OVERVIEW

I. Therapeutic Formulations of Topical Medications

Drops come as solutions (drug dissolved in solute) or suspensions (drug suspended in solute). Ointments have the drug suspended in an oily base. Temperature and pH determine the stability of the compound. Some ophthalmic preparations need to be refrigerated.

II. Routes of Administration

A. Topical

The concern with topical medications is the ability of the drug to enter the eye. Corneal penetrability is affected by the anatomy of the cornea. The epithelium has a high lipid content, and the stroma has a high water content; therefore, drugs applied to the cornea must have different solubility in water and lipid in order to penetrate. Keratitis (inflammation or ulceration of the cornea) negates the barrier. If a corneal ulcer is present, all topical medications will penetrate. The major limitation is availability of many drugs in topical formulation.

Pulsed delivery is a periodic bolus of a given mass of drug. This can occur anywhere from once daily to every hour. Non-pulsed (continuous) delivery ensures that the drug concentration stays in the therapeutic range. This can be accomplished with the use of a subpalpebral lavage system and continuous infusion pump, or with a collagen shield pre-soaked in medication.

Topical medications come in several formulations. Solutions and suspensions have the following advantages: less vision disturbance; lower incidence of contact dermatitis; less toxic to inside of eye if penetrating injury present; easier for some owners to apply. They also have some disadvantages: very short contact time; diluted if tearing; often more expensive than ointment; suspensions need a lot of shaking; more systemic absorption.

Ointments have the advantages of longer contact time, not diluted by tearing, protect cornea from drying, often less expensive and the disadvantages of adding to the amount of discharge from eye, more difficult for some owners to apply, more contact dermatitis, may interfere with (delay) epithelial wound healing, imprecise dosage.

**Tissues reached by topical route: conjunctiva, cornea, anterior uvea, occasionally lids. Disposition of topical drugs: ocular tissues, nasolacrimal duct, face spillage, systemic absorption

Antibiotics, mydriatics, miotics, anti-glaucoma drugs, and anti-inflammatories are commonly administered topically.

Placement of topical drugs is an important concept. Most containers are multiple use; care must be taken not to touch container tip to hair or cornea. Solutions should be applied so that the drop falls onto the eye rather than have the container held onto the eye and squeezed. The amount of fluid that the ventral fornix (cul-de-sac) can hold is approximately 30 µl; drops from bottle are usually 50 µl. Bottom line: if one drop hits the eye it is more than enough, and 2 drops is excessive, wasteful, and increases the potential of systemic side effects. Ointments--harder to quantify; a 1/8 to 1/4 inch ribbon is adequate for small animals and up to ½ inch for large animals.

About half of a typical drop is spilled from the eye almost immediately due to the small size of the ventral fornix. This overflow accounts for the majority of systemic exposure. The tear volume returns to its normal size 2-5 minutes after drug instillation. Thus, instilling two drugs at intervals less than this will cause the displacement of the first drug by the second. To maximize drug delivery, the interval between drug administration should be 5 minutes.

Increasing the drug concentration and frequency of administration result in increased drug concentrations in the tears. Ointments also prolong tear film MIC levels. Drug concentrations in the superficial cornea are higher than deeper corneal layers. This is ideal for superficial infections. Aqueous humor levels of drugs are reduced by aqueous humor flow. Vitreal drug levels are generally subtherapeutic following topical administration.

B. Subconjunctival

Method--injection under sedation and topical anesthesia; separate lids, tent dorsal conjunctiva, insert 25 gauge needle tangential to plane of eye, inject material, result is bleb. Maximum volumes: 0.5 cc for small animals (dog, cat) and 1 cc for large animals (horse, cow). Not commonly used, but can be used for antibiotics or corticosteroids.

Disposition--soak through sclera (enter iris and ciliary body), or systemic via uveal tract, or regurgitate out needle hole and soak through cornea.

Tissues reached--cornea, anterior uvea, little into vitreous.

Advantages--long duration, higher anterior chamber concentration than topical.

Disadvantages--limited number injections, scar tissue, can't remove once given!

C. Intracameral

Method--injection of drug into eye (aqueous, vitreous); rarely used. Main indication is for intraocular infection. Tremendous drug concentration but most drugs are irritating. Risks include hemorrhage, retinal detachment, cataract, and retinal degeneration.

