Week 9 - Medical management of glaucoma Flashcards by Bradley Brown

How do we treat glaucoma?

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

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How low does pressure need to be?

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

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Target IOP:

• 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

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

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

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What is the aim if glaucoma treatment?

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

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What treatment options are available?

• 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

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

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

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Order of prescribing for glaucoma:

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

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

• 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

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

• 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

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

• 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

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

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

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Prostaglandin analogues:

• 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

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PG Mechanism of action:
Time taken for effects:

• 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

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Prostaglandin Analogues - Contraindications

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)

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Prostaglandin Analogues - Side Effects

• 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)

Carbonic Anhydrase inhibitors:

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

Carbonic Anhydrase Inhibitors - Mechanism

• 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

Carbonic Anhydrase Inhibitors Ocular Side Effects

• 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

Carbonic Anhydrase Inhibitors Systemic Side Effects

• 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

Autonomic nervous system:

• 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)

Adrenergic receptors:

• 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

Adrenergic Agents:

• 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)

Beta-Blockers - mechanism of action

• 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%

Beta-blockers - Ocular side effects

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

Beta-blockers - Contraindications

• 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

Alpha-2 Agonists

• 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)

Alpha-2-Agonist - Ocular Side Effects

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

Alpha-2-Agonist - Systemic Side Effects and Contraindications

**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

Cholinergic Agents

• 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

Pilocarpine - Side Effects

• 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

ROCK Inhibitors - mechanism

• 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

ROCK Inhibitors - side effects

• 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

ROCK Inhibitors - availability

• 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

General principles of concordance:

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

Further side effects and efficacy issues:

• 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

Preservatives:

• 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*

Future therapies:

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