New and old uses for corticosteroids in small animals (Proceedings)

Glucocorticoids are possibly the most commonly used single drug class in veterinary medicine. The fact that they are useful in a wide variety of conditions, cheap, versatile, relatively safe, and can have potent and dramatic effects when used properly ensures they will continue to be popular with veterinarians. It may be this popularity that has led to the statement "no animal should die without the benefit of steroids!" However, because glucocorticoids have been around for so long and are used so routinely we as veterinarians may sometimes overlook some basic, but vital, information about these drugs.

What DON'T steroids do?

Glucocorticoids affect nearly every body system and produce a wide range of effects depending on the drug concentration and specific location. You may recall some of this information from introductory physiology...

• Metabolism: glucocorticoids raise blood glucose through increasing gluconeogenesis and antagonizing insulin. They also alter protein and fat metabolism.

• Anti-inflammatory effects: inhibits arachadonic acid formation leading to ( prostaglandin, thromboxane, and leukotrienes. Can also ( neutrophil migration into tissue and increase membrane stability.

• Water balance: increase in glucose and/or sodium can osmotically increase plasma volume, often resulting in PU/PD (especially in dogs).

• CNS: steroids can improve mood, behaviour, and appetite, but may lower seizure threshold.

• GI: steroids are ulcerogenic due to increased secretion of gastric acid, pepsin, and trypsin. This effect is synergistic with NSAIDs.

• Adrenal axis suppression: exogenous glucocorticoids will suppress ACTH secretion, which can lead to adrenal gland atrophy.

• Immunosuppression: at high doses, the anti-inflammatory effects resulting from altered leukocyte movement and function can become immunosuppressive.

Glucocorticoid formulations

• Phosphate and succinate esters are water-soluble and act the most rapidly. These are the "shock" treatment steroids.

•Methylprednisolone sodium succinate (Solu-Medrol® )

•Prednisolone sodium succinate (Solu-Delta-Cortef®)

•Dexamethasone sodium phosphate (Dexaject SP®)

• Free steroid alcohol solutions are not quite as rapid acting, but can be given IV or IM and are useful for acute conditions like vaccine reactions and insect bite hypersensitivity.

•Dexamethasone (Azium(, Dexaject®)

•Flumethasone (Flucort®)

• Acetate and acetonide esters are poorly water-soluble and given IM, SC, or intraarticular. They are absorbed slowly and will cause adrenal gland suppression.

•Methylprednisolone acetate (Depo-Medrol®)

• Oral formulations are well absorbed in dogs and cats and come in numerous brands and concentrations.

•Prednisone/prednisolone tablets

•Dexamethasone tablets and powder

Adverse effects of glucocorticoids

As we all know, steroids can cause adverse effects in small animals, especially if given at high doses or for extended periods of time. Negative effects include:

• Metabolic: diabetes mellitus, hyperlipidemia, hepatopathy

• Musculoskeletal: muscle atrophy, ligament weakness

• Immunosuppression: increased risk of infection and septicemia

• Endocrine: hypothalamo/pituitary axis suppression, thyroid and parathyroid suppression

• GI: gastric ulcers, pancreatitis

• Fluid balance: water retention, PU/PD

• Anaphylactic reactions

• Abortion

Planning Steroid Therapy

All veterinarians understand the risks associated with long-term steroid therapy for chronic conditions. Utilizing the lowest possible effective oral dose, every other day or less, can minimize these risks (though not eliminate them). Weaning animals off long-term steroids rather than stopping "cold turkey" will give the adrenal gland time to regain activity and prevent hypoadrenocorticism. Acetate formulations should only be used for intra-articular injection or when oral medication is not feasible.

So what's new in steroid therapy?

Because steroids have been around for years and are used commonly, many clinicians feel comfortable prescribing empirical doses that have been passed down through the years. Often these dosage regimens and the indications for their use were not determined from controlled clinical trials. The evidence that is available may be ambiguous because of concurrent drug administration in patients receiving steroids. Appropriate outcome criteria in clinical trials can also be difficult because glucocorticoids have such broad, nonspecific effects. Despite these problems, some new data is accumulating which may shed some light on historical "myths" of steroid use.

