Glucocorticoids in the cat

340 © 2008 The Authors. Journal compilation © 2008 ESVD and ACVD. 19; 340–347

DOI: 10.1111/j.1365-3164.2008.00717.x

Blackwell Publishing Ltd

Glucocorticoids in the cat

Andrew D. Lowe*, Karen L. Campbell† and

Thomas Graves†

*Fox Valley Animal Referral Center, Appleton, WI, USA†Department of Veterinary Clinical Medicine, University of Illinois, Urbana-Champaign, IL, USACorrespondence: Andrew D. Lowe, Fox Valley Animal Referral Center, Appleton, WI, USA. E-mail: [email protected] Sources of funding

Self-funded. Conflict of interest None.

Abstract

Glucocorticoids are one of the two main classes of

hormones, along with mineralocorticoids, which are

secreted from the adrenal cortex. Since the discovery

of the anti-inflammatory properties of the natural

glucocorticoid hydrocortisone, a large number of

artificial glucocorticoids have been synthesized to

attempt to increase efficacy and decrease side effects.

These drugs are now considered one of the most

commonly prescribed agents in veterinary practice.

The effect of these drugs has been shown to vary

significantly between species. Cats appear to tolerate

glucocorticoids well, resulting in these drugs being

recommended for a wide variety of conditions; however,

there are few studies on the effects of glucocorticoids

in cats. In this paper we review some of the available

literature on glucocorticoid use in the cat.

Accepted 29 May 2008

Introduction

Glucocorticoids (GCs) are among the most commonlyprescribed drugs in veterinary medicine. GCs exert abroad range of activities, and have consequences on everyorgan system. Cats are often considered less susceptibleto GC-induced side effects than other species. Whenclinical signs do occur, however, they can be severe, andcan include marked cutaneous atrophy, skin fragility, con-gestive heart failure (CHF) and increased susceptibility todiabetes mellitus (DM). Pharmacological studies evaluatingeffects of GCs in cats are lacking. Most of the currentlyrecommended GC dosing regimens for cats are extrapo-lated from human or canine studies and modified based onclinical experience. Here we present a review of publishedstudies on GC use in the cat, as well as a basic review ofgeneral GC pharmacology.

Mechanism of action

GCs exert their effects through both genomic and non-genomic mechanisms. Genomic events involve binding ofa GC to an intracellular GC receptor (GR), located primarilyin the cytoplasm (Fig. 1). GRs are composed of three mainprotein domains – an amino-terminal domain with trans-criptional activating properties, a central DNA-bindingdomain containing two zinc fingers, and a carboxy-terminalligand-binding domain.1 On binding a GC ligand, the GRdisassociates from a series of chaperone proteins includingheat shock protein 90 (Hsp90), Hsp70, Hsp40, co-chaperonep23 and immunophilins FKBP52 and Cyp40. Disassociationfrom these proteins was thought to expose nuclearlocalization domains on the GR which, upon binding toproteins known as importins, prompted the migration ofthe ligand-bound GR into the nucleus.1 Recent work hassuggested that the binding of importins with GRs isindependent of GC binding, but that hormone bindingmight affect downstream pathways.2 The protein 14-3-3has been proposed as a cytoplasmic tether for the GR in theabsence of GC, and release from 14-3-3 may be important inGR migration.1

Regardless of whether it is required, transport of the GRthrough the nuclear membrane is facilitated by ligand binding.

Figure 1. Mechanism of action of glucocorticoids. (1) Glucocorticoids(GCs) enter the cell and bind to glucocorticoid receptors (GRs), whichare found primarily in the cytoplasm bound to chaperone proteins. (2)Binding of a GC causes release of chaperone proteins and migrationof the GC–GR complex into the nucleus. (3) GC–GR complexes areable to dimerize and bind to glucocorticoid response elements (GREs)in the DNA. Binding to a positive GRE (pGRE) promotes transcriptionwhile binding to negative GREs (nGREs) decreases transcription ofthe regulated gene. (4) GC–GR complexes are also able to interfere,as monomers, with the transcriptional activating properties of otherfactors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1).

© 2008 The Authors. Journal compilation © 2008 ESVD and ACVD. 341

GCs in the cat

Once present within the nucleus, the GR binds, throughthe zinc fingers, as a homodimer to specific regions ofDNA known as GC response elements (GREs). ThroughDNA binding, GRs are able to either up-regulate or down-regulate transcription.1 Many proteins, such as lipocortin-1,IκB, IL-10, and the GC-induced leucine zipper (GLIZ), areup-regulated through GR-mediated transcriptional activationand have potent anti-inflammatory actions. Others, suchas tyrosine amino transferase and phosphoenolpyruvatecarboxykinase are responsible for gluconeogenic effects.1,3

GCs can repress transcription of specific genes as well.Mechanisms include squelching, tethering and interactionwith negative GC response elements (nGREs).1 Squelchinginvolves the competitive inhibition by a GR of transcriptionalactivators for necessary co-activating molecules. Tetheringinvolves the GR interfering with DNA-bound transcriptionalactivators. In tethering there is no direct GR-DNA interaction,but rather a protein–protein interaction between the GRand another transcriptional activator. Squelching andtethering are proposed mechanisms by which GCs inter-fere with nuclear factor-κB (NF-κB) and activator protein-1(AP-1), two transcriptional activators with products thatinclude a host of inflammatory cytokines, chemokinesand adhesion molecules.1 Tethering is the most widelyaccepted model, and the importance of squelching iscontroversial. One study showed no relationship betweenGC-mediated repression of NF-κB or AP-1 and co-activatorlevels.1 Co-activators are proteins that are unable to binddirectly to DNA but increase gene expression by interactingwith transcription factors containing a DNA binding domain.Negative GREs are regions of DNA at which GR bindingcauses direct repression of gene transcription. NegativeGREs regulate expression of many proteins includingCRH and pro-opiomelanocortin, the precursor to adreno-corticotropic hormone, melanocyte-stimulating hormone,β-endorphin, β-lipotropic hormone and corticotrophin-likeintermediate polypeptide.1,3,4

