Ocular Pharmacology

DR. KEERTHI SAGAR J

OCULAR PHARMACOLOGY

ANATOMY

Factors which influence penetration of the drugs into ocular structures

Nature of the drug

Chemical structure

Molecular weight

Physicochemical properties

Lipid water solubility ratio or partition co-efficient

Polarity

Ionization

Factors which influence penetration of the drugs into ocular structures contd..

Topical Ophthalmic Solution Ophthalmic

Suspension Gel forming solution Ophthalmic ointment Ophthalmic emulsion Ophthalmic gels Ocular inserts

Subconjunctival injections

Subtenon injections Retrobulbar injections Intraocular injections Intravitreal injections

or implants

Method of administration

Nature of the ocular structure Integrity of the corneal epithelium(particularly polar

compounds)- abrasion, ulceration Inflammation(dilated vasculature- increases the

permeability of the ciliary and iris vessels and increases drug concentration in the eye)

Status of the lacrimal outflow passages and conjunctival vasculature(which carry the drug away from the eye)

Presence of the lens(influences drug penetration into the vitreous body)

Factors which influence penetration of the drugs into ocular structures contd..

Ocular pharmacokinetics

Absorption

Distribution

Melanin binding

Metabolism

Local enzymatic biotransformation

Glaucoma

Major cause of irreversible visual disability

Accounts for 10-20% of diagnosed causes of blindness

Characterized by progressive damage to the optic nerve resulting in increased cupping of optic disc and subsequent loss of retinal nerve fibers

Formation of aqueous humor

Mechanisms

Ultra filtration

Secretion (by active transport)

Diffusion

Drainage of aqueous humor

Ciliary processes

Aqueous in the posterior chamber

Anterior chamber

Trabecular meshwork

Ciliary body

Suprachoroidal space

Venous circulation of ciliary body, choroid and sclera

Schlemm’s canal

Episcleral veins

Classification of anti-glaucoma agents

Topical drugs Beta blockers

Timolol Carteolol Levobunolol Metipranolol Betaxolol

Prostaglandin analogues Latanoprost Bimatoprost Travoprost Unoprostone

Adrenergic agonists Epinephrine Dipevifrene Brimonidine Apraclonidine

Carbonic anhydrase inhibitors Dorzolamide Brinzolamide

Cholinergic agents Pilocarpine Carbachol Demecarium bromide Echothiophate

Classification of anti-glaucoma agents contd..

Systemic Carbonic anhydrase

inhibitors Acetazolamide Methazolamide

Osmotic agents Glycerine Mannitol Urea

Miscellaneous drugs Ethacrynic acid ACE inhibitors Forskolin

Neuroprotective agents Brimonidine Latanoprost Memantine- NMDA

antagonist Iomarizine-CCB Riluzole-glutamate

antagonist

Pilocarpine

Alkaloid of pilocarpus jaborandiPK

OOA: rapid Peak effect: 30-60min Duration:4-8hrs MOA: ciliary body contraction- increased aqueous

outflowSide effects

Superficial punctate keratitis Ciliary muscle spasm Retinal detachments

Formulations of pilocarpine

Topical ophthalmic solution form Pilocapine hydrochloride Pilocarpine nitrate

Gel 1%,2%,4%Device

Membrane controlled delivery system Ocusert P 20, Ocusert P 40

Beta blockers

Timolol maleate MOA: Acts directly on ciliary epithelium to block

active transport or ultra filtration Side effects

ocular irritation, Conjunctivitis, blepharitis, decreased corneal sensitivity

dosage: Ophthalmic solution 0.25%, 0.5% Gel form in solution 0.5%

Carteolol Preferred in hypercholesterolemic patients Metabolite has 2-3 times longer half-life Dosage

1% ophthalmic solution

Levobenolol Longer half-life than timolol Side effects: transient ocular burning,

blepharoconjunctivitis, decreased corneal sensitivity Dosage: 0.25%, 0.5% topical drops

Beta blockers contd..

Metipranolol Associated with more eye burning and stinging Risk of respiratory and cardiac toxicity Dosage: 0.3%, 0.6% (BD)

Betaxolol Cardioselective Less efficaceous More burning and stinging than non selective beta

blockers Neuroprotective action Dosage: 0.25%, 0.5% ophthalmic solution BD

Beta blockers contd..

