Ophthalmic drugs: What's new?

New ocular pharmacologic agents or new uses for familiar products are discovered every year. This article discusses a select few of these newer therapies in veterinary ophthalmology. For convenience, the medications have been grouped by drug category or ocular disease process.

TEAR SUBSTITUTES (LACRIMOMIMETICS)

While stimulating tear production is the most effective method of treating keratoconjunctivitis sicca (KCS), often an agent is needed to improve lubrication and provide comfort until sufficient tear production is attained. If you have only used petroleum-based artificial tear ointments for your patients with KCS or other tear-film deficiencies, try some of the newer lacrimomimetic tear substitutes. Lacrimomimetic agents are preferred; they have an aqueous base more similar to natural tears than do petroleum-based agents, allowing for improved corneal health and animal comfort. However, owners must be able to apply these agents multiple times a day. Also note that if a lacrimomimetic agent is applied more than six times daily, use preservative-free preparations to avoid corneal epithelial damage. If owners cannot apply medications frequently, the petroleum-based artificial tear ointments remain the best choice, as they coat the cornea and slow tear evaporation.

Many tear substitutes are available over the counter. These products are typically polyvinyl alcohol, cellulose, dextran, or viscoelastic-substance (sodium hyaluronate or chondroitin sulfate) based. Because of the large number of choices, try to recommend specific products to owners. The following three products work well for dogs and cats.

GenTeal

GenTeal (Novartis Ophthalmics) is a cost-effective over-the-counter preparation that contains a small amount of hydrogen peroxide as a preservative. When placed on the eye, the hydrogen peroxide is converted into oxygen and water. GenTeal is sold in multidose vials and is available in gel and liquid formulations. The severe and PF formulations of GenTeal are preferred since they contain the highest concentration of hydroxypropyl methylcellulose (0.3%) and, thus, will remain on the cornea longer.

Lubrithal

Lubrithal (Aventix Animal Health), a veterinary product, is a carbomer gel with sodium hydroxide and benzalkonium chloride as preservatives. The drop is well-tolerated and provides excellent corneal coverage. Lubrithal also comes in a multidose container and is slightly more viscous than GenTeal.

I-Drop Vet

I-Drop Vet and I-Drop Vet Plus (I-MED Pharma) differ from GenTeal and Lubrithal because they contain sodium hyaluronate (hyaluronic acid), which has excellent mucinomimetic properties and is an excellent ocular protectant. I-Drop Vet and I-Drop Vet Plus also contain glycerin to help retain the lubricant and better disperse it after each blink, thus they require less frequent application—twice-daily application may be sufficient.

TEAR STIMULANTS (LACRIMOSTIMULANTS)

Many practitioners are familiar with using cyclosporine (Optimmune—Schering-Plough Animal Health) in dogs to stimulate tear production. The benefit of cyclosporine in patients with kcs stems from its selective t-helper lymphocyte suppression1 and direct lacrimostimulatory properties.2 Because of its selective immunosuppressive properties, cyclosporine is often also beneficial in treating pannus and other immune-mediated corneal disorders.1

If cyclosporine therapy fails in a patient with KCS or the patient is sensitive to cyclosporine or the lipid bases in which it is formulated by a compounding pharmacy, consider using tacrolimus.

Tacrolimus

Tacrolimus is available through compounding pharmacies and should be compounded in a 0.02% ointment or solution. Tacrolimus is similar to cyclosporine in structure and mechanism of action, but few efficacy and safety studies have been performed. In one study, 0.02% tacrolimus administered topically twice daily was effective in increasing tear production in dogs that had never received tear stimulation therapy and in some patients that had responded insufficiently to cyclosporine.3 Since only limited information concerning the efficacy and safety of tacrolimus is available, its use should be reserved for dogs with KCS that are sensitive to or insufficiently respond to cyclosporine.

Pimecrolimus and sirolimus

Two other drugs, pimecrolimus and sirolimus, are under investigation for use as lacrimostimulants.4,5 However, little is known about their clinical efficacy or safety.

