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Anti-inflammatory Agents in Animals

By

Nick Whelan

, BVSc, Animal Eye Clinic of Waterloo Region, Ontario, Canada

Last full review/revision Oct 2021 | Content last modified Nov 2021

Corticosteroids for Ocular Disorders in Animals

Glucocorticoids are commonly used to manage extraocular and intraocular inflammation. Their mechanism of action is to cause an increase in lipocortin that in turn inhibits cell membrane phospholipase A2. This inhibits release of arachidonic acid, which is required to form precursors of inflammatory mediators via the eicosanoid pathway by enzymes such as cyclooxygenase (COX 1 and COX 2) and lipoxygenase. The result is decreased formation of prostaglandins, leukotrienes, thromboxane, and platelet-activating factors. Many infectious and noninfectious diseases cause intraocular inflammation. Unless this inflammation is controlled early, irreversible damage and blindness may result. Glucocorticoids are used clinically to control this existing inflammation or preempt control of future intraocular inflammation such as before cataract or other intraocular surgery.

In all species, control of noninfectious intraocular inflammation involves use of higher initial doses of systemic corticosteroids (prednisone 1–2 mg/kg) in combination with topical corticosteroids (0.5% or 1% prednisolone acetate or 0.1% dexamethasone alcohol, every 6–8 hours). Some cases of infectious disease (eg, rickettsial infections Rocky Mountain Spotted Fever in Dogs Spotted fevers are diseases caused by a set of related bacteria in the Rickettsia genus, of which Rocky Mountain spotted fever is the most severe. After transmission of the pathogen through... read more ) can be treated with low doses of systemic corticosteroids; this should not begin until 24–48 hours after starting antimicrobial treatment. Topical steroids can be started at the same time as systemic antimicrobial treatment.

Benefits of glucocorticoid use are a decrease in fibrin, phagocyte formation, fibrocyte activity, and formation of granulation tissue, limiting scarring and formation of posterior synechiae. By controlling intraocular inflammation, glucocorticoids can prevent the irreversible consequences associated with these changes. However, glucocorticoids also inhibit epithelial regeneration and can augment the action of collagenase, leading to a melting corneal ulcer. If the inflammation has caused endothelial degeneration, there may be persistent corneal edema. With longterm use of topical glucocorticoids, animals can develop Cushing disease Cushing Syndrome (Hyperadrenocorticism) Cushing syndrome refers to any cause of elevated cortisol concentrations. Pituitary-dependent hyperadrenocorticism (PDH; Cushing disease) is the most common form of hyperadrenocorticism and... read more Cushing Syndrome (Hyperadrenocorticism) due to suppression of the hypothalamic-pituitary-adrenal-axis.

Topical Corticosteroids

Topical formulations are primarily used to treat conjunctival, corneal, and anterior uveal inflammation. They are not as effective at treating eyelids. Their aqueous and lipid solubility determines how well they penetrate the cornea into the anterior chamber.

Different corticosteroids vary in their levels of potency. In order of decreasing topical potency are 1% prednisolone acetate, 0.1% dexamethasone. 0.5% prednisolone, and 2.5% hydrocortisone. Prednisolone acetate is the activated form, and it and dexamethasone are the more commonly used. Dexamethasone is available as a 0.1% alcohol and a sodium phosphate. The alcohol formulation has better corneal penetration. Topical corticosteroids are used for their anti-inflammatory effects. There is no contraindication using these with topical or oral NSAIDs NSAIDs Glucocorticoids are commonly used to manage extraocular and intraocular inflammation. Their mechanism of action is to cause an increase in lipocortin that in turn inhibits cell membrane phospholipase... read more .

Before use, the cornea should be stained with fluorescein to check for ulcers. Corticosteroids are contraindicated both topically and systemically when a corneal ulcer is present. Their action in the eye is predominantly by blocking arachidonic acid synthesis and production of prostaglandins and leukotrienes. The most effective topical steroids in animals are 1% prednisolone acetate or 0.1% dexamethasone. Steroids are used every 6 hours initially. They are typically combined with topical antimicrobials and are also combined with other immunosuppressive drugs such as cyclosporin (1%–2% cyclosporine/0.1% dexamethasone) and tacrolimus (0.02–0.03% tacrolimus/0.1% dexamethasone). Many diseases (eg, anterior uveitis, immune-mediated keratitis, episcleritis) require longterm topical use because the condition can only be controlled, not cured. Steroids are absorbed across the conjunctiva and, over a period of 2–3 weeks, cause notable pituitary-adrenal suppression.

It is entirely possible to induce Cushing syndrome in small dogs from topical steroid use. Similar to treatment with systemic steroids, topical steroids should be tapered slowly, not only for the suppression, but also to monitor if the inflammation is under control. In cats, topical steroids can reactivate feline herpesvirus, resulting in corneal ulcers and in some cases a corneal sequestrum.