Some GC-mediated effects happen too quickly to beexplained by genomic events. Several mechanisms ofaction have been proposed for these non-genomic effects,including specific interaction with the cytosolic GRs, non-receptor-mediated interactions with cellular membranes,and specific interactions with membrane-bound GRs.5 Inbinding to the cytosolic GR, GCs induce the release of avariety of proteins, some of which may possess signallingproperties of their own. For example, the release of onesuch protein, Src, leads to activation of lipocortin-1 whichcan in turn inhibit the release of arachadonic acid, leadingto a reduction of subsequent eicosanoid production.5

Through non-receptor-mediated interactions with cellularmembranes, GCs have been shown to inhibit mitogen-stimulated respiration of cells such as thymocytes.5 It hasbeen proposed that this effect is due to GCs incorporatinginto the plasma membrane, thereby altering its physico-chemical properties. This can result in inhibition ofmembrane-associated ion channels, and alteration ofcalcium and sodium flux.5 Transient increases in cytoplasmiccalcium concentrations are essential for the immediateand sustained activation of lymphocytes. GC-inducedalterations in transmembrane currents could have myriadeffects.5 Finally, membrane-bound GRs have beendetected,5 but their roles are not known.

The molecular effects of GCs in the cat have not beenreported, but there are many possible mechanisms thatcould explain the perceived resistance of cats to GCeffects. For example, after binding to DNA, GRs are rapidlyrecycled back to the nucleoplasm within a matter ofseconds. Increased duration of DNA binding is associatedwith increased transcriptional activation.1 Also, in humanbeings, two isoforms of the GR have been discovered –a steroid-binding GRα and a non-steroid-binding GRβ.3

In GC-resistant human asthma patients, increasednumbers of GRβ-positive cells have been found, suggest-ing GRβ may play a role as a negative modulator of theactive GRα isoform.3 Such a mechanism could play a rolein the GC resistance perceived in cats relative to otherspecies.

Dosing GCs in cats

Recommended GC doses for cats are widely discrepant.The predominant opinion, however, is that the cat requiresa higher dose than the dog. This is supported by one studyshowing that cats have approximately half the density ofGRs in skin and liver as compared to dogs.6 Receptordensities in other tissues have not been reported. Thestudy also found lower binding affinity of feline GRs.

It has been suggested that cats respond better to themetabolically active drug prednisolone than to the pro-drugprednisone.7 A recent study provided the first scientificevidence to support this commonly held belief.8 The studyshowed that only 21% of orally administered prednisoneappears in the blood as prednisolone.8 For this reason,prednisone and prednisolone should not be viewed asequipotent when given orally in cats. Because prednisoneis a commonly used GC, its poor absorption may contrib-ute in part to some of the perceived GC resistance in cats.

GC doses are commonly divided into anti-inflammatoryand immunosuppressive ranges. These divisions arearbitrary, and, it is probably more important that GCs beadministered to desired effect, especially given the lack ofpublished evidence. Nonetheless, reported ranges doprovide a useful starting point when choosing an initialdose for cats, depending on the condition to be treated. Ingeneral, recommended anti-inflammatory doses of pre-dnisolone in dogs and cats range from 0.55 to 1.1 mg kg–1

per day, divided once or twice daily. Many authors recom-mend, however, that cats be given doses twice that ofdogs to achieve anti-inflammatory effects.9–12 Additionally,some authors have stated that prednisolone is moreeffective when given twice daily,13 while others see noadvantage to dividing the dose.14,15 Studies supportingeither of these recommendations are lacking, but in theabsence of any indication to the contrary, once-daily dosingis reasonable, especially in cats that are difficult tomedicate. One early study of four cats suggested acircadian rhythm of cortisol secretion in the cat, with peakconcentrations occurring in the evening.16 This rhythm isthe inverse of the circadian pattern of cortisol secretion inpeople, and evening dosing was recommended as mostappropriate for cats. Subsequent larger studies, however,have documented episodic secretion, with no circadianrhythm, of cortisol in cats,17–19 so time of day is probablynot a consideration with GC dosing in the cat.

342 © 2008 The Authors. Journal compilation © 2008 ESVD and ACVD.

Lowe et al.

Immunosuppressive doses of prednisolone recom-mended for the cat range from 2.2 to 8.8 mg kg–1 perday.11,20 At these higher doses some authors believe thatdivision of the daily dose is indicated to decrease gastroin-testinal irritation.15 Doses for other GCs can be extrapo-lated from the relative potencies given in Table 1. It shouldbe noted that these potency values were derived primarilyfrom human studies. More recent studies using updatedtechniques, such as cell trafficking dynamics, haverevalidated these data,21 but whether the same relativepotencies exist in cats has not been evaluated. There is aparticular discrepancy in the veterinary literature on therelative potency of triamcinolone. While typically cited asfive times more potent than hydrocortisone, some authorsclaim that triamcinolone may, in fact, be up to 40 timesmore potent than hydrocortisone.14

GCs are normally classified as short-, intermediate-, andlong-acting based on the expected durations of their bio-logical activities. Because many of the effects induced byGCs are due to the induction or suppression of gene trans-cription, their biological activities may exceed the plasmahalf-lives of the drugs. Biological half-life, the time fordrug-induced effects to reduce by one half, is a moreimportant parameter to asses when evaluating a GC. Inpeople, the potency and duration of a GC’s anti-inflammatoryeffects roughly parallel the potency and duration of itssuppression on the hypothalamic-pituitary-adrenal (HPA)

axis.22 Such information is summarized in Table 1. Again,similar studies are lacking in cats. Table 2 summarizespublished studies of pharmacokinetics and duration ofHPA suppression of GCs in cats. None of these studiesexamined biological half-lives. Pending further studies it isassumed, although supported by clinical experience, thatbiological half-lives in cats are similar.

