Pharmacotherapy of glaucoma

1. Pharmacotherapy of
Glaucoma
Dr.Renuka. S. Harwani
JRII, MD Pharmacology

3. • Trabecular outflow = 70-
80%
• Uveoscleral outflow =
20-30%

4. Glaucoma
• Glaucoma is characterized by
progressive damage to the optic
nerves resulting in increased
cupping of the optic disc and
subsequent loss of retinal nerve
fibres.

6. Epidemiology
• 2nd leading cause for blindness globally.
• 12.3% of total blindness globally
• 3rd leading cause of blindness in India
• 11.9 million cases in India in 2010 – 12.8% of
total Indian blindness
• Females have high incidence of Angle Closure
Glaucoma (4:1) & Ocular Hypertension (2:1)
• Prevalence ↑ with age (2% in 40 years to 5-9%
in 65 years)
http://www.glaucomaindia.com (accessed 18/02/16)
http://www.glaucoma.org/glaucoma/glaucoma-facts-and-stats.php (accessed 18/02/16)

7. Types:
1. Primary Open Angle Glaucoma
2. Normal Tension Glaucoma
3. Ocular Hypertension
4. Primary Angle Closure Glaucoma
5. Secondary Glaucoma
• pigmentary glaucoma
• neovascular glaucoma
• traumatic glaucoma
• pseudoexfoliative glaucoma
6. Congenital Glaucoma

8. Primary open angle glaucoma
• Primary open angle glaucoma is a chronic,
progressive optic neuropathy causing
characteristic morphological changes at
the optic nerve head and retinal nerve
fibre layer in the absence of other ocular
disease or congenital anomalies.
• Progressive retinal ganglion cell loss leads
to corresponding visual field defects.

9. Normal tension glaucoma
• Subtype of primary open angle glaucoma
where IOP constantly remains within the
statistically determined normal range, but
progressive optic neuropathy and visual
defects typical of glaucoma occur.
• Very common
• Require repeated tonometry including 24
hour phasing and short term visual field
assessment.

10. ocular hypertension
• Intraocular pressure is consistently outside
two standard deviations from the normal
mean.
• All other ocular findings- optic nerve head
and visual fields –are within normal limits.
• In this subtype the cornea is often thicker
than normal

11. Primary angle closure
• Primary angle
closure is caused by
appositional or
synechial closure of
the anterior chamber
angle, resulting in
raised intra ocular
pressure which may
cause structural
optic nerve damage.

12. Secondary glaucoma
• Elevated intraocular pressure causes
progressive typical glaucomatous optic
neuropathy and visual field loss
• caused by other ophthalmological or
extraocular diseases, drugs and
treatments.

13. congenital glaucoma
• A developmental malformation of the
anterior chamber angleglaucomatous
damage to the optic nerve head and
prevents visual development.
• Early assessment and surgical
intervention to prevent structural damage
to the optic nerve head and allow visual
development.

14. Risk factors:
Primary Open-Angle
Glaucoma
• Elevated intraocular pressure
• African or Hispanic descent
• Family history of glaucoma
• Older age
• Thinner central corneal
thickness
Possible Risk Factors
• Systemic hypertension
• Diabetes
• Myopia
• Low diastolic perfusion
Primary Angle-Closure
Glaucoma
• Advancing age
• Asian or Eskimo
ethnicity
• Female gender
• Hyperopia
• Shallow anterior
chamber
• Family history of angle-
closure glaucoma

15. • Increased intraocular pressure-major risk
factor of glaucoma
• other factors
– increased glutamate levels
– alterations in nitric oxide (NO) metabolism
– vascular alterations
– oxidative damage caused by reactive oxygen
species

16.  Gonioscopy (measure anterior-chamber
angles).
 Applanation tonometry ( measure IOP).
 Pachymetry (measures central corneal
thickness).
 Automated perimetry (evaluates visual
fields).
 Retinal fibre layer analyzer( detects
glaucomatous damage to retinal fibres)
Diagnostic Tests (POAG)

17.  Gonioscopy.
 Applanation tonometry.
 Slit-lamp biomicroscopy.
Diagnostic Tests (PACG)

18. • Optic disc changes with visual field loss
with or without rise in IOP
• Optic disc findings:
– Cup disc ratio>0.5
– Progressive increase in cup size
– Cup disc ratio asymmetery>0.2
– Vertical elongation of cup
– Excavation of cup
– Increased exposure of lamina cribrosa
– Pallor of cup
– Spilnter haemorrhages
– Notching of cup
– Nerve fibre defects
Diagnosis of POAG

