PHARMACOTHERAPY & RECENT ADVANCES IN

GLAUCOMA MANAGEMENTJeffrey Pradeep Raj,

Post graduate demonstrator,Dept. of Pharmacology, SJMC

22-02-2016

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

Eye - relevant anatomy

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

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

Aqueous Humor Dynamics (1/2)

Aqueous Humor Dynamics (2/2)

• Trabecular outflow = 70-80%• Uveoscleral

outflow = 20-30%

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

INTRODUCTION TO GLAUCOMA

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

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)

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

Pathophysiology (2/2)

• ↑ IOP

• ↑ glutamate levels

• Alterations in NO metabolism

• Vascular insufficiency

• Oxidative damage by reactive O2 species

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

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)

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)

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

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

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 ↓

Management overview

Treatment

Pharmacological

Ocular Hypotensives

Neuroprotectives

Non - Pharmacological

LASERs

Surgery

Pharmacotherapy of glaucoma

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

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.

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)

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

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

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

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

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

Ophthalmic Drug Delivery Systems

(DDS)

Oral • Carbonic anhydrase inhibitors, hyperosmotic agents

used orally

• Other drugs less effective

• Advantage:• Rapid fall of IOP in acute cases

• Disadvantage:• Systemic side effects

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

Topical - gel• Gel form: drug + water soluble polymers

• ↑ viscosity

• Advantage:• Less washing out by tearing• Decrease no of doses

• Limitation:• Blurring of vision

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

Non-Pharmacological

Therapy

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 (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

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

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

Treatment Outline

Management of POAGPG / B - blocker

Β-blocker/ PG

Β-blocker+PG/ CAI Β-blocker/ PG/ CAI/a agonists

Management of PACGCAI/ Hyperosmotic agents as 1st line of treatment in acute condition

Recent Advances - Pharmacotherapy

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

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.

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.

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.

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

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.

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.

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

Recent Advances – Drug Delivery

Systems

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

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

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

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.

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

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

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

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.

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

Summary (1/2)

Rho kinase inhibitors

CNTF

β blockersα agonist

CAI

Miotics

α agonistPG analogues

5FU, mitomycin C

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

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

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)

THANK YOU

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

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

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

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