Formulation also affects the duration of action of a GC.Although oral GC preparations usually contain the freesteroid alcohol form of the drug and have the duration ofaction of the base GC, parenteral formulations come invariety of forms that affect drug solubility.12 Sodiumphosphate and sodium succinate are commonly bound toparenterally administered GCs. These compounds arehighly water soluble giving the drug a rapid onset of action.The duration of action is similar to that of the base GC.Acetate and diacetate are poorly water soluble, whilepivalate, dipropionate, hexacetate and acetonide are theleast soluble. GCs bound to poorly soluble compounds areslowly released from tissue and absorbed over periods ofdays to months, resulting in long-lasting, low concentrations.One of the most commonly used, poorly soluble GCs ismethylprednisolone acetate. Methylprednisolone is anintermediate-acting GC with a duration of action of approxi-mately 12–36 h, but when given as methylprednisoloneacetate the duration of action ranges from 3 to 6 weeks.15

In general, rapidly acting oral or parenteral formulationsare preferred over repositol GCs because there is lessprolonged suppression of the HPA axis, a greatly enhancedability to monitor and adjust the dose, and less pronouncedside effects.12 The use of repositol GCs should bereserved for those cats in which oral dosing is not possibledue to patient or owner compliance. When treating anychronic condition long term with GCs it is thought that thegoal should be to achieve alternate-day dosing using anintermediate-acting GC to allow the HPA axis to recover onthe ‘off’ days. While this has not been proven to be signifi-cant, such a strategy is not possible using repository formsof GCs.

Tissue-specific effects

Inflammation and the immune system

Through the mechanisms previously discussed, GCsexhibit a wide array of effects on the immune system.

Table 1. Relative glucocorticoid (GC) potencies and duration of action of selected GCs7,12

GC potency relative to hydrocortisone

Duration of action (hours)

Short actingHydrocortisone 1 < 12Cortisone 0.8 < 12

Intermediate actingPrednisolone 4 12–36

Methylprednisolone 5 12–36Triamcinolone 5 12–36

Long actingDexamethasone 30 > 48Bethamethasone 25–40 > 48Paramethasone 10 > 48

Table 2. Available pharmacokinetic parameters of various glucocorticoid (GCs) in cats

Tmax T1/2

Bioavailability after oral administration Duration of HPA suppression

Prednisone 1.44 h8 2.46 h8 21%8† NAPrednisolone 0.77 h8 0.66 h8 100%8 NAMethylprednisolone 0.5 h23 Multiphasic: 82%23 4 mg/kg/day for 7 days:

< 7 days after the drug withdrawal25From 0–30 min T1/2 = 0.25 hFrom 60–120 min T1/2 = 1.7 h24

Methylprednisolone acetate 0.75 h23 NA 93%23 NADexamethasone 0.25 h26 1.41 h26* NA 0.01 mg/kg: 6–12 h27

0.1 mg/kg: 32 h17

Tmax, time to peak plasma concentration after oral administration.T1/2, elimination half-life.†Relative bioavailability of the active metabolite, prednisolone, after administration of prednisone.*Information not calculated by authors and graphically estimated from manuscript.NA, information not available.


GCs in the cat

Marked differences exist in the response of the immunesystem of differing species to GCs and these differencescan be significant. Much of the information regarding theeffects of GCs on the immune system has been derivedfrom studies on rodents or human beings, and may notapply to cats. This review will summarize general informationfollowed by available feline-specific information.

LipocortinLipocortin-1 belongs to a family of phospholipid-bindingproteins. The gene encoding lipocortin-1 has been shownto possess a positive GRE, and transcription of lipocortin-1is up-regulated by GCs.3,10,20 As previously mentioned,the binding of a GC to a GR can also lead to activation ofpreviously synthesized lipocortin through the release ofsecondary messengers present in the cytosolic GR–proteincomplex.5 Phospholipase A2 cleaves arachadonic acidfrom phospholipid membranes. Arachadonic acid canthen be converted, by cyclooxygenase and lipoxygenaseenzymes, to inflammatory eicosanoids. Lipocortin-1 is aninhibitor of phospholipase A2. The induction of lipocortin-1contributes to the potent anti-inflammatory effects ofGCs.28,29 Lipocortin-1 is also responsible for shedding ofL-selectin from the surface of neutrophils.29 L-selectin isinvolved in the adhesion of neutrophils to vascularendothelium. Inhibition of L-selectin is likely involved in theobserved decrease in margination and migration ofneutrophils seen with GC use. GCs were shown toinduce lipocortin expression in cats in one study whereindexamethasone induced a 220% increase in lipocortinconcentrations from feline airway secretions for 24 h.30

LeucocytesOne of the primary methods by which GCs are proposedto mediate their effects is by modifying leucocyte trafficking.This effect is reflected in the ‘stress leucogram’, whichcan be induced by endogenous or exogenous GCs. The‘stress leucogram’ varies from species to species buttypically includes mature neutrophilia, lymphopenia andeosinopenia.20 The effect of GCs on other monocytes ismore variable. Monocytosis can be observed in dogswhile monocytopenia is a more common stress responsein humans.20 Neutrophilia is attributed to release ofneutrophils from the bone marrow as well as decreasedmargination and diapedesis of neutrophils into tissues.20

