CHAPTER 14 Glucocorticoid Therapy
Claudia E. Reusch
CHAPTER CONTENTS
Chemistry of Glucocorticoids and Structure-Activity Relationship, 555
Molecular Mechanism of Action, 556
Genomic Effects, 556
Nongenomic Effects, 558
Biologic Effects of Glucocorticoids, 559
Effects on Carbohydrate, Protein, and Lipid Metabolism, 559
Effects on Other Tissues, 559
Anti-Inflammatory and Immunosuppressive Effects, 562
Pharmacokinetics and Clinical Pharmacology, 563
Duration of Action, 563
Route of Administration, 563
Distribution, Metabolism, and Excretion, 565
Dose Equivalents of Glucocorticoids, 565
Galenic Formulations and Steroid Esters, 566
Combination Products, 567
Therapeutic Application and Classes of Glucocorticoid Usage, 567
Goals and General Guidelines, 567
Physiological Replacement Therapy, 568
Anti-Inflammatory Therapy, 568
Immunosuppressive Therapy, 569
Antineoplastic Therapy, 569
Shock, 569
Neurological Diseases, 570
Adverse Effects, 570
Iatrogenic Hyperadrenocorticism, 570
Alteration of the Hypothalamic Pituitary Adrenal Axis, 571
Diabetes Mellitus, 572
Gastrointestinal Hemorrhage and Ulceration, 572
Laboratory Abnormalities, 573
Pancreatitis, 573
Miscellaneous, 573
Glucocorticoid Reduction Protocol, 574
In 1949, Hench and colleagues reported on the first therapeutic
use of a glucocorticoid in nine patients with rheumatoid arthritis.
The substance had been known under the term “compound E”
and was then named “cortisone.” Later it was found that the true
hormone is in fact cortisol, which is reversibly converted to its
inactive metabolite cortisone. In 1950, Edward Kendall, a bio-
chemist at the Graduate School of the Mayo Foundation, the
Swiss chemist, Tadeus Reichstein, and a Mayo Clinic physician,
Philip Hench, were awarded the Nobel Prize for their work on
the adrenal gland hormones. The Noble Lecture held by Kendall
on December 11, 1950, was titled, “The Development of Cor-
tisone as a Therapeutic Agent” (Kendall, 1950). The finding of
Hench and colleagues (1949) introduced the world to a new type
of therapy and there was a saying, “Therapy was now dated BC
(before cortisone) or after (AC)” (Goulding and Flower, 2000a).
The initial discovery was followed by the development of synthetic
steroids mainly for use in inflammatory and immune-mediated
diseases. However, it soon became obvious that their efficacy is
not without costs in terms of potentially serious adverse effects
(Goulding and Flower, 2000b).
Currently, glucocorticoids are among the most frequently used
(and misused) drugs in veterinary medicine. Despite the wide-
spread use of glucocorticoids, scientifically based information on
optimal dose, dose interval, and physiological and pharmacologi-
cal effects in dogs and cats is scarce. Therefore, treatment protocols
are often extrapolated from human medicine or rodent studies or
are the result of clinical experience (Ferguson et al, 2009; Boothe
and Mealey, 2012). Knowledge on effects, different potencies of
synthetic glucocorticoids, adverse effects, and contraindications
will help the veterinarian to make informed decisions and to avoid
serious complications as much as possible.
CHEMISTRY OF GLUCOCORTICOIDS AND
STRUCTURE-ACTIVITY RELATIONSHIP
All hormones of the adrenal cortex are derivatives of cholesterol
and contain the cyclopentanoperhydrophenanthrene nucleus
(Fig. 14-1). The main products of the adrenal cortex are C21
and C19 steroids. The C19 steroids have a keto or hydroxyl
group at position 17 and display androgenic activity. The C21
steroids have a two-carbon side chain at position 17 and are
classified as mineralocorticoids and glucocorticoids. Those C21
steroids that have an additional hydroxyl group at position 17
are often called 17-hydroxycorticoids or 17-hydroxycorticosteroids
(Barrett et al, 2012).
Cortisol (hydrocortisone) has glucocorticoid as well as miner-
alocorticoid properties due to its ability to stimulate both gluco-
corticoid and mineralocorticoid receptors (Parente, 2000). Certain
structures and groups on the steroid base, as well as the orientation
of the groups in the ring system, are essential for the biological
activity. The groups lying below the plane of the steroid ring are
indicated by α and a dashed line (.... OH), the groups lying above
the ring are indicated by β and a solid line (– OH) (Parente, 2000;
Barrett et al, 2012). The important features for biological activity
are: a ketone group at C-3 and C-20, a double bond between C-4
and C-5, a hydroxyl group in β-orientation at C-11, a two-carbon
chain in β-orientation, a hydroxyl group in α-orientation at C-17,
and a methyl group in β-orientation at C-18 and C-19 (Parente,
2000) (Fig. 14-2).
Chemical modifications of the cortisol molecule have generated
compounds with higher glucocorticoid activity and less mineralo-
corticoid activity (Fig. 14-3). Modifications of the molecular struc-
ture also alter the protein binding and hepatic metabolism thereby
prolonging duration of action. High anti-inflammatory properties
are unfortunately also associated with higher glucocorticoid activity
555
556 SECTION 4    THE ADRENAL GLAND

12 17 (i.e., effects on carbohydrate and protein metabolism) (Boothe and

13 Mealey, 2012). Introduction of a double bond between C-1 and
11 C-2 resulted in prednisone and prednisolone, revealing increased
C D 16 anti-inflammatory and reduced mineralocorticoid activity com-
1 9 pared with cortisone and cortisol. Of note, cortisone and predni-
10 14
sone are inactive compounds (or prodrugs) until the 11-keto group
2 is converted into a hydroxyl group in the liver by the enzyme 11-β
8 15
B
hydroxysteroid dehydrogenase (11β-HSD) type 1 (Parente, 2000;
A
Ferguson et al, 2009). The addition of a methyl group in position
3 7 C-6α resulted in methylprednisolone, which has slightly higher anti-
5
inflammatory and less mineralocorticoid effect than prednisolone.
4 6 The insertion of a 16α-hydroxy group decreases mineralocorticoid
FIGURE 14-1 Basic chemical structure of the glucocorticoids (steroid nucleus). activity and leads to the synthesis of triamcinolone (which also has
a 9α-fluoro group). The most potent anti-inflammatory glucocorti-
coids, dexamethasone and betamethasone, were designed by adding
a fluorine atom at C-9α, which increases glucocorticoid activity, and
a methyl group at C-16, reducing mineralocorticoid effects (add-
ing was in α-orientation for dexamethasone and β-orientation for
betamethasone) (Parente, 2000). The effects of glucocorticoids are
21
dose dependent, and they are classified according to their potency
CH2 OH
in relation to the potency of cortisol (Table 14-1). There is an ongo-
ing search to identify compounds or mechanism by which adverse
20 effects can be minimized (McMaster and Ray, 2007; Vandevyver
C=O
18 et al, 2013). One mechanism is the topical administration of drugs,
12
CH3 which are rapidly metabolized if absorbed into the systemic circu-
17 lation. This goal is mainly reached by manipulation of chemical
HO OH
11 13
groups of the D ring of the steroid base (Ferguson et al, 2009).
19 Examples of those so-called “soft” glucocorticoids include beclo-
CH3 16 methasone, budesonide, fluticasone propionate, ciclesonide, and
1 9 loteprednol etabonate (Ferguson et al, 2009; Boothe and Mealey,
10 14 2012). In particular the use of budesonide as an oral drug for the
2
8 15 treatment of inflammatory bowel disease and budesonide and fluti-
casone propionate as inhaled medications for chronic inflammatory
3 airway disease has recently gained popularity in dogs and cats (Bex-
5 7 field et al, 2006; Padrid, 2006; Dye et al, 2013; Galler et al, 2013;
0
4 6
Pietra et al, 2013).

