A Practical Guide to Veterinary Ophthalmic Pharmacology for General Practitioners

Ophthalmic disease accounts for an estimated 10.5% of general practitioners’ caseload.¹ Ocular medications face unique delivery challenges—tears rapidly dilute drugs, drainage down the nasolacrimal duct reduces contact time, and the hydrophobic corneal epithelium limits penetration—all of which necessitate more frequent application than systemic or topical dermal medications.^2,3 Higher-viscosity formulations (e.g., ointments, gels) are retained longer on the ocular surface and should be used when possible to improve drug absorption.^2,3 Systemic absorption through the nasal (and oral) mucosa may cause adverse effects and should be considered with respect to patient size and the medications administered.³ Adverse events and timely response to therapy should be considered for referral to a veterinary ophthalmologist (TABLE 1).

Commonly managed diseases include dry eye disease (DED), glaucoma, uveitis, and corneal ulcers, each of which cause discomfort and require early treatment to prevent disease progression and blindness. This guide provides practical, first-line recommendations for the 4 ophthalmic conditions most commonly encountered in general practice.

Dry Eye Disease

DED includes disorders of tear quantity and quality. The most commonly diagnosed form of DED, aqueous-deficient DED (also known as keratoconjunctivitis sicca [KCS] or quantitative dry eye), reflects inadequate aqueous tear production and is confirmed by a low Schirmer tear test and concurrent clinical signs.⁴ Qualitative dry eye (also known as evaporative DED) is defined by insufficient production of the lipid or mucous layer of the tear film.⁴ Early management is recommended to limit the progression of chronic sequelae from DED. Immune-mediated gland destruction is the predominant cause and may require lifelong management.^4,5

Treatment Options

Ocular Lubricants

Lubricants provide comfort and a healthier environment for the cornea. Not all formulations are equal; highly viscous products (ointments and gels) have more prolonged corneal retention than aqueous solutions.⁶ Typical frequency for ointment or gel application is every 4 to 8 hours, whereas, for similar effectiveness, aqueous drops should be applied every 1 to 2 hours. Product selection can also be guided by client and patient compliance (e.g., different bottle/tube preferences, ease of administration). Patients with qualitative tear deficiency benefit from lubricants with hyaluronic acid, which promote tear film stability.^7,8 Although beneficial in the management of DED, lubricants do not increase tear production and should be used alongside tear stimulants.

Tear Stimulants

Cyclosporin A and tacrolimus block T-cell activation, thereby reducing immune-mediated lacrimal gland destruction and increasing tear production over time.³ They have also been shown to help promote tear film stability in dogs with qualitative dry eye.⁸ When applied topically, they reach therapeutic concentrations in the cornea, conjunctiva, sclera, and lacrimal tissues but have limited intraocular penetration due to their hydrophobic nature.^3,9 Use of these medications is often required for life, and therapy may need to be escalated because the disease may become refractory to treatment.

An appropriate starting point for managing DED is use of 0.2% cyclosporine ointment (Optimmune, Merck Animal Health), which is the only FDA-approved preparation and is formulated to improve drug absorption.¹⁰ Higher concentrations may be compounded (0.5% to 2%) and may be more effective for refractory cases, although side-to-side comparison has not been investigated.^10-12

Compounded tacrolimus (0.02% to 1%) is approximately 100 times more potent by weight than cyclosporine^10,13 and is especially useful for patients with severe DED or significant corneal pigmentation because it has been shown to reduce corneal pigmentation, a common sequela of DED.¹⁴

It is recommended to use a reputable compounding pharmacy that specializes in veterinary ophthalmic medications and follow their instructions on best vehicles, storage, and application practices. Drugs can be compounded into oils, aqueous suspension, or ointments; however, the different formulations have pros and cons that may affect your patient. Because of their mechanism of action, tear stimulants may take 4 to 6 weeks to take effect.³ Thus, it is recommended to reassess clinical signs and conduct Schirmer tear testing at 6 weeks to determine if medications may need to be changed or concentrations increased. Typical dosing frequency is every 8 to 12 hours.