D. Retrobulbar

Primarily for local anesthetic prior to enucleation.

E. Systemic

Routes--oral, intramuscular, intravenous, subcutaneous. Reaches eye by hematogenous route (vasculature into ciliary body) or secreted into tear film (very low percentage). Ocular inflammation results in breakdown of the blood-aqueous barrier, so systemic drugs will enter the eye.

Tissues reached--posterior segment, optic nerve, lids; +/- uvea; 0% in cornea.

Summary of routes of administration:

SPECIFIC DRUG CLASSES

I. Topical Autonomics

Drugs of the same class or same mechanism of action may have different effects within the eye (therefore different indications) due to differences in corneal penetration and/or receptor binding.

Ocular structures of the autonomic nervous system:

A. Sympathomimetic Drugs

MOA--stimulate adrenergic receptors.

Direct acting drugs, such as epinephrine, are sometimes used to treat glaucoma by decreasing the production of aqueous humor. Epinephrine also helps to control hemorrhage during intraocular surgery. Phenylephrine is used for diagnostic pupil dilation and to localize Horner's syndrome (if the lesion is post-ganglionic lesion, and a drop is placed on both eyes, both pupils will dilate but Horner's eye dilates faster due to denervation hypersensitivity).

Indirect acting drugs include hydroxyamphetamine, which stimulates release of norepinephrine from postganglionic neurons and therefore amplifies the sympathetic response, as well as cocaine, which prevents re-uptake of norepinephrine into postganglionic neurons.

B. Sympatholytic Drugs

MOA--block adrenergic receptors

Examples of topical ophthalmic formulations include timolol maleate (non-selective -blocker), betaxolol (1-blocker), and levobunolol (non-selective -blocker) which are used as anti-glaucoma medications. These medications all decrease aqueous production by the ciliary body epithelium. Not commonly used, but is used for antibiotics, corticosteroids.

C. Parasympathomimetic Drugs

MOA--These drugs work by one of two mechanisms. The direct acting drugs act like acetylcholine. Pilocarpine is used topically for glaucoma (by increasing the outflow of aqueous humor) and also orally to help stimulate tear production in animals with dry eye (keratoconjunctivitis sicca). The indirect acting agents inhibit acetylcholinesterase. Examples include demecarium bromide and echothiophate iodide, both of which increase aqueous humor outflow and help to treat glaucoma.

II. Antibiotics

Basic pharmacology principles apply with ophthalmic antibiotics: you should choose a drug based on culture and sensitivity (C&S), but make a reasonable initial choice based on cytology findings.

There are some unique aspects with ophthalmic antibiotics. With corneal infection, the organism might be sensitive to a drug that C&S predict should not be because of the ability to deliver high drug concentrations to the cornea. Also, many antibiotics are not available in ophthalmic formulation and even if a topical is available, you may want a stronger concentration therefore fortified preparations are made. Because of the unique pharmacokinetics of the ocular tissues, "polypharmacy" is routinely used with drugs that have seemingly conflicting mechanisms of action (e.g., bactericidal and bacteriostatic).

Bacteriocidal agents are best due to rapid washout of drugs by tears and/or aqueous. Aminoglycosides and fluoroquinolones exhibit concentration dependent killing such that drug levels in excess of MIC are desired. These two drug classes also exhibit a post-antibiotic effect of continued suppression of bacterial growth after concentrations fall below the MIC.

Resistance by bacteria to gentamicin and tobramycin are reported in horses, but not in dogs.

Antibiotics can be administered topically, systemically, subconjuctivally, and intracamerally. Topical and systemic are the two most common administration routes, depending on the tissue you are trying to treat.

Table of Antibiotics showing drug, mechanism of action (MOA), main organism spectrum, and if topical, ophthalmic formulations exist.

III. Antifungal Drugs

Topical antifungal drugs are primarily used in this part of the country for horses with fungal corneal infections (ulcers and stromal abscesses). Systemic fungal infections also have ophthalmic signs and antifungal drugs are used systemically. All currently available drugs are fungistatic. Most are irritating/toxic, therefore be sure of your diagnosis. The only approved ophthalmic antifungal drug available commercially is Natacyn® (natamycin).

Table of Antifungals showing drug, mechanism of action (MOA), examples, and if topical, ophthalmic formulations exist.

