Extraocular structures: conjunctiva, cornea, tears

Iris

Ciliary body and drainage angle

Lens

Vitreous and retina

Posterior orbit

Target tissue

amount of drug needed at site

characteristics of drug

convenience and safety (o/s vs o/o; hazardous drugs

Client compliance (frequency, physical limitations)

Cost

Topical

Subconjunctival injection

intraocular injection

systemic

lids

conjunctiva

cornea

sclera

anterior uvea

cornea

sclera

anterior uvea

vitreous

anterior segment

posterior segment

oral or parenteral

eyelids

sclera

anteroir and posterior uvea

vitreous

retina

optic nerve

orbit

limited to cornea

Topical administration

Cornea

First barrier->multiple layers

lipophilic: epithelium and endothelium

hydrophilic: stroma

the first barrier is epithelium: affected by different pathologies

tear layer: combination of water and lipids

eyelids, conjunctival, corneal and uveal dz

two possible ways for absorption:

1. Penetration through the cornea

2. Systemic absorption through the conjunctiva and nasolacrimal duct

Topical administration

increased drug concentration

1. increase frequency

2. increase concentration

solution/suspension (saturated solution)

easy to apply

suspension-saturated solution with poorly soluble drugs

particles seen-shake well

short contact time-75% lost through lacrimal drainage

Multiple drops administration-first drop with dilute and wash the first one->wait 5 minutes between different types of drops

Topical

Ophthalmic ointment

longer contact time

reduce loss through lacrimal drainage

more stable than drops

lubricant

application is more challenging than drops (SA)

may slow down ulcer healing

Dz ex-dystechia-cause corneal ulcer, secondary infections

Topical

Effect on drug penetration and side effects

pH-7.2 (5-9 tolerate)

molecule size

drug concentration

vehicle and preservatives

Topical

Subpalpebral lavage (SPL)

Can be used in horses to facilitate frequent or long term treatment

more than few days

very problematic

drugs interaction-pH, precipitation, stability

refrigeration

exposure to light

suspensions

He likes injection cup not a pump

if put more than 1 drug in pump->drug interaction

75% lost through lacrimal drainage

only a small amount absorbed

Absrobed through cornea->aqueous->taken up in uvea or lens or lost to aqeous outflow

penetrates conjunctiva->into/thru the sclera->uvea or lost in venous blood (no lymphatics in eye)

Periodic drops (topically or via SPL) or ointments

continuous lavage

soft contact lenses

extended delivery membranes

liposome

microbeads

Subconjunctival injections

Penetration:

Bypass conjunctiva and cornea barriers for direct scleral absorption

Leaks back onto surface of eye->absorbed through the cornea

Only small amount absorbed into the eye but injection site has large amount of drug (depot effect)

Subconjunctival injections

how it is applied/works

drug may las several days in the "depot"

no better than frequently applied topical medication

treats anterior segment of eye and vitreous

Subconjunctival injections

indications/advantages

for animals that will not permit repeated topicals, wildlife

for water soluble drugs that poorly penetrat cornea

for long acting drugs (ex: methylprednisolone acetate)

to achieve high concentrations of drug for short time

confine the drug's effect to the eye

Subconjunctival injections

disadvantages

cannot change medication once injected

occasionally painful due to drug or vehicles

may develop granuloma at injection site

no better than frequently administered topical medication

into anterior chamber or vitreous

seldom done if systemic admin works

drug/vehicle may have deleterious effect on ocular structures

should be done by ophthomologist-can damage eye

usually limited to regional anesthesia

drug may penetrate the posterior sclera and enter choroid

can damage the ON or globe

Can cause retrobulbar hemorrhage

Systemic administration

sites and uses

Oral, IV, IM, SC

more effective when blood-ocular barrier disrupted

mostly for tx of posterior segment of eye or orbital disease

Antibiotics

indication

Antibiotics

drug choice

choice depends on culture and sensivity or common flora

most antibiotics have poor corneal penetration

when empiric a/b tx doesn't help->culture and sensitivity->look for underplaying cause for recurrent infection

