pathogenesis of glaucoma and glaucoma drugs

Question 1

What is the common feature in glaucoma?

Answer 1

The loss of retinal ganglion cells leading to thinning of retinal nerve fibre layer and cupping of the optic disc

Question 2

What are the different types of glaucoma?

Answer 2

open angle glaucoma
primary: primary open angle glaucoma, normal tension glaucoma, juvenile glaucoma
secondary: pigment dispersion syndrome, pseudo exfoliation, uveitic

closed angle glacuoma
primary: primary angle closure glacuoma
secondary: rubeitic, uveitic

Question 3

what are the treatments for open angle glaucoma?

Answer 3

lowering IOP drops
trabecular laser
glaucoma surgery

Question 4

what are the treatments for closed angle glaucoma?

Answer 4

open drainage pathway
laser periphery iridectomy
lens extraction
lowering IOP drops
glaucoma surgery

Question 5

what are the risk factors of glaucoma?

Answer 5

raised IOP (greater than 26mmHg)
black ethnicity is a risk factor of open angle glaucoma
angle closure: East Asian, high myopia, DM, FH

Question 6

what are the clinical features of open angle glaucoma?

Answer 6

Asymptomatic
loss of neural tissue is associated with Suttle changes in NRR (thinning or notching)

Advanced glaucoma: NRR is thin, disc is really cupped, associated with posterior bowing of lamina cribrosa and loss of overlying neural tissue
Retinal ganglion loss is associated with VF defect. Inferior loss. Asymmetric either side of the midline.
Diagnosed based on looking at stereoscopic evaluation of optic nerve head, visual field test, IOP measurement
Further investigation using OCT: can measure thickness of RNFL, monitoring glaucoma
Ocular hypertension associated feature

Question 7

how can you investigate angle closure glaucoma?

Answer 7

Narrowing or closure of anterior chamber angle best visualised using as gonioscope: contact lens that sits on the surface of the eye. Incorporates a mirror which looks into the angle. Visualisation of TMW.

Van Herricks test.

Pupil block: pupil margin is attached to anterior surface of the lens. iris balloons forward.

Anterior segment oct: can look at anatomical anterior features

Question 8

what caused increased IOP in OAG and CAG?

Answer 8

OAG: increased IOP due to increased resistance to outflow within TMW

CAG: raised IOP due to pupillary block (attachment between iris periphery and iris TBW narrows angle, you get irido-trabecular contact)

Question 9

In what 2 ways can IOP impact the pathogenesis of glaucoma?

Answer 9

1.Mechanical (DIRECT): on RNFL and retinal ganglion cells
2.Vascular (INDIRECT): ischaemic mechanism due to reduction in blood flow

Question 10

where is aqueous produced and drained?
what is level of IOP determined by?

Answer 10

Aqueous is produced by ciliary epithelium (pars plicata)
* From the site of production, the aqueous is secreted into the posterior chamber
* Passes through the pupil where it circulates within anterior chamber

Can leave the eye by 2 mechanisms:

canal of Schlemm is conventional pathway.
Uveoscleral outflow pathway is the other mechanism

• Level of IOP is determined by the balance between rate of aqueous production and rate of drainage

Question 11

What is the mechanism of aqueous production?how can aqueous secretion be inhibited?

Answer 11

Ciliary epithelium is a double epithelium: pigmented and non-pigmented layer.
These cells work together as a functional unit.
Aqueous production occurs through metabolically driven ion transport systems.
Ions are picked up from stromal side of ciliary epithelium.
Ions are taken up by transport proteins into pigmented epithelium.
Ions Pass via gap junctions into non pigmented epithelium.
Active transport from NPE into posterior chamber
This is a ATP demanding pathway

Carbonic anhydrase is a enzyme that catsylses chemical reaction of carbon dioxide and water to give carbonic acid (important source of bicarbonate ions that play a role in transporter proteins). If you inhibit this enzyme it deprives pathway of a raw material so inhibits aqueous secretion.

