Glaucoma B

Question 1

2 targets for aqueous outflow

Answer 1

conventional outflow - TM & Canal of Schlemm
unconventional outflow (uveosclera) - via CB to choroid & sclera

Question 2

Conventional aqueous humor outflow pathway

Answer 2

-dynamic

Key determinants
* resistance in TM; influenced by tone of TM cells (sm muscle actin) & ECM remodeling (drain analogy)
* tone of iris sphincter & ciliary muscles (contraction one/both opens up trabecular meshwork)
* Transmitters implicated include Ach, NO (nitric oxide), & adenosine

Question 3

Unconventional aqueous humor outflow pathway (target for PG Analogs)

Answer 3

Influences on dynamics:
* ECM matrix: resistance influenced by ECM remodeling
* Tone of ciliary muscle: flow decreased by contraction of ciliary muscles (closes “channels” between muscle fibers)

Question 4

5 potential drug groups for conventional outflow target

Answer 4

• Miotics
• Dipivefrin (prodrug for epinephrine)
• Rho kinase (ROCK) inhibitors
• NO donors
• Adenosine A1 receptor agonists

Question 5

Miotics/ Parasympathomimetics drugs

Answer 5

DA drugs/muscarinics: pilocarpine & carbachol
IDA drugs/anticholinesterases: echothiophate (irreversible)

Question 6

Clinical uses of miotics, esp. for POAG, now very limited

Answer 6

• enhance conventional outflow
  Applications:
• POAG as substitute for beta-blockers
• AACG (pilocarpine) - ineffective at IOP >60
• some 2ndry glaucomas (including pigmentary glaucoma)

Question 7

pilocarpine effects and reduced effects in

Answer 7

• very short duration (4-8 hrs; quickly metabolized)
  >maximum reduction of IOP 1-2 hrs
  >rationale for special formulations (gels, Ocuserts discontinued)
• decreases diurnal fluctuations
• reduced effect:
  >brown/dark irides
  >increasing age
  >at high IOP due to ischemic iris

Question 8

Carbachol (muscarinic/nicotinic agonist + indirect actions)

Answer 8

• more potent than pilocarpine
  >more pronounced ocular side-effects
• poorer corneal penetration
• longer duration of action b/c resistant to hydrolysis
• mostly used as miotic & reducing IOP post-surgery increase Ach release and decrease Achesterase activity

Question 9

Miotics drugs: Ocular side-effects

Answer 9

• ciliary spasm
• miosis
• iris sphincter rigidity/ posterior synechiae (possible reason for drug holidays)
• vascular congestion (ciliary/conjunctival)
• retinal detachment (high myopes at incr risk)
• lacrimation
• lid myokymia
• allergic reactions (pilocarpine)
• band keratopathy (preservative effect?, use EDTA)
• paradoxical increase IOP (decr. uveoscleral flow?)

Question 10

Muscarinic drugs: Systemic side-effects

Answer 10

• cardiovascular - bradycardia, hypotension?
• respiratory - pulmonary edema, bronchospasm
• gastrointestinal distress - diarrhea, vomiting
• bladder (incontinence)
• enhanced glandular activity (dribbling)
• generalized weakness
• headache

Question 11

Contra-indications for muscarinic drugs

Answer 11

• young patients (<40 yr)
• peripheral retinal disease (incr risk of retinal detachment)
• aphakics/pseudophakics
• inflammation/uveitis history?
• central cataract (esp IDs)
• neovascular glaucoma
• heart disease
• urination problems (2ndy to BPH/cancer)
• asthma or Parkinson’s disease (dangerous drug interaction)

Question 12

Echothiophate (Phospholine) Iodide - an irrev. cholinesterase inhibitor

Answer 12

Better control over diurnal fluctuations (very potent, long acting) BUT

extra contra-indications
* phakic glaucoma
* central cataract?

extra drug interactions
* pesticides
* succinylcholine
* myasthenia gravis drugs
* Alzheimer’s disease drugs?

extra ocular side-effects
* iris cysts
* pigment dispersion
* lens opacities/cataracts
* activation of latent uveitis?

extra systemic side-effects
* decrease cholinesterase levels (RBCs & serum)
* CNS excitation?

Question 13

Newly approved drugs

Answer 13

• Available as stand-alone drug or combination
• ROCK inhibitor+
  >Rhopressa (netarsudil)
  >Roclatan (netarsudil 0.02% + latanoprost 0.005%)
• NO donor combined with PG analog
  >Vyzulta (latanoprostene bunod 0.024%)

Question 14

ROCK inhibitor (+ NET inhibitor)
Rhopressa (netarsudil)

Answer 14

• Prolonged IOP lowering action, given as 0.02%, qd
  >metabolized by corneal esterases to more potent analog
• ROCK (Rho kinase) inhibition enhances conventional outflow
  >inhibits smooth muscle contraction
  >relaxes trabecular meshwork cells
  >reduced episcleral venous pressure
• NET inhibition
  >decreases aqueous production in rabbits (VC effect in ciliary body?)

Question 15

Netarsudil Side-effect Profile

Answer 15

Ocular Side effects - most common hyperemia
> also corneal verticillata
> pain on instillation
> conjunctival hemorrhage
> others include corneal staining, increased lacrimation, blurred vision/reduced VA
> safety for children & pregnant/lactating mothers yet
to be established although animal studies suggest risk
of adverse fetal effects very low

Question 16

Dipivalyl epinephrine (dipivefrin; Propine): Mechanism of action

Answer 16

• sympathomimetic (nonselective (a/b) adrenergic receptor agonist)
• active drug released during transfer across cornea by metabolism by corneal esterases
• long lasting increased outflow:
• conventional & unconventional?
• b2 mediated/cAMP (Cltransport)?
• slight early increase aqueous production?!