19. • Gonioscopcy:narrow
iridocorneal angle
• IOP: 40-90 mmhg
• Additional signs:
– Hyperemic conjuctiva
– Cloudy cornea
– Shallow AC
– Occasionally
oedematous & hyperemic
optic disc
Diagnosis of POCG

20. Classification of
antiglaucoma agents
Topical drugs:
1. Cholinergic agents
e.g:pilocarpine, carbachol,demecarium bromide and
echothiophate iodide.
2. Adrenergic agonists
e.g. epinephrine, dipivefrin,brimonidine and apraclonidine.
3. Beta blockers
e.g. timolol, carteolol, betaxolol,levobunolol and
metoprolol
4. Prostaglandin analogs
e.g. PGF2a, latanoprost,unoprostone and PHXA-85

21. Classification of
antiglaucoma agents
5. Carbonic anhydrase inhibitors
e.g. dorzolamide and brinzolamide.
Systemic drugs:
1. Carbonic anhydrase inhibitors
e.g. acetazolamide and methazolamide.
2. Osmotic agents
e.g. glycerine, mannitol and urea
Miscellaneous
forskolin, ethacrynic acid, steroid antagonists,
cannabinoids, angiotensin converting enzyme inhibitors,
atrial natriuretic peptide and neuroprotective agents..

22. Mechanism:
• PG analogues
• Cholinergic drugs
• Adrenergic agonists
Increase
aqueous
humour
outflow
• Βeta-blockers
• Carbonic anhydrase
inhibitors
Decrease
aqueous
humour
formation

23. Miotics in angle
closure glaucoma
contraction of
sphincter pupillae
removes papillary
block and
reverses
obliteration of the
iridocorneal angle
Miotics in open
angle glaucoma
contraction of
the ciliary
muscle pulls on
the scleral spur
improves
trabecular
patency

24. ß-blockers and
carbonic anhydrase
inhibitors
Reduce aqueous
humor secretion by
the ciliary body
Prostglandins alters
permeability or
pressure gradients
Increase
uveoscleral out flow

25. Pharmacokinetics of topical
drugs
Drug+ tears
(cul-de-sac)
Major-lacrimal
drainage
Small portion-
cornea
Drug kinetics in the
conjunctival cul-de-sac

26. •Pilocarpinedirect acting
miotics
• physostigmine
ecothiophate iodide
demecarium bromide
cholinesterase
inhibitors
• Carbachol (weak
anticholinesterase activityDual action
Cholinergic drugs

27. Pilocarpine
• Muscarinic alkaloid obtained from the
leaves of tropical American shrubs (genus
Pilocarpus)
• Used as a first line therapy in patients
wherein ß-blockers are contraindicated
• Side effects- miosis, induced
accommodation, brow ache, myopic shift,
increase risk of retinal detachment and
iritis
Pilocarpine:

28. stimulates the
muscarinic receptors of
ciliary muscle
widens the anterior
chamber angle
an increased outflow of
aqueous humor through
the trabecular
meshwork

29. • Delivery systems for pilocarpine
• Pilocarpine gel:
o Pilocarpine hydrochloride 4% in a highly viscous
acrylic vehicleapplied once daily at bedtime
• Membrane-controlled delivery system:
o placed in the cul-de-sac it gradually releases
pilocarpine at the rate of 20mg/hour (roughly
equivalent to 2% eye drops)
o Effective for seven days
o follows zero order kinetics
• Electronic medication alarm device:
o enhances compliance

30. Pilocarpine
Lowers IOP
direct receptor-related
reduction of aqueous
humor production
decreases
blood flow in the ciliary
body
Adrenergic agonists:

31. PilocarpineEpinephrine:
• Direct acting sympathomimetic amine.
• Stimulates both a and ß-adrenoreceptors
within the eye
• Increases aqueous humor outflow through
the trabecular meshwork and uveoscleral
pathway
• Reduction in IOP ranges from 15-25%
• Adverse effects: blurred vision, headache,
palpitations, high blood pressure,and
anxiety.

32. PilocarpineDipivefrine:
• prodrug of epinephrine, formed by the
diesterification of epinephrine and pivalic
acid.
• Lipophilicpenetrates easily into the
anterior chamber (penetrates
approximately 17 times more than
epinephrine)
• liberated epinephrinedecreases
aqueous production and enhances
outflow facility.
• onset of action: about 30 minutes &
maximum effect seen at about one hour.

