Glucocorticoid use in cats

Since the discovery of their anti-inflammatory potential, glucocorticoids have become invaluable to the medical profession. In veterinary medicine, glucocorticoids now are one of the most commonly prescribed classes of drugs. Advances have been made to improve the efficacy and decrease the adverse effects of newer synthetic glucocorticoids compared with the endogenously produced glucocorticoid, cortisol. A common example is the additional unsaturation present in ring A of the common steroid nucleus of prednisolone. This modification leads to increased anti-inflammatory effects and reduced mineralocorticoid effects.

Nonetheless, important risks still accompany glucocorticoid use. Few studies have been performed on the effects of glucocorticoids in cats, despite the drugs' widespread use in feline medicine and cats' physiologic differences from other species. Understanding these feline-specific differences is important when prescribing these commonly used drugs. This review covers basic glucocorticoid pharmacology and attempts to summarize the evidence-based information on glucocorticoid use in cats.

MECHANISMS OF ACTION

Glucocorticoids have effects on nearly every organ system in the body. They are most commonly used, however, for their beneficial effect on the activity of the immune system. Glucocorticoids mediate their effects through various mechanisms, the most important of which seems to be through modulation of gene transcription. Glucocorticoids, like thyroid hormones, can enter the nucleus and access the DNA. Certain genes in the DNA carry regions known as glucocorticoid response elements (GREs). Binding of GREs by a glucocorticoid can result in either an increase or decrease in gene transcription and subsequent protein production.1,2 Glucocorticoids also can interfere with the ability of other factors that regulate gene transcription (Figure 1).2 Because glucocorticoids can induce the production of new proteins, the effects of these drugs, or biologic half-life, can persist beyond their pharmacokinetic half-life.1,2

Figure 1. Mechanism of action of glucocorticoids: 1) Glucocorticoids (GCs) enter the cell and bind to glucocorticoid receptors (GRs) in the cytoplasm. 2) GR-associated chaperone proteins are released, and the GC-GR complex moves through the nuclear membrane into the nucleus. 3) The GC-GR complex binds to positive or negative glucocorticoid response elements (pGREs and nGREs) on genes in the DNA, leading to increased or decreased mRNA production, respectively. 4) A GC-GR complex also may interfere with the action of other transcription factors bound to DNA. (Adapted from reference 2.)

DOSING

A large number of synthetic glucocorticoids have been developed with the goal of increasing efficacy while decreasing the number of adverse effects (Table 1). In most cases, the mineralocorticoid-related effects of sodium and water retention and potassium excretion are unwanted consequences of glucocorticoid use. Most synthetic glucocorticoids have been designed to reduce or eliminate these properties.

Table 1. Relative Glucocorticoid Potencies and Duration of Action of Selected Glucocorticoids*

Prednisone vs. prednisolone

One of the most commonly used glucocorticoids in veterinary medicine is prednisone, or prednisolone, though this is based more on familiarity and common practice than on a proven increased efficacy of this particular corticosteroid. No studies in cats suggest that any particular glucocorticoid is more effective for the treatment of a specific disease, provided equipotent doses are used. For prednisone to be effective, however, it first must be converted to the active form, prednisolone, in the liver. In dogs, this process occurs efficiently, and prednisolone and prednisone can be considered to be bioequivalent.3 In cats, the absorption and conversion of prednisone to prednisolone is less efficient, and after the oral administration of prednisone, only about 21% of the drug occurs in the bloodstream as the active form prednisolone.4 For this reason, prednisone and prednisolone should not be considered bioequivalent in cats, and the active form, prednisolone, should be used preferentially.

Potency

The relative potency data presented in Table 1, while commonly cited in the veterinary literature, are based predominantly on studies performed in other species, as well as clinical experience. Similar relative potencies are likely in cats, but no specific studies have been performed in this area. In particular, a discrepancy exists regarding the estimated potency of triamcinolone.

