New Drugs for Small Animal Ophthalmology
Kirk N. Gelatt, VMD, Dipl ACVO
University of Florida
Gainesville, FL, USA
I. Routes of administration
Most drugs are administered for ophthalmic disorders topically. However, the topical route often needs supplementation to be effective. More recently, enhancement methods include the injection of drugs intraocularly and implants that slowly release drugs for weeks to months. Other methods include: (a) more concentrated solutions (watch for local toxicity); (b) soft contact/collagen lens/shields (give initial 'burst' of drug release); (c) tarsorrhaphy (if temporary and complete can maintain drugs in longer corneal contact; drug loss is via the nasolacrimal drainage system), and (d) subpalpebral lavage (quite effective when combined with E-collar and temporary and complete tarsorrhaphy in small animals)
In veterinary ophthalmology antibiotics are administered to prevent infection as well as treat infection. Most antibiotics do not penetrate the normal cornea very well. Tetracyclines are bacteriostatic and broad spectrum. They are particularly useful in cats for mycoplasma and chlamydia infections, and systemically for the rickettsial infections. Chloramphenicol is still a useful antibiotic in veterinary ophthalmology that is broad spectrum, bacteriostatic, and penetrates corneal well. The aminoglycosides are bacteriocidal, fairly broad-spectrum antibiotics, especially against gram negative bacteria, and includes neomycin, gentamicin (especially good against Pseudomonas melting ulcers), but penetrate intact epithelium poorly. May delay corneal healing. Also includes tobramycin/amikacin. The peptide antibiotics-gramicidin, bacitracin, polymyxin B are bacteriocidal, and for topical use. Lastly, the fluoroquinolones (topical ciprofloxin and ofloxacin) may be used in small animals, are quite expensive, and often have efficacy against Pseudomonas.
III. Antifungal drugs
All currently available drugs are fungistatic. Mycotic (fungal) corneal infections are primarily seen in equine but occur in small animals (often secondary to a corneal foreign body). Topical Natacyn (Natamycin) is very expensive, least irritating and least toxic in group. Available as a 5% suspension or a 1% ointment. Systemic use in dogs with systemic mycosis includes: ketoconazole (10-20 mg/kg every 24 hrs for 60 to 90 days; or itraconazole (5 mg/kg twice a day for 60 days).
IV. Antiviral drugs
Ocular viral infections are primarily seen in the feline. Agents include: (1) Trifluorothymidine (Viroptic-Burroughs-Wellcome) - Best tolerated, only available as a solution. First choice for FHV-1 infections in cats. Acts by incorporating into the viral DNA, producing DNA that is too small. (2) Idoxuridine-poorly soluble, therefore requires long tissue contact time to be effective. Fairly well tolerated, although some will develop severe conjunctivitis. Available as solution and ointment. Acts by stopping viral replication-drug is incorporated into the viral DN. And (3) Adenine arabinoside (Vira-A- Parke-Davis)- 3% ointment. Use 5 times daily.
V. Anti-inflammatory drugs
Decrease cellular infiltration, inhibit fibroblastic and collagen-forming activity, retard epithelial regeneration, diminish neovascularization, and stabilize lysosomes. In man can cause cataracts and glaucoma. In the glaucoma Beagle topical 0.1 dexamethasone q 8 h can increase IOP (5-10 mm Hg) within 2 weeks. In normal cats topical prednisolone and dexamethasone cause posterior cataracts within 4 to 6 weeks. Topical application can cause systemic side effects. Prednisolone acetate 1.0% and dexamethasone 0.1% are the best choices for corneal and anterior uveal diseases. Most systemic steroids penetrate the blood-aqueous barrier and are used to treat intraocular inflammations. Anti-inflammatory oral prednisolone doses are 0.5 to 1.0 mg/kg once daily (dog) and 0.5 to 2.0 mg/kg once daily (cat); the immunosuppressant oral prednisolone doses are 2.2 mg/kg once daily (dog), and 2.2 to 6.6 mg/kg once daily (cat).
B. Nonsteroidal anti-inflammatory drugs
Include the prostaglandin synthetase inhibitors and are used as steroid substitutes. Systemic use can cause gastrointestinal ulceration, and renal damage. Topically may slow corneal epithelization and corneal vascularization. Systemic preparations include: (1) flunixin meglumine (Banamine) is effective in reducing protein content in the aqueous, and high cost. Use short term to avoid side effects. Used perioperatively for intraocular surgery. (2) carprofen (Rimadyl- PO) is approved for dogs PO.(3) Indomethacin (Indocin)-an anti-rheumatic drug not used frequently in ophthalmic conditions, but has been used for non-granulomatous uveitis associated with immune-mediated disease in man. Topical ophthalmic agents include: flurbiprofen (Ocufen) and suprofen (Profenal).By reducing prostaglandin synthesis, they can be used alone or with steroids to reduce inflammation, and also to enhance mydriasis by reducing miosis mediated by inflammatory products. Generally, the nonsteroidals are reasonable substitutes for the corticosteroids, but are less effective.