Prostaglandin analogues

Latanoprost PK

Highly lipophillic prodrug Undergoes enzymatic hydrolysis Selective action on FP receptor OOA: 3-4hrs

MOA: increase uveo-scleral outflow Dosage: 0.005% Side effects: increased iris pigmentation, lengthening

and thickening of eye lashes, punctate corneal erosions, blurred vision, burning and stinging sensation

Bimatoprost Appear to mimic prostamides Highly efficacious and long acting drug Active parent drug Stable in solution MOA: reduction in tonographic resistance to outflow-

enhances the pressure sensitive outflow pathway Decreases episcleral venous pressure Dosage: 0.03% topical ophthalmic solution

Prostaglandin analogues contd..

Unoprostone isopropylate

Docosanoid derivative

Dosage: 0.15% topical ophthalmic solution

Travoprost

Highly selective affinity for FB receptor

Prostaglandin analogues contd..

Adrenergic drugs

Epinephrine MOA:

decreased aqueous humor formation- α-adrenergic effect Increased trabecular outflow – β2 adrenergic effect

PK: OOA: 1hr DOA: 72hrs

Dosage: available as salts of hydrochloride, bitartarate, borate 0.25-2%(BD)

Side effects: conjunctival decongestion, transient mydriasis, ocular allergy, adenochrome deposits

Adrenergic drugs contd..

Dipevefrine Prodrug- de-esterification of epinephrine Lipophillicity(penetration) more than 17 times PK

OOA: 30min Peak effect: 1hr

Advantage over epinephrine Lower CV side effects Lower incidence of adenochrome deposits Dosage: 0.1% salts of hydrochloride and bitartarate Side effects: follicular conjunctivitis and ocular allergy


Apraclonidine Increased polarity of apraclonidine decreases cns

effects MOA:

increased trabecular meshwork outflow by decreasing episcleral venous pressure

Increase in prostaglandin synthesis Incresed uveo-scleral outflow

Side effects: local allergic reaction


Brimonidine High α2 selectivity Lower incidence of ocular side effects High systemic safety profile PK

Metabolized in liver Excreted in urine Due to its high selectivity no adverse effects such as

mydriasis, lid retraction, intra ocular vasoconstriction Dosage: 0.2% ophthalmic solution, brimonidine purite

0.15% Side effects: less than 3%

Carbonic anhydrase inhibitors

Topical Dorzolamide

Hydrophillic in nature Less CV side effects compared to other topical blockers Less ocular side effects than pilocarpine MOA: inhibits carbonic anhydrase 2-decreases local

bicarbonates Dosage: 2% dorzolamide HCl TID Adverse effects:

irreversible corneal oedema ocular burning and stinging, conjunctival hyperemia,

blurred vision; low incidence of conjunctivitis, keratoconjunctivitis, diplopia

Carbonic anhydrase inhibitors contd..

Topical contd.. Brinzolamide

Patient compliance better with brinzolamide than topical dorzolamide

Low incidence of burning and stinging But increased incidence of blurred vision TID

Systemic Acetazolamide

PK Oral absorption is good Peak plasma concentration: 2hrs and persists for 4-6hrs Sustained effect is seen with coated granules form

Dosage: orally 250mg 6th hourly IV – powder 500mg(sodium) per vial

Side effects: 40-50% of patients are unable to tolerate Malaise, metallic taste, fatigue, depression, anorexia,

weight loss, loss of libido


Systemic contd..Methazolamide

More potent than acetazolamide Better penetration(50 times)

Good lipid solubility Low protein binding

Dosage: 50-100mg TID


Hyperosmotic agents MOA: enhances the osmotic pressure of plasma with

respect to intraocular pressure Indications:

Acute angle closure glaucoma Pre operative control of raised IOP

Side effects: Systemic HTN, nausea, vomiting, diuresis, electrolyte

imbalance, pulmonary edema, hyperglycemia, diarrhea, headache

Systemic drugs

Systemic drugs contd..

Hyperosmotic agents contd.. Glycerol

50% and 75% lime flavored oral solutions Topical glycerine – to clear corneal oedema

Isosorbide 45% mint flavoured solution

Mannitol 25-100ml slow IV push

Miscellaneous drugs Forskolin

Methanolic extract of roots of Coleus forskohlii Doesnot have cell membrane receptors Potent stimulator of adenylate cyclase Available as 1% solution

Ethacrynic acid Substantially lowers IOP on topical administration

ACE inhibitors Controls aqueous humor production, retinal blood flow

Systemic drugs contd..

Neuroprotective agents

Brimonidine tartarate α2 agonist Preserves retinal ganglion cell survival and photo

receptor functionalityMemantine – NMDA receptor antagonist

Blockade of toxic effects of glutamate

Thank you

Ocular Pharmacology

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