Updated as on 22-02-2016

1. PHARMACOTHERAPY &
RECENT ADVANCES IN
GLAUCOMA
MANAGEMENT
Jeffrey Pradeep Raj,
Post graduate demonstrator,
Dept. of Pharmacology, SJMC
22-02-2016

2. Overview
• Eye - Relevant anatomy
• Introduction to glaucoma
• Pharmacotherapy & limitations
• Ophthalmic delivery systems
• Non – pharmacological management
• Treatment outline
• Recent advances in pharmacotherapy
• Recent advances in drug delivery systems
• Summary
• References

3. Eye - relevant anatomy

4. SEGMENTS / CHAMBERS OF EYE
• Anterior Seg –
structures ant. to lens
• 2 chambers
• Ant (AC) – Cornea &
Iris
• Post (PC) - Iris & Lens
• Posterior Seg –
structures post. to
lens

5. Angle of Anterior Chamber
• Angle recess formed between
posterior surface of the
cornea & anterior surface of
iris
• Bounded from anterior to
posterior by
• Schwalbe’s line (SL)
• Trabecular meshwork (TM)
• Scleral spur (SS)
• Anterior surface of ciliary body
along with root of iris (CBB)
• SL – termination of Corneal
Descemet’s membrane

6. Aqueous Humor Dynamics (1/2)

7. Aqueous Humor Dynamics (2/2)
• Trabecular
outflow = 70-80%
• Uveoscleral
outflow = 20-30%

8. Applied Physiology
• Volume of aqueous: 0.25ml in AC & 0.06ml in PC
• 99.9% water
• Functions:
• IOP maintenance
• Nutritional source to avascular cornea & lens
• Optical function – maintains transparency
• Clearing function – wastes & Inflammatory
exudates

9. INTRODUCTION TO
GLAUCOMA

10. Definition
• Disease of the optic nerve
• Characteristic changes in the optic nerve head
(optic disc)
• Typical defects in the visual field with/without
↑Intra ocular pressure (IOP > 21mm Hg)
• Slow progressive degeneration of retinal ganglion
cells (RGCs) & optic nerve axons

11. 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)

12. Pathophysiology (1/2)
Renu Agarwal et al. Current concepts in the pathophysiology of glaucoma.Indian J Ophthalmol. 2009 Jul-Aug; 57(4): 257–266.
TNF-A - Tumor necrosis factor-alpha, ECM - Extracellular matrix, NOS-2 - Nitric oxide synthase-2

13. Pathophysiology (2/2)
• ↑ IOP
• ↑ glutamate levels
• Alterations in NO metabolism
• Vascular insufficiency
• Oxidative damage by reactive O2 species

14. Classification (1/2)
• Ocular hypertension: Elevated IOP without disc
changes
• Normal tension glaucoma: Optic disc changes
despite normal IOP
• Primary Open Angle Glaucoma (POAG): Patency of
trabecular meshwork affected
• Primary Angle Closure Glaucoma (PACG): Shallow
ant. Chamber, narrow iridiocorneal angle

15. Classification (2/2)
• Secondary Open Angle Glaucoma: Substances
mechanically blocking TM – exudates / pigments /
pseudoexfoliation
• Secondary Angle Closure Glaucoma: Alteration in
anatomy due to trauma, Sx, Inflammation or
Ischaemia
• Congenital: 1st month of life – malformation of
angle of AC - CYP1B1, GLC3A, GLC3B genes involved
• Juvenile : First 2 decades of life. Gene involved –
MYOC - encodes trabecular meshwork induced
glucocorticoid response protein (TIGR)

16. Corticosteroid induced POAG
• ↑ 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)

17. 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
• Antibiotics: Sulfa drugs, Quinine

18. 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

19. Clinical features
Symptoms
• Photophobia
• Lacrimation
• Large bulging eyeballs
(Buphthalmos)
• Involuntary spasm of
muscles of eyelid
(Blepharospasm)
• Painful only in ACG
Signs
• ↑ in IOP >21mmHg
• Optic disc cupping
• Visual field area ↓

20. Management overview
Treatment
Pharmacological
Ocular
Hypotensives
Neuroprotectives
Non -
Pharmacological
LASERs
Surgery

