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Y3 Patient sem 1 > Drugs used for glaucoma > Flashcards

Drugs used for glaucoma Flashcards

1
Q

What are the risk factors for glaucoma?

A
  • high IOP (>21mmHg)
  • family history of glaucoma
  • race (African more likely to develop)
  • systemic hypertension
  • cardiovascular disease
  • migraine
  • previous ocular disease
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2
Q

What is normal IOP?

A

12-16 mmHg

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3
Q

What is the cause of glaucoma?

A

Impaired drainage of aqueous humour - pressure of fluid in the eye builds up and exerts a greater pressure inside the eye (increased IOP)

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4
Q

What are the 2 types of glaucoma?

A
  • Primary
  • Secondary (from another eye condition)
  • can also be divided into open and closed angle - this lecture focuses on drugs that treat OPEN angle, closed angle tends to be treated with surgery
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5
Q

Where is aqueous humour produced?

A

In epithelial cells of the ciliary muscle (large blood supply helping it to flow and be secreted out)

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6
Q

What is meant by open angle?

A

Angle between iris and sclera

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7
Q

What is presented at the open angle?

A

Trabecular meshwork of cells

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8
Q

What features does the trabecular meshwork have that allows aqueous humour to flow through?

A
  • lots of spaces between cells allowing humour flow
  • flows due to pressure in the anterior chamber being higher than in the episceral vein
  • allows 80% of aqueous humour to flow
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9
Q

What is another route of aqueous humour outflow?

A

Uveoscelral outflow route - bypasses trabecular meshwork and goes through the cells of the scelra and ciliary body

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10
Q

Why is the Uveoscleral route less preferred to the trabecular route?

A

Cells of the sclera and ciliary body are more tightly packed together, meaning there is more resistance and pressure compared to the ‘holey’ trabecular meshwork.
Travels much more slowly

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11
Q

What are the aims in antiglaucoma treatment?

A
  • reduce IOP <16-20 mmHg
  • drug to have sufficient duration of action
  • provides:
    • Preservation of visual field
    • No loss of effect over time (lifetime treatment)
    • Compatibility with other treatments
    • No topical or systemic side effects
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12
Q

What causes neuropathy and damage to vision?

A

high IOP

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13
Q

What patient compliance do eye drops have?

A

LOW - inconvenient, multiple uses per day, cause temporary blurred vision

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14
Q

What is the first line treatment for glaucoma?

A

Prostaglandin and prostamide analogues

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15
Q

What features does prostaglandin E have?

A

Has great control in production of aqueous humour - however is very unstable and breaks down quickly so cannot be used

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16
Q

What prostaglandin is used as a drug ?

A

Prostaglandin F2alpha and its analogues.

It is an acid, less unstable than E

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17
Q

What are the analogues of Prostaglandin F2alpha?

A
  • Latanoprost
  • Travoprost
  • Tafluoprost

*ESTERS - more stable, less charged, last longer in formulation. Unique mechanism to decrease IOP

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18
Q

What is the analogue of Prostamide F2alpha?

A

Bimatoprost

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19
Q

Where are prostaglandins produced?

A

Naturally in most cells

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20
Q

What roles do prostaglandins play?

A

Decrease IOP - most efficacious

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21
Q

Where do the Prostaglandin analogues act?

A

Via the FP receptor

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22
Q

What reaction needs to happen in order for the prostaglandin analogues to be able to work on the FP receptor?

A

The ester analogues need to be converted back to acids (converted by esterases in the cornea)
*this means the ester analogues are PRODRUGS

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23
Q

What type of receptor is the FP receptor?

A

G-protein-coupled receptor (G-alpha-q), so when analogues bind, it causes activation of phospholipase C , which will increase diacyl glycerol and triphosphate within tissue.

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24
Q

Where are FP receptors present?

A
  • Predominantly Ciliary body & muscle, sclera
  • Iris sphincter
  • Trabecular meshwork cells (few present)
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25
Q

What characteristics do the prostaglandin analogues have?

A
  • prodrugs (need to be converted)
  • long duration of action (once daily preparation at night)
  • Greatest efficacy - can lower IOP up to 35%
  • well tolerated
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26
Q

Where do the Prostamide analogues act?