Cortisol (hydrocortisone) MOLECULAR MECHANISM OF ACTION

A
Genomic Effects
CH2 OH Glucocorticoid activities can roughly be divided into genomic
and nongenomic effects. The classical genomic effect is medi-
ated by a cytoplasmic glucocorticoid receptor (GR) that belongs
C=O to the nuclear receptor superfamily, which includes all of the
steroid receptors. GRs are widely distributed throughout the
CH3 body: every cell appears to have GRs (Boothe and Mealey,
O OH 2012). The GRs consist of three domains with different func-
tions: a poorly conserved N-terminal domain, a highly con-
served DNA-binding domain, and a well-conserved C-terminal
CH3 glucocorticoid-binding domain. Several splice variants of the
GR exist, of which GRα is the most widely expressed and is the
variant exerting most of the glucocorticoid actions. The vari-
ant GRβ is unable to bind glucocorticoids, but it may act as an
inhibitor of GRα. The β variant may play a role in glucocorti-
coid resistance and possibly in autoimmune and inflammatory
0 disorders (Ferguson et al, 2009; Nixon et al, 2013). In the rest-
ing (ligand-free) state, GR is located in the cytoplasm, where it
Cortisone exists as a multiprotein complex containing several heat-shock
proteins (Hsp90, Hsp70, Hsp56, Hsp40); there is also interac-
B tion with other molecules, such as immunophilins and several
FIGURE 14-2 Structure of (A) cortisol (hydrocortisone) and its inactive additional factors (Stahn et al, 2007; Vandevyver et al, 2013).
metabolite cortisone (B). The GR is inactive until bound to a glucocorticoid ligand.

Glucocorticoids enter the cell by passive diffusion through the
cell membrane, although there may also be an active trans-
port mechanism. After binding of the glucocorticoid, the heat
shock proteins dissociate from the GR, resulting in confor-
mational changes that unmask nuclear localization sequences.
Thereafter, the GR/glucocorticoid complex is translocated
into the nucleus, where it activates or represses target gene
transcription (Nixon et al, 2013). Although the main actions
of glucocorticoids are mediated through the GR, some effects
are also mediated through another nuclear receptor, the min-
eralocorticoid receptor (MR). The MR has a high affinity for
endogenous glucocorticoids, which are generally present in
much higher concentrations than mineralocorticoids. One of
the major mechanism by which the body limits the access of
endogenous glucocorticoids to the MR is through the activ-
ity of the enzyme 11β-HSD type 2 that converts cortisol to
inactive cortisone. Therefore, when the MR is co-expressed
with 11β-HSD type 2, its activation results in mineralocor-
ticoid activity; in the absence of 11β-HSD type 2, the MR is
CH2 OH
C=O
CH3
OH
HO
CH3
0
0
Prednisolone
CH2 OH
C=O
CH3
HO OH
CH3
0 0
CH3
Methylprednisolone
FIGURE 14-3 Structure of selected synthetic glucocorticoids.
CHAPTER 14 |   Glucocorticoid Therapy 557
a high-affinity GR (Nixon et al, 2013). The best character-
ized mechanism of transcriptional activation is the binding of
the GR/glucocorticoid complex to specific DNA binding-sites
(glucocorticoid response elements [GREs]) in the promoter
regions of target genes after entering the nucleus (Vandevyver
et al, 2013). Binding to positive GRE induces synthesis of
anti-inflammatory proteins as well as regulator proteins that
are important for metabolism (e.g., enzymes involved in glu-
coneogenesis). The process mediated through positive GRE
is also called transactivation and is considered to be respon-
sible for numerous side effects of glucocorticoids. Binding
to negative GRE leads to inhibition of gene transcription
(transrepression) of the pro-opiomelanocortin (the precursor
of adrenocorticotropic hormone—ACTH), α-fetoprotein,
and prolactin gene, as well as suppression of inflammatory
genes, such as interleukin-1β (IL-1β) and interleukin-2 (IL-
2) Löwenberg et al, 2007; Stahn et al, 2007). Besides binding
to GRE, other mechanisms for the upregulation and down-
regulation of genes exist. For instance, suppressed target gene
CH2 OH
C=O
CH3
OH
O
CH3
Prednisone
CH2 OH
C=O
CH3
OH
HO
OH
CH3
Triamcinolone
558 SECTION 4    THE ADRENAL GLAND
CH2 OH
C=O
CH3
OH
HO
CH3
CH3
F
0
0
Dexamethasone
CH2 OH
C=O
CH3
HO
CH3
Budenoside
FIGURE 14-3, cont’d
expression can be achieved through direct protein-protein
interaction with pro-inflammatory transcription factors,
such as activator protein-1 (AP-1), nuclear factor kappa-
light-chain-enhancer of activated B cells (NF-κB), nuclear
factor of activated T-cells (NFAT), or signal transducers and
activator of transcription (STAT; Löwenberg et al, 2007). It
takes approximately 30 minutes for the activation of the GR,
nuclear transportation of the GR/glucocorticoid complex,
binding to promoter regions, and initiation of transcription
and translation. Hours to days are required until changes on
cellular, tissue or organism level become obvious (Stahn et al,
2007). For many years, it was thought that the undesirable
side effects of glucocorticoid therapy are due to dimer-medi-
ated transactivation, whereas its beneficial anti-inflammatory
activity is mainly caused by monomer-mediated transrepres-
sive effects. Research was therefore focused on the develop-
ment of dissociated compounds that only exhibit those actions
of glucocorticoids that are monomer-dependent. The dimer/
monomer dogma has recently been challenged, because it was
demonstrated that the GR dimer-dependent transactivation is
CH2 OH
C=O
CH3
HO OH
CH3
CH3
F
Betamethasone
O
CH3
O
essential for the anti-inflammatory actions (Nixon et al, 2013;
Vandevyver et al, 2013).
Nongenomic Effects
In addition to the classic genomic mode of action, glucocorticoids
may exert effects through nongenomic mechanisms. It has been
recognized that some of the immunosuppressive, anti-inflamma-
tory, anti-allergic effects, and effects when used during shock occur
too fast to be regulated via transcription. Rapid clinical effects may
be seen when glucocorticoids are administered intravenously or
intra-articularly at high doses. Various underlying mechanisms for
the nongenomic effects have been described, such as nonspecific
interactions of glucocorticoids with cellular membranes, nonge-
nomic effects that are mediated by the cytosolic GR, and specific
interactions with a membrane-bound GR (Löwenberg et al, 2007;
Stahn et al, 2007).
It has been shown that glucocorticoids at high concentrations
intercalate into membranes, thereby changing their physiological
properties and the activities of membrane-associated proteins. For
 CHAPTER 14 |   Glucocorticoid Therapy 559

