Drugs in the management of glaucoma Flashcards
What is Glaucoma?
Glaucoma is a blanket term for a variety of conditions
- Common factor is acquired progressive neuropathy
- Optic nerve damage
- Visual field loss
- Eventual blindness – big portion of people who are blind – due to untreated glaucoma
Risk factors & Types of glaucoma?
- Normally asymptomatic
- High IOP (>21mmHg)
- Family history of glaucoma
- Race (afro carribean more at risk)
- Systemic hypertension
- Cardiovascular disease
- Migraine
- Previous ocular disease
- Usually due to impaired drainage of aqueous humour
Describe the sites of aqueous humour production and outflow?
- Ciliary muscle has ligaments that join onto lens
- Within ciliary muscle, there are epithelial cells that produce aqueous humour
- Have large blood supply
- AH goes past lens out of the pupil and to the side
What is the trabecular network?
- Trabecular meshwork – network of cells in a mesh formation that allows the AH to move through it – into the collector channel and to the episcleral vein (does that as the pressure in the anterior chamber is higher than in the episcleral vein)
What are the two routes of AH outflow?
The trabecular meshwork will allow 80% of the AH to outflow through it, however there is another route called the uveoscleral.
This bypasses the trabecular meshwork and goes through the cells of the schlera and the ciliary body and goes to the venous system that way (20%).
Why does the schlera route have more resistance?
as the cells are more tightly packed together therefore a lot slower.
What do we look for in antiglaucoma treatment
- Reduce IOP (<16-20mmHg depending on patient)
- Drug to have sufficient duration of action
- Patient compliance – blurred vision from eyedrops issues for driving etc
Provides:
- Preservation of visual field
- No loss of effect over time
- Compatibility with other treatments
- No topical or systemic side effects
What IOP do we look to achieve with glaucoma treatment?
(<16-20mmHg)
Role of prostaglandin E?
known for a very long time that prostaglandin E in particular has a great role in production of AH in the eye.
Why isn’t prostaglandin E used in drug treatment and what is used instead and why?
as its broken down very rapidly.
Prostaglandin F2a is a bit more stable so drugs were designed around this structure.
Is prostaglandin F2a an acid or base?
Acid - forms analogies which are esters to increase the stability e.g. latanoprost
Name the analogue for prostamide F2a?
Bimatoprost
What are prostaglandins?
- Prostaglandins produced naturally in most cells
- Involved in a variety of physiological processes including
- Aqueous humour outflow
Prostaglandin involvement in clinical use?
First choice clinically as unique mechanism to decrease IOP
How do prostaglandin analogues work?
Act via the PGF2a receptor: FP receptor
- Gprotein coupled receptors
- Gaq (once its simulated it will activate PLC, DAG & IP3
FP receptors are present on:
- Ciliary body & muscle, sclera
- Iris sphincter
- Trabecular meshwork cells (few present)
Latanoprost, Tafluprost,Travoprost factors:
- Prodrugs (ester converted to acid)
- Long duration of action. Use once daily (at night)
- Efficacy - Lower IOP by up to 35%
- Tolerability – good
(therefore good first line drug)
Prostamide analogues factors:
- Analogues of prostaglandin F2a 1-ethanolamide (prostamide F2a)
- Increases uveoscleral and trabecular outflow
- Action via prostamide receptors?
- Not a prodrug
- Minor metabolism to bimatoprost acid
- Potent FP receptor agonists
- Efficacy, tolerability & side effects
- Same as for prostaglandin analogues
Mechanism of Action – lowering IOP:
- Receptors being primarily expressed on the ciliary muscle and the scerla means we can Increase uveoscleral outflow through these receptors.
- Once the receptors have been stimulated the intracellular signalling will cause a change in the structure of those cells therefore more enzymes produced which help to break down the collagen of the sclera cells to make them more “holey”, similar to the trabecular meshwork = less resistance.
- Reduce resistance to outflow by remodelling extracellular matrix which is achieved by:
- Increase matrix metalloproteinases
- Degrades collagen and extracellular matrix
- Decreases resistance of ciliary muscle and sclera to increase outflow
- Most likely via FP receptors
- Direct effect on trabecular meshwork too?
Side effects of prostaglandin analogues:
- Red eye (initial usage)
- Increase pigmentation in iris, eyelashes & periocular skin
- Eyelash growth – glaucoma usually only exists in one eye, might be a problem if one eye has excessive eyelash growth
- Precipitate or worsen cystoid macular oedema in aphakic eyes
- Sensitivity to light
- Contraindicated in pregnancy
- Theoretical general effect on cell division
Beta receptor-induced aqueous production:
- b2 activation stimulates cAMP production (Gs coupled; activates adenylate cyclase)
- cAMP regulates ion transport in the ciliary epithelium
- cAMP activates Na+K+2Cl- cotransporter in pigmented epithelial cells
- cAMP stimulates Cl- efflux in non-pigmented epithelial cells
- Increased ion transport increases aqueous humour production due to osmotic gradient
- Therefore beta blockers PREVENT this, thus decreasing aqueous humour production
Beta Blockers - mechanism:
- Decreased ion concentration
- Decreased fluid along gradient
- Decreased volume of aqueous humour
- Better balance of production and drainage
Beta blockers advantages:
- Very well tolerated
- Rapid onset of action
- Effective in ~75% of patients
- Lower IOP by 20-30%
- Compatible with other drugs
Beta blockers disadvantages:
- Can observe effects on treated AND untreated eye (systemic absorption)
- Systemic side effects
- Efficacy declines over time
Beta blockers side effects:
- Generally systemic
- Cardiovascular
- Bradycardia, hypotension, peripheral vasoconstriction, impotence
- Contraindicated in heart block, heart failure
- Bronchial
- Constricts bronchioles
- Contraindicated in asthma & chronic obstructive airways disease
- Diabetic - Masks hypoglycaemia
What are fixed dose combinations and the advantages?