33. PilocarpineDipivefrine:
• produces 20-24% reduction in IOP.
• indicated for initial therapy or as an adjunct with
other ocular hypotensive agents
• side effects: burning, stinging, follicular
conjunctivitis,blurry vision, headache, and
allergic reaction

34. PilocarpineAlpha-2-AGONISTS:
Clonidine
• Clonidine is the first available a-2 agonist, for the
treatment of glaucoma.
• Lipophilic molecule
• Relatively selective a-2 adrenoceptor agonist
with some a-1 adrenoceptor agonistic activity.
• Crosses the blood brain barrier and causes
systemic hypotension.
• Not used now

35. Apraclonidine
• para aminoclonidine is a derivative of a-2
adrenergic agonist
• decrease the aqueous humor secretion (deceases
cAMP) and the episcleral venous pressure(α2>α1)
• mean reductions in IOP-20% to 27%
• indicated for
– short-term use for the prevention or control of post-
surgical increases in IOP
– as an adjunctive agent for POAG
• Long-term therapyallergic blepharoconjuctivitis &
tachyphylaxis.
• available as 0.5 and 1% concentrations, to be
applied twice daiy.l

36. • Brimonidine
• a-2 agonist of choice in glaucoma
• Acts by decreasing the aqueous humor
secretion and increasing the uveoscleral
outflow
• does not cross the blood-brain barrier
• 30 times more selective than apraclonidine
• neuroprotective effect
• used as a first-line therapy in patients who
have contraindications to ß blockers
• available as 0.2 and 0.5%, to be applied
twice daily

37. Pilocarpineβ-blockers:
(Timolol, betaxolol, levobunolol,metipranolol,and carteolol)
Β2 receptor
blockade in
ciliary
epithelium
Down
regulation of
adenylcyclase
Decreases
aqueous
formation
•Ocular b blocker-lipophilic & weak local anaesthetic activity
•Occular side effects- stinging, redness, dryness of eye,
corneal hypoesthesia, allergic blepharoconjuctivitis &
blurred vission
Systemic side effects-
•Life threatening bronchospasm in asthmatic & COPD pts
•Bradycardia, accentuation of heart block, & CHF-especially
in elders

38. Timolol:
• First ß adrenocpetor antagonist approved
for the treatment of glaucoma
• decreases aqueous humor
formationlowers IOP
• Non selective with no intrinsic
symphathomimetic activity
• Reduces IOP by 20-35%
• It is very effective during waking hours and
causes less reduction in IOP in night.

39. Timolol:
• available as 0.25% and 0.5% ophthalmic
solutions, to be applied twice daily and also as
once-daily gel (0.5%)
• Smooth & sustained effects on chronic dosing
• Ocular side effects:superficial punctate keratitis,
ocular pain or discomfort, corneal anesthesia,
and vague visual disturbances.
• Avoided in Reactive airways disease and with
various cardiovascular conditions

40. • Betaxolol
• relatively selective ß-1 blocker,
• Less efficaious in lowering iot than timolol.
• onset of action-within 30 minutes &
maximum effect-2 hours after topical
administration.
• Stinging upon instillation
• plays an additional neuroprotective role in
blocking N-methyl-Daspartate (NMDA)
gated calcium channels.

41. • Levobunolol
• acts by reducing aqueous humor formation
and increasing outflow facility.
• onset of action- within one hour and the
maximum effect:2-6hrs
• metabolized into an active metabolite di-
hydrolevobunolol,
• concentration 0.5 to 1%, twice or once a
day.

42. • Carteolol
• nonselective beta-adrenergic blocking
agent with associated intrinsic
sympathomimetic activity
• Median percent reduction of IOP 22 to
25%
• ocular hypotensive effect and a safety
profile,similar to those of timolol 0.5%
solution
• Better tolerated, with regard to stinging
and irritation.

43. Pilocarpine
carbonic anhydrase
inhibitors
• On ciliary epithelium, carbonic anhydrase
isoenzyme II catalyses conversion of CO2 and
H2O to HCO3 and H+
• Used-to supplement ocular drugs for angle closure
glaucoma before & after surgery
• Systemic:
– Acetazolamide (125 mg and 250 mg) four times daily
– Methazolamide (25 and 50 mg) two or three times daily
• side effects:
– paresthesia of fingertips and toes, fatigue,
depression,kidney stones, thrombocytopenia,
agranulocystosis, and aplastic anemia.

