Proceedings of the International Congress of the Italian Association of Companion Animal Veterinarians

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1 Proceedings of the International Congress of the Italian Association of Companion Animal Veterinarians June 8-10, Rimini, Italy Next SCIVAC Congress: Mar. 8-10, 2013 Pisa, Italy SCIVAC International Congress Canine Leishmaniasis and other Vector-Borne diseases. Current State of Knowledge Reprinted in the IVIS website with the permission of the Congress Organizers

2 73 CONGRESSO INTERNAZIONALE MULTISALA SCIVAC RIMINI, 8-10 GIUGNO 2012 Ocular pharmacology which drugs when David Maggs DVM, BVSc, Dipl ACVO, USA WHAT OPHTHALMIC DRUGS SHOULD I HAVE IN MY PHARMACY? Obviously, no answer to this question is correct for every practice but here are some basics I could not manage without for canine and feline practice. The list is compiled without consideration of availability and price which vary frequently and widely across the world. Antibiotics Triple antibiotic ointment and solution Ofloxacin solution Cefazolin compounded solution (see below) Doxycycline Anti-inflammatory/Immunomodulatory agents Neopolydex ointment and solution Prednisolone acetate1% suspension Diclofenac solution Cyclosporine ointment and suspension Tacrolimus suspension Oral prednisone/prednisolone Oral NSAIDs Glaucoma Dorzolamide solution Dorzolamide/timolol combo solution Latanoprost solution Antivirals Idoxuridine solution Cidofovir compounded solution Famciclovir tablets Tear substitutes Hyaluronate solution Petrolatum ointment Other Atropine ointment and solution Serum ANTIBIOTICS Topically applied antibiotics are principally indicated for treatment of corneal ulcers and conjunctivitis. Although no bacteria are believed to be primary corneal epithelial pathogens and initiate ulcers in small animals, disruption of epithelium does predispose the corneal stroma to infection. Triple antibiotic (neomycin, polymyxin B and bacitracin or gramicidin) is an excellent first choice for prophylaxis because it is broad-spectrum, and polymyxin B is effective against many Pseudomonas spp. There are some concerns that it may induce fatal anaphylaxis in cats; however this appears to be extraordinarily rare. Although chloramphenicol is bacteriostatic, it has broad antimicrobial spectrum and will penetrate intact corneal epithelium. It may have activity against It is therefore a good choice, especially if an ulcer has healed but residual organisms are suspected within the corneal stroma. Gentamicin and tobramycin are widely used and inexpensive. They have better efficacy against Gram-negative than Grampositive organisms. Gentamicin is relatively cytotoxic. Topical oxytetracycline/polymyxin (Terramycin) has typically been recommended for treatment of feline conjunctivitis due to its efficacy against Mycoplasma spp. and Chlamydophila felis. There are now strong data confirming that cats harbor and shed C. felis from non-ocular sites and that systemic doxycycline is more effective at decreasing clinical signs and shedding of C. felis than topical therapy with a tetracycline-containing ophthalmic ointment alone. I usually recommend a 3 week course of doxycycline (10 mg/kg PO SID) and I include in-contact cats if reasonable. The usual precautions regarding esophageal stricture apply. There is a range of fluoroquinolones suitable for topical ophthalmic use. These are particularly effective against Gramnegative organisms, including Pseudomonas spp. Therefore widespread use of these preparations for prophylaxis in noninfected ulcers is actively discouraged. They are relatively ineffective against anaerobes (which rarely cause surface ocular disease) and against Gram-positive organisms (which are the major component of the ocular conjunctival flora). Therefore for serious infected corneal ulcers, an agent with additional Gram-positive spectrum should be added. This can be done relatively easily by use of a compounded cefazolin eye drop (see recipe below). 321