Inhibition of neutrophil trafficking to sites of inflammationis one of the major anti-inflammatory effects of GCs. GCscan also inhibit neutrophil phagocytosis and killing ofbacteria. These effects are variable, and may not be assignificant as the effect of GCs upon neutrophil kinetics.Several studies have not shown any biologically significantdecrease in phagocytosis or killing by GC-treated neutrophilsonce they have reached sites of inflammation.20 In con-trast, macrophages are more sensitive to GC effectsthan neutrophils, and do display significant decreases inphagocytic and bactericidal activity after even low therapeuticdoses of GCs are administered.10,20,28,31 In addition,macrophage accumulation at sites of inflammation mayalso be decreased by GCs, possibly due to a decrease in theproduction of chemotactic factors.12 The lymphocytopeniaobserved in steroid-resistant species, such as dogs andcats, is attributed to redistribution of lymphocytes to

extravascular compartments such as the bone marrow.12,20

T lymphocytes are affected more than B lymphocytes andCD4-positive T cells more than CD8-positive cells.12 Incats, the classic ‘stress leucogram’ is not observed asfrequently. In a report of 45 cats with naturally occurringhyperadrenocorticism, a mean white blood cell countdifferential of > 86% neutrophils, < 5% lymphocytes and< 2% eosinophils was seen in 53, 56 and 58% of cats,respectively.32 In cats given approximately 0.4 mg kg–1

per day of dexamethasone for three consecutive days, asignificant increase in leucocytes was seen by day 5.33

This increase was predominantly due to an increasednumber of neutrophils with a lesser increase in monocytesand B cells. In that study, no decreases in the absolute orrelative numbers of CD4+ or CD8+ lymphocytes wereseen. There was a decline in the number of particlesphagocytosed by peripheral blood monocytes, but nochange in the phagocytic activity of neutrophils wasreported. Neutrophils and monocyte oxidative burst activitydecreased.33 In cats administered approximately 2 mg kg–1

per day of prednisone for 2 weeks, a similar lack of effecton lymphocytes was seen with no change in percentagesof CD4, CD8, CD21 (pan-B cell marker) or CD5 (pan-T cellmarker) lymphocytes.34 Another study demonstrated nosignificant changes in the number of any nucleatedwhite blood cell when prednisone at 2 mg kg–1 day–1 wasadministered to cats for 2 weeks.35 The results of thesetwo studies may have been affected by the poor oralabsorption, or metabolism, of prednisone in cats.

Cell-mediated immunityCell-mediated immunity is a complex process involvingthe interaction of antigen-presenting cells, such as dendriticcells and macrophages, with T lymphocytes and effectorcells. GC effects on these processes are summarized inTable 3. Survival, uptake of antigen, migration to lymph nodes,and maturation of dendritic cells are all down-regulated byGCs.1 In addition, by inhibiting the transcriptional activatorsNF-κB and AP-1, many cytokines, such as GM-CSF,tumour necrosis factor-α, IL-1, IL-4, IL-5, IL-6, IL-8 and IL-12,are effectively decreased. These cytokines are normallysecreted by macrophages and are necessary to direct the

Table 3. Effects of glucocorticoids on the different arms of the immune system

Cellular immunity– Decreased antigen survival, uptake and migration– Decreased maturation of dendritic cells– Inhibition of transcriptional activators (e.g. NF-κB and AP-1)– Decreased macrophages expression of some inflammatory

cytokines (e.g. IL-1, TNFα)– Increased expression of some anti-inflammatory cytokines

(e.g. IL-10)– Decreased T lymphocyte proliferation in response to mitogens– Decreased T cell activation– Decreased T cell cytokines (e.g. IL-2 and IFN-γ)– Decreased NK cell-mediated lysis of target cells

Humoral immunity– Decreased antibody synthesis only after high dose, long-term

therapy– Lesser degree of suppression of B lymphocyte proliferation in

response to mitogens


Lowe et al.

immune response.1 In contrast, the gene encoding theanti-inflammatory cytokine IL-10 is up-regulated by GCs.3

The proliferation of T cells in response to mitogens(lymphocyte blastogenesis), and T cell activation, are alsoreduced by GCs, as are the T cell-derived cytokines IL-2and interferon (IFN)-γ.1,10,20 Natural killer cell-mediatedlysis of target cells is inhibited by GCs in humans.28,36

Prednisone administered at 2 mg kg–1 per day for 2 weeksdecreased T lymphocyte blastogenesis and increasedIL-10 mRNA transcription in cats in one study, but IL-2, IL-4and IFN-γ were not affected.34

Humoral immunityThe effect of GCs on humoral immunity is not as profoundas the effect on cell-mediated immunity (see Table 3). Ingeneral, animals are capable of producing normal antibodyresponses to vaccines or other antigens when receivingtherapeutic doses of GCs.20 As the dose or duration of GCtherapy increases; however, antibody synthesis maydecrease.12 When using typical therapeutic doses, thedecrease in antibody concentrations is usually mild tomoderate, with IgG and IgA being most affected while IgEconcentrations tend to remain unchanged.12 Most of theeffects of GCs on humoral immunity are considered indirect,and are due to effects of GCs on antigen-presenting cellsor T helper cells. Lymphocyte blastogenesis in responseto B-cell mitogens is less suppressed by GCs than isthe blastogenic response to T cell mitogens.20 Serum IgMand IgA levels were unchanged in cats after receiving2 mg kg–1 day–1 of prednisone for 2 weeks,34 whereasallergen-specific IgE levels were significantly decreased.35

Cats receiving extremely high doses of methylprednisoloneacetate at 20–80 mg kg–1 week–1 showed a sharp declinein serum antibody concentrations within 2 weeks,37 althoughcats receiving therapeutic doses of GCs are able to mountnormal antibody responses to vaccination.20

