment of glaucoma. Expert Review of Ophthalmology. 2007: 537:5

BETA-BLOCKERS – ADRS

Common: Stinging, bradycardia Infrequent:

hypotension (more frequent in elderly → falls) Confusion, hallucinations bronchospasm (less with β 1 selective)

Interactions Can cause heart block with Verapamil

Avoid if possible

Simultaneous oral and topical β-blocker use ↓ IOP reduction benefit1

Pregnancy: Cat C1. Goldberg I, Adena M (2007) Co-prescribing of topical and systemic beta-blockers in patients with glaucoma: a quality use of medicine issue in Australian practice. Clinical and Experimental Ophthalmology

CARBONIC ANHYDRASE INHIBITORS

CO2 + OH¯ Carbonic Anhydrase HCO3 ¯

Carbonic Anhydrase II is predominant subtype in the eye

In ciliary process, HCO3 ¯ linked to Na+ secretion Na+ required for aqueous production

Inhibition causes ↓ HCO3 ¯ = ↓ Na+

CARBONIC ANHYDRASE INHIBITORS

Eye drop:

Brinzolamide (AzoptTM) Suspension – Shake well ↓ 15-20% IOP

Dorzolamide (TrusoptTM) Low pH (5.6) - Stinging

1 drop bd – tds (usually tds if used alone or bd when used as adjunct)

Oral:

Acetazolamide (DiamoxTM) ↓ 25-30% IOP 125mg bd – 250mg qid with food

Precaution: Sulphonamide allergyImages from: http://www.unitedpharmacies.co.uk/General_orderby0_page_1_c_18.htmlhttp://www.planetdrugsdirect.com/Prescription-Drugs/T/

CARBONIC ANHYDRASE INHIBITORS - ADRS

Eye drop Common: Conjunctivitis, ocular irritation, bitter taste Infrequent: Blepharitis, vision changes, GI disturbances,

headache, dizziness. Oral Gout may worsen C/I if Na or K depletion or acidosis. Common:

metabolic acidosis, ↓ Na or K, fatigue, polyuria, drowsiness, depression Paraesthesia (hands, feet, face), GI upset, renal stones, metallic taste

50% cannot tolerate this medication Pregnancy: Cat B3

ALPHA2- AGONIST

Apraclonidine (IopidineTM) - ↓ 25% IOP Effect ↓ after 1 month Only indicated for short term (3 months)

Pregnancy: Cat B3

Brimonidine (AlphaganTM , Alphagan PTM) - ↓ 20% IOP Pregnancy: Cat B1

Usually they are used 1 drop bd-tds Common ADRs:

Ocular irritation, dry mouth and nose, taste disturbances,

Dizziness and drowsiness (Brimonidine) Infrequent/rare ADRs: HypotensionImages from: http://www.medical-look.com/reviews/Alphagan.html

http://www.avclinic.com/iopidine.htm

APRACLONIDINE VS. BRIMONIDINE

Apraclonidine Ocular allergic reactions reported up to 20-50% in long-term users.1

Allergy mainly due to thiol conjugation of hydroquinone subunit

Brimonidine lacks this subunit Ocular allergic reactions being reported up to 9%1

Images from: Thompson C. MacDonald T. Garst M. Wiese A. and Munk S (1997). Mechanisms of adrenergic agonist induced allergy bioactivation and antigen formation.1. Bartlett J and Jaanus S. (2008) Clinical Ocular Pharmacology. 5th Ed. Butterworth Heinemann Elsevier. Missouri.

ALPHAGAN VS. ALPHAGAN P

P stands for Purite preservative 9% allergic to Alphagan – can occur up to 9 months after

initiation Partly due to preservative – BAC

Significantly less allergic reactions seen in Alphagan P.

Purite preservative also pH of solution bioavailability in aqueous fluid

Alphagan P 0.15% has the same effect as Alphagan 0.2%1

1. Mundorf, T., Williams, R., Whitcup, S., et al. 3-month comparison of efficacy and safety of brimonidine-purite 0.15% and brimonidine 0.2% in patients with glaucoma or ocular hypertension. J. Ocul. Pharmacol. Ther. 19:37–44, 2003

MIOTICS

Cholinergic agonist Contracts ciliary muscles → pulls scleral spur → opens trabecular meshwork.