Question 12

what is the outflow pathway for vast majority of aqueous?

what treatments target this pathway?

how much aqueous does uveoscleral pathway drain?

what treatments target this pathway?

Answer 12

TMW-canal of schlemm-intrascleral venous plexus-sclera- episcleral veins onto surface of eye

surgical procedures, laser therapies, few drugs

10-30%. aqueous passes through ciliary body and return into vasculature along posterior segment of eye.

postaglandin analogues

Question 13

what are the three layers of trabecular meshwork?

what treatments affect trabecular meshwork?

Answer 13

Has 3 distinct layers: uveal trabeculae, corneal scleral trabeculae, and juxta canicular tissue adjacent to canal of Schlemm
* Resistance to outflow is generated in JCT.

drugs which open the pathway or laser therapy to burns hole in meshwork to open spaces to enhance aqueous drainage and lower resistance to outflow.

Question 14

what surgical mechanisms are there to improve drainage in glaucoma?

Answer 14

Selective laser trabeculoplasty: punching little holes in trabecular meshwork and opening the pathway.

Trabeculectomy: Creating a new aqueous outflow pathway from posterior chamber through to ocular surface

Minimally invasive glaucoma surgery (MIGS): Surgical implants put into the eye (tubes or stents) take aqueous from aqueous humour by passing the resistance.

Question 15

what are the pharmacological options for regulating IOP?

Answer 15

Inhibit aqueous production: Beta blockers, alpha receptor agonists
Pilocarpine: muscarinic agonist. Opens up TMW.

Most used: prostaglandin agonists. latanoprost. Enhance uveoscleral outflow

Question 16

how is trabecular meshwork involved in OAG?

Answer 16

OAG is associated with an increased resistance to outflow in the JCT

Thought to relate to changes in extracellular matrix of JCT, slow the rate of aqueous production through layers of meshwork.

Difficult to differentiate between pathological changes and age changes

Plaque like deposits have been described in JCT, specific to glaucoma

Question 17

how is trabecular meshwork involved in secondary glaucoma?

Answer 17

can arise from intertrabecular spaces being blocked by cellular or non-cellular material. Pigment (pigment dispersion syndrome), inflammatory material (uveitis), pseudo exfoliation glaucoma (material from lens capsule deposits in TMW)

Question 18

Describe the direct mechanism of optic nerve damage in glaucoma?

Answer 18

*High IOP induces stress at lamina cribrosa (perforated plate made of collagen and glial tissues). Has pores which axons of RGC pass.
*This is vulnerable to raised IOP.
*Lamina cribrosa becomes compressed and deformed.
*This Interrupts axoplasmic flow along axons that pass through it.
* Leads to apoptosis and degeneration of RGC.
*Associated with shrinkage and atrophy of RGC axons.
*We see this at disc as loss of NRR tissue and a posterior extravasion and bowing backwards of lamina cribrosa.
*Axoplasmic flow delivers essential trophic factors to neural cell body. Interfering with this pathway leads to RGC death

Question 19

Describe the indirect mechanism of optic nerve damage in glaucoma?

Answer 19

*Interruption to blood supply of ONH
*Raised IOP can reduce ocular blood flow.
*This deprives axons of nutrients. Occurs at level of lamina.
*Ischaemic mechanism
*Primary mechanism in those people with normal IOP.

Ischaemia can still occur with normal IOP.
Can be failure of auto regulation.

Question 20

what are the classes of topical drugs used in glaucoma?

Answer 20

• Prostaglandin agonists/analogues
• Beta receptor antagonists
• Alpha 2 receptor agonists
• Carbonic anhydrase inhibitors
• Cholinergic agonists

Question 21

what was the first glaucoma drug?

Answer 21

pilocarpine- cholinergic agonist

Question 22

what should you consider before prescribing any new drop in glaucoma?

Answer 22

*General medical history-need to identify risk of developing adverse reactions
*Drug history-may be interactions with other anti-glaucoma meds
*History of topical allergy
*Find out if px can use eyedrops (memory, dexterity, carers)

Question 23

what are the mechanism of glaucoma drugs to lower IOP?