In the veterinary literature, triamcinolone is commonly estimated to be five times more potent than hydrocortisone; however, some authors think it may be up to 40 times more potent.5 This is supported by studies in people in which the ability of triamcinolone to suppress lymphocyte proliferation was used as a measure of the immunosuppressive potential of a glucocorticoid. Triamcinolone was shown to be more potent than dexamethasone in this respect.6

Moreover, the binding affinity of a glucocorticoid to the glucocorticoid receptor correlates with anti-inflammatory potential. Triamcinolone also has a higher glucocorticoid-receptor binding affinity than dexamethasone, suggesting equivalent or increased anti-inflammatory activity.6 I consider an estimate of 40 times that of hydrocortisone to be a more accurate approximation of triamcinolone's glucocorticoid potency in dogs and cats, and I adjust doses accordingly.

Dosing and intended effect

Glucocorticoid doses are commonly separated into physiologic, anti-inflammatory, and immunosuppressive ranges. These terms can be somewhat misleading because there is no exact dose at which a glucocorticoid changes from providing merely anti-inflammatory to immunosuppressive effects. Some cited dose ranges in veterinary medicine may not specify to which species they refer, and in most of these situations the doses are often most applicable to dogs. These ranges do provide a useful guide when selecting an initial glucocorticoid dose, depending on the condition to be treated.

Physiologic doses of prednisolone, such as would be used as replacement therapy in dogs with hypoadrenocorticism, are estimated to be 0.2 to 0.3 mg/kg given orally or parenterally once a day. Anti-inflammatory doses of prednisolone in dogs are cited to be 0.55 to 1.1 mg/kg orally or parenterally once a day and would be appropriate for treating conditions such as atopic dermatitis. Immunosuppressive doses in dogs range from 2.2 to 4.4 mg/kg once a day and are needed when treating immune-mediated or autoimmune conditions such as pemphigus foliaceus or autoimmune hemolytic anemia.7

These dose ranges have not been verified scientifically in cats, but it is anecdotally noted that cats often require higher glucocorticoid doses than dogs do in order to achieve equivalent effects. This is supported by a study that showed cats had fewer numbers of glucocorticoid receptors than dogs in the organs that were evaluated (liver and skin).8 The binding affinity of the feline glucocorticoid receptor also was shown to be less than that of the dog.8 Consequently, many authors suggest that glucocorticoid doses in cats be doubled to achieve equivalent effects, resulting in anti-inflammatory and immunosuppressive dose ranges of prednisolone extending to 2.2 mg/kg/day and 8.8 mg/kg/day, respectively.7,9,10 Doses for other glucocorticoids should be adjusted based on the relative potencies shown in Table 1 with the exception of triamcinolone, whose potency may be closer to that of dexamethasone, as noted above.

Once- vs. twice-daily dosing

Initial studies suggested that cortisol secretion in cats followed a circadian rhythm and that evening dosing would be preferred, as it would most closely mimic this natural rhythm.11 However, subsequent larger studies failed to document a consistent pattern of cortisol secretion in cats, indicating that the time of administration is probably not important.12,13 Likewise, no evidence of an advantage exists in dividing a once-daily glucocorticoid dose into two doses. Because it can be difficult to administer pills to cats, giving glucocorticoids once daily is a reasonable treatment plan. A possible exception occurs with higher, immunosuppressive doses as some authors think dividing the dose can reduce gastrointestinal irritation.14

Formulations

Glucocorticoids are available in various formulations that can have marked effects upon their activity. Orally administered glucocorticoid preparations usually have the same duration of effect as the base glucocorticoid (Table 1). However, parenterally administered glucocorticoids come bound to various compounds that affect solubility, absorption, and duration of effect. Glucocorticoids often are bound to one of two highly water-soluble compounds, sodium succinate or sodium phosphate. A common example is dexamethasone sodium phosphate. Glucocorticoids bound to highly water-soluble compounds are absorbed rapidly. Their duration of action is similar to that of the base glucocorticoid.

