Pharmacotherapy of . Glaucoma

Dr Manjuprasad

Moderator: Dr Vijayalaxmi M.K

Overview

• Introduction

• Anatomy

• Aqueous humour dynamics

• pathophysiology

• Drugs used in the treatment

• Recent advances

• Conclusion

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Introduction• Glaucoma – ancient greek

meaning clouded or blue- green hue

• In Hippocratic aphorisms

Glaucoma – blindness coming from advancing years

• Second leading cause of blindness

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• Glaucoma is not a single disease process but a group of disorders characterized by a progressive optic neuropathy resulting in a characteristic appearance of optic disc & specific pattern of irreversible visual field defects that are associated frequently but not invariably with ↑IOP

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Anatomy of the eye

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Aqueous humor• Derived from the plasma

• 2.3µl/min

Production:

• Ultrafiltration

• Secretion

• Diffusion

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Aqueous humor dynamics

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Classification

• Congenital glaucoma

- Primary congenital glaucoma

- Developmental glaucoma

• Primary adult glaucoma

- Primary open angle glaucoma

- Primary angle closure glaucoma

- Primary mixed mechanism glaucoma

• Secondary glaucoma 8

Pathogenesis • All types of glaucoma – progressive optic neuropathy due to the

death of retinal ganglion cells(RGCs)

• RGCs death is initiated – block in transport of neurotrophins

from brain to RGCs

damaging cascade activation

Apoptosis of RGCs

• RGCs death – loss of retinal fibers – optic neuropathy & visual

field defects 9

• Mechanical theory :

↑IOP – mechanical stretch of lamina cribrosa – axonal deformation & altered capillary blood flow -- ↓neurotrophinsto reach RGC`s

• Pressure independent factors

- Failure of autoregulation

- Vasospasm

- Systemic hypotension

- Blood / fluid loss

• Excitotoxicity theory:

glutamate , oxygen free radicals, nitric oxide10

Congenital glaucoma

• Seen in 1 in 10,000 births

• Pathology- mal development of trabeculum

• True congenital glaucoma• Infantile glaucoma• Juvenile glaucoma

• Diagnosis – corneal diameter measurement- ophthalmoscopic evaluation of disc- gonioscopic examination 11

Primary open angle glaucoma

• No obvious cause

• Polygenic inheritence

• ↑incidence in smokers

• Blacks > whites

• Pathology:

- Age related thickening & sclerosis of trabeculae

- Absence of giant vacuoles in cell lining canal of schlemm

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Primary angle closure glaucoma• Increase in IOP – due to closure of angle of anterior chamber.

Acute & chronic

• Chronic PACG:- progress slowly with / without symptoms

• Acute PACG:-

-Is an emergency

-Severe eye pain

-Nausea, vomiting, prostration

-Redness, photophobia, lacrimation

-Rapid, progressive impairment of vision13

Risk factors:

• Hypermetropic eye

• Small eye

• 5th decade

• Female > male

• > in rainy season and dim light

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Secondary glaucomas• Lens induced glaucoma

• Pigmentary glaucoma

• Neovascular glaucoma

• Glaucoma associated with intravascular tumor

• Traumatic glaucoma

• Steroid induced glaucoma

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Drugs used in the treatment

DRUGS THAT REDUCE AQUEOUS HUMOUR PRODUCTION

I. Beta-Blockers : levobunolol, timolol, carteolol, betaxolol

II. Alpha-2 Adrenergic Agonists : apraclonidine, brimonidine

III. Carbonic Anhydrase Inhibitors :acetazolamide, dorzolamide 17

DRUGS THAT INCREASE AQUEOUS OUTFLOW

I. Nonspecific Adrenergic Agonists :epinephrine, dipivefrin

II. Parasympathomimetics : pilocarpine, carbachol, echothiophate

III. Prostaglandin Analogues : latanoprost

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Cholinergic agonists• Most commonly used – Pilocarpine