Answer 23

reducing aqueous production or act on ciliary epithelium and reduce production of aqueous humour

-increase aqueous outflow through trabecular meshwork

-act on uveoscleral pathway to increase aqueous outflow

Question 24

when are systemic drugs used in glaucoma?
what are the names of these drugs?

Answer 24

Used to lower IOP in those with acute angle closure glaucoma

• Oral carbonic anhydrase inhibitors e.g., acetazolamide (Diamox)
• Osmotic agents e.g., glycerol, mannitol

Question 25

what should you consider when choosing a drug?

Answer 25

• Efficacy-how effective is it in lowering IOP
• Safety
• Compliance-dosage
• cost

Question 26

what is the order of efficacy for glaucoma drugs?

Answer 26

1.prostaglandin agonists
2.beta antagonists
3.alpha 2 agonists
4.cholinergic agonists
5.carbonic anhydrase inhibitors

Question 27

Name all the available prostaglandin analogues

which is the cheapest

Answer 27

latanoprost
travoprost
tafluprost

prostamide:
bimatoprost

cheapest is non-proprietary (not branded) latanoprost

Question 28

what are the side effects of prostaglandin analogues?

Answer 28

conjunctival hyperaemia- more pronounced in early stages of treatment
(latanoprost is least likely to cause conjunctival hyperaemia)

darkening, thickening, and lengthening of eyelashes

increased iris pigmentation. Tends not to effect blue/grey iris or if they have a dark iris to begin with.

Question 29

what are the available beta antagonists?
which is the cheapest?

Answer 29

timolol maleate
betaxolol
levobunolol HCI

timolol non-proprietary is cheapest

Question 30

what type of beta blocker is timolol and betaxolol ?

Answer 30

timolol: nonselective beta blocker
betaxolol: beta 1 blocker selective

Question 31

what is the major side effect of timolol?

Answer 31

*bronchoconstriction, especially in people with obstructive airways disease or px with asthma

lungs have beta 2 receptors in them so blocking these receptors causes bronchoconstriction

Question 32

what should you ask/do before prescribing beta blocker for glaucoma?

Answer 32

Ask about COAD (chronic obstructive airways disease)/SOBOE (shortness of breath on exertion)/inhalers

Check peak flow
Check pulse
Consider drug interactions
Recheck peak flow one month after starting treatment – stop if fall of 15%

Question 33

what alpha agonists are available?

what are they used for?

Answer 33

brimonidine tartrate
apraclonidine HCI

Brimonidine reduces aqueous production and increases uveoscleral outflow. Less effective in lowering IOP than timolol so not used as first line therapy.

Apraclonidine is used in pre and post operative setting as it’s an effective short term IOP lowering agent.

Question 34

what are the side effects of alpha agonists?

Answer 34

Higher incidence of ocular and systemic side effects

Follicular conjunctivitis: toxic rection

Systemic side effects: hypotension (lowered pressure), syncope (fainting), dry mouth and nose, headache, anxiety, depression, and fatigue

Question 35

what carbonic anhydrase inhibitors are available?

are they used often?

what combinations of beta blockers and CAI are available?

Answer 35

dorzolamide HCI

brinzolamide HCI

oral acetazolamide used in acute angle closure

no-not first line therapy
not as efficacious as beta blockers and PGA
used in fixed combinations with beta blockers

dorzolamide with timolol, brinzolamide with 0.5% timolol

Question 36

what are the side effects of carbonic anhydrase inhibitors?

Answer 36

topical: metallic taste, rashes, polyuria (excessive urination), irritation, blurred vision

systemic (oral): allergy, hypokalaemia, polyuria, acidosis, depression, paresthesia (burning sensation), kidney stones, blood dyscrasia *blood disorder)

Question 37

what cholinergic agonists are available?
what is their cost?
how often are they prescribed?
what are the side effects?

Answer 37

pilocarpine HCI
pilocarpine nitrate

expensive

rarely

mitosis, myopia, symblepharon, post synechia, retinal detachment, confusion, vomiting, nausea