In contrast, acetate and diacetate are poorly water-soluble, and glucocorticoids bound to these compounds accumulate in the tissues and are slowly released during subsequent days and months. A common example in veterinary medicine is methylprednisolone acetate. While the base glucocorticoid, methylprednisolone, has a duration of action of 12 to 36 hours, methylprednisolone acetate's activity can last for three to six weeks.14

Tapering doses

If long-term use of any glucocorticoid is deemed necessary, a common goal of veterinarians is to reach a treatment stage whereby dosing every other day with short- and intermediate-acting glucocorticoids and dosing every 72 hours with long-acting glucocorticoids, such as dexamethasone, are appropriate. While not proven to be important, such dosing may minimize the suppressive effects of glucocorticoids on the hypothalamic-pituitary-adrenal (HPA) axis by allowing the HPA axis to recover on the "off" treatment days. Such a strategy is impossible when using the long-acting repositol corticosteroids, such as methylprednisolone acetate. Use of such glucocorticoids also decreases your ability to monitor and adjust the glucocorticoid dose based on the patient's response. Oral or rapidly acting parenteral forms of glucocorticoids are preferred, with repositol formulations reserved for cases in which oral dosing is not feasible because of patient or owner noncompliance.

Topical administration

Topical corticosteroids may also be beneficial in cats, although the propensity of this species to be fastidious groomers can reduce the local efficacy of these products when applied to areas easily accessible to the tongue. Systemic absorption may also be increased by this activity. Few studies specific to cats are available on the effects of topical corticosteroids, but side effects such as cutaneous atrophy, alopecia, localized pyoderma, and percutaneous absorption are seen in other species. Cutaneous atrophy in cats treated with systemic glucocorticoids can be severe, as discussed below, and is, therefore, also of potential concern with the use of topical corticosteroids in this species. Studies are lacking to document how frequently this occurs. The strength of topical corticosteroids increases with increasing glucocorticoid potency and vehicle occlusiveness. Cutaneous atrophy would be expected to be more severe with potent topical formulations such as betamethasone dipropionate or mometasone furoate ointments or creams. Although potent products may be necessary initially, attempt to switch to low-potency products such as hydrocortisone sprays if long-term treatment is necessary.

GLUCOCORTICOID EFFECTS ON FELINE PATIENTS

In general, cats tolerate glucocorticoids well, and adverse effects seem to occur less frequently in cats than in other species.

Clinical signs of adverse effects

In one study, daily immunosuppressive doses of either prednisolone or dexamethasone for two months caused no clinical signs of adverse effects with the exception of possible mild polyuria and polydipsia (PU/PD) in 13 of 14 treated cats.15 One cat in the study developed anorexia, pruritus, icterus, and medial curling of the pinna, some of which were suspected to be caused by the glucocorticoid. A separate study in four cats treated with methylprednisolone acetate at 5 mg/kg given subcutaneously once a week for a month also failed to detect any adverse clinical effects.11 In contrast, most dogs receiving even short courses of glucocorticoids quickly develop PU/PD, polyphagia, and panting, with additional adverse effects common during treatment for longer periods.9 Both of these studies support the clinical experience that suggests glucocorticoid-induced adverse effects are less common in cats, although marked and unique problems still may occur.

Effects on the complete blood count

One important method by which glucocorticoids produce their beneficial effects is through inhibiting immune cell recruitment to inflammation sites. Neutrophils are prevented from attaching to blood vessels and entering tissues, while lymphocytes are redistributed to other compartments such as the bone marrow or lymph nodes. These changes can be reflected in the complete blood count (CBC) and often are termed the stress leukogram or leukemoid response. In most species, a stress leukogram involves mature neutrophilia, lymphopenia, and eosinopenia. Lymphopenia and eosinopenia are seen in about 80% of dogs with hyperadrenocorticism, with 20% to 25% having increases in the total white blood cell count.16 In response to glucocorticoid administration, monocytes are increased in dogs but decreased in people.17

In the few studies that examined the typical stress leukogram in cats, the response seems more variable. Cats with naturally occurring hyperadrenocorticism displayed neutrophilia only 53% of the time, while lymphopenia and eosinopenia are seen 56% and 58% of the time, respectively.18 In two separate studies in which cats were treated with prednisone at 2 mg/kg once a day for two weeks, no effect was seen on the number of white blood cells; however, the low bioavailability of prednisone may have affected these results.19,20 In contrast, after three doses of dexamethasone at about 0.4 mg/kg once a day, cats did develop a significant increase in leukocytes.21 Another study showed that after two months of daily immunosuppressive doses of either prednisolone or dexamethasone, cats developed significant increases in white blood cells, neutrophils, and monocytes, although overt instances of leukocytosis, neutrophilia, or monocytosis were rare.15 Significant decreases in lymphocytes and eosinophils also were seen in this study, and lymphopenia was the most common CBC abnormality, present in 57% of the cats.15

