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OCULAR PHARMACOLOGY Tom Miller DVM, MS, DACVO Tampa Bay Veterinary Specialists Topical application of medication can

have the advantage of establishing high local drug levels, with reduced systemic side effects / toxicity. In general, ointments or suspensions can increase bioavailability by increasing corneal contact time. Dosage should be limited to one drop. (Increasing volume actually increases drug clearance from the surface). If higher drug exposure is required, increase concentration or frequency of medication. Other methods of increasing drug levels can be using collagen shields (VetShield, Oasis, Glendale CA) pre-soaked with medication (retention can be a problem), constant irrigation with pump systems, or subconjunctival injection. In addition to providing high drug levels, subconjunctival injections can also provide prolonged effect if depo forms of medication are used. If more than one medication is being used, they should be applied in order in increasing viscosity (drops before gels before suspensions before ointments), and several minutes should elapse between applications of each medication to avoid washout. There can be significant systemic uptake of topical medications, either by direct surface absorption, or passage through the nasolacrimal duct to the oropharynx. Nasolacrimal duct passage may be slowed by puncta occlusion, keeping the eye closed, or by using ointments instead of solutions. ANTIBIOTICS - Aminoglycosides are commonly used veterinary ophthalmology. There are generally bactericidal against a wide range of Gram (+) and Gram (-) bacteria. Neomycin (generally in various combinations with polymyxin B, gramicidin and /or bacitracin) penetrates cornea poorly, but the combinations remain a good choice for nonspecific infections because they are broad spectrum, are slow to induce resistance, and are cheap. Allergic sensitivity can develop with prolonged use. Gentamicin and tobramycin are also commonly used, particularly for established infections, or prophylactic use in horses. Penetration of intact corneas is poor, but reasonable in cases of ulceration. Resistant Pseudomonas infections are becoming more common, but these are still reasonable choices. Tobramycin has less epitheliotoxic effect than gentamicin. Drug effect can be enhanced by fortification, or supplementing with subconjunctival or parenteral injections. Amikacin can be compounded for use in resistant infections, but its main use may be for intravitreal injection in endophthalmitis cases. Cephalosporins are not available in ophthalmic preparations, but can be useful in Gram (+) infections. They achieve high ocular drug levels after IV injection, and are useful as a perioperative systemic antibiotic. Tetracyclines are bacteriostatic, but have a wide range of activity, including both Gram (+) and (-) including Moraxella, Chlamydophila and Mycoplasma. Topical tetracycline can be a drug of choice for feline conjunctivitis. Oxytetracycline can be used subconj or IM for pink eye infections in cattle. Oral doxycycline may be superior to topical tetracycline for clearing chronic Chlamydial conjunctivitis in cats, as well as clearing internal foci of infection. It is also a drug of choice for treating tick-borne disease.

Chloramphenicol has fallen from favor because of fear of creating aplastic anemia, but, although it is only bacteriostatic, may still be a good alternative in cases of feline conjunctivitis because of its activity against Mycoplasma and Chlamydophilia, as well as a range of Gram (+) and (-) bacteria. It may also be useful in corneal ulcers infected with Staph or Strep spp. Fluoroquinolones are increasingly popular in veterinary ophthalmology. They are bactericidal for a wide range of Gram (+) and (-) bacteria, including good activity against Pseudomonas, Mycoplasma and Chlamydophila. A variety of topical preparations are available; ciprofloxacin (Ciloxan), Norfloxacin, ofloxacin (Ocuflox), Levofloxacin (IQUIX / Quixin), gatifloxacin (Zymar) and moxifloxacin (Vigamox). They also have the advantage of excellent corneal penetration, even in intact corneas, and having low tissue toxicity. Systemic use also reaches therapeutic intraocular levels. Because of the fear of inducing drug resistance, their use should be limited to treating established infections. Systemic use, especially with enrofloxacin, can cause retinal degeneration in cats. Systemic daily dose for cats should