Compounding pharmacies can formulate ophthalmic cyclosporine and tacrolimus together into a combined suspension, but to the authors’ knowledge, no studies have evaluated the efficacy or safety of these medications in patients. Furthermore, because their mechanisms of action have a common final pathway, their effects are unlikely to be additive.

Topical Anti-Inflammatory Medications

Proper treatment of DED with tear stimulants (topical immunosuppressants) and lubricants should be sufficient to dramatically improve the secondary keratitis and discomfort associated with the disease. However, on a case-by-case basis, additional anti-inflammatory medications can be helpful.¹⁰ Short-term topical corticosteroid use may help with significant keratitis or granulation tissue but must be avoided in cases of active corneal ulcers due to the risk for infection.¹⁰ Topical NSAIDs are an alternative that may be safer for patients that are at high risk for corneal ulcers or would benefit from long-term use due to persistent keratitis.³ The most commonly used NSAIDs are ketorolac, diclofenac, and flurbiprofen. However, chronic, high-frequency use of topical NSAIDs is associated with some risk for gastrointestinal ulcers, and ketorolac in particular has been shown to lead to the most severe lesions.^15,16 Thus, diclofenac or flurbiprofen should be considered over ketorolac, the least amount necessary should be used (usually twice-daily administration is sufficient), and the patient should be monitored for systemic signs of gastric ulcers.

Glaucoma

Glaucoma affects an estimated 1% to 2% of dogs and results in irreversible damage to the retina and optic nerve. Preserving vision requires rapid reduction of intraocular pressure (IOP).¹⁷ Primary glaucoma should be managed differently from secondary glaucoma because it is inherently bilateral and prophylactic medications can delay onset in the contralateral eye (BOX 1). In addition, secondary glaucoma requires identification and treatment of the underlying cause. Management typically consists of administering medications every 8 to 12 hours, often using multiple agents because they act through different mechanisms.^3,18 Treatment is lifelong, continuing until the eye becomes end stage or enucleation is elected.

Treatment Options

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs) are frequently used for long-term management of glaucoma. Through competitive binding and subsequent inactivation of carbonic anhydrase, CAIs reduce aqueous humor production by an average of 43%.³ As monotherapy, they are more effective than β-blockers.¹⁹ Although systemic effects (e.g., hyperkalemia, metabolic acidosis) are rare,20 local reactions to CAIs (e.g., blepharitis, keratitis) have been more frequently noted.¹⁹ In veterinary medicine, the most commonly prescribed CAI is dorzolamide due to its lower price; however, brinzolamide is associated with less stinging at application.^21,22 CAIs are effective for emergency reduction of IOP and for long-term use in patients with glaucoma. Dorzolamide efficacy peaks 2 hours after administration and is lowest at 8 hours after administration.²³

β-Blockers

Although the exact mechanism of action is uncertain, topical β-blockers reduce IOP by decreasing aqueous humor production.³ By far the most common ophthalmic β-blocker is timolol due to its low price. β-Blockers are used primarily in combination with topical CAIs; when used alone in dogs, they result in only mild IOP reduction (≤ 5 mm Hg^24-26). Because topical β-blockers can cause bradycardia²⁷ and bronchoconstriction,²¹ they should be avoided in animals with bradyarrhythmias and cats with feline lower respiratory tract disease. They should be used with caution in patients weighing less than 10 kg (22 lb) because systemic absorption is proportionally more significant on a mg/kg basis in smaller patients.²⁸

Prostaglandin Analogues

The most potent topical antiglaucoma medications for dogs are prostaglandin analogues (PGAs). They are highly effective for emergency IOP reduction, onset of action is within approximately 20 minutes, and they are useful for long-term management of primary glaucoma.³ PGAs work by increasing aqueous outflow through the uveoscleral pathway.²⁹ In veterinary medicine, the most widely used PGA is latanoprost due to its low price, although tafluprost, travoprost, and bimatoprost have also been shown to be effective in dogs.²⁸