The polyenes have poor corneal penetration. Natamycin is very expensive, but is the least irritating and least toxic in group. It is available as a 5% suspension or a 1-% ointment, and is a good choice for superficial infections if the owner can afford it. Efficacy is better in some parts of the US than others. Amphotericin B has broad antifungal activity as is made as a 0.15% solution. It does not penetrate the blood-ocular barrier well.

The imidazoles have low toxicity and broad activity; unfortunately they are not available as ophthalmic preparations. Practitioners often use the vaginal preparation of miconazole for equine keratomycosis. Do not use the dermatologic forms, as these contain alcohol which may be very irritating to some horses! Compounding pharmacies can also make itraconazole in DMSO as well as a miconazole solution for patient use.

Dilute betadine (5% povidone iodine) solution has efficacy against fungi. If used, it should only be used once daily and rinsed off well after about 5 minutes as it is very topically irritating.

IV. Antivirals

Ocular viral infections are primarily seen in cats. There are no approved antiviral medications for animal use. The drugs are expensive, irritating, and the effectiveness is not well proven so there is a need to establish diagnosis prior to prescribing. All available drugs are static, so prolonged treatment regimen is needed. The efficacy of topical antivirals against feline herpesvirus is trifluridine > idoxuridine > vidarabine > acyclovir.

Trifluridine (Viroptic®) is a fluorinated pyrimidine nucleoside. It is the most well tolerated of the antivirals by the cat, and is available as a 1% solution. The MOA is unknown, but it does interfere with DNA synthesis in cultured mammalian cells. It is recommended to treat every 2 hours initially, then slowly decrease treatment. If there is no response in 2 weeks, another antiviral should be tried.

Idoxuridine (Herplex®, Stoxil®) is poorly soluble, therefore requires long tissue contact time to be effective. It is available in solution and ointment forms. It is fairly well tolerated, although some will develop severe conjunctivitis. MOA--competes with thymidine for incorporation into viral DNA, thereby producing a defective genome.

Vidarabine or adenine arabinoside (Vira-A®) inhibits viral DNA polymerase. It is poorly soluble, and available as an ointment to be used 5 times daily.

Systemic antivirals do exist (acyclovir, valacyclovir), but have varying efficacy in cats. Systemic interferon may be beneficial in cats that are refractory to other therapies. Alpha-2 interferon (Roferon®) is compounded to 30 units/ml and administered orally once daily for 7 days, off for 7 days, on for 7 days, etc. Oral lysine (250-500 mg by mouth 1-2 times daily) has been shown to decrease viral shedding by antagonizing arginine, which is essential to herpesvirus replication.

V. Corticosteroids

The effects of corticosteroids are: decrease cellular infiltration, inhibit fibroblastic and collagen-forming activity, retard epithelial regeneration, stabilize lysosomes, inhibit arachidonic acid metabolism, and inhibit neovascularization. These effects can be beneficial in some conditions, but devastating and vision threatening if used inappropriately!

Indications for ophthalmic use include inflammatory disorders, immune mediated disorders, and potentially to decrease scar tissue. Contraindications include active infections, corneal ulceration, and undiagnosed ulcer disease. It is considered MALPRACTICE to use corticosteroids on equine corneal ulcers.

Side effects include retardation of corneal epithelialization, activation of latent collagenase, encouragement of infection, as well as systemic side effects (PU/PD, hepatomegaly).

Drug choice, concentration, and frequency of application depend on the severity of the disease process being treated. They can be administered topically, subconjuctivally, retrobulbar, or systemically.

All steroid preparations are not the same! Factors influencing potency in vivo: steroid base (dexamethasone vs. prednisolone), steroid salt (sodium, acetate, phosphate), and corneal penetrability. Availability--acetate penetrates > alcohol preparations > phosphate preps. Activity--a combination of bioavailability and efficacy. Prednisolone acetate 1.0% and dexamethasone 0.1% are good choices for topical administration when high level of corticosteroid activity is desired. Dexamethasone is more potent and longer acting, but does not have as high a degree of penetration as prednisolone acetate. Fluorometholone is very potent but is very short acting and requires frequent administration. Betamethasone is potent and long-acting, but does not penetrate well. Hydrocortisone is substantially less potent than the others, but is frequently used (combination with triple antibiotics for conjunctivitis in dogs).