TOPICAL ANTIBIOTICS

Although they are not new, you may be unfamiliar with topical fluoroquinolones available for use in people, such as 0.3% ofloxacin, 0.3% norfloxacin, 0.3% gatifloxacin, and 0.3% ciprofloxacin. None of these medications should be used for routine antimicrobial prophylaxis; however, these topical fluoroquinolones can be effective in treating infected corneal ulcers or stromal abscesses, particularly infections involving gram-negative organisms.

To treat these infections, topical fluoroquinolones should be applied six times daily until the infection resolves. Fluoroquinolones are effective against Pseudomonas species and Escherichia coli; Staphylococci species are also often susceptible. Fluoroquinolones are usually not recommended to treat Streptococci species infections because those bacteria demonstrate variable susceptibility to fluoroquinolones. Gatifloxacin, ofloxacin, and ciprofloxacin all penetrate an intact corneal epithelium; however, gatifloxacin offers the best penetration.6-8 The only other topical antibiotic capable of penetrating intact corneal epithelium is chloramphenicol, which is infrequently used because, though rarely, it can cause aplastic anemia in people.

ANTIVIRAL MEDICATIONS

Antivirals that are now available include idoxuridine, trifluridine, cidofovir, famciclovir, and lysine.

Idoxuridine and trifluridine

Idoxuridine and trifluridine are available as topical antiviral drugs. Both are nucleoside analogues, structurally similar to the nucleosides used in viral and host DNA and RNA synthesis. Their substitution into viral DNA disrupts the virus replication cycle.9

Idoxuridine must be compounded and is typically used as a 0.1% solution. One drop is applied four to six times daily for one week past the resolution of clinical signs. While it is fairly efficacious, some irritation (blepharospasm and redness) may be noted.

Trifluridine is available commercially for use in people as a 1% solution. Apply one drop four to six times daily for one week past the resolution of clinical signs. Trifluridine has excellent in vitro activity against feline rhinotracheitis virus (FHV-1) but is often not well-tolerated by patients.9 For example, it may cause ocular irritation and a stinging sensation upon application. Moreover, trifluridine costs about $100 for a 7.5-ml bottle.

With either drug, the required frequent application often leads to poor owner compliance and undue stress for the patient.

Cidofovir

In a 0.5% solution, cidofovir, an acyclic analogue of cytosine,9 decreases clinical signs of FHV-1 infection when administered topically twice daily.10 The drug also causes little irritation.10 The lack of irritation and decreased frequency of administration make compliance much easier than treating with idoxuridine or trifluridine. Cidofovir must be compounded for ophthalmic use.

Famciclovir

Systemic antivirals may be required for animals that resist topical application or for those cats with dermatologic or other systemic signs related to FHV-1 infection. Famciclovir (Famvir—Novartis) is a new oral antiviral medication that shows promise in cats. At a dosage of 90 mg/kg given orally three times a day for 21 days, no signs of toxicosis were reported, and the treated cats had significantly lower clinical disease scores than the untreated cats had.11 Anecdotally, some practitioners are administering 1/8 to ¼ of a 125-mg tablet of famciclovir once daily and seeing an improvement in clinical signs.

Lysine

For cats that suffer frequent bouts of recrudescent disease, lysine may help. While lysine alone will not eliminate a herpesvirus infection, lysine can decrease the severity of clinical signs and increase the time between recurrences.12 Lysine is typically dosed at 250 mg orally twice daily for kittens and lifelong at 500 mg orally twice daily for adult cats. Lysine is safe; however, it should be administered with food since it may induce vomiting if given on an empty stomach.12 Several veterinary and human formulations (e.g. powder, paste, gel, tablet) of lysine are available, and ease of administration should be considered when selecting which formulation to use.

GLAUCOMA MEDICATIONS

Several relatively new topical medications are available to assist in controlling intraocular pressure (IOP) in dogs and cats with glaucoma. While these medications do not cure glaucoma, they do aid in maintaining better control of iop and in preventing IOP increases in the normotensive eye of patients with primary glaucoma.