• Derived from shrub – pilocarpus jaborandi

MOA:-

• Acts on M3 receptors

– contraction

of sphincter pupillae

• Causes contraction of

longitudinal ciliary muscle →

trabecular outflow19

• Onset of action – rapid

peak effect – 30min

lasts for 4 – 6hrs

• S/E:-

• LOCAL:- Superficial punctate keratitis , brow ache, induced myopia, increased risk of retinal

detachment & iritis

• SYSTEMIC – rare

• Available as 0.5 to 10 % eye drops

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• Pilocarpine gel (pilocarpine HCl 4%) HS

• Membrane controlled delivery system:-

-Insert placed in cul-de-sac that gradually release drug at rate of 20mcg/hr

-Effective for 7 days

• Pilocarpine soaked contact lens

• Liposomal pilocarpine

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ADRENERGIC AGONISTS

Includes:

• Non selective – epinephrine & dipivefrin

• Selective alpha2 agonists- Apraclonidine, Brimonidine

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• EPINEPHRINE:-

• Directly acting sympathomimetic

• MOA:

• Reduced aqueous production due to alpha action

• trabecular outflow via Beta receptor stimulation

• Due to its CVS s/e , allergic reaction – no longer used

• DIPIVEFRIN:-

• Is a prodrug

• Formed by di-esterification of epinephrine –lipophilicity– increased penetration to anterior chamber .

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• Onset of action-30min, peak effect – 1hr

• Used as an adjuvant therapy

• Available as 0.1% solution , dosage BD

A/E :

• Less compared to epinephrine

• Follicular conjunctivitis, blurring of vision, stinging

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ALPHA2 AGONISTSMOA:-

• Decrease aqueous humour production by alpha2 action on ciliary epithelium.

APRACLONIDINE:

• Also known as para amino clonidine

• Available as 0.5 – 1 % , dosage BD

• Short term use – Post op rise in IOP & adjuvant in POAG

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BRIMONIDINE:-

• 30 times more selective α2 agonist than apraclonidine

• Additional neuroprotective effect

• Available as 0.2 - 0.5% , applied BD

• Uses:- in patients with contraindications to beta blockers,

-short term use in post op raise in IOP

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BETA BLOCKERS

• Introduced in 1979

• Considered to be 1st line therapy for all types of glaucoma

• Good efficacy

• Minimal S/E

MOA:

• Decreases aqueous humour production by blocking beta2 receptors on ciliary epithelium.

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TIMOLOL:

• Introduced 1978 as 1st approved beta blocker for glaucoma

• Most widely used ocular hypotensive agent

• Due to its non selective beta action – cautious in COPD, asthma & heart failure

• Available as 0.5 % solution & gel

• S/E:-

• Systemic

• Local:- superficial punctate keratitis, corneal anesthesia

CARTEOLOL:

• Available as 1% solution28

• LEVOBUNOLOL

• Available as 0.5 – 1% solution, applied BD /OD

• Metabolized to di- hydrolevobunolol

• BETAXOLOL

• Introduced in 1980s as 1st topical β1 blocker used in glaucoma

• Clinical trials – lesser efficacy in reducing IOP compared to timolol

• Additional neuroprotective effect.

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CARBONIC ANHYDRASE INHIBITORS

2 types:-

• Systemic CA inhibitors:-

• Acetazolamide, Methazolamide

• Topical CA inhibitors:-

• Dorzolamide, Brinzolamide

MOA:-

• Blocks CA enzyme reversibly in ciliary body – reduces aqueous humour production

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SYSTEMIC CARBONIC ANHYDRASE INHIBITORS

DOSAGE:-

• Acetazolamide 125mg, 250mg p.o TID or QID

• Methazolamide 25mg, 50mg p.o BD or TID

SIDE EFFECTS:-

• High risk of systemic S/Es.

• Paraesthesias, Kidney stones, aplastic anaemia, depression

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TOPICAL CARBONIC ANHYDRASE INHIBITOR

• DORZOLAMIDE:-

• 1st topical CA inhibitor launched in market

• Advantage – not absorbed systemically

• Available as 2 % solution- applied TID

• S/E:- systemic is minimal

- local S/E includes corneal edema, allergic reaction, burning & stinging sensation

• BRINZOLAMIDE

• Available as 1% solution

• Better tolerated than dorzolamide – its pH is 7.4 32

PROSTAGLANDIN ANALOGUES

• Includes latanoprost, unoprostone, bimatoprost, travoprost.

