Transcript Glaucoma - Learnblock

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



Image from: http://www.biographixmedia.com/human/eye-anatomy.html
Anterior Chamber
 In front of iris
Posterior Chamber
 B/w iris and vitreous
Vitreous cavity
 B/w lens and retina
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


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
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
Adapted from NHMRC Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma
Cup:disc ratio
asymmetry
Central
corneal
thickness
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
RNFL – Retinal nerve Fibre layer
VF – Visual Field

Visual loss at later stage (need to lose > 30% axons)
 “Tunnel Vision” – initially lose peripheral vision
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
1.
2.
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
3.

Visual field assessment
Intraocular pressure (IOP)1
4.

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
POAG stage
Risk status
Suspect
Low
- <5% (Low)
- 5-15% (Moderate)
- >15% (High)
↓ IOP
Spcified level
No treatment
Moderate
20%
High
20%
≤24mmHg
Early
Unspecified
Established
Moderate
20%
≤16mmHg
High
30%
≈ episcleral
venous pressure
30-50%
≤14 - 18mmHg*
Advanced
Unspecified
*Specified level is still unclear
≤19mmHg
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)
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
?
•Prostamide
analogue
↑ trabecular outflow
•Miotics
↑ 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)
Bimatoprost (LumiganTM) – Prostamide?
 PGF2α agonists

↑ Matrix Metalloproteinases 1
 → degrade collagen and ciliary muscle extracelluar matrix


- ↓ 25-30% IOP
→ ↓ 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.
2
 But poorer adherence at night
 Can use in morning if adherence is a problem

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
TM 0.25, 0.5% eye drop
 Timoptol – XE
– 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
Carbonic Anhydrase

CO2 + OH¯

Carbonic Anhydrase II is predominant subtype in the eye

In ciliary process, HCO3 ¯ linked to Na+ secretion


HCO3 ¯
Na+ required for aqueous production
Inhibition causes ↓ HCO3 ¯ = ↓ Na+
CARBONIC ANHYDRASE INHIBITORS
Eye drop:
Brinzolamide (AzoptTM)

↓ 15-20% IOP
Suspension – Shake well
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)
 Effect ↓ after 1 month
 Only indicated for short term (3 months)

Pregnancy: Cat B3
Brimonidine (AlphaganTM , Alphagan PTM)

- ↓ 25% IOP
- ↓ 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


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


Purite preservative also pH of solution


Significantly less allergic reactions seen in Alphagan P.
 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


Pilocarpine 1%, 2%, 4% and 6% (Isopto CaprineTM, PiloptTM)


Contracts ciliary muscles → pulls scleral spur → opens trabecular meshwork.
↓ 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
Timolol + Bimatoprost
Timolol + Travoprost
Timolol + Dorzolamide
Timolol + Brinzolamide
Timolol + Brimonidine
(XalacomTM)
(GanfortTM)
(DuoTravTM)
(CosoptTM)
(AzargaTM)
(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


Mainly used in:


Prefer 1-1.5g/kg due to ADR.1, 2
Shifts intracellular water to extracellular space


Acute closed angle glaucoma and ocular hypertension
Dose: IV 1-2g/kg over 30 minutes


Rapid (30 min) but temporary ↓ IOP.
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

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



Dyscompliance
(physical obstacles to self-administering medication)



Glaucoma is asymptomatic
50% of patients use their eye drop
incorrectly
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.
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