TABLE 14-1   COMPARISON OF THE CHARACTERISTICS OF THE MAJOR GLUCOCORTICOID PREPARATIONS

GLUCOCORTICOID/ANTI- MINERALOCORTICOID
DRUG INFLAMMATORY POTENCY POTENCY EQUIVALENT ORAL DOSE (mg) BIOLOGIC HALF-LIFE (h)
Short-Acting
Cortisol (hydrocortisone) 1 1 20 8-12
Cortisone 0.8 0.8 25 8-12
Intermediate-Acting
Prednisolone/Prednisone 4 0.8 5 12-36
Methylprednisolone 5 0.5 4 12-36
Triamcinolone 5 0 4 12-36
Long-Acting
Betamethasone 25-30 0 0.7-0.8 36-72
Dexamethasone 25-30 0 0.7-0.8 36-72
Mineralocorticoids
Aldosterone 0 200-1000
Fludrocortisone 10 125-200

Data from Parente L: The development of synthetic glucocorticoids. In Goulding NJ, Flower RJ, editors: Glucocorticoids, Basel, 2000, Springer Basel AG; and Boothe DM, Mealey KA:
Glucocorticoids and mineralocorticoids. In Boothe DM, editor: Small animal clinical pharmacology and therapeutics, ed 2, St Louis, 2012, Saunders/Elsevier.

instance, this results in reduced calcium and sodium cycling across
the cell membrane of immune cells, which contributes to rapid
immunosuppression and reduction of the inflammatory process.
Binding of glucocorticoids to the cytosolic GR leads to dissociation
of signaling molecules, which mediate rapid responses; the cyto-
solic GR is also involved in inhibition of the release of arachidonic
acid, an essential mediator for cell growth and various metabolic/
inflammatory reactions. Binding of glucocorticoids to a membrane-
bound GR, which may be a variant of the cytosolic GR, seems to be
involved in apoptosis and T cell receptor–mediated signal transduc-
tion (Stahn et al, 2007). The physiological significance of the non-
genomic effects is not totally clear. It is assumed that they play an
important role during stress when the concentration of endogenous
glucocorticoids is high (Jiang et al, 2014). Fig. 14-4 summarizes
genomic and nongenomic mechanisms of glucocorticoids.
BIOLOGIC EFFECTS OF GLUCOCORTICOIDS
The name glucocorticoid is derived from the words glucose and
cortex, and it relates to the role of glucocorticoids in glucose
metabolism and their origin from the adrenal cortex. Glucocorti-
coids, however, have a much broader spectrum of function, they
influence most cells in the body, and without them an individual
will not survive a stressful event.
Effects on Carbohydrate, Protein, and Lipid Metabolism
The physiological effects of glucocorticoids in the fed state are
small; however, during fasting, they contribute to the mainte-
nance of blood glucose levels by increasing hepatic gluconeogen-
esis and decreasing uptake of glucose in peripheral tissues (muscle,
fat). These effects protect glucose-dependent organs (e.g., brain
and heart) from starvation. Glucocorticoids stimulate glycogen
deposition and inhibit glycogen-mobilizing enzymes. This allows
other hormones (e.g., glucagon and epinephrine) to mobilize glu-
cose when needed (e.g., between meals). Glucocorticoids exert
catabolic effects on muscle (i.e., decreased glucose uptake and
metabolism), decreased protein synthesis, and increased release of
amino acids, providing precursors for gluconeogenesis in the liver.
In adipose tissue, glucocorticoids stimulate lipolysis, which gener-
ates free fatty acids and glycerol, thereby providing energy and
substrate for gluconeogenesis (Carroll et al, 2011; Hall, 2011).
In healthy individuals, the increase in blood glucose is coun-
terbalanced by an increase in insulin secretion. High levels of
glucocorticoids (endogenous or exogenous) reduce the sensibility
of many tissues, in particular muscle and fat, to the stimulatory
effects of insulin on glucose uptake and utilization (i.e., lead to
insulin resistance). In this way, glucocorticoids may induce glu-
cose intolerance and diabetes mellitus or worsen glycemic control
in an individual with pre-existing diabetes. Glucocorticoid excess
also leads to increased breakdown of protein, clinically seen as
muscle wasting, thinning of the skin, and delayed wound healing
(Boothe and Mealey, 2012). Although glucocorticoids stimulate
lipolysis, increased fat deposition is a common clinical sign. The
paradox has been explained by steroid-induced stimulation of
appetite and the lipogenic effect of hyperinsulinemia. The reason
for the abnormal fat distribution is unknown (Carroll et al, 2011).
Effects on Other Tissues
Growth and Development
Glucocorticoids play an important role in normal fetal development.
They stimulate lung maturation through synthesis of surfactant pro-
teins in the near-term fetus, allowing adaption to air breathing. In
physiological concentrations, glucocorticoids stimulate gene tran-
scription of growth hormone (GH); glucocorticoid excess, however,
inhibits skeletal growth by catabolic effects on bone, muscle, and
connective tissue and inhibition of insulin-like growth factor-1
(IGF-1) effects (Ferguson et al, 2009).
Bone, Cartilage, and Calcium
The effects of glucocorticoids on bone are complex and include
direct and indirect effects. Under physiological circumstances,
bone formation and bone resorption are tightly coupled; in cases of
560 SECTION 4    THE ADRENAL GLAND

