Week 9 - Medical management of glaucoma

Question 1

How do we treat glaucoma?

Answer 1

• Reduce IOP
• Consider aqueous dynamics
- Reduce inflow rate
- increase outflow rate
• Neuroptotection?

Question 2

How low does pressure need to be?

Answer 2

Historically, less than 22mmHg…
• BUT we now know it depends on:
• Presenting pressure
• Severity of disease
• Rate of progression
• Risk of visual loss within patient lifetime

Question 3

Target IOP:

Answer 3

• Mild damage 30% reduction from baseline
• Moderate damage 35%
• Severe damage 35-40%
Target IOP needs to be reviewed regularly to consider effectiveness of treatment - rate of progression informs next stage of patient management

Question 4

What 5 factors come into play when considering how much IOP should be reduced by?

Answer 4

• Glaucoma damage
• Life expectancy
• Untreated IOP
• Additional risk factors
• Rate of progression

Question 5

What is the aim if glaucoma treatment?

Answer 5

preservation of visual function adequate to the individuals needs with minimal or no side effects, for the expected lifetime of the patient without any disruption of his/her normal activities at a sustainable cost

Question 6

What treatment options are available?

Answer 6

• Topical hypotensives (monotherapy to maximal therapy)
• Selective Laser Trabeculoplasty (SLT)
• YAG laser peripheral iridotomy if narrow angles
• Trabeculectomy
• Deep Sclerectomy
• oral acetazolamide
• Angle Surgery (Phaco, istent, trabectome, canaloplasty)
• Cyclodiode Laser Ciliary Ablation
• Tube or valve surgery

Question 7

What are the classes of drug when it comes to topical treatment of glaucoma?

Answer 7

6 classes of topical IOP lowering drugs currently available in the UK:
1. Prostaglandin analogue/prostamide
2.Beta blocker
3.Carbonic anhydrase inhibitor
4.Alpha 2 agonist

5.Miotic
6.ROCK inhibitor

Question 8

Order of prescribing for glaucoma:

Answer 8

Order of prescribing
• 15 Line: Prostaglandin analogue (generic latanoprost per NICE CG81)
• 2nd Line: beta blocker OR carbonic anhydrase inhibitor OR alpha
agonist
• 3rd Line: as for 2nd line, add from a different therapeutic class
• 4th Line: used rarely but as for 3rd line, or pilocarpine in some
cases

Question 9

Prostaglandin analogue: Dosing, treatment affect, Mechanism, time to take affect, washout period:

Answer 9

• Dosing: o.i.d at night
• Treatment affect: 25-35%
• Mechanism: Increase uveoscleral outflow
• Time to take affect: 3-5 weeks
• Washout period: 4-6 weeks

Question 10

Beta Blocker: Dosing, treatment affect, Mechanism, time to take affect, washout period:

Answer 10

• Dosing: O.i.d (gel) or d.i.d (standard form)
• Treatment affect: 20-25%
• Mechanism: Reduce aq production
• Time to take affect: 2 weeks
• Washout period: 4 weeks

Question 11

Carbonic Anhydrase inhibitor: Dosing, treatment affect, Mechanism, time to take affect, washout period:

Answer 11

• Dosing: Twice a day (combination) or thrice a day (mono-therapy)
• Treatment affect: 20%
• Mechanism: Reduce Aq production
• Time to take affect: 2 weeks
• Washout period: 1 week

Question 12

Alpha 2 Agonist: Dosing, treatment affect, Mechanism, time to take affect, washout period:

Answer 12

• Dosing: Twice a day
• Treatment affect: 20-25%
• Mechanism: Reduce Aq production, increase uveoscleral outflow
• Time to take affect: ?
• Washout period: 4-6

Question 13

Prostaglandin analogues:

Answer 13

• Latanoprost (Xalatan) od
• Travoprost (Travatan) od
• Bimatoprost 0.01/0.03% (Lumigan) od
• Tafluprost (Saflutan) od

• Increased uveoscleral outflow by ciliary muscle relaxation
• 25-35% reduction in IOP

Question 14

PG Mechanism of action:
Time taken for effects:

Answer 14

• Prostaglandins are pro inflammatory molecules
• They are produced when arachidonic acid is metabolized by COX 1 and 2 enzymes
• Prostaglandin analogues act at F2-alpha receptors in ciliary muscle
• Increase aqueous outflow via uveoscleral route by inducing ciliary muscle relaxation
• ?remodeling of extracellular matrix in uveoscleral pathway
• ?Some increase in outflow by conventional trabecular route