A

On FP receptors as well, however also work on more specific prostamide analogues present in higher concentrations in trabecular meshwork (better action)

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27
Q

What do prostamide analogues do?

A

Increase Uveoscleral and trabecular meshwork outflow

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28
Q

Is the prostamide analogue a prodrug?

A
  • NO - minor metabolism to bimatoprost acid

- Potent FP receptor agonist

29
Q

What is the efficacy and tolerability of the prostamide analogue?

A

Same as for prostaglandin analogues

30
Q

What is the mechanism of action for lowering IOP with prostaglandin/prostamide analogues ?

A
  • As FP receptors are highly expressed on ciliary body and scelra, we can increase uveoscleral outflow
  • Once receptors are stimulated, intracellular signalling causes a change in the structure of these cells
  • more enzymes are introduces (matrix metalloproteinases) to break down collagen and structure of scelral cells (to make more mesh-like)
  • When we get a decrease in collagen in the extracellular matrix, we get a decrease in structure, meaning more flexibility and less resistance of ciliary muscle to increase outflow aqueous humour flowing through cells
31
Q

What do matrix metalloproteinases do?

A

Break down collagen and structure of sceral cells to make more holey

32
Q

What are the side effects of prostaglandin/prostamide analogues?

A
  • Red eye (initial usage) - vasodilation
  • Increase pigmentation in iris, eyelashes & periocular skin (darker eyelashes)
  • Eyelash growth

Precipitate or worsen cystoid macular oedema in aphakic eyes (rare)

  • Sensitivity to light (rare)
  • Contraindicated in pregnancy (can induce labour)
    • Theoretical general effect on cell division
33
Q

Does glaucoma affect both eyes?

A

NO - usually only one, but drug side effects can affect both eyes

34
Q

What is the second line of glaucoma treatment?

A

Beta 2 receptor blockers

35
Q

What does B2 activation stimulate?

A

cAMP production (Gs coupled; activated adenylate cyclase)

36
Q

What does cAMP do?

A
  • INCREASES ion transport in cells in ciliary epithelium
  • cAMP activates Na+K+2Cl- cotransporter in pigmented epithelial cells
  • cAMP stimulates Cl- efflux in non-pigmented epithelial cells
37
Q

What happens when we have a greater efflux of ions across epithelial cells into the posterior chamber? (caused by b2 receptors)

A
  • cause an osmotic gradient
  • more fluid will flow into the posterior chamber and therefore more aqueous humour production

*BLOCKING this with b2 blockers will prevent/reduce aqueous humour production

38
Q

What do B2 blockers do?

A
  • Reduce aqueous humour production by blocking Na+K+2Cl- cotransporter, meaning a reduction of ions coming IN to non pigmented cells and a reduction of ions going OUT into the posterior chamber
  • This reduces humour volume flowing along gradient
  • reduced production and reduced drainage of aqueous humour
39
Q

What are the advantages of beta blockers?

A
  • Very well tolerated
  • Rapid onset of action
  • Effective in ~75% of patients
    • Lower IOP by 20-30%
  • Compatible with other drugs
40
Q

What are the disadvantages of beta blockers?

A
  • Can observe effects on treated AND untreated eye (systemic absorption)
  • Systemic side effects
  • Efficacy declines over time (doesn’t work as well as prostaglandin anagloues for chronic treatment)
41
Q

How often are beta blockers administered?

A

At least Twice daily or once daily with certain preparations

42
Q

What are the side effects of beta blockers?

A
  • Generally systemic
  • Cardiovascular (b2 receptors location)
    - Bradycardia, hypotension, peripheral vasoconstriction, impotence
    - Contraindicated in heart block, heart failure
  • Bronchial
    - Constricts bronchioles
    - Contraindicated in asthma & chronic obstructive airways disease
  • Diabetic
    • Masks hypoglycemia
43
Q

Are beta receptors used in glaucoma treatments specific?

A

NO, nonspecific, block b1 receptors too

44
Q

What are fixed dose combinations?

A
  • Multiple drugs with different mechanisms can be used at the same time to have additive effects.
  • Both drugs are formulated into one ‘drop’ (“FIXED”)
45
Q

What are the advantages of fixed dose combinations?