Pilocarpine 1%, 2%, 4% and 6% (Isopto CaprineTM, PiloptTM) ↓ 20-25% IOP

Common ADR: Miosis, blurred vision headache/browache (↓ 2-4 weeks, can use simple analgesic to relieve

pain)

Pregnancy: Cat B2

Image from: http://www.alcon.com.tw/consumer/pro_images/Isopto-carpine1%25-2%25-4%25.jpg

COMBINATION PRODUCTS

Timolol + Latanoprost (XalacomTM)

Timolol + Bimatoprost (GanfortTM)

Timolol + Travoprost (DuoTravTM)

Timolol + Dorzolamide (CosoptTM)

Timolol + Brinzolamide (AzargaTM)

Timolol + Brimonidine (CombiganTM)

↓ 25-30% IOP May aid compliance All contain timolol

Image from: http://www.alcon.com/en/alcon-products/pharmaceutical.asphttp://www.lorenabosso.com/2010/01/colirios-que-prometem-aumentar-os.htmlhttp://drugtopics.modernmedicine.com/drugtopics/data/articlestandard/drugtopics/442007/469739/Combigan.jpghttp://www.inhousepharmacy.com/eyes/cosopt.htmlhttp://www.happyrx.com/images/LATTIM-BB0025.jpg

TREATMENT INITIATION

Acute Angle Closure Topical Medicines

Beta-blocker, carbonic anhydrase inhibitor and 2-agonist Pilocarpine

If attack lasts >1-2 hours or IOP >50mmHg iris sphincter muscles likely ischemic Pilocarpine ineffective

Use Pilocarpine in unaffected eye to prevent pupil block.

Unaffected eye has a 75% chance of developing ACG in the future

Image from: http://theglaucomaguide.com/book14LPI.htm

TREATMENT INITIATION

Acute Angle Closure Oral/IV Medicines – Use if IOP > 50mmHg or sig. visual loss

Acetazolamide IV mannitol or oral glycerol.

Carbonic Anhydrase Inhibitors Avoid if ACG due to Sulfonamides or Topiramate Caution in patients with Sickle Cell Anemia

Definitive treatment for pupil block ACG: Surgery –peripheral laser iridotomy

Image from: http://theglaucomaguide.com/book14LPI.htm

MANNITOL ↑ Plasma osmolality → dehydrates vitreous body

Rapid (30 min) but temporary ↓ IOP.

Mainly used in: Acute closed angle glaucoma and ocular hypertension

Dose: IV 1-2g/kg over 30 minutes Prefer 1-1.5g/kg due to ADR.1, 2

Shifts intracellular water to extracellular space ADRs: Hyponatremia, Pulmonary congestion, congestive heart failure

Note: Mannitol crystallizes at low temps Re-dissolve by warming in hot water and shaking

1. Singh A. Medical therapy of glaucoma. Ophthalmol Clin North Am 2005;18(3):397-408, vi.2. Hill K. Ocular osmotherapy with mannitol. Am J Ophthalmol 1964;58:79-83.

HOW TO USE EYE-DROPS (1)

Wash handsRemove the seal and/or lid (take care not to

contaminate the lid)Lie down or sit with head tilted backShake gently if it is a suspension (eg.

