Pharmacotherapy & recent advances in glaucoma management
-
Upload
jeffrey-pradeep-raj -
Category
Health & Medicine
-
view
1.133 -
download
1
Transcript of Pharmacotherapy & recent advances in glaucoma management
![Page 1: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/1.jpg)
PHARMACOTHERAPY & RECENT ADVANCES IN
GLAUCOMA MANAGEMENTJeffrey Pradeep Raj,
Post graduate demonstrator,Dept. of Pharmacology, SJMC
22-02-2016
![Page 2: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/2.jpg)
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
![Page 3: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/3.jpg)
Eye - relevant anatomy
![Page 4: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/4.jpg)
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
![Page 5: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/5.jpg)
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
![Page 6: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/6.jpg)
Aqueous Humor Dynamics (1/2)
![Page 7: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/7.jpg)
Aqueous Humor Dynamics (2/2)
• Trabecular outflow = 70-80%• Uveoscleral
outflow = 20-30%
![Page 8: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/8.jpg)
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
![Page 9: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/9.jpg)
INTRODUCTION TO GLAUCOMA
![Page 10: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/10.jpg)
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
![Page 11: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/11.jpg)
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)
![Page 12: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/12.jpg)
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
![Page 13: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/13.jpg)
Pathophysiology (2/2)
• ↑ IOP
• ↑ glutamate levels
• Alterations in NO metabolism
• Vascular insufficiency
• Oxidative damage by reactive O2 species
![Page 14: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/14.jpg)
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
![Page 15: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/15.jpg)
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)
![Page 16: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/16.jpg)
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)
![Page 17: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/17.jpg)
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
![Page 18: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/18.jpg)
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
![Page 19: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/19.jpg)
Clinical featuresSymptoms
• 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 ↓
![Page 20: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/20.jpg)
Management overview
Treatment
Pharmacological
Ocular Hypotensives
Neuroprotectives
Non - Pharmacological
LASERs
Surgery
![Page 21: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/21.jpg)
Pharmacotherapy of glaucoma
![Page 22: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/22.jpg)
Ocular Hypotensive Agents• Prostaglandin (PG) Analogues• β blockers• α agonist • Carbonic Anhydrase (CA) Inhibitors• Miotics• Hyperosmolar agents
![Page 23: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/23.jpg)
PG analogues – 1st line Latanoprost, Bimatoprost, Travoprost, Tafluprost,
UnoprostoneMOA i. Ciliary muscle relaxation - ↑
uveoscleral outflow ii. Upregulate metalloproteinases →
remodelling of ECMADRs 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.
![Page 24: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/24.jpg)
β blockersTimolol, levobunolol, metipranolol, β1 selective:
betaxololMOA Block β mediated cAMP-Protein Kinase A
pathway → ↓ ocular blood flow & ↓ ultrafiltration → ↓ aqueous production
ADRs Systemic absorptionAdvantage Gel formulation ↓ frequency of dosing
FDC with other drugs that ↑ outflowLimitations ↑ rise of acute attack in asthma / COPD Pts
Safety compromised in concomitant use of oral β blockers (Bradycardia / Heart block)
![Page 25: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/25.jpg)
α agonist Dipivefrin HCl, Apraclonidine HCl, Brimonidine
TartrateMOA α2 mediated constriction of afferent
ciliary process ↓ aqueous production, ↑ uveoscleral outflow
ADRs Blepharitis, Blepharo conjunctivitis, hyperaemia, blurryvision, dry mouth, ocular allergy,systemic hypotension, fatigue
Limitations Ocular allergies – discontinuationStructurally similar to anti-HTN drugs
![Page 26: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/26.jpg)
CA inhibitorsTopical: 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 derivativesMetabolic acidosis
![Page 27: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/27.jpg)
MioticsPilocarpine 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 accommodationOlder →↑risk of lenticular opacitiesLimited use due to common Side effects
![Page 28: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/28.jpg)
Hyperosmotic AgentsOral- Glycerine, isosorbide. IV - Mannitol
MOA Lower aqueous fluid volume in the eyeADRs 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-opLimitations Reduce IOP only transiently
![Page 29: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/29.jpg)
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
![Page 30: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/30.jpg)
Ophthalmic Drug Delivery Systems
(DDS)
![Page 31: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/31.jpg)
Oral • Carbonic anhydrase inhibitors, hyperosmotic agents
used orally
• Other drugs less effective
• Advantage:• Rapid fall of IOP in acute cases
• Disadvantage:• Systemic side effects
![Page 32: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/32.jpg)
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. Tearingii. Low corneal transportiii. Low conjunctival and scleral transport
![Page 33: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/33.jpg)