Ex: ectopic cilia, dry eye, foreign body

Not all antibiotics available topically

Antibiotics

polypeptides

Bacitracin

Gramicidin

Polymyxin

Antibiotics

Aminoglycosides

Neomycin

Gentamicin

Tobramycin

Antibiotics

Quinolones

Ciprofloxacin

Ofloxacin

Lomefloxacin

Antibiotics

Others

Tetracyclines

Erythromycin

Chloramphenicol

Sulfonamides

Cephalosporin

Penicillin

Bactericidal

effective empiric tx

topical use only-toxic systemically

Usually in combos->

neomycin+polymyxin+bacitracin (NeoPolyBac)-ointment

neomycin+polymyxin+gramicidin (NeoPolyGram)-solution

Bacteriocidal, broad spectrum, mainly for G-

toxic systemically

epitheliotoxic

tobramycin, amikacin, gentamicin-pseudomonas (melting corneal ulcer)

Tobramycin is cheap and more effective, less epitheliotoxic than gentamycin

Neomycin variable efficacy vs pseudomonas

Cephalosporins

Cefazolin

Mainly for staph/strep

well tolerated

low corneal permeability

effective vs resistant staph

no ophthalmic prep

can be compounded easily

Sulfonamides

Bacteriostatic, broad spectrum

inactivated in combo with discharge/topical anesthesia

limited permeability

may irritate eye

commercially available

Bacteriastatic, broad spectrum

well tolerated

effective against: mycoplasma and chlamydophila (kittens) rickettsia

"pink eye" cattle (mixed Moraxella bovis/Mycoplasma)

Ophthalmic prep:tetracycline Hydrochlorid Ophthalmic Ointment-sometimes in combo with other antibiotics

anti-inflammatory

anti-protease

faciliatates healing of indolent ulcers

Ophthalmic prep tetracycline hydrochloride ophthalmic ointment

systemic doxycycline-secrete in tears

only disadvantage-only ointment

Bactericidal, non-toxic

Staphy and strep

no topical prep

rare in ophtho

used for Bovine keratoconjunctivitis IBK or pink eye in cattle by subconjunctival injection

Broad spectrum, limited against anaerobes

use it when really needed (C&S)

Quinolons

ophthalmic prep

Ciprofloxacin

Ofloxacin

Moxifloxacin

Lomefloxacin-good corneal penetration; use for anterior segment

Bacteriostatic

broad spectrum

G+

not to be used in food animals

Side effects: irritation, redness, itching, aplastic anemia

Antifungals

Miconazole

Natamycin

Voriconazole

Antifungals

Miconazole

effective against aspergillus spp and G+ cocci

aspergillus spp. common in equine eye infection

low corneal permeability

use 4-6 times/day

cheap

no commercial ophthalmic preparation-needs to be compounded as both ointment or solution

Antifungals

Natamycin

only commerical antifungal ophthalmic preparation

5% ophthalmic suspension

3% for SPL

effective against Fusarium spp.

Low corneal permeability

use 4-6 times/day

Expensive-amphotericin B is cheaper, less effective

Antifungals

Voriconazole

Third generation of azole

effective against Fusarium (2nd most common in equine eyes) and Aspergillus spp.

 Better corneal penetration than miconazole

use 4-6 times/day

Expensive

Nucleoside analogs (and interferons) are currently used in vet ophthalmology

most frequently for feline herpesvirus (<<horses)

inhibit or alter DNA synthesis

virostatic-require functional cellular immunity and Ig's in tears

unable to eradicate latent infection

expensive (new generation's)

Antiviral

Idoxuridine

effective

no commerical opthalmic prep

compounded as solution or ointment

use q 2h for 2 d, then 4-6x/day for 3-5 wks

cheap

can be very irritative-makes difficult to admin

antiviral

new generation

Ganciclovir-same efficacy idoxuridine, double penciclovir and cidofovir

penciclovir

cidofovir-effective can be given BID (less issues with admin to a cat)

expensive

no commerical prep

Acyclovir not effective vs feline herpes

Antiviral

Interferon

compounded from IV preparation

affect transcription

stimulat the immunological defense

-immune cell-mediated lysis of virus-infected cells)