Diabetes mellitus

Diabetes mellitus in cats is most analogous to type II (non-insulin-dependent) diabetes in humans. In this disorder,hyperglycaemia is caused by insulin resistance rather thanby absolute insulin deficiency. Insulin resistance can becaused by impaired insulin-dependent control of hepaticglucose production, or impaired insulin-mediated glucoseuptake by peripheral tissues. GCs interfere with a varietyof pathways that result in insulin resistance and, poten-tially, overt DM.38 GCs antagonize the effects of insulin onthe liver and increase hepatic glucose production, in alarge part by up-regulating a rate-limiting enzyme in thegluconeogenesis pathway, phosphoenolpyruvate carboxy-kinase.38 Glycogen synthesis is also stimulated throughinhibition of glycogen phosphorylase and activation ofglycogen synthase.3 In peripheral tissues (primarily skeletalmuscle), the insulin-dependent transportation of the glucosetransporter GLUT4 to the cell membrane is inhibited byGCs. This results in a decreased cellular uptake of glucose.38

Glucose uptake is also regulated by the gradient ofglucose concentrations across the cell membrane. Theglucose gradient is a factor of glucose delivery by the bloodvessels and glucose removal from the tissues by oxidationof pyruvate. Insulin stimulates increased glucose delivery,and therefore uptake, by promoting vasodilation through

nitric oxide pathways. Studies in humans have shown thatGCs are able to inhibit this vasodilation, providing a furthermechanism by which GCs may decrease insulin-mediatedglucose uptake.38 GCs may also stimulate lipolysis in adiposetissue, resulting in increased circulating concentrations offree fatty acids. These free fatty acids serve as substratesfor gluconeogenesis, and also competitively inhibit theoxidation of pyruvate, thereby decreasing the transmem-brane glucose gradient and subsequent glucose uptake.38

In addition to their effects on insulin sensitivity, GCs can inhibitsecretion of insulin from pancreatic β cells.38 All of theseeffects serve to increase blood glucose concentrations.

There is a strong association between high endogenousGC levels and DM in cats. In fact, approximately 80% ofcats with naturally occurring hyperadrenocorticism sufferfrom the disease.32 Exogenous GCs have also been asso-ciated with DM in cats, and some authors believe thatthese drugs are more potent hyperglycaemic agents incats than in other species.12,39 Glucose tolerance is theability of an animal to dispose of an oral or intravenousglucose load. Prednisone decreases glucose tolerance incats,40 providing further evidence of the diabetogeniceffects of GCs in cats. Measurement of insulin sensitivity,defined as the ability of insulin to dispose of glucose, is acommon method to assess changes in carbohydratemetabolism associated with DM. Diabetic cats have beenshown to have decreased insulin sensitivity values comparedto healthy cats.41 In a recent study, cats administeredequipotent immunosuppressive doses of prednisoloneand dexamethasone showed significant decreases ininsulin sensitivity values.42 In addition, a greater decreasein insulin sensitivity was seen with dexamethasone, sug-gesting this GC may possess greater diabetogenic effectsthan prednisolone in the cat.42

The cause of the polyuria and polydipsia (PU/PD), whichmay accompany GC use in the cat, is controversial. Incontrast to the dog, cats becoming polyuric on GCs maymaintain concentrated urine, suggesting that there is lessinterference with the release, or action, of antidiuretichormone than is proposed for dogs.39 Some authors havestated that GC-induced PU/PD in cats occurs secondary toDM, but, in some cases, the onset of PU/PD occurred priorto significant hyperglycaemia or glucosuria. This suggeststhat additional factors could be involved.32,39

Skin

GCs exhibit atrophic effects on the skin that may lead toepidermal and dermal thinning, follicular atrophy, easybruising and poor wound healing.3 These effects are due tothe suppression of both keratinocyte and dermal fibroblastproliferation, as well as suppression of various fibroblast-derived proteins.3 Perhaps the most important of thesuppressed proteins is collagen, but other components ofthe extracellular matrix such as tenascin-C, hyaluronic acid,sulphated glycosaminoglycans and elastin, are also down-regulated by GCs.3 Suppression of collagen synthesisand the necessary early inflammatory phase is likelyresponsible for the deleterious effect of GCs on woundhealing.3 A decrease in epidermal lipids and an increase intransepidermal water loss have also been documentedwith GC use.3 Similar clinical signs of skin thinning, alopeciaand easy bruising have been observed in cats secondary


GCs in the cat

to both endogenous and exogenous GC excess.43 In anon-peer-reviewed series of 62 cats with naturally occurringhyperadrenocorticism, 61% of cats were reported to havethin skin, 23% had hair loss, and 14% displayed bruising.32

Published reports of iatrogenic hyperadrenocorticismare rare in the cat. The cutaneous signs observed in 18cats reported in the literature are summarized in Table 4.The reason for GC administration in many of these caseswas a pruritic skin disorder and it is therefore unclear insome cases whether the cutaneous signs noted were dueto the disease being treated, or the GCs themselves. Twounique side effects of GCs in cats are fragile, easily tornskin and curling of the pinna.43 The skin can become sofragile that even routine handling and restraint may lead totearing and sloughing of large areas of skin resulting inlarge wounds which are difficult to repair. Curling of thepinna is rare and is suggested to occur more commonlywith iatrogenic disease.43