not exceed 5 mg/kg/day. Clindamycin finds it main use in ophthalmology for treatment of toxoplasmosis, at a dose of 25 mg/kg for 2-6 weeks. Erythromycin is used topically for use in Mycoplasma and Chlamydophila infections in cats, and can be a good choice for corneal ulcers associated with Gram (+) infections. Azithromycin has a better Gram (-) spectrum, and includes Bartonella, Borrelia, and Chlamydophila. Sulfonamides are available topically alone or in combination with corticosteroid, but have gained little popularity in veterinary medicine. Oral preparations, however, can achieve good intraocular levels, making them good choices for endophthalmitis. Dry eye is a common side effect in dogs, and tear production should be monitored. Bottom line triple antibiotics and aminoglycosides (especially in horses) are good choices for non-specific infections. For feline conjunctivitis, tetracyclines, erythromycin or chloramphenicol are better choices because their spectrum includes Mycoplasma and Chlamydophila. Aminoglycosides (commercial strength or fortified) or fluoroquinolones are better choices where Pseudomonas is suspected (progressive ulcers). Consider systemic azithromycin or doxycycline for cases of chronic upper respiratory infection in cats. ANTIVIRALS - These are predominantly used for feline herpes virus (FHV) infections (and equine to some degree). Medications are virustatic, requiring frequent application, and do not resolve latent infections. Idoxuridine and trifluridine (Viroptic) are pyrimidine nucleoside analogues with good FHV activity. Trifluridine is the only topical antiviral commercially available, but may be less well tolerated than Idoxuridine. Purine analogues include vidarabine, which may be less effective clinically. Acyclovir (Zovirax) and its prodrug, valacyclovir (Valtrex), are systemic preparations that also may be less effective for FHV, and are not well tolerated by cats. Valacyclovir can be particularly toxic. Ganciclovir (Cytovene), cidovir (Vistide), and famciclovir (Famvir) are becoming more popular because they have better activity with less toxicity. Famciclovir is used at doses starting at 31 mg/kg b.i.d. for 10-21 days, although higher doses also seem to be well tolerated.

Interferon can reduce virus replication and release, as well as stimulate cellmediated lysis of virus-infected cells, and can be used topically (1000 IU/ml artificial tears q.i.d.) or orally to help control FHV infection. L-lysine reduces FHV replication by being a competitive antagonist for arginine. Supplementation with 500 mg PO b.i.d. will reduce the severity of both ocular and respiratory signs, and once daily dosing will reduce viral shedding in latent infections. ANTIFUNGALS - Fungal keratitis is common in horses, but rare in small animal practice, where antifungals may be more important when dealing with dermatophyte infection or systemic mycoses. Polyenes include amphotericin B and natamycin (Natacin). Amphotericin is limited by poor corneal penetration, irritation with topical use, and poor spectrum against filamentous fungi (the most common in keratomycosis). Natamycin is the only commercial antifungal preparation available, and has a much better spectrum especially for Fusarium spp. Imidazoles (miconazole 1%, ketoconazole 1% and econazole 2%) and triazoles (fluconazole 0.2% and itraconazole) tend to be well tolerated topically, and have good spectrum against common fungi, although they tend not to penetrate intact cornea well. Itraconazole may be most useful in treating systemic mycosis but has gained popularity with general practitioners as a 1% ointment with 30% DMSO to treat keratomycosis in horses. CORTICOSTEROIDS Steroids have diverse anti-inflammatory an immunesuppressive effects, as well as inhibiting corneal vascularization, fibroblast and collagen formation. They will also potentiate bacterial, viral and fungal infections, and enhance corneal collagenases. They can be used topically, subconjunctivally, or systemically. Phosphate salts stay in solution, but penetrate poorly; acetates penetrate well, but stay in suspension. Hydrocortisone is least potent, but can be useful in low grade inflammations. Prednisolone is more potent, and the acetate penetrates the eye well, making it a useful choice for uveitis. Dexamethasone is more potent still, but the phosphate penetrates less well, making it a better choice for eyelid / keratoconjunctivitis cases. NONSTEROIDAL ANTI-INFLAMMATORIES NSAID can be