Topical carbonic anhydrase inhibitors

Topical carbonic anhydrase inhibitors offer the same decreases in IOP that systemic carbonic anhydrase inhibitors such as acetazolamide and methazolamide do but without the systemic side effects. Topically administering 2% dorzolamide (Trusopt—Merck) or 1% brinzolamide (Azopt—Alcon) every eight hours significantly decreases IOP by decreasing the rate of aqueous humor formation.13 Therapy will continue as long as the IOP can be controlled. Many patients with glaucoma undergo enucleation once vision is lost and the IOP cannot be adequately controlled.

The combination of dorzolamide with oral methazolamide does not result in any greater decrease in IOP than administration of either product alone,14 so only administer a topical carbonic anhydrase inhibitor.

Topical beta-blockers

Topical beta-blockers can also be used to decrease aqueous humor production and, thereby, decrease IOP. The two most commonly used beta-blockers in veterinary medicine are 0.5% betaxolol (beta1-selective) and 0.5% timolol (nonselective). These medications may be administered every eight to 12 hours. Since beta-blockers can produce bradycardia and heart block (beta1 effects) and bronchospasm (beta2 effect), use these medications with caution in patients with cardiac or pulmonary disease. Cosopt (Merck) combines dorzolamide and timolol, which may increase ease of administration and, thus, improve owner compliance. Cosopt may be given every eight hours.

Prostaglandin analogues

Prostaglandin analogues, an exciting new drug class for glaucoma therapy, are highly effective ocular hypotensive agents with a rapid onset.15 Prostaglandin analogues decrease IOP by increasing outflow through the uveoscleral or unconventional outflow pathway.16 In my experience, this IOP reduction can occur within 45 to 60 minutes; thus, prostaglandin analogues may replace mannitol as the initial therapy during management of a glaucomatous crisis.

The two prostaglandin analogues with proven comparable efficacy in dogs are latanoprost 0.005% (Xalatan—Pharmacia & Upjohn) and travaprost 0.004% (Travatan—Alcon) ophthalmic solutions.17 An advantage travaprost offers over latanoprost is increased stability over a wide range of temperatures. Prostaglandin analogues cause marked miosis and mild breakdown of the blood-aqueous barrier and result in a low-grade anterior uveitis, so these drugs should be used with caution in patients with secondary glaucoma due to uveitis or lens luxation.

While effective in dogs and horses, prostaglandin analogues have not proved as effective in decreasing IOP in cats.15,18 Prostaglandin analogues are labeled for use in people for administration once a day; however, administration every eight to 12 hours may be required in certain cases to maintain control of the IOP.

SUMMARY

New pharmaceuticals for ophthalmologic problems become available every year. Veterinary ophthalmologists frequently use many of these drugs in referred cases. General practitioners may want to try these medications in their practices as well.

SUGGESTED READING

Veterinary Clinics of North America: Small Animal Practice on Ocular Therapeutics edited by Cecil Moore, DVM, MS, DACVO, May 2004.

Wendy M. Townsend, DVM, MS, DACVO

Department of Small Animal Clinical Sciences

College of Veterinary Medicine

Michigan State University

East Lansing, MI 48824

REFERENCES

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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. Nell B, Walde I, Billich A, et al. The effect of topical pimecrolimus on keratoconjunctivitis sicca and chronic superficial keratitis in dogs: results from an exploratory study. Vet Ophthalmol 2005;8:39-46.

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7. Mather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002;133:463-466.

8. Kern TJ. Antibacterial agents for ocular therapeutics. Vet Clin North Am Small Anim Pract 2004;34:655-668.

9. Galle LE. Antiviral therapy for ocular viral disease. Vet Clin North Am Small Anim Pract 2004;34:639-653.

10. Fontenelle J, Powell C, Gionfriddo J, et al. Effect of topical cidofovir on experimentally induced FHV-1 conjunctivitis (abstract). Vet Ophthalmol 2005;8:444.

11. 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.

12. 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.

13. 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.

14. Gelatt KN, MacKay EO. Changes in intraocular pressure associated with topical dorzolamide and oral methazolamide in glaucomatous dogs. Vet Ophthalmol 2001;4:61-67.

15. 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.

16. Xalatan [package insert]. Pharmacia and Upjohn, Division of Pfizer Inc., New York, NY.

17. 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.

18. 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.