A
  • Patient compliance – only need to use 1 drop
  • Reduce exposure to preservatives (which can damage the eye with long term use)
  • Avoids washout effect of use of 2nd drop
  • Decreases cost of treatment
  • Decreases cost to patient – one prescription charge
46
Q

What is used as a 3rd line treatment in glaucoma?

A

Carbonic anhydrase inhibitors

47
Q

What preparations are available for carbonic anhydrase inhibitors?

A

systemic and topical use (systemic use limited to emergencies)

48
Q

What do carbonic inhibitors do?

A

Inhibit carbonic anhydrase in ciliary epithelium

49
Q

Where is the carbonic anhydrase enzyme expressed and why does this have bad effects?

A

Expressed in many major organs - blocking it has significant systemic side effects

50
Q

What reaction does carbonic anhydrase catalyse?

A

CO2 + H2O H2CO3 H+ + HCO3-

51
Q

Where are HCO3- (bicarbonate) ions excreted?

A

Into the posterior chamber, and when this happens, fluid follows these ions

52
Q

Therefore what effect does blocking the reaction catalysed by carbonic anhydrase have do?

A

Reduces aqueous formation and secretion, lowering IOP

53
Q

What systemic Carbonic anhydrase inhibitor is available?

A

Acetazolamide (not absorbed topically)

54
Q

What is Acetazolamide used in?

A

Open angle secondary glaucoma and peri-operatively in acute angle closure glaucoma (when IOP very highly elevated)

  • side effects limit use
  • short term use only (can be injected as a one off in emergencies)
55
Q

What are the side effects of Acetazolamide?

A
  • Sulfonamide derivative (Increased risk of allergy and blood disorders)
  • Enzyme present throughout body
    • Gastrointestinal problems
    • Diuresis
    • Acid / base balance disturbances
    • Drowsiness, depression
    • Parasthesias

HOWEVER, unlikely to get systemic side effects is administered directly to the eye

56
Q

How are carbonic anhydrase inhibitors made more specific, and what are examples of topical CAIs?

A

Make more selective – CA-2 enzyme
Led to Dorzolamide and brinzolamide (analogues)
Good lipid solubility

57
Q

What are topical CAIs used with?

A
  • Used in conjunction with beta blockers OR prostaglandin analogues
58
Q

How much reduction in IOP is seen with CAIs?

A

20% - less efficacious than other mechanisms

59
Q

What are the side effects of topical CAIs?

A
  • Transient burning, stinging (acidic drop)
    • 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
60
Q

What is the 4th line treatment for glaucoma?

A

Alpha 2 adrenoceptor agonists

61
Q

Where are alpha 2 receptors expressed?

A

On the ciliary, conjunctival and corneal epithelial cells

62
Q

What are the advantages of alpha 2 adrenoceptors?

A
  • No mydriasis
  • No vasoconstriction
  • Little effect on CV system (because they are alpha 2 selective)
  • very few side effects
63
Q

What is the mechanism for alpha 2 adrenoceptors?

A
  • Decrease secretion of aqueous
    - Decreases cAMP (Gi coupled; inactivates adenylate cyclase)
    - Decreases ion transport – decrease in osmotic gradient and therefore aqueous humour
    - 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
64
Q

What are examples of alpha 2 adrenoceptors ?

A
  • 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
65
Q

What are the side effects and contra-indications for alpha2 adrenoceptors?

A
  • Local
    Allergy, stinging / burning
    Blurred vision, photophobia
  • Systemic
    Hypotension
    Drowsiness, fatigue
    Dry mouth, taste disturbances

Tend to only be used pre/post surgery

66
Q

What is the last class of drug used in glaucoma?

A

Parasympathomimetics

67
Q

What is an example of a Parasympathomimetics?

A

Pilocarpine

68
Q

What is the mechanism of pilocarpine?

A

Acts at M3 receptors (muscarinic agonist), binds to M3 and ciliary muscle contracts - pulls scleral spur which opens up trabecular meshwork - allows more drainage to occur by reduction in resistance

69
Q

How long does pilocarpine work for?

A

Effects last for 6 hours (cyclical reduction)

- not an ideal drug - needs to be used at least 4 times a day

Y3 Patient sem 1 (22 decks)

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