We still have the same mydriatics; those used most frequently include the parasympatholytics-atropine, scopolamine, and tropicamide. Used for control of uveitis, and for relief of ocular pain associated with inflammation. They can decrease significantly tear production. The sympathomimetics moderately dilate the pupil by stimulation of the iridal dilator musculature; most often used is 10% phenylephrine.
The parasympathomimetic miotics are divided into two groups: direct (mimic acetylcholine at the motor-end plates) and anticholinesterase (block cholinesterase, therefore prolonging the action of acetylcholine). All are miotics and affect the trabecular meshwork to improve aqueous humor outflow, therefore, are very useful in the treatment of many forms of the glaucomas. No new miotics have been introduced in the last 20 years. Those used most frequently include: pilocarpine, and demecarium.
The sympathomimetics mainly include 2.5% phenylephrine(for diagnosis of Horner's syndrome)and the 10% concentration as a moderate or additive mydriatic.
Sympatholytics consists of beta-adrenergic blockers (timolol, betaxolol, etc), and alpha agonists. A major drug class for the control of glaucoma in people, but of less proven benefit in domestic species. Also, alpha agonists are available to reduce IOP with limited IOP effects in dogs and side effects in cats (usually emesis).
Introduced as new glaucoma agents to lower IOP a few years ago. Effectiveness is somewhat dependent of specific animal species prostaglandin receptors, and drug concentration. The dog has primarily PG- F- receptors; the cat has mainly PG- A receptors. Available agents include latanoprost, bimatoprost, and travoprost. Can cause profound reduction in IOP and variable miosis.
IX. Carbonic anhydrase inhibitors
Carbonic anhydrase inhibitors are used in the treatment of the glaucomas, and act by blocking the enzyme, carbonic anhydrase, within the nonpigmented ciliary body epithelium reducing the rate of aqueous formation. Systemic preparations include acetylzolamide, dichlorphenamide, methazolamide, and ethoxzolamide. The systemic agents are being gradually replaced with topical agents that have very low frequency of side effects. New topical CAIs -2% dorzolamide (Merck) and 1% brinzolamide (Alcon) are now available.
X. Hyperosmotic agents
IV mannitol (1-2 gm/kg) reduces IOP within in 1 hr, and is maximum in 4 to 6 hrs. IOP can return to pre-drug (or even rebound) levels within 8 to 10 hrs.
XI. Topical anesthetics
Topical anesthetics (proparacaine and tetracaine) are used to facilitate diagnostic procedures. Can cause local irritation (conjunctival hyperemia and chemosis), and corneal epithelial toxicity. Also reduce tear production by about 50%.
XIII. Lacrimomimetics and tear substitutes include
(1) cyclosporine 0.2% (Optimmune)is available for the topical therapy of keratitis, uveitis, plasma cell infiltration of the nictitans, and KCS; and oral pilocarpine-2%, 2 drops/10 kg q 12 h per os well mixed in the food. Overdose will cause vomition and diarrhea. The tear substitutes use wetting agents (methylcellulose and polyvinyl alcohol) to prolong corneoconjunctival contact. Numerous brands available as drops, several as ointments.
XIV. Other drugs
1. Ophthalmic adhesives: polycyanoacrylates primarily used. Multiple uses, primarily for corneal stromal ulcers and refractive erosions in animals. Must apply very small amount and 'dry' cornea defect. Glue will slough within 1 to 3 weeks; causes variable corneal inflammation and vascularization.
2. Anticollagenase drugs used to stop "melting" effect of collagenases and proteases in cornea ulcerations. Primary treatment for halting the melting process is to stop the underlying cause (usually bacterial infections). These agents supplement the antibiotics to decrease the 'melting process.'
a. Acetylcysteine (Mucomyst: dilute to a 5% solution). Works against metalloproteinases.
b. EDTA-reversible, requires frequent applications; and (3) Serum-alpha macroglobulins act as anti-proteases for serine proteases.
3. Antifibrin agents: Used to either prevent formation of anterior chamber fibrin (must be at levels that do not impair blood clotting mechanisms)using intraocular surgeries, or enzymatic 'digest' the fibrin in recent hyphema without causing secondary hemorrhages.
a. Heparin (primarily used at 1-2 units/ml for intraocular surgery). Used to prevent formation of fibrin.
b. TPA (tissue plasminogen activator) 25-50 Fg injections intracamerally. Used to dissolve anterior chamber fibrin of 10-14 days duration or less.
Kirk N. Gelatt, VMD, Dipl ACVO