Cardiovascular system

GCs have been associated with hypertension in both dogsand people.3,10 The mechanisms are unclear but couldinclude increased vascular sensitivity to the vasoconstric-tive effects of catecholamines, sodium and water retentionby the kidney due to mineralocorticoid activity, anddecreased amounts of vasodilatory substances such as nitricoxide.3,10 In cats GCs have been associated with CHF in anumber of cases.49 A recent study investigating the mech-anism of CHF in cats administered methylprednisoloneacetate suggested that plasma volume expansion due tothe hyperosmotic effect of hyperglycaemia was the mostlikely cause.49 In that study, despite the increase in plasmavolume, systemic hypertension was not observed, norwas there an increase in total body water, or a decrease inpotassium concentration, to suggest that a significantmineralocorticoid effect was involved.49 A small but signifi-cant increase in interventricular septal thickness was alsonoted, its clinical significance was unclear.49

Liver

Steroid hepatopathy, which is an enlargement of the liverwith typical histological changes, has been consideredunique to dogs.12 The hepatic histopathological changescaused by GCs in dogs are hepatocellular swelling andcytoplasmic vacuolation. The vacuoles contain glycogen.50

Although there is substantial individual variation, with GCuse, dogs can also exhibit palpable hepatomegaly,increases in serum alkaline phosphatase activity, and lessdramatic increases in alanine aminotransferase, γ-glutamyl

transferase and cholesterol.12 Because dogs have a GC-induced isoform of alkaline phosphatase, increased activitydoes not necessarily reflect hepatic effects of GCs.Hepatocellular swelling and vacuolization, however, can causecholestasis-associated increases in alkaline phosphataseactivity.

Although cats have been said not to develop a steroidhepatopathy,12 it may be that steroid hepatopathy in catssimply occurs less frequently, or is more difficult to induceor detect. A GC-induced isoenzyme of alkaline phosphatase,present in dogs, has not been found in cats.51 The half-lifeof alkaline phosphatase in cats is also only approximatelyone-twelfth that of dogs.51 These factors would make themarked enzymes elevations seen in GC-treated dogsless likely in cats. Mild to moderate, and rarely marked,elevations of hepatic enzymes are, however, occasionallyseen in cats secondary to GC use.39,44,45,52 In addition, inboth natural and iatrogenic feline hyperglucocorticism,hepatomegaly and histopathological changes consistentwith a steroid hepatopathy, including glycogen deposition,have been detected.32,39,45 Similar changes have alsobeen found in healthy cats experimentally administeredGCs, all of which suggest that a steroid-induced hepatopathycan also occur in the cat.52

Conclusion

While typically well-tolerated, GCs can potentially induceserious side effects in cats. Studies of GC pharmacologyin the cat are lacking. Special care should be taken in theadministration of GCs to cats at higher risk for diabetes, orto animals with pre-existing heart disease, due to theespecially potent hyperglycaemic effect of GCs in the cat.

References

1. Tuckermann JP, Kleiman A, McPherson KG et al. Molecularmechanisms of glucocorticoids in the control of inflammation andlymphocyte apoptosis. Critical Reviews in Clinical LaboratorySciences 2005; 42: 71–104.

2. Freedman ND, Yamamoto KR. Importin 7 and importin α/importinβ are nuclear import receptors for the glucocorticoid receptor.Molecular Biology of the Cell 2004; 15: 2276–86.

3. Schacke H, Docke W, Asadullah K. Mechanisms involved in theside effects of glucocorticoids. Pharmacology and Therapeutics2002; 96: 23–43.

4. Saklatvala J. Glucocorticoids: do we know how they work?Arthritis Research 2002; 4: 146–50.

5. Buttgereit F, Scheffold A. Rapid glucocorticoid effects onimmune cells. Steroids 2002; 67: 529–34.

6. Broek AHM, Stafford WL. Epidermal and hepatic glucocorticoidreceptors in cats and dogs. Research in Veterinary Science 1992;52: 312–5.

7. Bondy PJ, Cohn LA. Physiological effects and pharmacologic con-siderations of glucocorticoids. Veterinary Medicine 2002; 97:836–40.

8. Graham-Mize CA, Rosser EJ, Hauptman J. Absorption, bioavaila-bility and activity of prednisone and prednisolone in cats. In:Hiller A, Foster AP, Kwochka KW, eds. Advances in VeterinaryDermatology, Vol. 5. Oxford: Blackwell, 2005: 152–8.

9. Bondy PJ, Cohn LA. Choosing an appropriate glucocorticoid treat-ment plan. Veterinary Medicine 2002; 97: 841–9.

10. Behrend EN, Kemppainen RJ. Glucocorticoid therapy: pharmacology,indications and complications. Veterinary Clinics of North America:Small Animal Practice 1997; 27: 187–213.

Table 4. Reported cutaneous signs in 18 cats with iatrogenic hyperadrenocorticism39,44–48

Abnormality Number Percentage

Hair loss 15 83Thin or inelastic skin 8 44Skin tears 4 22Hyperpigmentation 4 22Medially curled pinna 3 17Bruising 2 11Poor hair coat 2 11


Lowe et al.

11. Rhodes KH. Feline immunomodulators. In: Kirk RW, BonaguraJD, eds. Current Veterinary Therapy XII: Small Animal Practice.Philadelphia, PA: W.B. Saunders, 1995: 581–4.

12. Feldman EC, Nelson RW. Glucocorticoid therapy. In: Feldman EC,Nelson RW, eds. Canine and Feline Endocrinology and Reproduction,3rd edn. St. Louis, MO: W.B. Saunders, 2004: 464–83.

13. Behrend EN, Greco DS. Clinical applications of glucocorticoidtherapy in nonendocrine disease. In: Kirk RW, Bonagura JD, eds.Current Veterinary Therapy XII: Small Animal Practice. Philadelphia,PA: W.B. Saunders, 1995: 406–13.