Topical administration must take into account the tissue you are trying to target. Hydrocortisone works well for lid inflammation, but not for intraocular inflammation. Prednisolone acetate is the drug of choice for uveitis, but is much too powerful for conjunctivitis. Systemic steroids are used to treat posterior segment and optic nerve inflammation as well as immune mediated conditions in many segments of the eye.

Be very careful with subconjunctival dosing. Your diagnosis must be correct before administering because once the dose is placed it is impossible to remove! We advise the It is advise the use of injectable rather than ophthalmic preparations to avoid complications associated with vehicles or preservatives. Repository forms can provide extended drug levels. Triamcinolone may be the drug of choice based on solubility and penetration.

Systemic administration is employed with corticosteroids. Most penetrate the blood-aqueous barrier and are used to treat intraocular inflammations. You must be cautious about using steroids in horses because of the association with laminitis. You must be careful to avoid systemic side effects. In small animals, prednisone is dosed according to the condition being treated (immunosuppressive or anti-inflammatory dose), and an effort is made to taper the dose as soon as possible.

Combination antibiotic/corticosteroid drugs--widely available topical formulations that are frequently misused. Primary use is prior to surgery, to prevent infection while treating inflammatory disease. Disadvantages include altering normal bacterial flora, development of resistant strains of bacteria, and misuse in corneal ulceration.

VI. Nonsteroidal Anti-Inflammatory Drugs

MOA--prostaglandin synthetase inhibition, therefore decrease prostaglandin synthesis.

Indications--uveitis, inflammatory conditions.

Contraindications--use with care if corneal ulceration is present; they can decrease epithelialization.

Topical drugs include flurbiprofen (Ocufen®), suprofen (Profenal®) and diclofenac (Voltaren®).

Systemic drugs include phenylbutazone and flunixin meglumine (Banamine®) for large animals and aspirin, carprofen (Rimadyl®), and etogesic (Etodolac®) for small animal patients.

Precautions: Can cause gastrointestinal ulceration or renal damage if misused. Aspirin can prolong clotting times, and can cause vomition, so use with care post-operatively.

VII. Osmotic Agents

Hyperosmotic agents increase the osmotic pressure of blood plasma relative to the vitreous and aqueous humor, therefore dehydrating the ocular tissues. They are useful to lower intraocular pressure quickly, but not useful on a long-term basis. These are drugs for emergency treatment of glaucoma. Remember that they act on the whole animal, and can cause whole body dehydration. Use with extreme caution in animals with cardiac disease (acute expansion of extracellular fluid volume).

Mannitol--1-2 grams/kg of 20% solution given intravenously SLOWLY (over 15-20 min). Remember to remove water from the animals cage. Do not offer any water for 2-3 hours, then reintroduce water slowly. Make sure your technicians know to take the animal out frequently to urinate. Glycerol--1-2 mg/kg given orally. Acts more slowly than mannitol, and is less effective and less of a diuretic. May induce vomition. DO NOT administer to diabetics.

VIII. Carbonic Anhydrase Inhibitors

Carbonic anhydrase (CA) is the enzyme that causes the following reaction to occur:

CA is present in the ciliary process epithelium of the eye, as well as in the renal cortex, gastric mucosa, pancreas, and central nervous system. Carbonic anhydrase inhibitors (CAI) are used in the treatment of glaucoma, and act by blocking carbonic anhydrase reaction of water and CO₂. They are believed to reduce aqueous formation by causing acidosis of the ciliary body epithelium (a local effect). The diuresis produced does not significantly affect the intraocular pressure.

Side effects include metabolic acidosis, anorexia, vomition in high doses. May cause significant potassium loss.

Systemic drugs: Methazolamide (Neptazane®), Dichlorphenamide (Daranide®), and Acetazolamide (Diamox®) are intermittently available. Acetazolamide causes more side effects than the others, so is used less frequently. Dichlorphenamide causes the fewest side effects in animals, but is currently not on the market.

Topical formulation: 2% dorzolamide (Trusopt®) is a relatively new topical CAI. Fewer side effects due to less systemic absorption. The topical formulation is as effective as the systemic drugs, so there is currently little reason to use systemic CAI's.