• Prednisone/prednisolone in cats: Prednisone must be converted by the liver to the active compound prednisolone for physiological effect. In dogs, hepatic metabolism occurs very quickly and the pharmacokinetic differences between the two are minimal. However, a 2004 trial in cats found that serum prednisolone concentrations and AUC after oral prednisone administration were much lower than those after using the same dose of oral prednisolone. The authors speculated this may be due to lower absorption of prednisone versus prednisolone, or decreased hepatic conversion to prednisolone in cats. They concluded that oral prednisolone was superior to prednisone in cats. These results should be taken with a grain of salt however, as this trial was only performed in 6 cats and only the abstract (as opposed to the full results) has yet been published. I could find no other data to validate their finding.

• Acute spinal trauma cases: Rapid-acting glucocorticoids (like methylprednisolone sodium succinate) have long been used in the immediate treatment of acute spinal cord injuries. Although not conclusively proven in any species, some pointed to mild evidence in humans that a high dose, 24-hr IV steroid infusion begun within 8 hours of trauma may improve long-term motor and sensory function. The data is questionable however and this treatment carries risks of severe side effects (namely increased incidence of sepsis and pneumonia). Recently Canadian human neurology and trauma specialists issued a statement that this practice is not a standard treatment nor a guideline for treatment, but rather a treatment option.

• IBD: Budesonide, an oral or rectal glucocorticoid designed for humans with Crohn's disease, undergoes extensive first-pass hepatic metabolism in people (therefore having a local effect in the intestine, but not systemically). A human controlled-ileal-release formulation of budesonide was examined in dogs in the hopes of using it for IBD. It did suppress pituitary-adrenal function (therefore showing some systemic effects), but did not induce other changes commonly seen with steroid use (like leukogram counts, serum ALP or ALT, or water intake and urination). Although anecdotally used with good results, efficacy in clinical cases of IBD in dogs or cats is unknown at this point.

• Nephrosis: although some prednisolone products carry a label indication for nephrosis (immune-mediated glomerulonephritis) in dogs and cats, no controlled studies have documented any benefits. In fact, one small retrospective trial in dogs found that prednisolone may have been detrimental, and the USP veterinary drug committee does not recommend its use in these cases.

• Atopic dermatitis: a recent meta-analysis found that cyclosporine was no more effective than glucocorticoids in treating dogs with atopic dermatitis, either short-term or long-term. It was just a whole bunch more expensive!

References

USP Veterinary Pharmaceutical Information Monographs--Anti-inflammatories. J Vet Pharmacol Ther 2004;27 Suppl 1:1-110.

Graham-Mize CA, Rosser EJ. Bioavailability and activity of prednisone and prednisolone in the feline patient. Veterinary Dermatology 2004;15:7-10.

Hugenholtz H. Methylprednisolone for acute spinal cord injury: not a standard of care. CMAJ 2003;168:1145-1146.

Ployngam T, Tobias AH, Smith SA, et al. Hemodynamic effects of methylprednisolone acetate administration in cats. Am J Vet Res 2006;67:583-587.

Stroup ST, Behrend EN, Kemppainen RJ, et al. Effects of oral administration of controlled-ileal-release budesonide and assessment of pituitary-adrenocortical axis suppression in clinically normal dogs. Am J Vet Res 2006;67:1173-1178.

Steffan J, Favrot,C, Mueller,R,. A systematic review and meta-analysis of the efficacy and safety of cyclosporine for the treatment of atopic dermatitis in dogs. Veterinary dermatology 2006;17:3-16.

Lowe AD, Campbell KL, Barger A, et al. Clinical, clinicopathological and histological changes observed in 14 cats treated with glucocorticoids. Vet. Record 2008;162:777-783.

Sharkey LC, Polyngam T, Tobias AH, et al. Effects of a single injection of methylprednisolone acetate on serum biochemical parameters in 11 cats. Vet Clin Pathol. 2007; 36:184-187.