PGAs cause marked miosis in dogs, and to a lesser extent in cats, due to the high density of PGF2α receptors on the canine iris sphincter muscle. This pharmacologic effect can be detrimental for patients with uveitis because miosis increases the risk for synechia formation and pupillary block.²¹ PGAs should also be avoided in cases of anterior lens luxation until the lens has been repositioned posterior to the iris because when the lens is anterior to the iris, miosis may lead to lens entrapment and pupillary block with subsequent further IOP elevation.²⁹ Conversely, when the lens is luxated but remains posterior to the pupil, PGAs are used to maintain miosis and trap the mobile lens in the posterior segment. In cats, the IOP-lowering response to PGAs is variable.^21,29

Uveitis

Uveitis has many potential causes, including ocular (e.g., trauma, lens-induced uveitis, reflex uveitis from an infected ulcer) and endogenous (e.g., systemic fungal infection, viral infection, neoplasia, immune-mediated inflammation).^29-31 Since approximately 50% of endogenous cases have an identifiable systemic cause, diagnostic workup is essential.³¹ Uveitis is typically controlled by anti-inflammatories administered every 6 to 12 hours, depending on severity,³⁰ but often requires a protracted course of treatment tapered over several months.

Treatment Options

Corticosteroids

For patients with active uveitis, the best initial treatment is corticosteroids, which are extremely effective at decreasing intraocular inflammation.³ Prednisolone acetate and dexamethasone alcohol (as seen in neomycin–polymyxin B–dexamethasone formulations) achieve adequate therapeutic levels in the anterior chamber.³⁰ However, dexamethasone sodium phosphate ophthalmic drops do not achieve adequate therapeutic levels in the anterior chamber because the salt formulation does not allow sufficient penetration through the cornea.³ Topical administration is typically preferred over systemic administration of steroids for patients with anterior uveitis due to decreased systemic effects. Although some systemic absorption of topical prednisolone acetate and dexamethasone can be observed, the effects of short-term use are minimal.^3,30,32 Systemic corticosteroids are indicated for patients with posterior segment involvement because topical drops do not achieve therapeutic levels in the posterior segment.^3,30,32 Because systemic steroids are almost always contraindicated for patients with systemic diabetes mellitus or hyperadrenocorticism, consultation with an ophthalmologist and/or internist is advised for those cases.

Ultimately, topical and systemic corticosteroids are not ideal for long-term use due to their adverse effects.^3,30 Slow tapering (over weeks) is recommended after active signs of uveitis have resolved or are minimal.³⁰ During tapering, initiation of therapy with NSAIDs is often recommended if long-term management is deemed necessary (i.e., recurrent or persistent immune-mediated or idiopathic uveitis).³⁰ An example of a common tapering schedule for corticosteroids is as follows: q6h administration for 2 weeks, q8h for 2 weeks, q12h for 2 weeks, then q24h for 2 weeks plus addition of a topical NSAID q12h if indicated for long-term control. Medication tapering should be tailored to an individual’s clinical response to therapy and altered if any complications are experienced.

NSAIDs

Topical NSAIDs are useful for long-term management in patients with conditions that lead to anterior uveitis (e.g., advanced cataracts). Their use is also valuable during and after tapering of topical corticosteroids.³⁰ However, topical ketorolac should be used with caution or avoided as it is associated with increased gastrointestinal ulceration compared with other NSAIDs evaluated for chronic, frequent use in dogs.^15,33 Systemic NSAIDs may also be used as adjunctive therapy for anterior uveitis or when corticosteroids are contraindicated.³⁰

