80th Western Veterinary Conference V218 A Top Ten of Newer Ophthalmic Drugs Michael H. Brown, DVM, MS, DACVO Veterinary Ophthalmology Services, Inc Little Falls, NJ, USA OBJECTIVES OF THE PRESENTATION To familiarize the practitioner with several new ophthalmic medications and their indications. GENERAL KEY POINTS There are several new lacrimomimetic, lacrostimulants, topical antibiotics, antiviral medications and glaucoma medications that should be considered when treating certain diseases of the eye. KEY CLINICAL DIAGNOSTIC POINTS In order to determine appropriate therapy for animals with ophthalmic disease, a Schirmer tear test, fluorescein stain and tonometry should be performed in every patient that presents with a “red” eye. KEY THERAPEUTIC POINTS Keratoconjunctivitis Sicca (KCS) (See Figure 1) is treated most effectively by using a topical therapy that stimulates tear production. Most animals will also benefit from topical lubrication agents to improve comfort and maintain corneal health. Lacromimetic agents have the advantage that they have an aqueous base that resembles natural tears more than petroleum-based ointments. GenTeal (Novartis Ophthalmics) is an over-the-counter preparation that contains hydrogen peroxide. When applied to the eye, the hydrogen peroxide is converted into oxygen and water. It is very effective in proving relief to patients with Keratoconjunctivitis Sicca. It is sold in multi-dose vials and is available in liquid and gel preparations. The severe formulation is preferred as is has the highest concentration of hydroxypropyl methylcellulose (0.3%) which increases retention on the corneal surface. Lubrithal (Aventix Animal Health) is a carbomer gel. It is an excellent corneal lubricant and is sold in a multi-dose container. It is slightly more viscous than GenTeal. It is packaged in a 30 gram tube and is well tolerated. I-Drop-Vet and I-Drop-Vet Plus (I-MED Pharma) contains sodium hyaluronate (hyaluronic acid) which affords excellent mucinomimetic properties. It also glycerin to help improve lubrication qualities. This may allow less frequent applications than traditional over-the-counter preparations. Cyclosporine (Optimmune-Schering Plough Animal Health) is a veterinary ophthalmic medication indicated for the treatment of Keratoconjunctivitis Sicca. Cyclosporine stimulates tear production by suppressing T-helper lymphocytes and direct lacrimal stimulation. Cyclosporine is also helpful in the treatment of inflammatory corneal disorders such as pannus and other immune-mediated conditions. Cyclosporine may cause irritation as a topical therapy due to the lipid base composition. Tacrolimus (FK-506, macrolide immunosuppressant)) is a compounded medication also used for the treatment of Keratoconjunctivitis Sicca and inflammatory ocular surface disorders. Tacrolimus is similar to cyclosporine in structure and mechanism of action. It has been used orally, as an immunosuppressant in human organ transplant patients, and topically, for immune-mediated skin condition such as eczema. It is a potent modulator of the immune response to antigens by inhibiting T-lymphocyte activation. The exact mechanism has not been determined. In one study involving 26 dogs with KCS, 96% of the treated eyes improved. Schirmer tear test values increased in 92% of eyes. Ocular irritation appears to be less than cyclosporine. In some patients where cyclosporine was not effective. Tacrolimus was effective in improving clinical signs associated with KCS. Newer generations of fluoroquinolones are available for use in animals with infectious ocular disease (0.3% ofloxacin, 0.3% norfloxacin, 0.3% gatifloxacin and 0.3% ciprofloxacin). These ophthalmic antibiotics should not be used for routine ophthalmic disease as susceptible flora may become resistant. Their use should be reserved for persistent infectious conditions (melting/infected corneal ulcer, stromal ulcer). (See Figure 2) They are very effective in treating infections caused by gram-negative organisms. They are typically applied 4–6 times daily. Fluoroquinolones are effective in treating conditions involving Pseudomonas species, Escherichia coli and Staphylococcus