Subconjunctival

Steroids can be administered via subconjunctival, sub-Tenon’s or retrobulbar injection. Slow-release formulations tend to be used when a longer duration of effect is required. Subconjunctival injections can supplement topical treatment, although for anterior segment treatment, frequent topical application with a steroid that had good corneal penetration results in the same levels in aqueous humor. The other advantage is minimizing interactions with animals that cannot be easily treated topically. This route can also decrease the adverse effects seen with systemic administration. However, the injection cannot be undone, so any adverse effects such as corneal ulceration and slower wound healing need to be managed until the steroid depot concentration is below that causing the effect.

If there is no response or the owner is unable to medicate frequently, subconjunctival injection of corticosteroids (betamethasone acetate, betamethasone sodium phosphate, or dexamethasone) can be administered. These drugs do not create subconjunctival plaques seen with depot steroids such as methylprednisolone acetate or triamcinolone acetonide. Duration of action is 2–4 weeks or longer. Retrobulbar injections can last 1 week or longer.

Intraocular

Intravitreal triamcinolone acetonide (2–4 mg) can be administered to assist with noninfectious chorioretinitis, steroid-responsive retinal detachments, recurrent uveitis in horses, and after cataract surgery. There is concern that the preservative in the formulation can be retinotoxic. A preservative-free formulation is available for use in humans; however, if that is not available, the preservative-containing formulation can be washed before injection to remove as much of the preservative as possible.

Systemic Steroids

The most commonly used systemic corticosteroids are prednisone, prednisolone, and dexamethasone. They are used primarily for treatment of inflammatory lid disease, conjunctivitis, episcleritis, anterior and posterior uveitis, optic neuritis and noninfectious orbital inflammation. They can be used in conjunction with topical steroids and topical nonsteroidal drugs and in combination with immunosuppressive drugs such as azathioprine, cyclosporine, and mycophenolate. Oral steroids have been used in cases of blastomycosis Blastomycosis Blastomycosis is a multifocal fungal infection caused by the dimorphic fungus Blastomyces dermatitidis. The fungus is often found in soil or decomposing organic matter, such as leaves. Infection... read more Blastomycosis to help minimize intraocular damage; however, the same benefits can occur if triamcinolone acetonide and voriconazole are administered intravitreally. Like topical steroids, oral steroids slow healing of tissues and can inhibit healing of corneal ulcers.

Corticosteroids are contraindicated both topically and systemically when a corneal ulcer is present. With longterm use, animals can develop Cushing disease due to suppression of the hypothalamic-pituitary-adrenal-axis. Care should be taken when treating animals long term to ensure that there is an appropriate weaning period to allow the hypothalamic-pituitary-adrenal-axis to return to normal function.

NSAIDS for Ocular Disorders in Animals

NSAIDs act by inhibiting the action of membrane-bound cyclooxygenase-1 (COX-1) and in some cases the inducible and constitutive cyclooxygenase-2 (COX-2). These enzymes are responsible for the production of proinflammatory prostaglandins that contribute to the characteristic signs of acute and chronic inflammation (heat, redness, swelling, pain, and loss of function). Most approved NSAIDs inhibit COX-1, although more recently there are approved families that preferentially or selectively inhibit COX-2 (COXIB).

Topical NSAIDs

Topical nonsteroidal drops are used to control intraocular inflammation. Drugs available include bromfenac, diclofenac, flurbiprofen, ketorolac, and nepafenac (prodrug of amfenac). They are used to help manage pain associated with keratitis and allergic conjunctivitis and to manage postoperative inflammation. They can also be used when the use of topical steroids is not needed or not appropriate (eg, management of low-grade anterior uveitis from cataracts in dogs [particularly those with diabetes]). They can promote mydriasis as well as reduce breakdown of the blood-aqueous barrier and provide analgesia. They should be not be used in the presence of corneal ulcers to provide analgesia or to manage uveitis secondary to ulcerative keratitis because they can cause ulcers to melt as well as retard corneal vascularization and healing.

Systemic NSAIDs

Myriad systemic NSAIDs Nonsteroidal Anti-inflammatory Drugs The importance of pain management and the use of NSAIDs in animals has increased dramatically in recent decades, with use of NSAIDs in companion animals being routine. NSAIDs have the potential... read more Nonsteroidal Anti-inflammatory Drugs are used to control extraocular and intraocular inflammation (disease associated and postoperative) and analgesia when systemic corticosteroids are not appropriate. A number of ocular diseases, such as corneal ulcer and glaucoma, can be very painful. Systemic analgesia, including the use of this family of drugs, should be part of the treatment protocol. Toxicity is mainly associated with the GI system. Some other potential toxicity issues can be associated with effects on kidney and liver function, and hemostasis. Duration of treatment is a factor affecting toxicity in all species; however, cats are more susceptible to kidney damage.

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