FIGURE 14-4 Genomic and nongenomic immunoregulation by glucocorticoids (GCs). GCs passively diffuse into
cells and bind to the cytoplasmic glucocorticoid receptor (GR), after which the GC-GR complex translocates into
the nucleus for gene regulation. Left: Ligated GR directly inhibits pro-inflammatory transcription factors (i.e.,
activator protein-1 [AP-1], nuclear factor of activated T-cells [NFAT], nuclear factor kappa-light-chain-enhancer
of activated B cells [NF-κB], and signal transducers and activator of transcription [STAT]) (a) or actively sup-
presses transcription (transrepression) of inflammatory genes (i.e., interleukin-1β [IL-1β] and IL-2) through
binding to negative glucocorticoid response elements (nGRE) (b). Activated GR induces transcription (transacti-
vation) of immunosuppressive genes (i.e., IκB, annexin-1, IL-10, mitogen-activated protein kinase [MAPK] phos-
phatase-1, lipocortin-1, and annexin-1) via positive GREs (pGRE) (c). GC-induced biological responses, which are
based on transrepression, are slow because some time is required before RNA and protein levels of target genes
are fully degraded (a,b). GC-dependent transactivation of genes that encode regulator proteins is less slow (“me-
dium slow”) compared with transrepression (c). Right: GCs induce rapid effects (occurring within minutes) on
transmembrane currents, signal transduction (e.g., T-cell receptor [TCR] and MAPK signaling pathways), second-
messenger cascades or intracellular Ca2+ mobilization. It is currently assumed that nongenomic GC effects
are mediated by cytosolic or membrane-bound GRs, or via nonspecific interactions with cell membranes. In this
simplified scheme, no GR-chaperones are depicted. (Reproduced with permission from Loewenberg M, Verhaar
AP, van den Brink GR, et al.: Glucocorticoid signaling: a nongenomic mechanism for T-cell immunosuppression,
Trends Mol Med 13:158, 2007.) cGR, Cytosolic glucocorticoid receptor; mGR, membrane-bound glucocorticoid
receptor; TF, transcription factor.

glucocorticoid excess, those processes are uncoupled (van Brussel
et al, 2009). Glucocorticoid excess decreases number and function
of osteoblasts, induces apoptosis of osteocytes, and increases the
formation of osteoclasts. Indirect effects include disturbed calcium
metabolism, muscle weakening, and decrease of GH and gonado-
tropin secretion (Canalis et al, 2007; van Brussel et al, 2009). In
humans, glucocorticoid-induced osteoporosis belongs to the most
devastating side effects of long-term glucocorticoid therapy (van
Brussel et al, 2009). In dogs and cats, effects of glucocorticoids are
rarely described. Recently, the effect of glucocorticoids on mineral
density of the vertebral spine was investigated. Application of
2 mg/kg prednisone over 30 days led to a significant loss of bone
mass (Costa et al, 2010). Pathological fractures were not seen in
the study by Costa and colleagues (2010) and also do not occur in
dogs with long-standing glucocorticoid excess (e.g., in dogs with
endogenous hyperadrenocorticism).
At physiological concentrations, glucocorticoids stimulate col-
lagen; glucocorticoid excess results in inhibition of collagen syn-
thesis, depression of chondrocyte metabolism, and decrease of the
proteoglycan content of cartilage (Boothe and Mealey, 2012).
Glucocorticoids inhibit calcium absorption from the intesti-
nal tract by antagonizing the effect of active vitamin D3 and by
decreasing the expression of specific calcium channels in the
duodenum. The inhibition is not due to decreased levels of
vitamin D3, as those are normal, or even increased in the pres-
ence of glucocorticoid excess. Glucocorticoids also increase renal