AzoptTM)Pull down lower lid form a ‘pouch’Do not let the dropper touch the eyeCarefully squeeze one drop into the eyeSome patients prefer to keep the drops in

the refrigerator in order to ‘feel’ the drop falling in the eye

Image from: http://glwach.amedd.army.mil/pharmacy/Images/eye.gif

HOW TO USE EYE-DROPS (2)

“Double DOT” technique ( ↓ 70% systemic absorption)Don’t Open the Eyelids TechniqueDigital Occlusion of the Tear duct

3 minutes

Wait ≥5 minutes before using any other eye drop Contact lenses may be worn ≥15 minutes after last drop

Image from: Goldberg I. Moloney G. and McCluskey P (2008) Topical Ophthalmic medications: what potential for systemic side effect and interactions with other medications? MJA 189(7): 356-357

HOW TO USE EYE-OINTMENTS

Wash hands Open tube

If a new tube, squeeze out 1cm and discard Lie down or sit with head tilted back Pull out lid to form a ‘pouch’ Do not let the tube touch the eye Apply a strip of ointment (~1cm) along lid Blink and twist tube to break off ointment Blink several times to spread the ointment May temporarily blur vision Always use last (It creates an oily barrier against drops)

PRESERVATIVES Inhibit or destroy micro-organism growth Most eye drops and ointments with preservative can only be

used for 28 days (4 weeks) after opening Write the date when the bottle is opened

Preservatives can cause: Allergic reactions

Patient may not be allergic to drug Toxicity to corneal epithelium

Consider if patient is on numerous eye drops

Benzalkonium chloride - Most common preservative Benzododecinium bromide - Timoptol XETM

Minims are preservative-free-Discard each minim after use

STORAGE

Temperature Some eye drops are stored in the refrigerator in the pharmacy stored at room temperature when dispensed (eg. XalatanTM)

Light Some eye drops should be protected from light

Store eye drop either in a box or produced in opaque bottle(eg. XalatanTM, Timoptol XETM)

PRACTICAL ISSUES

Poor adherence Glaucoma is asymptomatic 50% of patients use their eye drop

incorrectly

Dyscompliance (physical obstacles to self-administering medication) Eg from tremor, arthritis Medication aids such as Xal-Ease™ are available

Poor hygiene Particularly important for contact lens wearers

Image from: http://www.eyeupdate.com/pages/glaucoma/prostaglandin_analogs.html

LASER TREATMENT

Argon laser trabeculoplasty (ALT) Argon burns to trabecular meshwork (TM) to ↑ aqueous outflow. ↓ IOP 16-20% Not permanent - 50% failure rate at 5 years Can only be repeated twice

Selective laser trabeculoplasty Lower frequency laser that targets melanocytes in TM Less destructive than ALT Similar effect to ALT Repeat numerous times? – theoretical but unproven

Cyclodestruction Diode laser (usually) to ciliary body to ↓ aqueous production

SURGERY

Glaucoma filtration surgery (trabeculectomy) Surgically remove a piece of tissue in the drainage angle of the

eye

More effective than laser surgery Anti-fibrotic medications used to prevent scarring

5-Fluorouracil or Mitomycin CImage from: http://www.danatannenbaummd.com/images/treating_drainage.jpghttp://www.gcot.net/images/trabeculectomy-fig2.jpg

FUTURE DIRECTIONS

Some glaucoma patients with normal IOP still get worsening visual field loss

Other factors than IOP acting

Other pharmacological properties of interest: Improving ocular blood flow??1

Neuroprotective??2

Brimonidine inhibit apoptosis of retinal ganglion cells.

Simplified dosage regimens Latanoprost once a week equally effective as once a

day3

1. Costa, V. Harris, A. Stefansson, E. Flammer, J. Krieglstein, G. Orzalesi, N. Heijl, A. Renard, J. and Serra, L. (2003) The effects of antiglaucoma and systemic medications on ocular blood flow. Progress in Retinal and Eye Research; 22(6): 769-805

2. Galanopoulos, A. and Goldberg, I (2009) Clinical efficacy and neuroprotective effects of brimonidine in the management of glaucoma and ocular hypertension. Clinical Ophthalmology. 3:117-122

3. Kurtz S and Shemesh.G (2004) Journal of Ocular Pharmacology and Therapeutics. 20(4): 321-327.

PHARMACISTS ROLE

Facilitate correct use of eye drops Up to 50% of patients use it incorrectly

Consider simple dosage regimens to aid compliance

Monitor for Dyscompliance

Monitor for ADRs and interactions

Explain storage and shelf-life