44. Topical carbonic anhydrase inhibitors
Dorzolamide:
– reduces IOP by decreasing aqueous production
– used as a first-line therapy, When ß-blockers are
contraindicated
– commonly prescribed as an add-on therapy (has
excellent additivity with ß blockers and pilocarpine)
– IOP reduction of approximately 19-23%
– Systemic side effects-minimal
– Local side effects-stinging, burning and itching
corneal edema, borderline endothelial function,
decreased visual acuity and allergic reactions
– 2% ophthalmic solution applied TDS

45. • Brinzolamide
• Brinzolamide(pH-7.4) better tolerated than
dorzolamide (pH 5.5)
• available as 1% ophthalmic suspension

46. Latanoprost:
• selective prostanoid FP receptor agonist
• reduces IOP by increasing the aqueous
outflow through the uveoscleral pathway
• effective in reducing IOP during the
evening as well as during the day
Prostaglandin analogs:
bind to the
receptors of the
ciliary body
upregulate
metalloproteinases
enzymes remodel
the extracellular
matrix
make the
area more
permeable to
aqueous humor
•iot reduction:25-35%

47. • Conjunctival hyperemia occurs within the
first two days
• Irideal darkening
• Increase in no of eyelashes
• cystoid macular oedema or uveitis
(Previous surgery or a history of
intraocular inflammation)
• Available in 0.005% solution, administered
in the evening and requiring refrigeration
for long-term storage as well as protection
from sunlight and stability

48. Unoprostone
• Unoprostone Isopropylate is a docosanoid,
a structural analogue of an inactive
biosynthetic cyclic derivative of
arachidonic acid
• 22-carbon chain backbone (other PGAs
typical truncated 20-carbon structure)
• decreases IOP by increasing the outflow
facility without affecting aqueous humor
production
• available in 0.15% ophthalmic formulation,
to be applied twice daily

49. • increases blood flow in the choroidretina in
human eyes.
• Less incidence of Iris hyperpigmentation
and abnormal eyelash

50. Bimatoprost
• Synthetic prostamide
analog,unique structural
presence of an amide
ester group at the carboxy
terminal end of the a
carbon chain
interacts with
a prostamide
receptor in
the trabecular
meshwork
Enhances
pressure-
sensitive
outflow
pathway
Enhances
pressure-
insensitive
outflow
pathway

51. • used as a long-term monotherapy agent in
the treatment of POAG and ocular
hypertension.
• available in 0.03% ophthalmic solution and
administered once daily in the evening.
• does not require refrigeration to maintain
stability

52. • Travaprost
• Synthetic prostaglandin analouge
• Onset:2 hrs, peak 12 hrs, duration 24hrs
• full agonist at the PGF2a receptor
Free acid form
interacts with
prostanoid
receptor
enhance mainly
uveoosleral
aqueous humor
outflow
lower
intraocular
pressure

53. Drugs Mechanism
Cholinomimetics:
Pilocarpine, carbachol, physostigmine,
echothiohate
Ciliary muscle contraction, opening of
trabecular meshwork, increased outflow
alpha agonist:
Non selective- epinephrine, dipivefrin Increase outflow
Alpha 2 agonist- apraclonidine, brimonidine Decreased aqueous secretion
Beta blocker
Timolol, betaxolol, carteolol, levobunolol,
metipranolol
Decreased aqueous secretion from ciliary
epithelium
Carbonic anhydrase inhibitors:
Dorzalomide, brinzolamide,
Acetazolamide, dichlorphenamide,
methazolamide
Decrease aqueous secretion due to lack of
HCO3
Prostaglandins:
Latanoprost, bimatoprost, travaprost,
unoprostone
Increased outflow

54. condition Drugs avoided
Young patient
Acute iritis
Acute uveitis
Retinal detachment
Miotics
Bronchial asthma
COPD
Cardiac disease
Non selective beta blocker
Beta 1 blocker prefered
Nephrolithiasis CA inhibitors
Intact lens Anticholinesteres
Directly acting miotics prefered

55. Management of POAG
PG (latanoprost / B - blocker
Β-blocker/ PG
Β-blocker+PG/ CAI Β-blocker/ PG/ CAI/a
agonists
Management of POAG

56. Osmotic agents:
Mannitol 1-2 g/kg iv or
Glycerine 1-2 g/kg orally
Once IOP is controlled, pilocarpine every 6 hrs
Topical corticosteroids to reduce inflamation
and synechiae
Iridectomy is definitive treatment
Management of PACG

57. Fixed Dose Combinations
• 2 drugs in 1 container – aid patient
adherence
• Drugs with complimentary MOA ↑ outflow
& ↓ production
– Timolol with PG analogues (Bimatoprost,
Travoprost, Latanoprost)
– Timolol maleate with Brimonidine,
Dorzolamide
– Brinzolamide & Brimonidine
Fixed Dose Combination