• Initial effect after 2 hours
• Peak effect 8-12 hours
• Duration of effect up to 24 hours
• Several weeks from starting treatment to maximum effect

Question 15

Prostaglandin Analogues - Contraindications

Answer 15

Prostaglandins found throughout the body - act in different ways at different receptors.
Contra-indicated (?) in:
• Uveitis
• Cystoid Macular Oedema (CMO)
• Relative contraindication in pseudophakic and aphakic patients (due to risk of CMO)
• Recurrent herpes simplex keratitis (reactivation)

Not used in pregnancy due to potential effect of prostaglandin on the uterus (may induce labour)

Question 16

Prostaglandin Analogues - Side Effects

Answer 16

• Mild conjunctival hyperaemia ( up to 40%)
• Mild punctate keratopathy
• Foreign body sensation
• Ocular irritation
• Increased iris pigmentation (20%)
• Lengthening of eyelashes
• Cystoid macular oedema (pseudo or aphakic)
• Reactivation of herpes simplex keratitis
• Very rarely exacerbation of asthma
• Exacerbation of uveitis
• Lower Lid skin hyperpigmentation (rarely orbital fat atrophy)

Question 17

Carbonic Anhydrase inhibitors:

Answer 17

• Dorzolamide (trusopt) bd/tds
• Brinzolamide (azopt) bd
• ~20% reduction in IOP
• Drops are in suspension form, so need to be shaken before use

Question 18

Carbonic Anhydrase Inhibitors - Mechanism

Answer 18

• Reduces aqueous production by inhibiting the enzyme carbonic anhydrase which is found within the ciliary epithelium
• ?Possible improved optic nerve perfusion due to local vasodilatation but unproven

Question 19

Carbonic Anhydrase Inhibitors Ocular Side Effects

Answer 19

• blurred vision (transient)
• eye irritation
• eye pain
• foreign body sensation
• ocular hyperaemia

• CAls may affect metabolism of corneal endothelium, so use in caution as may cause corneal thickening and loss of clarity in unhealthy endothelium - eg Fuch’s endothelial dystrophy

Question 20

Carbonic Anhydrase Inhibitors Systemic Side Effects

Answer 20

• Sulphonamide hypersensitivity
• Stevens-Johnson syndrome
• Toxic epidermal necrosis
• Aplastic anaemia

All the above rare with topical medication and if occur are more likely with systemic acetazolamide

Question 21

Autonomic nervous system:

Answer 21

• Autonomic nervous system (sympathetic and parasympathetic) controls all vital organs
• Sympathetic : Norepinephrine and epinephrine neurotransmitters
• Parasympathetic: Acetylcholine neurotransmitter
• Post synaptic receptors
- Alpha 1 and 2 (sympathetic)
- Beta 1, 2 and 3 (sympathetic)
- Nicotinic and Muscarinic (parasympathetic)

Question 22

Adrenergic receptors:

Answer 22

• Present in many organs and tissues
• Heart, arteries and veins, airways, intestine, bladder, glands, smooth muscle in vessels/airways
• Effect of neurotransmitters or drugs that affect the receptors depends on the type of receptor (alpha 1,2 Beta1,2,3) and also on which organ or tissue
Heart: beta 1 stimulation results in faster rate while beta 1 blocking results in slow pulse rate
Lungs: Beta 2 stimulation opens airways and Beta 2 blockade causes constriction or closing of airway

Question 23

Adrenergic Agents:

Answer 23

• Propine (dipivefrin) and epinephrine
•Alpha-2 agonists (brimonidine [Alphagan], apraclonidine [lopidine])
• Beta blockers:
• Timolol, levobunolol, carteolol, metipranolol are all non- selective
• Betaxolol is cardioselective (Beta 1)

Question 24

Beta-Blockers - mechanism of action

Answer 24

• Timolol and others
• Decreases aqueous production by reducing ultrafiltration
• Ultrafiltration is one of the 3 processes by which aqueous is produced in the ciliary epithelium (the other two are diffusion and active secretion)
• 20-30% reduction in IOP
• Suffer from tachyphylaxis
• No difference with 0.25 or 0.5% or even 0.1%

Question 25

Beta-blockers - Ocular side effects

Answer 25

• Corneal hypaesthesia
• Punctate keratopathy
• Dry eye syndromes
• Burning/stinging
• Pseudopemphigoid