3 COMPOUNDED CEFAZOLIN RECIPE 1. Remove 2 ml from a 15-ml bottle of artificial tear solution and discard. 2. Reconstitute a 500-mg vial of cefazolin with 2 ml of sterile water. 3. Add entire 500 mg of the reconstituted cefazolin (2.4 ml) to the bottle of artificial tear solution. Final concentration = 33 mg/ml (3.3% solution). Shelf life: 28 days. Keep refrigerated. In all cases, frequency of antibiotic application is determined both by severity of the condition and the preparation used. Ointments have a longer contact time and can be applied less frequently. Ointments should be avoided when there is a risk of or actual corneal perforation since the petrolatum vehicle causes a severe granulomatous uveitis if it enters the eye. ANTI-INFLAMMATORY & IMMUNOMODULATORY DRUGS Anti-inflammatory and immunomodulatory drugs are essential for controlling often painful and sometimes blinding inflammation in many ophthalmic diseases. Of these, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclosporine warrant special mention for ophthalmic use. As a general rule, anti-inflammatory and immunomodulatory agents should not be used unless a diagnosis has been made and a specific immunologic or inflammatory response is to be inhibited. In addition, every eye should be stained with fluorescein before therapy with corticosteroids is initiated. Corticosteroids must not be used topically or subconjunctivally when fluorescein or rose bengal stain indicates a corneal epithelial defect. Commonly available ophthalmic corticosteroids include hydrocortisone, prednisolone and dexamethasone. Of these only prednisolone and dexamethasone are potent and penetrate the corneal epithelium to reach useful concentrations within the corneal stroma and intraocularly. For inflammatory disorders of the eyelids, posterior segment, optic nerve, or orbit, corticosteroids must be administered systemically, not topically. Topical NSAIDs such as diclofenac may be used in place of topical corticosteroids, compared with which they appear to be slightly less potent but also less likely to inhibit would healing. They are used for the same conditions as corticosteroids, but may be preferred in diabetic or Cushingoid patients owing to their lack of systemic adrenocortical effects. Topical NSAIDs inhibit breakdown of the blood-aqueous barrier by 80% to 99% in research studies. Cyclosporine is a potent immunosuppressive drug which affects cell-mediated immunity and possibly humoral immunity by inhibition of helper T cells, but does not affect epithelial wound healing. The drug commonly is applied topically as a 1% or 2% solution in various oils, or as a 0.2% ointment. An aqueous suspension can also be compounded. The topical route is used for moderating immune responses involving the lacrimal gland, conjunctiva, cornea, and sclera, especially treatment of keratoconjunctivitis sicca, corneal graft rejection, autoimmune keratitis (especially pannus), and immune-mediated episclerokeratoconjunctivitis. When applied topically it penetrates the eye poorly and is not useful via this route for treatment of intraocular inflammation. Cyclosporine s most important ophthalmic use is the treatment of canine keratoconjunctivitis sicca. Its major mechanism of action for this disease is potent reduction of immune-mediated destruction of the lacrimal gland and gland of the third eyelid, which permits spontaneous glandular regeneration. However, cyclosporine is also directly lacrimogenic, reduces corneal melanosis and vascularization, and stimulates canine conjunctival goblet cells to secrete mucin, which possibly accounts for some of its therapeutic effects in surface ocular disease resulting from qualitative tear film disturbances and other causes. Tacrolimus works via a similar mechanism to that of cyclosporine, in that it reduces T-cell activation by inhibiting calcineurin-dependent activation of lymphokine expression, apoptosis, and degranulation. However, the intracellular receptors for tacrolimus and cyclosporine are different, leading some veterinary ophthalmologists to use tacrolimus when cyclosporine is not effective for the treatment of keratoconjunctivitis in dogs. A 0.02% aqueous suspension was recently investigated in a double-masked study of 105 dogs with keratoconjunctivitis sicca. Dogs naïve to tear stimulation therapy, dogs maintained successfully on cyclosporine therapy, and dogs unresponsive to cyclosporine therapy were all included. Twice-daily tacrolimus administration was continued for 6 to 8 weeks. Schirmer tear test (STT) results improved by 5 mm/min in more than 85% of dogs never treated before and in 51% of dogs whose disease was unresponsive to cyclosporine. In March 2005 the U.S. Food and Drug Administration (FDA) issued a public health advisory to warn health care providers and patients about a potential cancer risk (lymphoma and skin cancer) associated with the commercial topical (dermatologic) preparation of tacrolimus for human use. This issue may be relevant to topical (ophthalmic) veterinary use. The FDA s concern was based on information from animal studies, case reports in a small number of patients, and