21. Pharmacotherapy of
glaucoma

22. Ocular Hypotensive Agents
• Prostaglandin (PG) Analogues
• β blockers
• α agonist
• Carbonic Anhydrase (CA) Inhibitors
• Miotics
• Hyperosmolar agents

23. PG analogues – 1st line
Latanoprost, Bimatoprost, Travoprost, Tafluprost, Unoprostone
MOA i. Ciliary muscle relaxation - ↑
uveoscleral outflow
ii. Upregulate metalloproteinases →
remodelling of ECM
ADRs Hypertrichosis, darkening of iris, Macular
edema in post surgical pts, Partially
reversible periorbital fat atrophy
Advantage Once daily dosing (except unoprostone)
Bimatoprost also acts on TM
Limitations Cannot be used in post-op & hazel eyed
pts. Latanoprost needs refrigeration.

24. β blockers
Timolol, levobunolol, metipranolol, β1 selective: betaxolol
MOA Block β mediated cAMP-Protein Kinase A
pathway → ↓ ocular blood flow & ↓
ultrafiltration → ↓ aqueous production
ADRs Systemic absorption
Advantage Gel formulation ↓ frequency of dosing
FDC with other drugs that ↑ outflow
Limitations ↑ rise of acute attack in asthma / COPD Pts
Safety compromised in concomitant use of
oral β blockers (Bradycardia / Heart block)

25. α agonist
Dipivefrin HCl, Apraclonidine HCl, Brimonidine Tartrate
MOA α2 mediated constriction of afferent
ciliary process ↓ aqueous production, ↑
uveoscleral outflow
ADRs Blepharitis, Blepharo conjunctivitis,
hyperaemia, blurry
vision, dry mouth, ocular allergy,
systemic hypotension, fatigue
Limitations Ocular allergies – discontinuation
Structurally similar to anti-HTN drugs

26. CA inhibitors
Topical: Brinzolamide, Dorzolamide. Oral/parenteral:
Acetazolamide, methazolamide
MOA Inhibit enzyme carbonic anhydrase
Doesn’t allow Na, HCO3 to enter
↓ aqueous production
ADRs Ocular surface irritation, ocular allergy,
transient blurred vision. Systemic:
Paraesthesia, anorexia, hypokalemia,
malaise & depression
Limitations Sulphonamide derivatives
Metabolic acidosis

27. Miotics
Pilocarpine HCl, Carbachol, Echothiophate
MOA Ciliary muscle & scleral spur
contraction, ↑ trabecular outflow.
Relives pupillary block in ACG
ADRs Pupillary constriction, ocular burning,
brow ache, reduced night vision.
Limitations Younger pts.→ spasm of
accommodation
Older →↑risk of lenticular opacities
Limited use due to common Side effects

28. Hyperosmotic Agents
Oral- Glycerine, isosorbide. IV - Mannitol
MOA Lower aqueous fluid volume in the eye
ADRs Fluid & electrolyte imbalances,
metabolic acidosis, dry mouth, marked
diuresis, urinary retention, peripheral
oedema, headache, blurred vision,
convulsions, nausea, vomiting,
dehydration, hypotension, tachycardia
Advantage Used in Emergency / pre-op
Limitations Reduce IOP only transiently

29. 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

30. Ophthalmic Drug
Delivery Systems (DDS)

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

32. 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
iii. Low conjunctival and scleral transport

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

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

35. Non-Pharmacological
Therapy

36. 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

37. 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

38. Surgical Management
• Trabeculectomy (Filtration Sx):
• Opening made in TM
• 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

39. 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

40. Treatment Outline

41. Management of POAG
PG / B - blocker
Β-blocker/ PG
Β-blocker+PG/ CAI Β-blocker/ PG/ CAI/a
agonists

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

43. Recent Advances -
Pharmacotherapy

44. 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

45. 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.

46. 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 published
Tanihara 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.

47. 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.

48. NMDA antagonists
• Blocks pathological raise 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

49. 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.