Effects on the serum chemistry profile

Several studies reveal the effects of glucocorticoids on the feline serum chemistry profile.11,15,22 Increases in albumin concentrations were documented in all of these studies. In one study, hyperalbuminemia was the most common glucocorticoid-induced biochemistry abnormality. Increases in total protein concentrations, but not globulin concentrations, were present concurrently.15 It has been suggested that glucocorticoids may directly affect albumin synthesis in cats, as has been documented in other species.15,23 Increased total calcium concentrations also were shown, although this could have been related to the increased albumin concentrations to which circulating calcium is bound.

Increases in serum glucose concentrations were also common abnormalities,15 with up to 75% of cats demonstrating hyperglycemia after as little as a single 5-mg/kg subcutaneous injection of methylprednisolone acetate.11 Concurrent increases in serum fructosamine concentrations in one study of 14 cats support the theory that true hyperglycemia, rather than transient stress-induced hyperglycemia, commonly may occur in glucocorticoid-treated cats.15

Increased alkaline phosphatase (ALP) and alanine transaminase (ALT) activities, which commonly are seen with glucocorticoid use in dogs, are seen inconsistently in cats. One study did show mild increases in the activities of these enzymes.22 Other studies found no change in the overall mean activity of either ALP or ALT secondary to glucocorticoid use, although there was wide interindividual variation, with some cats showing marked increases of one or both of these enzymes.11,15

Other abnormalities found repeatedly in these studies on the effects of glucocorticoids on the feline chemistry profile included increases in cholesterol concentration and amylase activity, along with decreases in phosphorus, chloride, and creatinine concentrations.11,15,22

Effects on the urinalysis

A common occurrence with glucocorticoid use in dogs is a rapid onset of PU/PD accompanied by a decrease in the urine specific gravity. In multiple studies, glucocorticoids have caused no significant changes in feline urine specific gravity.11,15,18,24 Increases in water intake and urine output can occur in glucocorticoid-treated cats, but longer treatment courses and higher glucocorticoid doses seem to be necessary to generate these signs than in dogs.15,24 Consequently, interference with the release or action of antidiuretic hormone does not appear to be a major factor in the onset of glucocorticoid-induced PU/PD, as is proposed for dogs.

Glucocorticoid-induced glucosuria has been documented in cats, and osmotic diuresis may be involved in the PU/PD seen in some cases.18,24-26 In other cases, PU/PD has been seen in the absence of concurrent glucosuria, suggesting additional mechanisms may be involved.18,25 Other urinalysis changes were seen in a study of five cats that received 2.2 mg/kg once a day of prednisolone for two weeks; these included a significant decrease in urine pH, as well as significant increases in the urinary excretion of creatinine, magnesium, phosphate, and potassium.27

Effects on carbohydrate metabolism

Glucocorticoids can antagonize the effects of insulin and promote increased circulating blood glucose concentrations. These effects are mediated through various pathways, including increased hepatic glucose production and decreased glucose uptake by the peripheral tissues.28 Glucocorticoids decrease insulin sensitivity and glucose tolerance measurements in cats.25,29 This induced insulin-resistance can, in some cases, lead to overt diabetes mellitus similar to type II diabetes in people. Some authors think that cats are particularly susceptible to this adverse effect and that glucocorticoids are more potent hyperglycemic agents in cats than in other species.9,24 Combined and controlled studies relative to other species would be required to confirm this theory.

However, weak support of the theory exists when comparing separate studies that showed no changes in blood glucose or glucose-tolerance measurements in dogs after 28 days of prednisone therapy at a dose of 1.1 mg/kg once a day with studies that revealed cats treated with similar doses of prednisolone (2 mg/kg once a day) developed hyperglycemia and impaired glucose tolerance after only eight days.29,30 Drug withdrawal should resolve the glucocorticoid-induced hyperglycemia and glucosuria in otherwise healthy cats. However, in cats with pre-existing subclinical diabetes mellitus, glucocorticoid therapy may be enough to "push" the patient into a clinical diabetic state that requires insulin therapy.