calcium excretion as well as the excretion of phosphorous. Serum
phosphate concentrations are reduced, whereas calcium concentra-
tions are usually maintained normal (Canalis et al, 2007; Carroll
et al, 2011). Theoretically, the reduced absorption and increased
secretion of calcium would promote secondary hyperparathyroid-
ism. In humans on glucocorticoid therapy, however, increased
parathyroid hormone (PTH) levels have not been consistently
demonstrated. Glucocorticoids may alter the secretory dynamics
of PTH with a decrease in its tonic release and an increase in pul-
satile bursts. Additionally, they may enhance sensitivity of skeletal
cells to PTH by increasing the number and affinity of PTH recep-
tors (Canalis et al, 2007). So far, no detailed studies on calcium
balance in dogs and cats with endogenous or exogenous glucocor-
ticoid excess have been performed. In dogs, the administration of
approximately 1 mg/kg prednisolone every other day for 6 weeks
did not result in significant changes in concentrations of total
and ionized calcium, phosphate, vitamin D metabolites (25(OH)
D and 1,25(OH)2D3), and PTH in blood and urinary fractional
excretion of calcium and phosphate (Kovalik et al, 2012). The
results contrast in part those of Ramsey, et al., (2005) who assessed
parameters of calcium metabolism in dogs with endogenous
hyperadrenocorticism. Total and ionized calcium concentrations
were not different to a matched control group. Different from
humans and the study of Kovalik, et al, (2012), phosphate and
PTH concentrations were significantly higher. Approximately one
third of the dogs had PTH concentrations greater than three times
the reference range. No explanation for the increased phosphate
concentrations could be given; it was assumed to play a role in the
increase in PTH concentrations (Ramsey et al, 2005).
Renal Function
Glucocorticoids increase the glomerular filtration rate, sodium
transport in the proximal tubule, and free water clearance. They
have an inhibitory effect on antidiuretic hormone (ADH) and
may decrease permeability of the distal tubules to water through a
direct effect (Boothe and Mealey, 2012). Cortisol and several syn-
thetic glucocorticoids have mineralocorticoid activity. Depending
on the concentration or dose and the activity of the 11β-HSD
type 2, they act on the MR and cause sodium retention and potas-
sium loss. The polyuria and polydipsia commonly seen in dogs
(infrequently in non-diabetic cats treated with glucocorticoids) is
considered to be mainly due to inhibition of ADH release and
action.
Cardiovascular and Respiratory Functions
Glucocorticoids have positive inotrope and positive chronotropic
actions on the heart. Because glucocorticoids are necessary for
maximal catecholamine sensitivity, they contribute to the main-
tenance of normal vascular tone. They decrease capillary perme-
ability through inhibition of the activity of kinins and bacterial
endotoxins and by decreasing the amount of histamine released
by basophils (Ferguson et al, 2009). Refractory shock may occur
when individuals deficient in glucocorticoids are exposed to stress
(Carroll et al, 2011).
Glucocorticoid excess may lead to hypertension through vari-
ous mechanisms, such as their intrinsic mineralocorticoid activity,
activation of the renin-angiotensin-aldosterone system; enhance-
ment of cardiovascular inotropic and pressor activity of vasoactive
substances, including catecholamines, vasopressin and angioten-
sin II; and suppression of the vasodilatory system, including the
nitric oxide (NO) synthase, prostacyclin and kinin-kallikrein sys-
tems. The exact mechanisms in dogs and cats have not been elu-
cidated (Reusch et al, 2010). The studies on the potential role of
CHAPTER 14 |   Glucocorticoid Therapy 561
aldosterone revealed conflicting results (Goy-Thollot et al, 2002;
Javadi et al, 2003; Wenger et al, 2004). Martinez and colleagues
(2005) demonstrated increased vascular reactivity to increasing
doses of norepinephrine in dogs with experimentally induced
hypercortisolism.
Glucocorticoids increase the number and affinity of β2 recep-
tors, thus promoting bronchodilatation (Boothe and Mealey,
2012).
Gastrointestinal Tract
Glucocorticoids are involved in normal function and integrity of
the gastrointestinal tract. Glucocorticoid excess is associated with
reduced gastric mucosal cell growth and renewal and decreased
mucus production, resulting in impairment of the protective bar-
rier of the gastric mucosa (Boothe and Mealey, 2012). Gluco-
corticoid therapy in dogs with neurological disease may result
in gastrointestinal hemorrhage, ulcers, and colonic perforations.
Gastric hemorrhage has also been described in healthy dogs given
high doses of methylprednisolone sodium succinate (Rohrer
et al, 1999a).
Central Nervous System Function
Glucocorticoids are involved in maintaining adequate blood glu-
cose concentrations for cerebral functions, maintaining cerebral
blood flow, and influencing electrolyte balance in the central
nervous system (CNS). They also decrease formation of cerebro-
spinal fluid, appear to regulate neuronal excitation, and appear
to have neuroprotective effects (Boothe and Mealey, 2012). In
humans, glucocorticoid excess initially causes euphoria, and pro-
longed exposure may result in various psychologic abnormalities,
including irritability, emotional lability, and depression; impair-
ment in cognitive functions is also common (Carroll et al, 2011).
In dogs treated with glucocorticoids, euphoric effects are also
commonly seen.
Blood Cells
Glucocorticoids have only little effects on erythrocytes, although
mild polycythemia may be seen. The underlying mechanism may
be glucocorticoid-induced enhancement of erythroid progenitor
proliferation (von Lindern et al, 1999).
Endogenous or exogenous glucocorticoid excess may induce
leukocytosis in dogs and cats. The leukogram (“stress leukogram”)
is characterized by mature neutrophilia, lymphopenia, and eosin-
openia. In dogs, monocytosis may be an additional finding, which
is usually not present in cats. The mature neutrophilia is due to
several factors, such as increased release of neutrophils from bone
marrow, shift of marginated neutrophils in the circulating neutro-
phil pool, and decreased movement of neutrophils from blood into
tissue. Lymphopenia is the result of a redistribution of circulating
lymphocytes; lysis of lymphocytes may occur with high doses of
glucocorticoids. Eosinopenia is caused by inhibition of eosinophil
release from the bone marrow and sequestration of eosinophils
within tissues (Schultze, 2010; Valenciano et al, 2010). In dogs,
glucocorticoid excess may provoke thrombocytosis (Neel et al,
2012); knowledge on potential glucocorticoid-induced thrombo-
cytosis in cats is scarce.
Hypothalamic Pituitary Adrenal Axis
Glucocorticoids inhibit synthesis and secretion of ACTH from the
corticotropic cells in the anterior pituitary and of corticotropin-
releasing hormone (CRH) and ADH from neurons in the hypo-
thalamus in a negative feedback fashion. Exogenous glucocorticoids
have profound effects on the hypothalamic pituitary adrenal
562 SECTION 4    THE ADRENAL GLAND
(HPA) axis. Even “physiological” doses of glucocorticoids (0.22
mg/kg prednisolone once daily) may result in suppression of
the HPA axis, which is reflected by reduced increase of cortisol
after ACTH stimulation and lead to a reduction of the zona fas-
ciculate and reticularis to the zona glomerulosa in the adrenal
gland (Ferguson et al, 2009). Generally, the degree and dura-
tion of suppression of the HPA axis depends on dose, potency,
half-life, and duration of administration of the glucocorticoid
preparation. HPA axis suppression can occur with any form of
glucocorticoid. Glucocorticoids possessing anti-inflammatory
effects but no suppressive effects on the HPA axis have not
yet been identified (Ferguson et al, 2009). For more details on
HPA axis suppression, see the Adverse Effects section.
Thyroid Function
Glucocorticoids have a major impact on the hypothalamic pitu-
itary thyroid axis and also influence peripheral metabolism of thy-
roid hormones. Main proposed mechanisms include inhibition of
synthesis and release of thyroid-stimulating hormone (also known
as thyrotropin; TSH), decrease in thyroxine (T4) binding proteins,
and impairment of peripheral 5′-deiodination. Studies in dogs do
not point as clearly to a suppressive effect on TSH secretion in
dogs as compared to humans. In dogs with hyperadrenocorticism,
reduced T4 and triiodothyronine (T3) concentrations were found
in more than 50% of cases. The concentrations of both hormones
normalized during treatment of the hyperadrenocorticism. The
T4 response after TSH administration was also reduced (Peter-
son et al, 1984). TSH concentrations in dogs with hyperadreno-
corticism were not different from that of control dogs in another
study (Meij et al, 1997). The effect of exogenous glucocorticoids
on thyroid hormones has been evaluated in various studies. The
duration and extent of thyroid hormone suppression varies with
type, dose, and route of administration, and duration of therapy
and is certainly also influenced by individual sensitivity. In dogs,
the application of immunosuppressive doses of prednisone/pred-
nisolone (1.1 to 2.0 mg/kg twice a day) for 3 weeks significantly
decreased T4; it also decreased free T4, albeit to a lesser extent.
The effect on T4 was seen as early as 1 day after start of therapy.
Endogenous TSH concentrations were not affected (Torres et al,
1991; Daminet et al, 1999; Daminet and Ferguson, 2003). See
Chapter 3 for more details.
Growth Hormone and Gonadotropins
Glucocorticoids decrease GH secretion, most likely by increas-
ing somatostatin release. Dogs with hyperadrenocorticism have
decreased response of GH after stimulation with xylazine, clonidine,
and growth hormone-releasing hormone (GHRH) (Frank, 2005).
Exogenous glucocorticoid excess presumably has the same effect.
Hyperadrenocorticism is also frequently associated with repro-
ductive disturbances, such as testicular atrophy, reduced libido,
and persistent anestrus. Similarly, exogenous glucocorticoid
(prednisone) leads to a decrease in circulating testosterone con-
centrations in male dogs. Prednisone treatment also resulted in a
reduction of basal luteinizing hormone (LH) concentration, which
suggested that glucocorticoids inhibit the gonadal axis at the hypo-
thalamic or pituitary level (Kemppainen et al, 1983; Kemppainen,
1984). Interestingly, however, basal LH concentrations in dogs
with hyperadrenocorticism were not different from controls. It was
hypothesized that glucocorticoids have a direct inhibitory effect
on gonads and/or on transport and metabolism of their secretory
products and influence the sensitivity of the feedback control at
the hypothalamic/pituitary level (Meij et al, 1997). Glucocorticoid
administration to pregnant dogs may lead to abortion.
Anti-Inflammatory and Immunosuppressive Effects
Glucocorticoids suppress inflammatory and immune-mediated
responses of the body, and this fact has been the stimulus for the
development of potent glucocorticoid preparations. The anti-
inflammatory and immunosuppressive effects only occur when
supraphysiological doses (i.e., pharmacological doses) are given.
Both effects are closely related, and which of the two predomi-
nates in a clinical situation is a question of the dose given. Many
hundreds of glucocorticoid response genes have been identified.
Additional to the genomic effects, rapid actions of glucocorti-
coids on inflammation are mediated by nongenomic mechanisms
(Rhen and Cidlowski, 2005). It is important to remember that
the encompassing properties render glucocorticoid therapy dan-
gerous, because it can mask severity and progression of the disease
and serious side effects may occur. Glucocorticoids limit early and
late manifestations of inflammation, including edema formation,
fibrin deposition, leukocyte migration, phagocytic activity, colla-
gen deposition, and capillary and fibroblast proliferation. Many of
these processes involve lymphokines, and other soluble mediators
of inflammation and glucocorticoids exert their anti-inflamma-
tory effects through those mediators (Boothe and Mealey, 2012).
Generally, due to the fact that GR expression is ubiquitous, gluco-
corticoids can affect nearly all cells of the immune system. Glucocor-
ticoids inhibit proliferation, growth and differentiation, adhesion,
migration, and chemotaxis of monocytes/macrophages, neutro-
phils, and T cells (Box 14-1). Antigen processing by monocytes/
macrophages is suppressed, and antibody production by B cells may
be impaired; apoptosis of monocytes/macrophages, T cells, and B
cells is increased (Vollmar and Dingermann, 2005). Of note, B
BOX 14-1    S
 elected Effects of Glucocorticoids
on the Immune System
Neutrophils
Neutrophilia
Depressed chemotaxis
Depressed margination
Depressed phagocytosis
Depressed antibody-dependent cellular cytotoxicity
Depressed bactericidal activity
Stabilization of membranes
Inhibition of phospholipase A2α
Macrophages
Depressed chemotaxis
Depressed phagocytosis
Depressed bactericidal activity
Depressed IL-1 and IL-6 production
Depressed antigen processing
Lymphocytes
Depressed proliferation
Depressed T-cell responses
Impaired T-cell mediated cytotoxicity
Depressed IL-2 production
Depressed lymphokine production
Immunoglobulins
Decreased antibody synthesis only after high dose, long-term therapy
Interference with antibody function
Modified from Tizard IR, Veterinary immunology, ed 9, St Louis, 2013, Elsevier.
IL, Interleukin.