how drugs of this class work. The FDA estimates that it may take human studies of 10 years or more in duration to determine whether use of tacrolimus is linked to cancer. In the meantime the agency advises that tacrolimus should be used only as labeled and for patients whose disease is unresponsive to or who are intolerant of other treatments. The FDA also recommends avoiding use of tacrolimus in children younger than 2 years, using tacrolimus only for short periods rather than continuously, and using the minimum amount needed to control the patient s symptoms. Owners of veterinary patients should be advised of these guidelines and maybe should wear gloves when applying this medication. Currently, the FDA advises that, in humans, tacrolimus should be used only as labeled and for patients whose disease is unresponsive to or who are intolerant of other treatments. The FDA also recommends avoiding use of tacrolimus in 322

4 children younger than 2 years, using tacrolimus only for short periods rather than continuously, and using the minimum amount needed to control the patient s symptoms. GLAUCOMA DRUGS The large range of glaucoma medications can be daunting. All work by at least one of three mechanisms: 1. Decrease aqueous production 2. Promote aqueous outflow (usually with miosis) 3. Dehydrate the vitreous Although some drugs are better studied than others, many are not well understood in humans, let alone small animals. Some general rules seem to apply though Topical drugs seem to be less potent but carry fewer side effects than systemic agents Dogs seem to tolerate these drugs better than do cats Expect primary glaucoma to go into remission with continued treatment with a single drug and later need additional or alternate drugs Always aim for synergy in mechanism of action when adding a new drug Drugs designed for human (typically open angle) glaucoma; do not work predictably on dogs or cats with (typically closed angle) glaucoma For maintenance of IOP or reduction of relatively minor increases in IOP, I generally prefer the topical carbonic anhydrase inhibitors (CAI s) such as dorzolamide (Trusopt ) or brinzolamide (Azopt ) which reduce aqueous humor production and are typically well tolerated. These require TID application in humans and dogs. Latanoprost (Xalatan ) represents a new class of drugs (synthetic prostaglandins) for treatment of glaucoma. It promotes non-conventional (or uveoscleral) outflow and also produces marked miosis after one or two applications. It produces a very potent and rapid reduction in IOP in dogs. However it failed to show an IOP-lowering effect in a recent clinical trial in cats. It should be used with great caution (if at all) in cases of glaucoma with significant uveitis since prostaglandins will exacerbate uveitis. I prefer to use it in acute congestive crises and then for maintenance in patients resistant to CAIs. ANTIVIRAL DRUGS Antiviral agents should be considered when signs are severe, persistent, or recurrent, or when there is corneal involvement, particularly ulceration. Antiviral agents are virostatic; therefore most require relatively frequent dosing or topical application. The effect of some antiviral drugs on FHV-1 replication in vitro has been studied and their relative potency reported as trifluridine >> idoxuridine ganciclovir >> cidofovir penciclovir >> acyclovir >> foscarnet. Therapy with antiviral drugs should be continued for at least one week beyond resolution of ocular lesions. Typically this is for 2-3 weeks. Drug Trade Name Formulation Dose Idoxuridine Compounded 0.1% Solution Apply at least 5 times daily 0.5% Ointment Vidarabine Compounded 3% Ointment Apply at least 5 times daily Trifluridine Viroptic & generic 1% Solution Apply at least 5 times daily Drug Trade Name Formulation Dose Cidofovir Compounded Apply twice daily Acyclovir Zovirax Tablets Effective plasma concentrations not Capsules reached with predictably safe doses Oral suspension Valacyclovir Valtrex Tablets Fatal in cats; DO NOT USE Famciclovir Famvir Tablets Not yet confirmed for cats (40 mg/kg PO TID) 323