Effects on the liver

Cats do not possess the glucocorticoid-induced isoenzyme of ALP, which is present in dogs.31 Consequently, a glucocorticoid-induced increase in ALP activity, while common in dogs, is rare in cats, though it may occasionally be seen in individual cases.15,32 Additionally, palpable enlargement of the liver is not a common feature of glucocorticoid use in cats as it is in dogs. Glucocorticoid-induced hepatomegaly in dogs is caused by a vacuolar hepatopathy from glycogen deposition. These changes have been termed a corticosteroid hepatopathy, which has been said to be unique to dogs.9 However, several studies have examined liver biopsy specimens of cats either with natural hyperadrenocorticism or after glucocorticoid treatment, and each consistently has shown excessive glycogen deposition in a typical vacuolar pattern that is characteristic of the corticosteroid hepatopathy.15,18,24,32,33

Thus, corticosteroid hepatopathy occurs in cats, but it may be difficult to detect without invasive tests such as liver biopsies. Even abdominal ultrasonography may fail to identify typical hepatic changes in affected cats.15

Effects on the skin

Through their inhibitory effects on keratinocyte and fibroblast proliferation, as well as on collagen synthesis, glucocorticoids can cause marked atrophy of the skin. With glucocorticoid use in people, epidermal lipids decrease and transepidermal water loss increases, both of which can lead to adverse effects such as scaling, hair loss, follicular atrophy, bruising, and thinning of the skin.34 These signs appear infrequently in cats receiving commonly used glucocorticoid-dosing protocols, although higher doses and longer treatment courses can cause similar signs.24

Table 2. Reported Cutaneous Signs in 18 Cats with Iatrogenic Hyperadrenocorticism*

Table 2 shows the cutaneous abnormalities seen in 18 cats with iatrogenic hyperadrenocorticism. In some of these cats, it is unclear whether glucocorticoids or the primary cutaneous conditions that were being treated were responsible for the observed signs. The glucocorticoid-induced cutaneous atrophy in cats can be extremely severe, leading to paper-thin skin that may tear either spontaneously or with only gentle manipulation (Figure 2).18,24 Curling of the pinna is another unique, but rare, adverse effect of glucocorticoid use in cats (Figure 3).15,24

Figure 2. Marked cutaneous atrophy and fragility leading to tearing of the skin in a cat.

Effects on the cardiovascular system

Several recent studies have documented cardiovascular risks associated with glucocorticoid use in cats. In two recent cases, a series of temporal associations were seen between glucocorticoid administration and the development of congestive heart failure in cats without pre-existing cardiac disease.35,36 The most common glucocorticoid associated with this adverse effect was methylprednisolone acetate; signs were seen as quickly as one day following administration.36 Congestive heart failure in affected cats was associated with hypertrophic cardiomyopathy; however, in cats that survived the initial crisis, the hypertrophic changes were observed to resolve in time after withdrawal of glucocorticoids.35,36 These cats had longer survival times compared with cats that had congestive heart failure caused by other forms of disease, leading the authors to propose that cats may develop a unique form of glucocorticoid-associated congestive heart failure.36 A follow-up study on the pathogenesis of this adverse effect suggested that plasma volume expansion caused by the hyperosmotic effect of glucocorticoid-induced hyperglycemia was responsible.37

Figure 3. Curling of the pinna secondary to chronic glucocorticoid use in a cat.

CONCLUSION

Cats exhibit several important differences from other species in their response to glucocorticoid therapy. I hope that knowledge of these species differences will enable practitioners to tailor the most effective and safe treatment plan for their feline patients. While cats typically tolerate glucocorticoids well, clinicians should be aware of, and monitor for, potentially serious adverse effects, such as diabetes mellitus, fragile skin, and congestive heart failure.

Andrew Lowe, DVM, MSc, DACVD

Fox Valley Animal Referral Center

Appleton, WI 54169

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