Cycloplegics

Atropine, the most commonly administered cycloplegic, provides pain relief via ciliary muscle paralysis and reduces synechia formation, in turn reducing the risk for secondary glaucoma.^30,34 Atropine is typically administered every 12 to 24 hours for treatment of acute uveitis.³⁰ An alternative and less expensive cycloplegic is cyclopentolate. Studies have determined that dogs reach maximal pupil dilation at 12 hours and retain some dilation until 72 hours, a duration similar to that of atropine. However, compared with atropine there are fewer data on cyclopentolate’s analgesic efficacy and side effects.^3,35,36 Cycloplegics should be avoided in patients with preexisting glaucoma.³

Corneal Ulcers

A corneal ulcer is a wound of the corneal epithelium but may involve the corneal stroma if infected.³⁷ Antibiotic therapy should be initiated at the time of diagnosis.³ On the basis of severity, adjunctive therapy may also be required. Corneal ulcers typically require short-term therapy and do not require treatment tapering.

Treatment Options

Antibiotics

Although superficial corneal ulcers can be empirically treated with broad-spectrum antibiotics, infected ulcers should be treated according to results of cytology and culture.³ Antibiotic choices should also be species specific, and treatment frequency should be guided by ulcer classification (TABLE 2). Simple and indolent ulcers should be treated every 6 to 8 hours for prophylaxis against infection. Infected ulcers should be treated every 1 to 4 hours until resolution of infection, then every 6 hours thereafter.

Adjunct Medical Therapy

Corneal ulcers are painful; therefore, appropriate analgesic therapeutics should be administered.³⁷ Although use of topical medications to limit systemic effects is recommended for most ophthalmic cases, analgesia for corneal ulcers often requires systemic therapy.³ Topical corticosteroids and NSAIDs can delay corneal healing, and topical corticosteroids can predispose the cornea to infection.³⁰ Thus, oral analgesics, such as NSAIDs, are often indicated for patients with corneal ulcers^37,42 Depending on the patient’s temperament, oral anxiolytics (e.g., gabapentin, trazodone) may also be indicated to decrease risk for self-trauma and improve compliance with medication administration.

Although uncomplicated corneal ulcers may not require therapy beyond topical antibiotics and systemic analgesics, treatment regimens for complicated ulcers are more complex. For example, as a common sequela to acute and complicated corneal ulcers, reflex uveitis may be present. In patients with moderate to marked reflex uveitis, topical cycloplegics should be administered for analgesia and prevention of posterior synechia.

Indolent ulcers, a specific type of nonhealing noninfected superficial ulcer, require prolonged therapy as they are slow to heal; however, oxytetracycline and bandage contact lenses have been shown to shorten the time required to heal indolent ulcers.³⁹

Deep corneal ulcers often require additional therapeutics to prevent keratomalacia, for which several preventive therapeutics are available (e.g., topical serum, plasma).^43,44 Oral antibiotics are indicated for deep corneal ulcers or corneal ruptures, and some studies show that oral tetracyclines may help reduce risk for keratomalacia.⁴⁵ Amnion eye drops have more recently been incorporated into topical treatment protocols due to their antiprotease and antifibrotic properties that help support healing of complicated corneal ulcers.⁴⁴ In addition, cross-linked modified hyaluronic acid gels (e.g., Dômes Pharma Oculenis BioHAnce Ocular Repair Gel) have been shown to accelerate healing of acute stromal ulcers.⁴⁶ However, multimodal treatment is best as there is no single drop that reliably heals complicated infected corneal ulcers; referral is often recommended as these cases can progress rapidly and ultimately require surgical intervention.

Summary

There are many things to consider when choosing a topical ophthalmic drug for veterinary patients (TABLE 3). In addition to the condition being treated, other factors to consider include severity of disease, delivery challenges, systemic absorption, and client and patient compliance with administration. For most conditions, failure to respond to appropriate topical therapy within an appropriate time frame requires urgent referral of the patient to a veterinary ophthalmologist.