58. Open angle glaucoma
• Opthalmic corticosteroids
(high risk)
• Systemic/nasal/inhaled
corticosteroids
• Fenoldapam
• Opthalmic
anticholinergics
• Succinylcholine
• Vasodilators
• cimetidine
Closed angle glaucoma
• Topical/systemic
anticholinergics
• Topical
sympathomimetics
• Heterocyclic
antedepressants
• Low potency
phenothiazines
• Antihistamines
• SSRI
Drug induced glaucoma

59. • ↑ Glycosaminoglycan, collagen, elastin,
fibronectin
• ↓ Outflow facility at TM
• Rx- stop steroids
• IOP returns to normal after 3-4 wks
• If not give topical anti-glaucoma drugs (PG
analogues/B-blockers)
Corticosteroid induced POAG

60. LASER (1/2)
• Laser iridotomy:
– Relieve pupillary block, equalize
pressure difference b/w anterior
& posterior chambers & open
anterior chamber angle
• Argon laser trabeculoplasty
(ALT)
– Targets trabecular meshwork -
allows aqueous to leave eye
more efficiently
– Requires 10-20 minutes & 80%
of patients respond well
LASER Procedure

61. LASER (2/2)
• Nd : YAG laser iridotomy:
– Used in closed-angle glaucoma
– Small peripheral hole made in iris - allow
aqueous fluid to flow easily
• Selective laser trabeculoplasty (SLT)
– Delivers energy to pigmented TM cells in a
process called photo-thermolysis
– Advantage: Nonpigmented TM cells sustain
less damage compared with ALT
LASER Procedure

62. Surgical Management
• Trabeculectomy
(Filtration Sx):
– Opening made in
TM
– useful when
corneal clouding
prevents
visualization of
the angle
Surgical management

63. Surgical Management
• Molteno tube:
– Drainage tube placed between cornea and iris
– Exits at junction of cornea & sclera
• Cyclo-destructive procedures:
– Cryotherapy, diathermy and photocoagulation
– Destroy ciliary body in refractory glaucoma
• Others – Retrobulbar alcohol injection,
enucleation
Surgical management

64. Post – Surgical Glaucoma
• Commonest surgery – filtration surgery
• Post surgery scarring –
– Hinders drainage of fluid
– Improper healing of bleb
• Treatment: Topical antimetabolites – Mitomycin
C, 5 FU
– Non specific
– Increased risk of bleb leak, hypotony, infection
• Scope for gene therapy:
– Controlling other modulators of inflammation
– Angiogenesis, growth factors, enzymes, inhibitory
substances
Post surgical Glaucoma

66. NMDA antagonists
• Blocks pathological raie in glutamate –
neuroprotective
• Memantine (Phase III) – did not meet
primary end point – NO benefit compared
to placebo
• All other antagonists (Eliprodil, Riluzole, L
– deprenyl) block all NMDA-R - failed in
glaucoma trials
NMDA Antagonists

67. NMDA antagonists
• Since resistance to high IOP is immune-
dependentT-cell induced
neuroprotection may vaccinate the RGC
from apoptosis.
• R16 is neuroprotective vaccine
Neuroprotective vaccines

68. • STAT 3 activation: Signal transducers and
activators of transcription protein-3 (STAT-
3)
– CNTF (form of IL6)
• Phosphorylation of STAT3
• ↓ RGC apoptosis
• ↓ caspase 3
– IL 10- neuroprotective promotes survival of
RGCs via STAT3
• Erythropoietin: Intra-vitreal injection in rats
↓ RGC apoptosis

69. • Caspase inhibitors
• reduce apoptosis by inhibiting caspase
• Gene therapy delivering BIRC4
significantly promoted optic nerve axon
survival in a chronic ocular hypertensive
model of rat glaucoma
• iNOS-2 Inhibitors:
• LN-6 (1-iminoethyl) lysine 5 tetrazole
amide: neuroprotective effect

70. • Latanoprostene bunod is a nitric oxide-
donating prostaglandin F2-alpha analog
• currently in phase 3 clinical trials
• Latanoprost-enhances uveoscleral outflow
• nitric oxide by itself-
– increases outflow facility across the trabecular
meshwork by direct action
– suppress the Rho signaling pathwaywhen
activatedcontracts the trabecular meshwork
to increase outflow resistance
niTric oxide-donaTinG
compounds