species. Fluoroquinolones have variable effectiveness in treating condition caused by Streptococcus species. They have an advantage over other topical antibiotics in that they penetrate the intact corneal epithelium. Gatifloxacin offers the best corneal penetration. Fluoroquinolones are more expensive than traditional topical antibiotics. There are several antiviral medications (idoxuridine, trifluridine, cidofovir, famciclovir and lysine) available to treat feline herpes virus. (See Figure 3) Idoxuridine and trifluridine are topical antiviral drugs that are nucleoside analogues, similar to the nucleosides used in viral and host DNA and RNA synthesis. They substitute into viral DNA to disrupt virus replication cycle. Both medications may be cause irritation when applied topically. Idoxuridine is a compounded medication whereas trifluridine a commercially available medication. Both medications are applied 3–4 times daily. Cidofovir is a compounded 0.5% solution applied topically to treat feline herpes infections. It decreases clinical signs of feline herpes infection as it is an acyclic analogue of cytosine. It is applied twice daily and causes less irritation than trifluridine and idoxuridine. Famciclovir (Famvir-Novartis) is a systemic antiviral medication used to treat cats with severe cases of feline herpes infection. Cats dosed at 90 mg/kg orally three times daily for 21 days did not exhibit signs of toxicity and clinical signs of herpes infection improved. Clinically, cats often improve with doses as small as 1/8 to ¼ of a 125 mg tablet once daily. For more severe infections in adult cats, 250 mg by mouth twice daily for 10 days may be effective. Lysine is used as adjunctive therapy to treat feline herpes. It can decrease the severity of clinical signs and increase the time between recurrences. Alone, it not an effective treatment for feline herpes. Lysine is dosed at 250 mg orally twice daily for kittens and 500 mg twice daily in adult cats. Lysine may cause vomiting and is formulated as a large tablet. Newer veterinary and human formulations are available that are easier to administer than tablets. Viralys Gel, Viralys Powder and Enisyl F are examples of such products. The introduction of newer glaucoma medications has improved the management of glaucoma in the veterinary patient. (See Figure 4) As there is no cure for glaucoma, newer topical medications are critical to control the intraocular pressure. Carbonic anhydrase inhibitors (methazolamide, acetazolamide) are used to decrease aqueous humor production. They are available as oral and topical medications for the treatment of glaucoma. Topical carbonic anhydrase inhibitors have the advantage of causing fewer side effects than the systemic medication. Two percent dorzolamide (Trusopt-Merck) or 1% brinzolamide (Azopt-Alson) three times daily significantly decrease the rate of aqueous humor production. The combination of oral and topical carbonic anhydrase inhibitors is not more effective than topical therapy alone for the treatment of glaucoma. Cosopt (Merck) combines dorzolamide and timolol (0.5%) as a topical anti-glaucoma therapy. It is applied every eight hours. The main disadvantage of this medication is increased expense. Prostaglandin analogues are a new drug class for the treatment of glaucoma. They are the most effective ocular hypotensive agents as they decrease the intraocular pressure by increasing uveoscleral outflow. The clinical efficacy of these medications may be noted in 60 minutes. Latanoprost 0.005% (Xalatan-Pharmacia & Upjohn) and travoprost 0.004% (Travatan-Alcon) are two prostaglandin analogues that have been studies for the treatment of glaucoma in dogs. These medications cause marked miosis and mild clinical signs of anterior uveitis as mild breakdown of the blood-aqueous barrier occurs. These medications should not be used in animals with secondary glaucoma, severe uveitis or anterior lens luxation. Figure 1. Canine patient with clinical signs of keratoconjunctivitis sicca (conjunctival hyperemia, seromucoid ocular discharge, blepharospasm). Figure 2. Infected corneal ulcer in a dog. Note the large fluorescein-positive area outlined by the white arrows. Corneal