Antiviral

L-lysine

Ties up arginine so it is not available for viral replication

add to food daily for life to limit chronic recurring infections

use 250-500 mg/cat q24h for prevetion

250-500 mg/cat q12h for active disease

available in health food stores and as prep for cats

-recommend prep for cats due to cat compliance

Anti-inflammatory corticosteroids

topical use

Anti-inflammatory corticosteroids

MOA

1. decrease arachidonic acid release from injured cell membranes

2. block degranulation of neutrophils, mast cells, basal cell

3. prevent protease, histamine, bradykinin release

4. reduce capillary permeability, vasodilation, neovascularization

Anti-inflammatory corticosteroids

effects

reduce edema, redness and pain

reduce cellular exudation

reduce leukocyte infiltration of lesions

suppress lymphocyte proliferation

epithlial and stromal dystophy/degeneration with long term use

Anti-inflammatory corticosteroids

uses

disadvantages

topical, subconjunctival, retrobulbar, systemic

increase intraocular pressure

does not cause cataracts like in people

inhibit fibrosis

interfere with epithelial regeneration

potential proteinases break down collage->corneal melting

reduce signs of inflammation and effects

redness, swelling, pain reduced

allergy, hypersensitivity and

immune-mediate disease (chronic superficial keratitis-Pannus, granulomatous episcleritis, uveritis)

Infection-careful!!!

Trauma-careful!!!

reduce scarring-fibrosis

preventrion of inflammation pre-op

Anti-inflammatory corticosteroids

corneal penetration and dosing

Corneal penetration: acetate>alcohol>phosphate

Prednisolone acetate 1.%-better corneal penetration->prefer for uveitis and intraocular inflammation

Dexamethasone Na phosphate 0.1%-more potent, longer action-poor corneal penetration, use for extraocular inflammation

Dexamethasone alcohol 0.1% for uveitis-corneal penetrate

Combo with antibiotics-hydrocortisone, dexamethasone, betamethasone

Short term: dexamethasone solution, triamcinolone (Kenalog) suspension

long term: greater granuloma risk at injection site

1. betamethasone (Betasone) suspension

2. methylprednisolone (Depo-Medrol) suspension

3. Triamcinolone (Kenalog) suspension

once there cannot remove->less than ideal option

limited to severe intraocular inflammation, orbit, optic nerve disease

Small animals-prenisone, prednisolone PO is adequate

Horse-dexamethasone but careful-laminitis

uncommonly used

ulcerative keratitis:

-inhibit fibroblast responses

-interfere with epithelial regneration

-potientiate proteinases that break down collagen

uncontrolled/severe infections

-may use with antibiotics to block uncontrolled inflammation (blindness)

Mature scars->no point, won't help anything

Corneal degenerations

Careful with metabolic dz-diabetes, especially in small animals

may facilitate fungal infections in prolonged use

may cause epithlial and stromal dystrophy/degeneration

may increase intraocular pressure

do not cause cataracts

NSAID's

indications

when steroids contraindicated

complimentary to corticosteroids

pre cataract surgery

NSAID's

MOA

prevent formation of prostaglandins from arachdonic acid

prostaglandins->primary mediators or ocular inflammation

NSAID's

topical

delay healing of epithelium but not as deleterious as corticosteroids

expensive compared to steroids

Flubiprofen-0.03% ophthalmic solution

Diclofenac-0.1% ophthalmic solution

best not to use any NSAID's or topical steroids with corneal ulcer->last resort use NSAID's before steroids

Small animals

Carprofen (Rimadyl)

Meloxican (Metacam)

Horses:

Flunixin meglumin (Banamine)-most effective in horses; monitor kidney function long term, protect GI with omeprazole

Piroxicam-tx SCC (80-160 mg/horse/day); limited data in literature

used in place or in combo with corticosteroids-synergic

Cyclosporine A (optimmune) ointment 0.2%-compounded 1-2% ophthalmic solution in oil

(irritating and rarely may cause alopecia)

Tacrolimus-no ophthalmic prep

compounded 0.02%-0.03% ophthalmic solution in veg. oil

T lymphocyte suppressor

inhibit lymphokine production and release

use for immune-mediate problems of lids, conj, cornea (KCS, pannus, episcleritis)