71. Activation of the Rho pathwaytightens
actomyosin networks in TMcontracting
the cells and strengthening cell-
extracellular matrix adhesion
this makes the trabecular meshwork,
especially the juxtacanalicular tissue,
stiffer and more resistive to the outflow of
aqueous humor
ROCK inhibition reduces actomyosin
contractility and relaxes the
meshworkaqueous
to pass through more easily
Rho associated kinase
(ROCK) inhibitors

72. • Rhopressa and Roclatan-currently in
phase 2 and 3 development
• Rhopressa:
• also inhibit norepinephrine transportersreduced
reuptake of norepinephrine higher extracellular
concentration of the neurotransmitter at neuro-
epithelial synapsesincrease norepinephrine
stimulation in ciliary epitheliumresulting in
decreased aqueous humor formation
• reduce episcleral venous pressure
• Roclatan, a fixed combination of
Rhopressa and latanoprost

73. • Ripasudil: a ROCK inhibitor
• has been in clinical use In Japan for about
a year
• Demonstrates modest but sustained IOP-
lowering effects,
• provide additive efficacy in combination
with timolol or latanoprost.

74. Adenosine receptor
agonists
Stimulation of the A1 adenosine receptor in
the trabecular meshwork
an increase or upregulation of proteases
such as Protease A or matrix
metalloprotease-2 [MMP-2]) that digest and
remove accumulated proteins
enhancies the aqueous outflow via the
conventional pathway

75. • Trabodenoson
• highly selective adenosine type 1 receptor
agonist
• phase 3 clinical trials
Adenosine receptor
agonists

76. Post – Surgical Glaucoma
• very little research has been done on the
majority of herbal remedies
• Forskolin
• diterpine derivative of the plant Coleus forskohlii
• acts on adenylate cyclase catalytic subunit to
increase intracellular cAMP
• Alpha lipoic acid
• a powerful antioxidant
• reduces nerve cell damage from oxidative stress
Complementary and alternative
system of medicine

77. • Gingko biloba
• increased ocular blood flow
• antioxidant activity
• platelet activating factor inhibitory activity
• nitric oxide inhibition,
• neuroprotective activity
• In a recent randomized, placebocontrolled,
double masked trial in Italyimprovement
in the visual fields in-patient, with normal
tension glaucoma after four weeks of
treatment with Ginkgo biloba

78. • Vitamin C Supplementationreduces the
viscosity of hyaluronic acid in trabecular
meshworkincrease aqueous humor
drainage
• In China, herb-derived eye drops for
glaucoma-
• pueraria flavonoids
• areca seed extract,
• alkaloids from erycibe
• Salvia miltiorrhiza injected intravenouslyhelps to
improve microcirculation of the retinal ganglion cells.
• Cannabinoidsenhances uveoscleral
outflowreduce intraocular pressure

79. Summary (1/2)
Rho
kinase
inhibitors
CNTF
β
blockers
α agonist
CAI
Miotics
α agonist
PG analogues
Summary

80. • Goodman gilman,12 th edition
• Recent advances in pharmacotherapy of glaucoma,S. K.
Gupta, Galpalli Niranjan D., S. S. Agrawal, Sushma
Srivastava, Rohit Saxena1, Indian J Pharmacol | Oct
2008 | Vol 40 | Issue 5 | 197-208
• Topics in glaucoma,CONTINUING MEDICAL
EDUCATION PuBLICATION SEPTEMBER 2015 •
ISSuE 3 A, Paul L. Kaufman, MD
• Comprehensive opthalmology, A K Khurana, 4th edition
References

82. Drug induced PACG (1/2)
• Antipsychotropic Agents: Phenothiazines
• TCAs: Amitryptaline, Imipramine
• SSRIs: Fluoxetine, Paroxetine (↑ serotonin
– mydriasis)
• MAO inhibitors: Phenylzine sulfate,
Tranycypromine
• H1 blockers: Ethanolamines, Orphenadrine
• H2 blockers: Rantidine / Cimetidine
• Anti-parkinsonian drugs: Trihexyphenydyl
HCl

83. Drug induced PACG (2/2)
• Antispasmolytic: Propantheline bromide,
Dicyclomine
• Sympathomimetic drugs: Epinephrine,
Ephedrine, Phenylephrine, Amphetamine
• Anticholinergics: Tropicamide, Atropine,
Cyclopentolate, Ipratropium, Tiatropium
• Cardiac agents: Disopyramide
• Botulinium toxin
• Rx: Stop drug; IV mannitol in resistant
cases/emergency