edema, deep limbal vascularization and malacia are present. Figure 3. Feline herpetic conjunctivitis. Severe chemosis and conjunctival hyperemia are present. Figure 4. Acute congestive glaucoma in the canine patient. Note the ciliary injected, diffuse corneal edema, elevated nictitans and dilated pupil. OVERVIEW OF THE ISSUE Over the past several years, many new medications have been introduced to treat various ocular diseases in animals. The practitioner should become familiar with their clinical indications as they may greatly improve the response to treatment. In some cases, the new medication may make the difference between saving the eye and enucleation. KEY DRUGS, DOSAGES AND INDICATIONS Key Drug Drug Class Dose Frequency Route Indications Range Lysine Nutritional 500 mg BID PO Adjunct for feline herpes supplement Famciclovir* Antiviral 250 mg BID x 10 PO Feline herpes (severe days conjunctivitis, keratitis) * Extra-label use, dose recommended based upon personal communication. SUMMARY Veterinarians should become familiar with the numerous newer ophthalmic medications available to treat conditions from dry eye, feline herpes, glaucoma and infectious ocular disease. Advancement in pharmaceutical technology continues to improve the clinical efficacy of ophthalmic medications. For animals with KCS, one should consider adjunct therapy by prescribing one of several improved topical lubricants to improve patient comfort. Tacrolimus may be used in place of cyclosporine to help stimulate tear production. For feline herpes, the clinician should consider topical antiviral and oral nutritional supplements. The newer fluoroquinolones are very effective for the treatment of infectious corneal disease in animals. In patients with glaucoma, consider topical prostaglandin analogues therapy for rapid and effective IOP control. REFERENCES 1. Veterinary Clinics of North America: Small Animal Practice on Ocular Therapeutics edited by Cecil Moore, DVM, MS, DACVO May 2004. 2. Kaswan RL, Salisbury MA, Ward DA. Spontaneous canine keratoconjunctivitis sicca. A useful model for human keratoconjunctivitis sicca: treatment with cyclosporine eye drops. Arch Ophthalmol 1989;107:1210–1216. 3. Berdoulay A, English RV, Nadelstein B. Effect of topical 0.02% tacrolimus aqueous suspension on tear production in dogs with keratoconjunctivitis sicca. Vet Ophthalmol 2005;8:225–232. 4. Grahn BH, Storey ES. Lacrimostimulants and lacrimomimetics. Vet Clin North Am Small Anim Pract 2004;34:739– 753. 5. Kern TJ. Antibacterial agents for ocular therapeutics. Vet Clin North Am Small Anim Pract 2004;34:655–668. 6. Galle LE. Antiviral therapy for ocular viral disease. Vet Clin North Am Small Anim Pract 2004;34:639–653. 7. Fontenelle J, Powell C, Gionfriddo J, et al. Effect of topical cidofovir on experimentally induced FHV–1 conjunctivitis (abstract). Vet Ophthalmol 2005;8:444. 8. Thomasy S, Maggs D, Lim C, et al. Safety and efficacy of famciclovir in cats infected with feline herpesvirus 1, in Proceedings. 37th Annu Conf Am Coll Vet Ophthalmol 2006;43. 9. Stiles J, Townsend WM, Rogers QR, et al. Effect of oral administration of L-lysine on conjunctivitis caused by feline herpesvirus in cats. Am J Vet Res 2002;63:99–103. 10. King TC, Gum GG, Gelatt KN. Evaluation of a topically administered carbonic anhydrase inhibitor (MK-927) in normotensive and glaucomatous beagles. Am J Vet Res 1991;52:2067–2070. 11. Gelatt KN, MacKay EO. Changes in intraocular pressure associated with topical dorzolamide and oral methazolamide in glaucomatous dogs. Vet Ophthalmol 2001;4:61–67. 12. Studer ME, Martin CL, Stiles J. Effects of 0.005% latanoprost solution on intraocular pressure in healthy dogs and cats. Am J Vet Res 2000;61:1220–1224. 13. Xalatan [package insert]. Pharmacia and Upjohn, Division of Pfizer Inc., New York, NY. 14. Carvalho AB, Laus JL, Costa VP, et al. Effects of travoprost 0.004% compared with latanoprost 0.005% on the intraocular pressure of normal dogs. Vet Ophthalmol 2006;9:121–125. 15. Willis AM, Diehl KA, Hoshaw-Woodard S, et al. Effects of topical administration of 0.005% latanoprost solution on eyes of clinically normal horses. Am J Vet Res 2001;62:1945–1951.