cells are thought to have greater resistance to the effects of gluco-
corticoids, although the inhibition of T-cell help will have indirect
consequences for B-cell activation. Glucocorticoids may inhibit the
action of complement molecules and interfere with the function
of immunoglobulins by down-regulation of Fc receptor expression
(Day, 2011). Usually, high doses of glucocorticoid are required to
suppress antibody production, and therapeutic doses do not signifi-
cantly decrease the antibody response to an antigenic challenge (e.g.,
vaccinations; Boothe and Mealey, 2012; Tizard, 2013).
Inflammatory and immunologic reactions are mediated by various
signaling pathways. The pathways that are associated with the activa-
tion of NF-κB are of particular importance (Fig. 14-5). In its inactive
state, NF-κB is sequestered in the cytoplasm by the inhibitory factor
IκB-α. Tumor necrosis factor alpha (TNFα), interleukin-1 (IL-1),
microbial pathogens, viral infections, and other inflammatory signals
trigger signaling cascades that activate IκB-α kinases, resulting in libe­
ration and translocation of NF-κB into the nucleus. NF-κB stimu-
lates the transcription of cytokines (e.g., IL-1, IL-2, IL-6, and TNFα),
chemokines (e.g., IL-8, monocyte chemotactic protein-1 [MCP-1]),
cell-adhesion molecules, complement factors, and receptors for these
molecules. After binding to its receptor, glucocorticoids inhibit NF-κB
by direct protein-protein interaction; glucocorticoids also induce the
synthesis of IκB-α, thereby inhibiting translocation of NF-κB into the
nucleus (Rhen and Cidlowksi, 2005; Steinfelder and Oetjen, 2009;
see also http://www.bu.edu/nf-kb/gene-resources/target-genes/).
Similar to NF-κB, the transcription factor AP-1 is one of the
key mediators of the inflammatory response; AP-1 is inhibited by
glucocorticoids as well (Busillo and Cidlowski, 2013). NF-κB also
induces the transcription of cyclooxygenase 2 (COX2), an enzyme
that is essential for prostaglandin production; glucocorticoids
inhibit COX2 through inhibition of NF-κB. Other mechanisms
by which glucocorticoids inhibit prostaglandin synthesis are medi-
ated through induction and activation of annexin I (also called
lipocortin-1) and through induction of mitogen-activated protein
kinase (MAPK) phosphatase 1. Annexin I is an anti-inflammatory
protein that inhibits phospholipase A2α, thereby blocking the release
of arachidonic acid and its subsequent conversion to eicosanoids.
Phospholipase A2α is also inhibited by MAPK phosphatase 1.
MAPKs are pivotal in the regulation of immune responses; they are
involved in the production of inflammatory mediators (e.g., TNFα,
IL-1, IL-6, prostaglandin, NO, and inducible nitric-oxide synthase)
and in T-cell development and function. Removal of the phospha-
tases (which is induced by glucocorticoids) renders MAPK inac-
tive (Rhen and Cidlowski, 2005; Liu et al, 2007). Glucocorticoids
reduce local inflammation by preventing the actions of histamine
and plasminogen activators (Stewart and Krone, 2011). In summary,
the anti-inflammatory and immunosuppressive effects of gluco-
corticoids are attributed to partial or complete suppression of an
extremely complex interplay of cells and cell mediators. The potent
effects of glucocorticoids on leukocytes are responsible for most of
the anti-inflammatory activity. These effects are also immunosup-
pressive, which explains their efficacy in immune-mediated disease.
It should be remembered, however, that glucocorticoids can lead to
an increased susceptibility to infection (Papich and Davis, 1989).
PHARMACOKINETICS AND CLINICAL
PHARMACOLOGY
Duration of Action
A distinction has to be made between plasma half-life and bio-
logical half-life of glucocorticoids. Plasma half-life is the amount
of time required for 50% of a drug’s concentration to disappear
CHAPTER 14 |   Glucocorticoid Therapy 563
from plasma, whereas the biological half-life refers to the dura-
tion of effect. The biologic half-life of glucocorticoids is dispa-
rate, because many of the biological effects are due to alterations
in genetic regulation of protein production; biological effects are
delayed and prolonged compared to the drug concentration in
plasma (Cohn, 2010). It is the biological half-life that needs to
be considered when a treatment protocol is established. Gluco-
corticoids are usually divided into three groups according to the
duration of HPA axis suppression. Cortisol (hydrocortisone)
and cortisone are considered short-acting (biologic half-life < 12
hours); prednisolone, prednisone, methylprednisolone, and tri-
amcinolone are intermediate-acting (biologic half-life 12 to
36 hours); and dexamethasone and betamethasone are long-acting
drugs (biologic half-life 36 to 72 hours) (see Table 14-1). Duration
of action is influenced by factors such as route of administration,
the preparation used (e.g., soluble or insoluble steroid ester), and
other variables, such as health of the patient and concurrent use
of other drugs.
Route of Administration
Glucocorticoids of varying potency are available in oral, paren-
teral, and topical formulations.
Oral
Cortisol (hydrocortisone) and synthetic glucocorticoids are
orally effective, and oral administration is the preferred route
for systemic application (except in emergency situations). It is
the safest, most convenient, and most economical route. The
main disadvantages and limitations of the oral route include
vomiting as a result of irritation of the gastric mucosa, variable
absorption due to many factors (gastrointestinal disease, local
blood flow, and/or presence of food or other drugs), and the
need for cooperation of the pet. The oral bioavailability differs
between glucocorticoids; it is generally highest for cortisol,
prednisolone, and methylprednisolone and lower for dexa-
methasone. Triamcinolone and budesonide have a very low oral
bioavailability; in the case of budesonide, the low bioavailability
is a desired effect because it is designed for local application
(e.g., for treatment of inflammatory bowel disease [IBD]).
Previously, it had been thought that prednisolone and the pro-
drug prednisone are equivalent in terms of dosing when used as
oral drugs. However, this belief does not seem to be correct. It
was shown in cats that only 21% of orally-administered predni-
sone appeared in the blood as active prednisolone. It is not clear if
the differences are due to decreased gastrointestinal absorption or
to decreased hepatic conversion of prednisone to prednisolone
(Graham-Mize and Rosser, 2004). According to these data, the
dose of prednisone must be three- to fivefold higher than that of
prednisolone to achieve equivalent activity (Boothe and Mealey,
2012). Because prednisone is commonly used in cats, its poor
absorption (or poor conversion) may contribute to the perceived
glucocorticoid resistance in cats (Lowe et al, 2008a). Also in dogs,
oral administration of prednisone may not result in systemic predni­
solone concentrations, which are achieved with oral prednisolone.
The relative bioavailability of prednisolone was only 65% when
prednisone was administered compared to the administration of
prednisolone (Boothe and Mealey, 2012). These data suggest that
prednisolone should be preferred over prednisone.
Parenteral
Most glucocorticoids for parenteral use are synthesized as glu-
cocorticoid esters, which either improves solubility or increases
564 SECTION 4    THE ADRENAL GLAND