Combinations – two or more drugs contained in a single dosage form
- Different classes of drugs have additive effects
- Several advantages:
- Patient compliance
- Reduce exposure to preservatives
- Avoids washout effect of use of 2nd drop
- Decreases cost of treatment
- Decreases cost to patient – one prescription charge
What are carbonic anhydrase inhibitors?
- Systemic and topical use
- Systemic use limited to emergencies
- Inhibit carbonic anhydrase in ciliary epithelium
- This enzyme catalyses the following reaction
- CO2 + H2O –> H2CO3 –> H+ + HCO3-
- Bicarbonate formation required for aqueous secretion
- Therefore, inhibition reduces aqueous formation and secretion, lowering IOP
CAIs – Mechanism?
- Decreased ion concentration
- Decreased fluid along gradient
- Decreased volume of aqueous humour
- Better balance of production and drainage
Systemic CAIs:
- Acetazolamide
- Not absorbed topically
- Used in OAG, secondary glaucoma and peri-operatively in acute angle closure glaucoma
- When IOP very highly elevated
- Side effects limit use
- Short term use only
Acetazolamide: side effects
- Sulfonamide derivative
- Increased risk of allergy and blood disorders
- Enzyme present throughout body
- Gastrointestinal problems
- Diuresis
- Acid / base balance disturbances
- Drowsiness, depression
- Parasthesias
Development of CAIs
- Modify acetazolamide to give better lipid solubility to allow corneal absorption
- Decreases likelihood of side effects
- Make more selective – CA-II enzyme
- Led to Dorzolamide and brinzolamide
- Good lipid solubility
Topical CAIs
- Adjunct treatment with beta blockers or prostaglandin inhibitors
- Indicated as sole therapy when patient cannot use beta blockers
- Produce an approximate reduction of 20%
- Local side effects
Topical CAIs – Side effects
- Transient burning, stinging
- pH brinzolamide drops 7.5
- pH dorzolamide drops 5.6-6.0
- Blurred vision, conjunctival hyperaemia, transient myopia, blepharitis, allergic conjunctivitis
- Taste disturbances, dry mouth, headache
a2 adrenoceptor agonists
- a receptor selective
- Receptors are on the ciliary, conjunctival and corneal epithelial cells
Advantages
- No mydriasis
- No vasoconstriction
- Little effect on the cardiovascular system (as they are alpha 2 selective)
a2 adrenoceptor agonists mechanism(s):
- Decrease secretion of aqueous
- Decreases cAMP (Gi coupled; inactivates adenylate cyclase)
- Decreases ion transport – decrease in osmotic gradient
- Decreases aqueous secretion
- Decreases ultrafiltration (less fluid being filtered through from capillaries) (reduced blood flow, vasoconstriction)
- Increases uveo-scleral outflow
- Neuroprotective?
- Optic nerve, retinal ganglion cells
Drugs (alpha 2 agonists)
- Brimonidine
- Selective for a2 receptors
- Rapid onset with peak effect in ~2hours
- Apraclonidine
- Less selective for a2 receptors
- Short term use due to tachyphylaxis
- Used post surgery to prevent rise in IOP following laser surgery
Drugs (alpha 2 agonists) side effects and contra-indications:
Local
- Allergy, stinging / burning
- Blurred vision, photophobia
Systemic
- Hypotension
- Drowsiness, fatigue
- Dry mouth, taste disturbances
Parasympathomimetics examples and mechanisms:
- Pilocarpine
Mechanism
- Contract ciliary muscle
- Pulls scleral spur
- Opens trabecular meshwork
- Increases trabecular outflow
- Decreases IOP
- Effects lasts for ~6hrs
- Cyclical effect on IOP lowering throughout day
- Use four times daily – patient compliance!
Which of the drugs used to treat glaucoma would bring an increased intraocular pressure of 32mmHg back within an acceptable range?
- Alpha 2 adrenoceptor agonist
- Beta blocker
- Carbonic anhydrase inhibitor
- Parasympathomimetic
- Prostaglandin analogue – only just into the normal range
Prostaglandin analogue – only just into the normal range
Which class of drug most effectively reduces ion transport in the ciliary epithelium?
- Alpha 2 adrenoceptor agonist
- Beta blocker
- Carbonic anhydrase inhibitor
- Parasympathomimetic
- Prostaglandin analogue
Beta blocker