14. Scott DW. Rational use of glucocorticoids in dermatology. In:Kirk RW, Bonagura JD, eds. Current Veterinary Therapy XII: SmallAnimal Practice. Philadelphia, PA: W.B. Saunders, 1995: 573–80.

15. Cohn LA. Glucocorticoid therapy. In: Ettinger SJ, Feldman EC,eds. Textbook of Veterinary Internal Medicine. St. Louis, MO:W.B. Saunders, 2005: 503–8.

16. Scott DW, Kirk RW, Bentinck-Smith J. Some effects of short-termmethylprednisolone therapy in normal cats. The Cornell Veterinarian1979; 69: 104–15.

17. Johnston SD, Mather EC. Feline plasma cortisol (hydrocortisone)measured by radioimmunoassay. American Journal of VeterinaryResearch 1979; 40: 190–2.

18. Kemppainen RJ, Peterson ME. Domestic cats show episodicvariation in plasma concentrations of adrenocorticotropin,alpha-melanocyte-stimulating hormone (alpha-MSH), cortisol andthyroxine with circadian variation in plasma alpha-MSH concentra-tions. European Journal of Endocrinology 1996; 134: 602–9.

19. Leyva H, Addiego L, Stabenfeldt G. The effect of different photo-periods on plasma concentrations of melatonin, prolactin, andcortisol in the domestic cat. Endocrinology 1984; 11: 1729–36.

20. Cohn LA. Glucocorticosteroids as immunosuppressive agents.Seminars in Veterinary Medicine and Surgery (Small Animal)1997; 12: 150–6.

21. Mager DE, Lin SX, Blum RA, Lates CD, Lusko WJ. Dose equivalencyevaluation of major corticosteroids. Pharmacokinetics and celltrafficking and cortisol dynamics. Journal of Clinical Pharmacology2003; 43: 1216–27.

22. Melby JC. Clinical pharmacology of systemic corticosteroids.Annual Review of Pharmacology and Toxicology 1997; 17: 511–27.

23. Garg DC, Ng P, Weidler DJ, Sakmar E, Wagner JG. Preliminary invitro and in vivo investigations on methylprednisolone and itsacetate. Research Communications in Chemical Pathology andPharmacology 1978; 22: 37–48.

24. Braughler JM, Hall ED. Pharmacokinetics of methylprednisolonein cat plasma and spinal cord following a single intravenous doseof sodium succinate ester. Drug Metabolism and Disposition: TheBiological Fate of Chemicals 1982; 10: 551–2.

25. Crager CS, Billon AR, Kemppainen RJ, Brewer WG, AngaranoDW. Adrenocorticotropic hormone and cortisol concentrationsafter corticotrophin-releasing hormone stimulation testing in catsadministered methylprednisolone. American Journal of VeterinaryResearch 1994; 55: 704–9.

26. Willis-Goulet HS, Schmidt BA, Nicklin CF, Marsella R, Kunkle GA,Tebbett IR. Comparison of serum dexamethasone concentrationsin cats after oral or transdermal administration using PluronicLecithin Organogel (PLO): a pilot study. Veterinary Dermatology2003; 14: 83–9.

27. Peterson ME, Graves TK. Effects of low dosages of intravenousdexamethasone on serum cortisol concentrations in the normalcat. Research in Veterinary Science 1988; 44: 38–40.

28. Cohn LA. The influence of corticosteroid on host defense mech-anisms. Journal of Veterinary Internal Medicine 1991; 5: 95–104.

29. Belgi G, Friedmann PS. Traditional therapies: glucocorticoids,azathioprine, methotrexate, hydroxyurea. Clinical and ExperimentalDermatology 2002; 27: 546–54.

30. Lundgren JD, Hirata F, Marom Z et al. Dexamethasone inhibitsrespiratory glycoconjugate secretion from feline airways in vitro bythe induction of lipocortin (lipomodulin synthesis). The AmericanReview of Respiratory Disease 1988; 137: 353–7.

31. Schaffner A. Therapeutic concentrations of glucocorticoids

suppress the antimicrobial activity of human macrophages withoutimpairing their responsiveness to gamma interferon. The Journalof Clinical Investigation 1985; 76: 1755–64.

32. Feldman EC, Nelson RW. Hyperadrenocorticism in cats(Cushing’s syndrome). In: Feldman EC, Nelson RW, eds. Canineand Feline Endocrinology and Reproduction. St. Louis, MO: W.B.Saunders, 2004: 358–93.

33. Hoffman-Jagielska M, Winnicka A, Jagielski D, Lechowski R.Influence of dexamethasone on some cellular aspects of theimmune system in cats. Veterinary Research Communications2003; 27: 643–52.

34. Reinero CR, Brownlee L, Decile KC et al. Inhaled flunisolidesuppresses the hypothalamic-pituitary-adrenocortical axis, buthas minimal systemic immune effects in healthy cats. Journalof Veterinary Internal Medicine 2006; 20: 57–64.

35. Reinero CR, Decile KC, Byerly JR et al. Effects of drug treatmenton inflammation and hyperreactivity of airways and on immunevariables in cats with experimentally induced asthma. AmericanJournal of Veterinary Research 2005; 66: 1121–7.

36. Nair MP, Schwartz SA. Immunomodulatory effects of corticosteroidson natural killer and antibody-dependent cellular cytotoxicactivities of human lymphocytes. Journal of Immunology 1984;132: 2876–82.

37. Dubey JP, Frenkel JK. Immunity to feline toxoplasmosis: modifi-cation by administration of corticosteroids. Veterinary Pathology1974; 11: 350–79.

38. Andrews RC, Walker BR. Glucocorticoids and insulin resistance:old hormones, new targets. Clinical Science 1999; 96: 513–23.