KCS common, painful, sight-threatening

post corneal transplantation

Cylosporine

clinical effects

most common tx for KCS

reverses immune-mediated changes to lacrimal gland (eventually)

stimulates tear production (lacrostimulation)-increase tear quantity and quality

reverse inflammatory changes in conj and cornea-slow

legal issues (still under patent), safety issues (gloves, wash hands)

used to stop devastating effects of proteinases (collagenases and gelatinases) on cornea

keratomalacia (melting cornea) commonly caused by infection

No ophthalmic prep

Antiprotease

Drugs

Serum

N-Acetylcysteine

EDTA 1%

Tetracycline

Antiprotease

Serum

Antiproteolitic properties-collagenase and gelatinases

due to presence of macroglobulins

has epitheliotrophic properties

promote corneal healing

Anti protease

N-Acetylcysteine

5%-10%

irritating

lower concentration

no effect on gelatinases

short shelf life

Antiprotease

EDTA

1%

irritating to eye

cheap

limited data on clinical effectiveness

Antiprotease

Tetracycline

concentrates in cornea following topical or systemic admin

chelation

inhibition of gene expression

Autonomic innervation of eye is primarily to iris, ciliary body, upper eyelid and orbital cone

arterioles in uvea

used:

Manipulate pupil

limit aqueous production

facilitate outflow of aqeous

mostly anti-gluacoma drugs

Parasympathomimetics (miotics)

Direct acting

cholinergic

directly stimulate Ach receptor of iris and ciliary body

act at myoneuronal junction (iris sphincter)

causes pupil to constrict (miosis)

produces accommodation, opens drainage angle

dilates blood vessels of conj and iris, increase vascular permeability

stimulates lacrimation

Parasympathomimetics

Inidirect acting

Cholinesterase inhibitors

inhibit hydrolysis of Ach at nerve ending resulting in prolongues presence of neurotransmitter

Direct acting parasympathomimetics

Pilocarpine

muscarinic

0.5-10% solution or ointment

inexpensive

constricts pupil

glaucoma to facilitate outflow

lacrimomimetic

10 minutes to onset, duration 8 hours

Direct acting parasympathomimetics

Pilocarpine

adverse effects

transient stinging

salivation, vomiting, diarrhea

ciliary spasm= "eye ache"

myopia=near sighted

blurred vision

poor dark adaption

bradycardia, hypotension, bronchospasm

Block Ach receptors in iris and ciliary body

Dilate pupil by paralyzing sphincter, dilator is unopposed->mydriasis

ciliary muscle paralysis (cycloplegia)->prevent ciliary muscle spasm induced by uveitis, reduce pain and discomfort

Accomadation is lost due to mydriasis

Parasympatholytics (Mydriatics)

uses

Control miosis cuased by ulcer and uveitis, help with prevention of posterior synechia

reduce pain of smooth muscle spasm in ciliary body and iris caused by corneal ulcers and uveitis

reduce clinical signs of uveitis->reduce vascular permeability

facilitate vision if animal has central corneal opacity or nuclear cataract

Parasympatholytics (Mydriatics)

Atropine

0.5-2% o/s or 1% o/o

inexpensive

onset 30-60 min; recovery 96-120 hr-dog; 60hr-cat

may extend more than 14 days in horse

dose to effect

readily absorved through cornea

affinity for pigmented tissue-iris and ciliary body

Parasympatholytics (Mydriatics)

Atropine adverse effects

affects autonomic nervous system

may cause colic in horses-gut stasis

increased intraocular pressure if narrow angle

blurred vision

dries tears, saliva, gastric secretions

bitter taste causes salivation, nausea (use ointment)

tachycardia

Parasympatholytics (Mydriatics)

Tropicamide

0.5-1% solution

short onset, 15-20 min

duration 3-4 hrs

best mydriatic for eye exam

Carbonic anhydrase inhibitors (CAI)

Anti-glaucoma

topical

block enzyme CA

synergic with Beta blockers

Carbonic anhydrase inhibitors (CAI)

Anti-glaucoma

ophthalmic preps

dorzolamide 2% o/s

Dorzolamide+Timolol o/s

Brinzolamide 1% o/s (doesn't work well in cats)

Prostaglandin analogues

Anti-gluacoma

Reduce IOP by increasing uveoscleral outflow

cause profound miosis

long lasting-usually SID-BID

Prostaglandin analogues

Anti-gluacoma

ophthalmic preps

Latanoprost 0.005% o/s

Travoprost 0.004% o/s