84. OPHTHALMIC DRUG
DELIVERY SYSTEMS (DDS)

85. Oral
• Carbonic anhydrase inhibitors,
hyperosmotic agents used orally
• Other drugs less effective
• Advantage:
– Rapid fall of IOP in acute cases
• Disadvantage:
– Systemic side effects

86. Topical – Eye drops
• Advantage of drops:
– Standard drug delivery system
– Deliver drug to vitreous, retina
• Limitations of drops:
– <1% drug delivered to aqueous
– Multiple daily dosing
– Barriers to transport:
i. Tearing
ii. Low corneal transport

87. Topical - gel
• Gel form: drug + water soluble polymers
• ↑ viscosity
• Advantage:
– Less washing out by tearing
– Decrease no of doses
• Limitation:
– Blurring of vision

88. Ocusert
• 2 membranes of polyethylene-co-vinyl
acetate
• Ring of pilocarpine
• Placed in inferior fornix
• Deliver drug for up to 7 days

89. NON-PHARMACOLOGICAL
THERAPY

90. Management of PACG
CAI/ Hyperosmotic agents as 1st line of treatment in acute
condition

91. Why new drugs?
• Neural damage irreversible – need for
neuroprotective agents
• Patients with asthma, bradycardia,
cataract, allergy to sulfa drugs or topical
brimonidine – not much options left other
than SX
• Need for preservative free drugs
– Benzalkonium – punctate / ulcerative
keratopathy
– Thiomersal – hypersensitivity
• Drugs for newer drug delivery systems

92. Rho associated kinase
(ROCK) inhibitors
• ROCK is a serine/threonine kinase
– MOA: inhibition of Rho kinase→ ↑outflow →↓ IOP
– ↑ MMPase expression in TM cells → ECM
reorganisation & Widening of empty spaces in TM
– Weaken cell attachment to ECM → relax TM tissue
– Anti scarring
– ↑intra ocular blood flow, improve RGC survival
,promote axon regeneration
• Side effects: Transient conjunctival hyperaemia
Daneshvar R, Amini N. Rho-Associated Kinase Inhibitors: Potential Future Treatments for
Glaucoma. J Ophthalmic Vis Res 2014; 9 (3): 395-398.

93. Ripasudil HCl (K-115)
Multicenter, prospective, randomized, placebo-controlled,
double-masked, parallel group comparison clinical study
Participants 210 POAG
Intervention 4 groups: placebo, 0.1%. 0.2%, 0.4% BD x 8
weeks
End point Dose Response on IOP reduction
Results IOP reductions at 8 wk from baseline: -2.2 mm Hg,
-3.2 mm Hg, -3.4 mm Hg, and -3.5 mm Hg resp. –
stat sign.
Current
status
Marketed in Japan. Phase III results to be
publishedTanihara H et al. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-
115, in primary open-angle glaucoma and ocular hypertension. Am J
Ophthalmol. 2013; 156(4):731-6.

94. Status of other ROCK inhibitors
Drug Name Status
Netarsudil mesylate (AR 13324)
Latanoprost/netarsudil mesylate (PG
324)
Phase III
AMA 0076, Y 39983 Phase II
ANS115644, INS-117548 Phase I
Verosudil (AR12286), ATS 907, DE
104
Discontinued
Phase II
Wang SK, Chang RT. An emerging treatment option for glaucoma: Rho kinase
inhibitors. Clinical Ophthalmology. 2014;8:883-890.

95. Neuroprotective agents
• Ciliary neurotrophic factor (CNTF)
supplementation (Phase I)
– Neurotropic factor for RGC
– Axogenesis factor
• Direct neurotropic agents (Pre-clinical
studies)
– Brain-derived neurotrophic factor (BDNF),
– Nerve growth factor (NGF), and
– Neurotropins NT-3, NT-4 and NT-5
Rong Wen et al. CNTF AND RETINA. Prog Retin Eye Res. 2012 March
Chang, E. and Goldberg, J. Neuroprotection, neuroregeneration,neuroenhancement. Ophthalmology.
2012; 119: 979–986.

96. Gene therapy
Target
tissue
Gene Target protein/ mechanism Cellular/molec
ular changes
Trabecula
r
meshwor
k
DN Rho Inhibiting Rho Disruption of
cellular
adhesions in
cultured cells
C3 Inactivating Rho by rebosylation
DNRK Inhibiting Rho kinase
caldesmon Inhibiting actin-myosin activating
myosin Mg ATPase
Ciliary
meshwor
k
PG synthase ↑MMP ase expression Degrade ECM
Retina ErK Mediate neuroprotective activity of
extracellular factors
↑RGC survival
MeK1 Upstream activity of Erk
CNTF neuroprotection
TNF Alpha Inhibit CNTF
BRICK-4 Inhibit caspasesXuyang Liu et al. Gene Therapy Targeting Glaucoma: Where Are We? Surv Ophthalmol. 2009 ; 54(4): 472–486.