IX. Topical Anesthetics

Topical anesthetics work by blocking sodium channels on the membranes of nerve fibers, thus preventing nerve excitation. They have a quick onset (0.5 to 1 minute), and relatively short duration of action (15 minutes (1 drop) to 25 minutes (2 drops) in dogs.

Drugs: Proparacaine--primarily used, and tetracaine (more irritating than proparacaine).

Indications: They are used to facilitate diagnostic procedures (cytology, tonometry).

Contraindications: Potent inhibitors of corneal healing! DO NOT use to treat corneal ulceration, no matter how painful the animal is! Also topical anesthetic should not be applied to the cornea until a sample is obtained for culture and sensitivity as the anesthetics can decrease bacterial load.

X. Anticollagenase Agents

Anticollagenase medications are used to stop the "melting" effect of collagenases and proteases on the corneal stroma. Primary treatment for halting melting process is to stop the underlying cause (usually bacterial infections).

Drugs:

1.  Serum--macroglobulins act as anti-proteases for serine proteases. Inexpensive and readily available. You can use serum from the patient or from another animal of the same species. It must be spun down and kept refrigerated, and is effective for up to 8 days.

2.  Acetylcysteine (Mucomyst®)--dilute to 5% solution as is irritating at full strength. Currently thought to be of questionable benefit in halting melting when caused by an infectious agent, but works against metalloproteinases.

3.  EDTA (0.05%)--reversible, requires frequent applications. Effective against matrix metalloproteinases.

XI. Lacrimomimetics / Tear Replacers

Dry eye (keratoconjunctivitis sicca or KCS) is a very common syndrome in small animals. The goals of therapy are to: 1) stimulate tear production, 2) replace tears, and 3) treat infection.

Cyclosporin 0.2% (Optimmune®)is available for the topical therapy of KCS. Although its direct anti-inflammatory effect is not well established, it has shown great promise as a lacrimomimetic. The mechanism of tear production is related in part to its immunosuppressive activity, as many cases of KCS are immune-related. However, a direct hormonal effect, possibly through its suppression of prolactin, is also proposed. Although very toxic given systemically, the low doses used for topical therapy are quite safe, although caution should be used in ocular viral infections. This is the DRUG OF CHOICE FOR KCS!

Pilocarpine 2%, 2 drops/20 lb BID per os well mixed in the food. Overdose will cause vomition and diarrhea. ONLY USED IF CYCLOSPORIN THERAPY FAILS!!!

Wetting agents--Methylcellulose and polyvinyl alcohol primarily used. To protect corneas from exposure keratitis. Numerous brands available as drops, several as ointments. Make sure to dispense brands with no preservatives.

Hylashield® is a topical drug that contains hylan A which is a viscous substance derived from a natural glycosaminoglycan, hyaluronan. It acts as an "elastoviscous" shield, and adds prolonged relief from ocular surface discomfort.

XII. Mydriatics

MOA--Mydriatics are parasympatholytics that are used for diagnostic purposes as well as to control uveitis and the pain associated with ciliary body muscle spasms. The relaxation of the ciliary body muscle spasms is called cycloplegia. They act by blocking the action of acetylcholine at the motor end plates of the iris sphincter (constrictor) muscle.

Drugs:

1.  Atropine--long acting (days-weeks), bitter taste, used therapeutically for uveitis and to break synechia; 1% and 3% concentrations available. Can decrease tear production in small animals.

2.  Tropicamide (Mydriacyl®)--short acting (4-6 hours); used as a diagnostic tool in the ophthalmic exam. Preferred drug for routine examinations.

3.  Scopolamine--similar to atropine, but shorter duration (days). Sometimes used prior to cataract surgery. Available in combination with phenylephrine (Murocoll®).

4.  Cyclopentolate--similar to atropine, but days of duration. Rarely used.

Summary

Ocular pharmacology is very complex. Many types of infectious and noninfectious diseases affect the eye. Therapy is varied depending on the region of the eye that is diseased, and the desire to suppress inflammation in order to maintain transparency of the various clear ocular structures.

References

1.  Gelatt KN (ed): Veterinary Ophthalmology, 3rd ed., Lippincott, Williams and Wilkins, Philadelphia, 1999.

2.  Leeming JP: Treatment of Ocular Infections with Topical Antibiotics. Clin Pharmcokinet 1999; 37(5): 351-360.