Question 26

Beta-blockers - Contraindications

Answer 26

• Do not prescribe to patients with arrhythmias, cardiac failure, COPD/Asthma
• Caution in patients taking calcium channel blockers due to additive effect
• Use in caution with patients already on systemic beta blockers
• Use in caution in the elderly

Question 27

Alpha-2 Agonists

Answer 27

• Apraclonidine and Brimonidine
• Reduction in aqueous production and increased uveoscleral outflow
• Acts on alpha-2 receptors which then inhibit enzymes involved in pathway causing production of aqueous
• 20-25% reduction in 10P
• Additive with other hypotensive agents, less effective as monotherapy
• Experimental neuroprotective properties?
• Tachyphylaxis (apraclonidine)

Question 28

Alpha-2-Agonist - Ocular Side Effects

Answer 28

• High rate of allergy (15-25% for Brimonidine)
• Conjunctival hyperaemia
• Follicular conjunctivitis (10%)

Question 29

Alpha-2-Agonist - Systemic Side Effects and Contraindications

Answer 29

Systemic Side Effects
• Dry mouth
• systemic blood pressure reduction (not used in children)
• Fatigue and drowsiness

Contraindications
• patients taking mono amine oxidase inhibitors or tricyclic antidepressants due to effect on drug metabolism and consequent risk of increased systemic side effects such as hypotension
• Severe cardiac disease

Question 30

Cholinergic Agents

Answer 30

• parasympathomimetics & miotics
• Increase trabecular outflow via ciliary muscle contraction plus some minor decrease in aqueous inflow
• Pilocarpine 1-4% gds
- ~ 20% reduction in IOP from baseline

Question 31

Pilocarpine - Side Effects

Answer 31

• Ciliary muscle spasm
• Brow ache
• Accommodative myopia
• Miosis with constriction of visual fields
• Increased risk of retinal detachment
• Keratopathy
• Hypersensitivity
• Exacerbation of uveitis / cataract formation
• Retinal detachment
• Acute or chronic angle closure

• Systemic: Bradycardia, nausea, sweating, diarrhea, bronchospasm

Question 32

ROCK Inhibitors - mechanism

Answer 32

• Rho Kinase Inhibitors
• Rho kinase is a protein kinase involved in regulation of cell shape and size by acting on the cytoskeleton
• Increase aqueous outflow by reducing outflow resistance via trabecular (conventional) outflow route
• Thought to achieve this by reducing cell stiffness in Schlemm’s canal, and possibly in the trabecular meshwork
• ROCK inhibitors are the only currently available glaucoma medication to act on the trabecular (conventional) outflow pathway

Question 33

ROCK Inhibitors - side effects

Answer 33

• Conjunctival hyperaemia - up to 50% of patients
• Conjunctival hemorrhages (often peri limbal) ?10-15% of patients
• Corneal verticillata 10% of patients
Not usually visually significant

Question 34

ROCK Inhibitors - availability

Answer 34

• In UK Roclanda = latanoprost 50mg/ml and netarsudil
200mg/ml in fixed combination
• No standalone ROCK inhibitor currently available in UK
• Available as Rhopressa (USA) and Rhokiinsa (EU) as netarsudil 200mg/ml

Question 35

General principles of concordance:

Answer 35

• Simpler treatment regimens
• Least side effects
• Education
• Reinforcement
• Regular review and reassurance
• Realistic expectations of treatment

Question 36

Further side effects and efficacy issues:

Answer 36

• Often preservative related
• Remember nasolacrimal duct occlusion
• Vaseline to lids
• Drops at least 5 mins apart
• Close eyes for 1 to 3 mins after drop

Question 37

Preservatives:

Answer 37

• Good evidence that preservatives in drops like Benzalkonium Chloride are harmful in the long term to the ocular surface
• Intolerance/ irritation
• Allergy
• Exacerbates dryness especially in susceptible patients and those on multiple drops
• Trend towards prescribing preservative free glaucoma medications (long term) in Europe places heavy demand on existing supplies
• Cost issues
• Current NICE guidance: Offer preservative-free eye drops to people who have an allergy to preservatives or people with clinically significant and symptomatic ocular surface disease

Question 38

Future therapies:

Answer 38

• Latanoprostene Bunod (Vyzulta -nitrous oxide releasing)
• Drug eluting implants
- Contact lenses punctal plugs
- Silicone rings
- Sub-conjunctival implants
- Intra-ocular drug implants