5 TEAR SUBSTITUTES Artificial tears are used when the normal tear quality or quantity is altered or when loss of tears is increased due to evaporation, or, in some cases, primary corneal pathology. These agents are lacrimomimetic and therefore not as physiologic as lacrimogenic agents, such as cyclosporine. If possible, the production of endogenous tears is always preferred over the replacement of tears with artificial tears. Artificial tears vary broadly in the nature of their vehicle and especially its viscosity, with saline solutions being the least viscous and having the shortest contact time on the eye; methylcellulose and polyvinyl alcohol solutions being intermediate in viscosity and petrolatum products (ointments) being the most viscous. Aqueous solutions such as normal saline are not preferred for tear replacement in animals because they do not adhere to the lipophilic corneal epithelium and have extremely brief ocular retention times. Additionally they dilute what endogenous tears are present, and the preservatives most contain may cause inflammation or worsening of primary disease. Therefore aqueous solutions modified by the addition of agents to bind the solution to the epithelium and/or increase viscosity of the preparation are preferred in veterinary medicine. In the normal precorneal tear film this function is performed by mucopolysaccharide molecules within the mucin layer of the tear film and having both hydrophilic and lipophilic ends. Solutions modified in this way, termed mucinomimetic, have longer contact time and better eye feel, and offer more anti-desiccant advantages than traditional saline solutions. My favorite is hyaluronate ( I also recommend use of petrolatum ointments at bedtime or for very severe dry eye. In general, tear substitutes can be used for: For treatment of exposure keratitis (e.g., facial nerve paralysis, buphthalmos, breedassociated lagophthalmos) For treatment of keratoconjunctivitis sicca ( dry eye ) Patients with abnormal volume or composition of the tear mucins or lipids (qualitative tear film disturbances) During and after general anesthesia to prevent corneoconjunctival desiccation As a lubricant, refractive/electroconductive, and cushioning solution during gonioscopy and electroretinography As a diluent for compounding of some ophthalmic solutions In patients with primary ocular surface disease, such as feline corneal sequestration and canine superficial punctate keratitis, and chronic conjunctivitis. ATROPINE Class: Parasympatholytic Ocular effects: Dilates pupil Paralyzes ciliary body (Analgesia) Collapses ciliary cleft (Increases IOP) Reduces tear production Formulation: Ointment Drops Indications: Anterior uveitis Posterior synechia less likely and in dilated position (Peripheral anterior synechia more likely) Reduces uveal surface area Tamponades radial iridal blood vessels Stabilizes vascular endothelium? Contraindications: Glaucoma Dry eye Comments: Long duration of effect Do not use for diagnostic pupil dilation Uveal melanocytes act as a reservoir Blue eyes quicker to dilate but stay dilated shorter Brown eyes slower to dilate but stay dilated longer Dose: To effect - sufficient to produce desired (analgesic) effect Usually SID (rarely BID) x 1-2 days and then EOD Taper rapidly Monitor IOP and STT SERUM We are discovering more and more uses for topicallyapplied serum. In addition to its broadspectrum anti-collagenase properties (to slow melting ulcer), benefits are presumed to arise from numerous growth factors contained in serum. It is also described by humans with ocular surface disease as helping to relieve discomfort. Since these factors are not unique to the patient being treated and found across species, serum from other individuals may be used. However, the donor should meet all criteria required of a blood donor (except for the need for crossmatching of blood type). The following are a few suggestions for the collection and use of serum for ophthalmic disease. Harvesting, preparation, and storage: A venous blood sample is collected and allowed to clot in a redtop tube. After centrifugation, serum is separated and stored in a commercially available eye-drop container ( or ). Aseptic technique should be practiced throughout. Since serum is a potential growth medium for infectious organisms and because anticollagenase properties and growth factors likely degrade over time, serum for ophthalmic use should be collected fresh at least weekly and stored in a refrigerator while in use. If necessary, larger volumes can be collected, aliquotted into suitable portions, and frozen for up to 3 months. Indications: We commonly use serum in ulcerated eyes of all species. Its major use is in melting (malacic) ulcers where its anticollagenase properties antagonize proteases that digest collagen. There is some evidence that it may also promote healing of indolent (chronic superficial) ulcers of dogs and cats. Serum can be applied to the affected eye as often as needed (as frequently as q minutes for a rapidly melting corneal ulcer). 324