Glaucoma

Question 1

What is Glaucoma?

Answer 1

• Glaucoma is a group of ocular disorders united by a clinically characteristic intraocular pressure-associated optic neuropathy.

Question 2

• Two main types of Glaucoma

Answer 2

– Open-angle glaucoma (>70% of all Glaucoma cases)
» Chronic condition – may be no symptoms until vision impaired

– Angle-closure glaucoma
prognosis is worse
» Often diagnosed during acute, painful medical emergency
» Acutely raised IOP can rapidly cause nerve damage - worse prognosis than OAG

Question 3

what results in a glaucoma

Answer 3

• Impairment in aqueous humor outflow results in elevation of the intraocular pressure (IOP)
– Increased pressure leads to damage to optic nerves, reduced peripheral vision, and eventually blindness

Question 4

Ciliary body role

Answer 4

aq humor produced in ciliary body behind iris

Question 5

Canal of Schlemm

Answer 5

drains liquid from eye

Question 6

Uveoscleral outflow

Answer 6

alternative route to drain aq humor

Question 7

Drainage Routes for Aqueous Humor

Answer 7

• Conventional outflow pathway via the trabecular network & Schlemm’s canal
• The uveoscleral outflow pathway (avoids trabecular meshwork)

Question 8

• Primary closed angle (or angle-closure)

Answer 8

– Iris presses forwards, adheres to trabecular network (closes the angle)
and impedes outflow
– Leads to acute but large increase in IOP rapidly causing nerve damage
– Less common but serious – 26% of cases of glaucoma, nearly half of cases of glaucoma-related blindness

Question 9

which condition is harder to diagnose

Answer 9

Primary open angle glaucoma

Question 10

Open angle Glaucoma leads to

Answer 10

large angle between iris and front of the eye. access to trabecular meshwork is open

Question 11

Glaucoma pathophysiology - Summary

Answer 11

• Glaucoma caused by optic nerve damage, normally secondary to increased ocular pressure
• Ocular pressure increased by altered balance between aqueous humor production and outflow
– Usually due to impaired outflow – Two routes of AH outflow
• Several types of glaucoma, but major distinction between open- angle & angle-closure types

Question 12

what causes loss of eye vision

Answer 12

optic nerve damage

Question 13

Overview of Therapeutic Strategies - OAG

Answer 13

Open Angle Glaucoma (see King et al. BMJ 2013)
• Increase outflow
– Prostaglandin F2α analogues increase outflow through uveoscleral path
• Decrease production of aqueous humor by ciliary body – β2 antagonists
– α2 agonists
– Carbonic anhydrase inhibitors
• Surgery to increase outflow through trabecular network (traeculoplasty)

Question 14

Overview of Therapeutic Strategies - CAG

Answer 14

Closed angle glaucoma (see Wright et al. Acta Ophthalmologica 2016)
• Primary management to acutely reduce IOP – Mannitol po, acetazolomide iv
• Miotics - open angle & allow increased trabecular outflow
• IOP control using aqueous suppression & prostaglandins as for Open Angle Glaucoma
• Surgery to reduce pressure difference between anterior & posterior chambers
Slide 15
(iridotomy or iridoplasty)

Question 15

how does manitol work

Answer 15

manitol has osomotic affects to decrease outflow of aq humor

Question 16

how do miotics work

Answer 16

miotics cause iris to contract and pupils to shrink, this pulls iris away from the eye

Question 17

iridotomy

Answer 17

making a small hole

Question 18

iridoplasty

Answer 18

making larger gaps to allow liquid to flow

Question 19

Increasing Outflow – Prostaglandin F2α analogues

Answer 19

• Latanoprost, Bimatoprost, travoprost
– increase outflow through uveoscleral path
– Mechanism unclear
» Relax ciliary muscle ?
» Remodelling of extracellular matrix ?
• In general, better efficacy, fewer systemic effects, fewer contraindications than other medical approaches

• PK – Topical admin
• ADR – Topical:
» Eyelash growth
» Irritation
» Iris pigmentation (brown)
– Systemic
» bronchospasm, hypertension
• Cautions – Asthma
• Interactions
– Hypotensive drugs

Question 20

Decreasing aqueous humor production How is AH produced?