• MOA:-

• Decreases IOP by increasing uveoscleral

outflow

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LATANOPROST:-

• Introduced in 1996

• An ester prodrug analogue of PGF2α

• Available as 0.0005% solution, OD (evening)

• Requires refrigeration & protection from sunlight

• S/E – conjunctival hyperemia ( initially), Iris

pigmentation, cystoid macular odema

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UNOPROSTONE:-

• Available as 0.15% solution, BD

• Additional neuroprotective effect – increasing microcirculation in optic nerve head.

BIMATOPROST:

• A synthetic prostamide analogue

• Available as 0.03% solution , OD

• Does not require refrigeration

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TRAVAPROST

• Synthetic PGF2α analogue

• Available as 0.004% solution, OD at evening

• Does not require refrigeration/ protection from sunlight

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Surgical procedures

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• Trabeculoplasty

• Iridotomy

• Iridectomy

• Filtering procedures

• Canaloplasty

• Goniotomy

• Goniocurettage

• Cyclodialysis

• Ciliarotomy

Other treatment modalitiesALPHA LIPOIC ACID:-

• Powerful antioxidant

• Useful in glaucoma by decrease in nerve cell damage due to oxidative stress

VITAMIN C :-

• Said to increase aqueous outflow by reducing viscosity of hyaluronic acid in trabecular meshwork

SALVIA MILTIORRHIZA:-

• Chinese herb, given i.v said to improve

microcirculation of RGCs 38

CANNABINOIDS

• Believed to improve uveoscleral outflow

• Not yet available for this purpose

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Herbal products

• Boerhavia Diffusa

• Emblica Officinalis

• Terminalia Chebulia

• Commiphora Mukul

• Curcuma Longa

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FUTURE GLAUCOMA THERAPY

• NMDA receptor antagonist:-

• Provides neuroprotection by blocking glutamate mediated death of RGCs

• Includes memantine & eliprodil

• Riluzole:-

• Is a presynaptic glutamate release inhibitor

• Neuroprotective nature

• Neuroprotective vaccines:- R16

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Erythropoetin:-

• Neuroprotective by inhibiting RGCs apoptosis

• In animal studies – intravitreal injection enhances RGC survival

Caspase inhibitors:-

• Inhibits apoptosis of RGCs

• Promising approach in terms of Rx of glaucoma

iNOS inhibitors:-

• Increased level of NO – neuronal damage via apoptosis

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DRUG ELUTING MICRO STENTS

• Microstents were coated with a polymer-drug compound and is implanted in the angle of iris and cornea

• Diffusion controlled

release of paclitaxel or

mitomycin is used to

avoid blocking of stent

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Acute angle closure glaucoma• IOP – 40-70 mmHg

• Systemic hyperosmotic agent- IV mannitol 1mg/kg

• Actazolamide 500mg IV followed by 250mg TID

• Analgesics and Antiemetics

• Corticosteroids e/d like dexamethasone 3-4/day to reduce inflammation

• Sx- periferal iridotomy

filteration surgery

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BIBLIOGRAPHY• Pharmacological aspects of therapeutics – Goodman and Gilman – 12th edition

• Principles of pharmacology Sharma and sharma 2nd edition

• Textbook of medical pharmacology – Dr.PadmajaUdaykumar – third edition

• Essentials of medical pharmacology – K.D.Tripathi

• A. K. Khurana - comprehensive ophthalmology

• Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–7

• Killer HE, Miller NR, Flammer J, Meyer P, Weinreb RN, Remonda L, Jaggi GP. Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol. 2012;96:544–8.

• Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126:498–505

• . Bergeå B, Bodin L, Svedbergh B. Impact of intraocular pressure regulation on visual fields in open-angle glaucoma. Ophthalmology. 1999;106:997–1004

• Rao HL, Addepalli UK, Jonnadula GB, Kumbar T, Senthil S, Garudadri CS. Relationship between intraocular pressure and rate of visual field progression in treated glaucoma. J Glaucoma. 2012 In press.

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