Cytokine

Glucocorticoid
Proinflammatory
proteins
Cell membrane

Cytokine receptor

Protein

Cytoplasm

P
IKBa Glucocorticoid
IKBa receptor

p50 p65

NF-KB p50 p65

IKBa mRNA
Nucleus

mRNA

Direct
interaction

p50 p65

Glucocorticoid Coding
response element sequence

IKBa-gene Proinflammatory
gene

FIGURE 14-5 Inhibition of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-κB) by glucocorticoids. NF-κB is a dimer and consists of two subunits (p50, p65). In its inactive state, it is
sequestered in the cytoplasm by the inhibitory factor IκB-α. Upon stimulation by, for example, cytokines NF-κB is
released and translocates into the nucleus. After binding to specific DNA sites, NF-κB increases the transcription
of target genes, which include genes of cytokines, chemokines, growth factors, cell adhesion molecules, comple-
ment factors, immunoreceptors, and cyclooxygenase 2 (COX2). Glucocorticoids inhibit NF-κB after their binding to
the glucocorticoid receptor (GR) through direct protein-protein interaction between the GR and the p65 subunit.
Glucocorticoids can also stimulate the transcription of the IκB-α gen, thereby augmenting the inhibition of NF-κB.
Inhibition of NF-κB is one of the major mechanisms of the anti-inflammatory and immunosuppressive effect of
glucocorticoids. (Redrawn from Steinfelder HJ, Oetjen E: Nebennierenrindenhormone. In Aktories K, Foerstermann U,
Hofmann F, Starke K, editors: Allgemeine und Spezielle Pharmakologie und Toxikologie, ed 10, 2009, Elsevier Urban
& Fischer.) mRNA, Messenger ribonucleic acid.
 CHAPTER 14 |   Glucocorticoid Therapy 565

TABLE 14-2   SOME CHARACTERISTICS OF COMMON ROUTES OF DRUG ADMINISTRATION

ROUTE ABSORPTION PATTERN SPECIAL UTILITY LIMITATIONS AND PRECAUTIONS

Intravenous (IV) Absorption circumvented
Potentially immediate effects
Subcutaneous (SC) Prompt, from aqueous solution
Slow and sustained, from repository
preparations
Intramuscular (IM) Prompt, from aqueous solution
Slow and sustained, from repository
preparations
Oral ingestion Variable, depends upon many
factors (see text)
Valuable for emergency use
Permits titration of dosage
Suitable for large volumes and for
irritating substances when diluted
Suitable for some insoluble suspensions
and for implantation of solid pellets
Suitable for moderate volumes, oily
vehicles, and some irritating substances May interfere with interpretation of certain diagnostic
Most convenient and economical;
usually safer than other routes
Increased risk of adverse effects
Must inject solutions slowly as a rule
Not suitable for oily solutions or insoluble substances
Not suitable for large volumes
Possible pain or necrosis from irritating substances
Precluded during anticoagulant medication
tests (e.g., creatine phosphokinase)
Requires patient cooperation
Absorption potentially erratic and incomplete for drugs
that are poorly soluble, slowly absorbed, or unstable