Answer 20

draw

• Aqueous humor is produced by non-pigmented epithelia of the ciliary body
• Water is osmotically pumped into aqueous humor. Osmotic gradient is produced by Na+/K+ ATPase
• Na+ and Cl- supplied from stroma via antiports in pigmented epithelial cells – electrochemical balance maintained by export of H+ and HCO3- produced by carbonic anhydrase

Question 21

Adrenergics & AH production

Answer 21

1. Increasing cAMP increases AH production
2. B-adrenergic activation increases cAMP production via Gs – B-adrenergic antagonists therefore reduce AH production
3. a-adrenergic activation decreases cAMP production via Gi – a -adrenergic agonists directly reduce AH production
4. a-adrenergic activation also reduces NE release from sympathetic nerves
   – a -adrenergic agonists indirectly reduce AH production by reduced B-adrenergic activation

Question 22

Glaucome therpeutics B-adrenoceptor antagonists (1)

Answer 22

OAG
• B receptors in eye are primarily B2
– regulate production of aqueous humor by ciliary body
– Decrease blood flow to eye – reducing fluid available to produce aqueous humor

• Drugs
– Timolol, levobunolol, carteolol - antagonise
- betaxolol - B1 selecttive
» Less efficacious – (B2 in eye)-but avoid effects on airway (B2 mediated)
» Useful in patients with asthma
• PK - TOPICAL ADMIN

Question 23

Glaucoma therapeutics B-adrenoceptor antagonists (2)

Answer 23

• ADR 
– Resulting from systemic exposure
– Bronchospasm
– Bradycardia
• Caution
– Systemic exposure may result so need to consider cautions associated with enteral/parenteral administration
– Asthma – see above
• Contraindications
– Systemic exposure may result so need to consider contraindications associated with enteral/parenteral administration
– Eg bradycardia, heart block, heart failure 
• Drug interactions
– Other B-adrenoceptor antagonists 
– Ca2+ channel antagonists
– Cardiac glycosides

Question 24

α2 Agonist - Brimonidine

Answer 24

• Mechanism:
– Pre-synaptic receptors inhibit NA release (sympathetic nervous system)
– Activation of α2 receptors on ciliary body directly inhibits formation of aqueous humor
• PK & ADR’s
– Topical admin therefore systematic ADR’s avoided

Question 25

Carbonic anhydrase inhibitors

Answer 25

OAG
• Brinzolamide, dorzolamide, acetazolomide
– Inhibit bicarbonate formation and hence fluid transport
• PK
– Topical: Brinzolamide/dorzolamide (p.o. acetazolamide – “final resort”)
– Renal elimination
• ADR
– Acetazolamide - paresthesia, hypokalaemia + acidosis (see diuretics lecture!)
– Dorzolamide/Brinzolamide: fewer - see PK!
• Caution
– Avoid in renal insufficiency (inhibits elimination)
• Contraindications
– Acetazolamide is a sulfonamide – avoid if hypersensitive
• Drug interactions
– Digoxin – see slide

Question 26

Closed Angle Glaucoma Therapeutics

Answer 26

Miotics
• Pilocarpine
– Muscarinic agonist
– Induces contraction of constrictor muscle in the iris – opens drainage channel
– Promotes aqueous outflow • Caution
– Retinal detachment can occur – examination advised first • ADR
– Myopia (blurred vision) leading to headache, brow-ache with prolonged use
Mannitol
• Reduces the secretion of fluid into the eye by osmotic effects
• ADR
– electrolyte imbalances, hypotension, fluid imbalance

Question 27

β antagonist contraindication in heart block

Answer 27

Heart block – signals through AV node are slowed. A β antagonist could make this worse!

Question 28

Closed angle Glaucoma leads to

Answer 28

iris pushed forward, much smaller angle. Occurs due to shortages between front and back of the eye, catarachts

Question 29

Primary open angle glaucoma

Answer 29

– Most common, but few obvious structural changes
– Angle is normal but outflow of aqueous humor is reduced e.g. by blockages in trabecular meshwork, Schlemm’s canal or veins draining the eye
– Increase in IOP less than in closed-angle glaucoma but causes nervve damage over long time period

Question 30

Aqueous humor production

Answer 30

• Aqueous humor produced by ciliary body
– 3mL /day, continually by ultrafilatrion from arterial blood + active secretion
– Passes from posterior to anterior chamber through the pupil
– 90% drains via trabecular meshwork and canal of Schlemm into episcleral vein – 10% drains via uveoscleral outflow (under ciliary muscle into choroidal vessels)
Provides two therapeutic strategies
• Intraocculuar pressure
– normally 10-20 mm Hg – increased in glaucoma
– Determined by:
» rate of production of aqueous humor » rate of drainage of aqueous humor
– Increased pressure causes damage to retina/optic nerve