50. Gene therapy
Target
tissue
Gene Target protein/ mechanism Cellular/molecul
ar changes
Trabecular
meshwork
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
meshwork
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 caspases
Xuyang Liu et al. Gene Therapy Targeting Glaucoma: Where Are We? Surv Ophthalmol. 2009 ; 54(4): 472–486.

51. Upcoming newer modalities
• STAT 3 activation: Phosphorylation of STAT3 - ↓
RGC apoptosis by ↓ caspase
• CNTF (form of IL6) & IL 10- neuroprotective via
STAT3
• Erythropoietin: Intra-vitreal injection in rats ↓ RGC
apoptosis
• iNOS2 inhibitors & Caspase inhibitors: via gene
therapy

52. Recent Advances – Drug
Delivery Systems

53. 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

54. 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

55. 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

56. 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.

57. 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

58. 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

59. 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

60. 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.

61. 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

62. Summary (1/2)
Rho kinase
inhibitors
CNTF
β blockers
α agonist
CAI
Miotics
α agonist
PG analogues
5FU,
mitomycin C

63. 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

64. References (1/2)
• Rang HP, Ritter JM, Flower RJ & Henderson G. Rang & Dales
Pharmacology. 8th ed. Elsevier Ltd: 2016; 162-3
• Katzung BG, Trevor AJ. Basic & Clinical Pharmacology. 13th
ed. McGraw Hill education: 2015; 160-1, 1057
• Brunton L, Chabner B, Knollman B. Goodman & Gilman’s The
Pharmacological basis of Therapeutics. 12th ed. McGraw Hill
medical: 2011 p: 1771-801
• Tripathi KD. Essentials of Medical Pharmacology. 7th Ed.
Jaypee brothers medical publishers Pvt lt: 2013; 151-7
• Khurana AK. Comprehensive Ophthalmology. 6th Ed. Jaypee
brothers medical publishers (P) ltd. 2015: 219-59

65. References (2/2)
• Deepak Sambhara et. al. Glaucoma management: relative
value and place in therapy of available drug treatments.
Ther Adv Chronic Dis.(2014) 5(1) 30–43
• S.K. Gupta et al. Recent advances in pharmacotherapy of
Glaucoma. Indian Journal of Pharmacology.2008
• For drugs status (http://adisinsight.springer.com/drugs )
• For various trial details (https://clinicaltrials.gov)

66. THANK YOU

67. Mechanism of neuroprotection
• RGCs express α2 & NMDA receptors
• NMDA overactivation- key contributing factor in
pathophysiology
• can cause intracellular Ca overload - neuronal cell death
(excitotoxicity)
• α2 stimulation- presynaptic inhibition of signaling
molecule release by
• inhibiting Ca channels, activating K channels
• Modulate glutamate & NMDA-elicited responses in
dissociated neurons
• Suppress cAMP production

68. Recent surgical advances
• Ab interno trabeculectomy (Trabectome)
• Focally ablating & cauterizing trabecular meshwork/inner wall
of Schlemm's canal
• Sustained 30% reduction in IOP. Does not generate a bleb
• Remarkable safety profile w.r.t early hypotonous or infections
• Associated with early postoperative intraocular pressure
spikes
• Ex-PRESS shunt
• Stainless steel implanted under a partial thickness scleral flap
• Appears to have similar efficacy to standard trabeculectomy

69. Complementary Alternative
Medicine
• Forskolin
• Derivative of Coleus forskohlli
• Inhibit adenyl cyclase →↑ cAMP
• Gingko biloba
• ↑ intra ocular blood flow
• Anti oxidant
• Neuroprotection
• Inhibition - PAF, nitric oxide
• α lipoic acid
• antioxidant
• Vitamin C supplements
• Antioxidant
• Cannabinoids
• ↑uveoscleral outflow
Long term
studies not
done
Not approved for ophthalmic use
Ginko biloba
Coleus forskohlii

70. Animal models for glaucoma
• Male sprague dawley rats 350-450gm
• Male Brown Norway rats (275?00 g)
• Male DBA/2J strain mice
• Male gerbils (4 months of age)
• Albino mutant quails
• Rabbits
http://www.oic.it/wgc2011/pdf/abstract/P124-P129.pdf