Topical - gel• Gel form: drug + water soluble polymers
• ↑ viscosity
• Advantage:• Less washing out by tearing• Decrease no of doses
• Limitation:• Blurring of vision
![Page 34: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/34.jpg)
Ocusert • 2 membranes of polyethylene-co-vinyl acetate• Ring of pilocarpine• Placed in inferior fornix • Deliver drug for up to 7 days
![Page 35: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/35.jpg)
Non-Pharmacological
Therapy
![Page 36: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/36.jpg)
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
![Page 37: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/37.jpg)
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
![Page 38: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/38.jpg)
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
![Page 39: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/39.jpg)
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
![Page 40: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/40.jpg)
Treatment Outline
![Page 41: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/41.jpg)
Management of POAGPG / B - blocker
Β-blocker/ PG
Β-blocker+PG/ CAI Β-blocker/ PG/ CAI/a agonists
![Page 42: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/42.jpg)
Management of PACGCAI/ Hyperosmotic agents as 1st line of treatment in acute condition
![Page 43: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/43.jpg)
Recent Advances - Pharmacotherapy
![Page 44: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/44.jpg)
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
![Page 45: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/45.jpg)
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 hyperaemiaDaneshvar R, Amini N. Rho Associated Kinase Inhibitors: Potential Future Treatments for Glaucoma. J ‑
Ophthalmic Vis Res 2014; 9 (3): 395-398.
![Page 46: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/46.jpg)
Ripasudil HCl (K-115)Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clinical studyParticipants 210 POAG Intervention 4 groups: placebo, 0.1%. 0.2%, 0.4% BD x 8 weeksEnd point Dose Response on IOP reductionResults 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.
![Page 47: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/47.jpg)
Status of other ROCK inhibitors
Drug Name StatusNetarsudil mesylate (AR 13324)Latanoprost/netarsudil mesylate (PG 324)
Phase III
AMA 0076, Y 39983 Phase IIANS115644, INS-117548 Phase IVerosudil (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.
![Page 48: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/48.jpg)
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
![Page 49: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/49.jpg)
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 MarchChang, E. and Goldberg, J. Neuroprotection, neuroregeneration,neuroenhancement. Ophthalmology. 2012; 119: 979–986.
![Page 50: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/50.jpg)
Gene therapyTarget tissue
Gene Target protein/ mechanism Cellular/molecular 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.
![Page 51: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/51.jpg)
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
![Page 52: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/52.jpg)
Recent Advances – Drug Delivery
Systems
![Page 53: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/53.jpg)
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
![Page 54: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/54.jpg)
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
![Page 55: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/55.jpg)
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
![Page 56: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/56.jpg)
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.
![Page 57: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/57.jpg)
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 HgIntervention 100mcl Lipo-Lat injected in superior bulbar conjunctivaEnd point IOP at 1 hour, 7 days, 1/2/3 monthsResults ↓ 10mm HG at 3 months. No redness/ pain or burning.
2 pts dry eyeCurrent 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
![Page 58: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/58.jpg)
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
![Page 59: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/59.jpg)
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
![Page 60: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/60.jpg)
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.
![Page 61: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/61.jpg)
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
![Page 62: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/62.jpg)
Summary (1/2)
Rho kinase inhibitors
CNTF
β blockersα agonist
CAI
Miotics
α agonistPG analogues
5FU, mitomycin C
![Page 63: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/63.jpg)
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
![Page 64: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/64.jpg)
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
![Page 65: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/65.jpg)
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)
![Page 66: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/66.jpg)
THANK YOU
![Page 67: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/67.jpg)
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
![Page 68: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/68.jpg)
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
![Page 69: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/69.jpg)
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
![Page 70: Pharmacotherapy & recent advances in glaucoma management](https://reader036.fdocuments.net/reader036/viewer/2022062823/5875a4791a28ab6d198b7713/html5/thumbnails/70.jpg)
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