used topically or systemically, both to treat uveitis, and to reduce miosis during intraocular surgery. Topical preparations include 0.03% Flurbiprofen (Ocufen), 0.1% Diclofenac (Voltaren), and 0.5% Ketolorac (Acular). These are nonspecific COX inhibitors, and may decrease corneal wound strength, epithelial healing, and corneal vascularization, as well as potentiating FHV infections, so they are not necessarily a safe substitute for topical steroids. Ketolorac may also be useful for relieving symptoms of allergic conjunctivitis. IMMUNOSUPPRESSIVES Cyclosporine 0.2 2% and tacrolimus 0.002 - 0.003% block lymphokines by differing pathways, inhibiting T & B cell responses. They stimulate tear production by suppressing lacrimal gland inflammation, making them useful in many cases of keratoconjunctivitis sicca. (Cyclosporine may also have a direct lacrimomimetic effect). Response is better in dogs having Schirmer tear tests of >2 mm / minute at the start of treatment, and full response may take 2-3 months. Because of their anti-inflammatory effects, clinical signs of KCS may improve even in cases where tear tests do not significantly improve. They are also useful in treating chronic superficial

keratitis (pannus), pigmentary keratitis, and episcleritis. In cases where topical treatment is not adequate, azathioprine can be used systemically, particularly in cases on episcleritis and uveodermatologic syndrome. Megestrol acetate also has corticosteroid effects and can be used to treat eosinophilic keratitis in cats (2.5 -5 mg daily to start, 2.5 5 mg q 7-14 days for maintenance). GLAUCOMA MEDICATIONS There are a variety of medications available, and they can be used in various combinations to get an additive effect. Parasympathomimetics create miosis and ciliary body contraction, enhancing aqueous outflow. Probably best used in open angle glaucoma, especially if used in early cases. Miosis effect will tend to aggravate existing uveitis and increase synechia formation. They can be direct acting, like Pilocarpine and Carbachol, or indirect, like demecarium bromide or phospholine iodide. Pilocarpine is available in a variety of strengths, but 2% solution produces maximal clinical effect, and requires t.-q.i.d. dosing. Pilopine-HS (4% gel) is longer acting, requiring once daily dosing. Carbachol is limited in clinical use because of frequent g.i. side effects. The indirect forms tend to be more potent, and require only b.i.d. dosing, but may potentiate any organophosphate exposure. The most commonly used sympathomimetic is dipifevrin 0.5% (Propine). This is a prodrug, converted to epinephrine after absorption into the cornea. (This conversion may be blocked by Demecarium or phospholine iodide). Alpha adrenergic agonists include Apraclonidine 0.5% and Brimonidine. They are not commonly used in veterinary practice because of relatively small IOP reductions and frequent side effects such as bradycardia, salivation and vomiting. Beta-adrenergic blockers include timolol 0.25% & 0.5% (Timoptic), levobunolol (Betagan), Betaxolol (Betoptic), and Metipranolol (Optipranolol). Only Betaxolol is beta1 selective; others are non-selective. They work to reduce aqueous production, and may be particularly useful in cats. Caution should be used in asthmatic or CHF patients. Carbonic anhydrase inhibitors (CAI) have a direct effect on the ciliary body to decrease aqueous production. Acetazolamide is commonly used in humans, but is often poorly tolerated in small animals. Dichlorphenamide (2-4 mg/kg b.-t.i.d. for dogs, 0.5-2 mg/kg for cats) or Methazolamide (Neptazane) (5 mg/kg) are better oral choices, although metabolic acidosis, anorexia, and hypokalemia may still be an issue. Topical CAI include Dorzolamide (Trusopt) and Brinzolamide (Azopt). Generally used t.i.d., topical treatment can produce as much IOP lowering effect as systemic dosing, with minimal risk of side effects. Prostaglandin derivatives act by enhancing both conventional and uveoscleral outflow. Products include latanoprost 0.005% (Xalatan), Travoprost 0.0045 (Travatan), Bimatoprost 0.03% (Lumigan). Typical dose is once daily, in evening, although twice daily may help resistant cases. Cats tend to be poorly responsive. Osmotics include mannitol and glycerol. Mannitol is generally preferred because it is given IV. Dose ranges from 1-2 grams/kg, given over 20-30 minutes. This is generally used for emergency situations, or in conjunction with intraocular surgery, not for long-term usage.