Jonathan Penm Clinical Pharmacist Sydney Eye Hospital 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 Glaucoma http://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 2005 2. Grehn, F. and Stamper, R. Essentials in ophthalmology: Glaucoma Springer –Verlag, Berlin, Heidelberg 2009 Image 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 of anterior chamber Acute (Emergency) Sudden closure Can cause blindness if not referred Images from: http://www.aafp.org/afp/990401ap/1871.html

Types of Glaucoma Secondary glaucoma Normal tension 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 50 Family History African-American – open angle Asian – closed angle Cup:disc ratio Cup:disc ratio asymmetry MODERATE (1.5x or more) Diabetes Myopia Rural location Optic disc rim haemorrhage LOW (Over 1x) Smoking Unknown statistic Steroid use Migraine and peripheral vasospasm Eye Injury High 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 layer VF – Visual Field Images from: http://www.moondragon.org/health/disorders/glaucoma.html Tunnel 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 Patient History (risk factors)1 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 Glaucoma Image 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 Eye Function1 Intraocular pressure (IOP)1 Visual field assessment 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 ≤24mmHg Early Unspecified ≤19mmHg Established ≤16mmHg 30% ≈ episcleral venous pressure Advanced 30-50% ≤14 - 18mmHg* Ocular hypertension – Tx by Murray’s rule Start at baseline 30mmHg Subtract 1.5mmHg for each MAJOR risk factor Compare to IOP measurement Tx if it is below real IOP Can also Tx based on risk calculator based on OHTS data Adapted from NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma

Medication choice Often start medication in one eye only Use other eye as control Accounts for diurnal changes If IOP not controlled, substitute med instead of adding another med (tolerance to meds) IOP is usually lower at night 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

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 Prostamide analogue ↑ uveoscleral outflow Prostaglandin analogues α2 agonists ↓ aqueous humour production β- blockers Carbonic anhydrase inhibitors Image from: http://www.aafp.org/afp/990401ap/1871.html

Prostaglandin analogues Travoprost (TravatanTM) Latanoprost (XalatanTM) - ↓ 25-30% IOP Bimatoprost (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 problem Xalatan – made by Pharmacia Lumigan – made by Allergan Travatan – made by Alcon. Pay Pharmacia $120 million and an undisclosed royalties for a specified time on future sales. Images 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.jpg 1. 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/FIGECS90151F1 http://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.html http://www.drug3k.com/drug/Betoptic-11746.htm http://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 98:2178-2181 2. 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 C 1. 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 allergy Images from: http://www.unitedpharmacies.co.uk/General_orderby0_page_1_c_18.html http://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: Hypotension Images from: http://www.medical-look.com/reviews/Alphagan.html http://www.avclinic.com/iopidine.htm

Apraclonidine vs. Brimonidine 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.asp http://www.lorenabosso.com/2010/01/colirios-que-prometem-aumentar-os.html http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard/drugtopics/442007/469739/Combigan.jpg http://www.inhousepharmacy.com/eyes/cosopt.html http://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 hands Remove the seal and/or lid (take care not to contaminate the lid) Lie down or sit with head tilted back Shake gently if it is a suspension (eg. AzoptTM) Pull down lower lid  form a ‘pouch’ Do not let the dropper touch the eye Carefully squeeze one drop into the eye Some 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 Technique Digital 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 Timoptol Azarga Contain Bezalkonium Chloride: Xalatan, Xalacom, Lumigan, Travatan, Ganfort, Duotrav, Betoptic, Betoptic S, Azopt, Trusopt, Alphagan, Iopidine, Combigan, Cosopt, Pilocarpine, Nyogel, Tenopt (Nearly ALL of them)

Storage Temperature Light 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 Dyscompliance 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 C Image from: http://www.danatannenbaummd.com/images/treating_drainage.jpg http://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. 46

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