39. Scott DW, Manning TO, Reimers TJ. Iatrogenic Cushing’ssyndrome in the cat. Feline Practice 1982; 12: 30–6.

40. Middleton DJ, Watson ADJ. Glucose intolerance in cats givenshort-term therapies of prednisolone and megestrol acetate.American Journal of Veterinary Research 1985; 46: 2623–5.

41. Feldhahn JR, Rand JS, Martin G. Insulin sensitivity in normal anddiabetic cats. Journal of Feline Medicine and Surgery 1999; 1:107–15.

42. Lowe AL, Graves TK, Campbell KL, Schaeffer DJ. A comparisonof the diabetogenic effects of dexamethasone and prednisolonein cats. Veterinary Dermatology 2007; 18: 184 (Abstract).

43. Helton-Rhodes K. Cutaneous manifestations of hyperadrenocor-ticism. In: August JR, ed. Consultations in Feline Internal Medicine3. Philadelphia, PA: W.B. Saunders, 1997: 191–8.

44. Ferasin L. Iatrogenic hyperadrenocorticism in a cat following ashort therapeutic course of methylprednisolone acetate. Journalof Feline Medicine and Surgery 2001; 3: 87–93.

45. Schaer M, Ginn PE. Iatrogenic Cushing’s syndrome and steroidhepatopathy in a cat. Journal of the American Animal HospitalAssociation 1999; 35: 48–51.

46. Lien Y, Huang H, Chang P. Iatrogenic hyperadrenocorticism in 12cats. Journal of the American Animal Hospital Association 2006;42: 414–23.

47. Greene CE, Gratzek A, Carmichael KP. Iatrogenic hyperadreno-corticism in a cat. Feline Practice 1995; 23: 7–12.

48. Smith SA, Freeman LC, Bagladi-Swanson M. Hypercalcemia dueto iatrogenic secondary hypoadrenocorticism and diabetes melli-tus in a cat. Journal of the American Animal Hospital Association2002; 38: 41–4.

49. Ployngam T, Tobias AH, Smith SA, Torres SM, Ross SJ. Hemody-namic effects of methylprednisolone acetate administration incats. American Journal of Veterinary Research 2006; 67: 583–7.

50. Fittschen C, Bellamy JEC. Prednisone-induced morphologic andchemical changes in the livers of dogs. Veterinary Pathology1984; 21: 399–406.

51. Hoffman WE, Renegar WE, Dorner JL. Alkaline phosphatase andalkaline phosphatase isoenzymes in the cat. Veterinary ClinicalPathology 1977; 6: 21–4.

52. Fulton R, Thrall MA, Weiser MG, Gasper PW. Characterization ofhepatic pathology, serum chemistry and immunologic effects ofprednisolone acetate administration in the cat. In: Proceedings ofthe 29th Annual American College of Veterinary Pathology Meeting,1988: 18.


GCs in the cat

Résumé Les glucocorticoides sont une des deux classes d’hormones, avec les mineralocorticoides,qui sont sécrétées de la corticosurrénale. Depuis la découverte des propriétés anti-inflammatoires del’hydrocortisone, un glucocorticoide naturel, un grand nombre de glucocorticoides artificiels ont étésynthétisés pour augmenter leur efficacité et diminuer les effets secondaires. Ces molécules sontdésormais une des classes thérapeutiques les plus utilisées en médecine vétérinaire. les effets de cesmolécules varient en fonction de l’espèce traitée. Les chats semblent bien tolérer ces molécules qui sontlargement prescrites dans un grand nombre de maladies, toutefois peu d’études sont disponibles sur leseffets des corticoïdes dans cette espèce. Dans cet article, nous passons en revue les données de la littératuresur l’utilisation des glucocorticoides chez le chat.

Resumen Glucocorticoides junto con mineralocorticoides son una de las dos principales clases de hormonassecretadas por las glándulas adrenales. Desde el descurbrimiento de las propiedades antiinflamatorias delglucocorticoide natural hidrocortisona, se han sintetizado un gran número de glucocorticoides para intentarincrementar la eficacia y reducir los efectos adversos. Estos fármacos se consideran uno de los agentesmas comúnmente recetados en la práctica veterinaria. El efecto de estos fármacos varía significativamenteentre especies. Los gatos toleran los glucocorticoides bastante bien, por lo que son recetados para una granvariedad de enfermedades, sin embargo hay pocos estudios acerca de los efectos de glucocorticoides engatos. En este artículo hacemos una revisión de alguna de la literatura disponible sobre el uso de glucocor-ticoides en gatos.

Zusammenfassung Die Glukokortikoide zählen zusammen mit den Mineralkortikoiden zu den zweiHauptklassen der Hormone, die von der Nebennierenrinde sezerniert werden. Seit der Entdeckung derentzündungshemmenden Eigenschaften des natürlichen Glukokortikoids Hydrokortison ist eine großeAnzahl von künstlichen Glukokortikoiden mit dem Bestreben, die Wirksamkeit zu erhöhen und die Neben-wirkungen zu vermindern, synthetisiert worden. Diese Medikamente werden heute als die am häufigstenverschriebenen Wirkstoffe in der tierärztlichen Praxis betrachtet. Es wurde gezeigt, dass die Wirksamkeitdieser Medikamente zwischen den Spezies signifikant variiert. Katzen scheinen Glukokortikoide gut zutolerieren, was dazu führt, dass diese Medikamente für eine große Vielfalt von Zuständen empfohlenwerden, obwohl es nur wenige Studien über die Auswirkung der Glukokortikoide bei Katzen gibt. In diesemArtikel erfolgt eine Review der zur Verfügung stehenden Literatur über die Verwendung von Glukokortikoidenbei Katzen.

Documents

Glucocorticoids in the cat