97. RECENT ADVANCES – DRUG
DELIVERY SYSTEMS

98. Need for Newer Drug delivery
systems
• Reduced dosing frequency
• Improve adherence
• Ensure proper application of drug
• Increased bioavailability
• Adequate delivery of drug to target site –
neuroprotective drugs

99. Surgical implant
• Intra vitreal device
• Deliver drug for 3-4 months
• Used for neuroprotective drugs - sustained
delivery
• Limitation:
– Surgical risks outweigh benefits
for pts with maintained vision
– Cost
– Invasive
• NT 501 CNTF – completed phase I trials in
Dec 2014 - unpublished

100. Punctal Plug
• Device inserted into puncta that elude
drug
• Blocked puncta reduces drug clearance
• Latanoprost, Travoprost, Bimatoprost
under Inv.
Manickavasagam D, Oyewumi MO. Critical Assessment of Implantable Drug Delivery
Devices in Glaucoma Management. J Drug Deliv. 2013. 2013; 895013

101. Liposomes
• Aqueous core enclosed by phospholipid
bilayer
• Topical / subconjunctival preparations
under trial for ocular hypotensives
• Intravitreal prep for neuro protectives
Mishra Gp, Bagui M, Tamboli V et al. Recent Applications of Liposomes in Ophthalmic Drug
Delivery J Drug Deliv. 2011;2011:863734.

102. Status of Liposomal Latanoprost
Open-label, single-arm, phase 1 study (lipo-lat CS-202)
Participants 6 patients with PAOG or OHT. On monotherapy &
IOP 22-36mm Hg
Intervention 100mcl Lipo-Lat injected in superior bulbar
conjunctiva
End point IOP at 1 hour, 7 days, 1/2/3 months
Results ↓ 10mm HG at 3 months. No redness/ pain or
burning. 2 pts dry eye
Current
status
Phase 2 multicentre trials – recruiting patients.
Other brand POLAT001 – PHASE I
Injection may replace drops to lower intraocular pressure – Medscape medical
news. Accessed from http://www.medscape.com/viewarticle/821582 on
19/02/2016

103. Nano particles
• 10nm – 1000nm size
• Better drug penetration at target site
• Prolong action
• Improved topical passage of poorly water soluble
drugs (Take intracellular route through cornea)
• Drugs for glaucoma: (Promising pre-clinical
results)
– Hybrid dendrimer Nano particle (HDNP) –
Brimonidine / Timolol
– Brimonidine tartarate loaded chitosan
– Methazolamide loaded Calcium phosphate NP (CaP
NP)
Zhou HY, Hao JL, Wang S et al. Nanoparticles in the ocular drug delivery. Int J
Ophthalmol. 2013; 6(3): 390–396

104. Contact Lenses as DDS
• Polymers of N,N-diethylacrylamide &
methacrylic acid
• Advantage:
– Deliver drug over long period of time
• Limitation:
– Needs to be worn all the time
– Stored in hydrated state, ? drug elution
• Example: Timolol
Haruyuki Hiratan et al. Timolol uptake and release by imprinted soft contact lenses made of N,N-
diethylacrylamide and methacrylic acid, Journal of Controlled Release. 2002; 83 (2): 223 - 30

105. Microelectromechanical System
(MEMS)
• Reservoir in subconjunctival space
• Electrolysis → bubbles → push drug out of
reservoir→ delivered via port
Saloomeh saati et al. Mini drug pump for ophthalmic use. Curr eye res. 2010 march ; 35(3): 192–201.

106. Limitations of newer DDS
• Long term safety yet to be studied
• Interaction and stability of drug in carrier
system unknown
• Amount of drug that maybe delivered
limited
• Complicated technology required to
produce

108. Summary (2/2)
• PGs – 1st line f/b B blockers in POAG
• Miotics / hyperosmotic agents 1st line in ACG
– clinical emergency
• LASER procedures preferred over Sx
• Pharmacological agents for Neuroprotection
under development – Rho kinase Inh, CNTF,
Gene therapy
• Newer DDS – liposomes / nanospheres /
punctal plug / MEMs – to reduce frequency &
better adherence