duration of action. Water-soluble esters of cortisol and synthetic
glucocorticoids can be given intravenously to achieve high con-
centrations rapidly. Prolonged effects are obtained by intramus-
cular (IM) injection of water-insoluble esters (suspensions) of
cortisol and its synthetic derivatives (see later). Injection of drugs
has certain advantages over oral administration. Absorption is
usually more predictable than oral application, and therefore, the
effective dose can be accurately selected. In particular, intravenous
(IV) administration circumvents absorption issues and permits
titration of dose. It also allows the administration of large vol-
umes. Disadvantages include the need for asepsis, possible pain
and necrosis, and costs. See Table 14-2 for some characteristics of
the major routes of glucocorticoids.
Topical
Topical steroids for dermatological indications are available in
ointments, creams, gels, solutions, shampoos, and rinses. Glu-
cocorticoids for ophthalmological indications come as eye drops
(aqueous solutions and suspensions) and ointments; intra-articular
application is usually in form of crystal suspensions. Glucocor-
ticoids are also used as inhalants in patients with lung disease.
Topical therapy can provide high concentrations of a potent glu-
cocorticoid at a specific site while reducing systemic side effects.
However, topical glucocorticoids can be absorbed to a certain
extent, exerting the same adverse reaction as systemically admin-
istered steroids. The extent of percutaneous absorption depends
on various factors, including the preparation vehicle, ester form of
the steroid (greater lipid solubility enhances percutaneous absorp-
tion), integrity of epidermal barriers (e.g., absorption is increased
in case of inflammation), size of treated area, and duration of treat-
ment. Absorption is enhanced by use of occlusive wraps and possi-
bly by clipping the skin (Behrend and Kemppainen, 1997; Boothe
and Mealey, 2012). Systemic effects (e.g., suppression of the HPA
axis) may also occur with inhaled glucocorticoids and in conjunc-
tion with intra-articular, intra-lesional, or ocular application.
Distribution, Metabolism, and Excretion
After absorption, cortisol and synthetic glucocorticoids are bound
to corticosteroid binding protein (CBP, also called transcortin) and
albumin. Only the unbound, free fraction of glucocorticoids is
active and can enter cells. CBP is α-globulin secreted by the liver,
which has a high affinity for glucocorticoids but a relatively low
binding capacity. Albumin, on the other hand, has a low affinity but
large binding capacity. Glucocorticoids compete with one another
for binding sites and will displace one another at high concentra-
tions (Boothe and Mealey, 2012). Compared to cortisol, binding
to CBP is less for synthetic glucocorticoids; they are mainly bound
to albumin or circulate as free hormones, thereby diffusing more
readily into tissues. Glucocorticoids distribute widely in all tissues
of the body, and they pass the blood brain and placental barrier.
Glucocorticoids are metabolized in the liver and to a lesser extent
in the kidney; synthetic drugs are metabolized slower than cortisol.
Metabolism is by oxidation or reduction followed by glucuronida-
tion or sulfation, and excretion of the metabolites is mainly via the
kidney. Only small amounts of glucocorticoids are excreted in the
unmodified form. Biliary and fecal elimination do not appear to
be significant; enterohepatic cycling takes place to a small extent
(Ungemach, 2010; Boothe and Mealey, 2012).
Synthetic steroids with an 11-ketogroup, such as cortisone and
prednisolone, must be enzymatically reduced to the 11-β-hydroxy
derivative before they become biologically active. The enzyme 11β-
HSD type 1, which catalyzes this reaction, is expressed mainly in
the liver but also in other tissues, including adipose tissue, immune
system cells, and brain tissue. Similarly, also in natural situations, this
enzyme generates active (endogenous) cortisol from inactive (endog-
enous) cortisone. The isoform 11β-HSD type 2 is predominantly
expressed in classic mineralocorticoid targets, such as distal nephron,
salivary glands, colon, and placenta. It inactivates cortisol by mediat-
ing the conversion to inactive cortisone and thereby ensures that only
aldosterone binds to the MR (Chapman et al, 2013; Fig. 14-6).
Dose Equivalents of Glucocorticoids
The glucocorticoid activity is closely related to the anti-inflam-
matory activity, and the effective anti-inflammatory time usually
equals the time of HPA axis suppression (Ferguson et al, 2009).
The anti-inflammatory and mineralocorticoid activities of corti-
sol (hydrocortisone) are used as a baseline for comparison with
the synthetic glucocorticoids and are arbitrarily assigned as being
1. Chemical modifications have generated glucocorticoids with
greater glucocorticoid/anti-inflammatory activity and less miner-
alocorticoid activity. Some derivatives (e.g., triamcinolone, dexa-
methasone) have no or negligible mineralocorticoid effects even
at high doses. Increased anti-inflammatory potency is also associ-
ated with longer duration of action. The latter can be prolonged
566 SECTION 4    THE ADRENAL GLAND
FIGURE 14-6 Interconversion of cortisol and
cortisone by 11β-hydroxysteroid dehydrogenase
(11β-HSD) type 1 and 2. Similar to the conver-
sion of cortisone to cortisol, prednisone has
to be converted to prednisolone to be able to
bind to the glucocorticoid receptor (GR). NAD+,
Nicotinamide adenine dinucleotide; NADH, nico-
tinamide adenine dinucleotide plus hydrogen;
NADP+, nicotinamide adenine dinucleotide
phosphate; NADPH, nicotinamide adenine di-
nucleotide phosphate plus hydrogen.
substantially by esterification. See the Chemistry of Glucocorti-
coids and Structure-Activity Relationship section and Box 14-1
for more details; the effects of esterification are discussed later.
There is a general belief that there are no relevant qualitative dif-
ferences between the various glucocorticoid preparations because
they all bind to the GR. Equipotent amounts of any glucocorticoid
exert similar effects, meaning that a higher dose of a less potent
glucocorticoid can achieve the same effect as a lower dose of a more
potent preparation (Cohn, 2010). When choosing a treatment
protocol, the veterinarian has to be aware of the equivalent doses
of glucocorticoids. Failure to make dose adjustments for different
glucocorticoids will result in the administration of inadequate or
excessive doses, leading to either inefficacy or dangerous overdose.
For instance, a dose of 1 mg/kg prednisolone in a dog is a reason-
able anti-inflammatory dose; the equivalent dose of dexamethasone
is only approximately 0.14 mg/kg (Calvert and Cornelius, 1990a).
Generally, the anti-inflammatory dose is considered to be approxi-
mately 10 times the physiological dose, and immunosuppressive
doses are roughly twice the anti-inflammatory dose. In contrast to
the aforementioned belief of equal effects, it is possible that there
are indeed some qualitative differences between the various syn-
thetic steroids. In an in vitro model, it was shown that dexametha-
sone was more effective than prednisone and cortisol in inhibiting
the clearance of immunoglobulin G (IgG)-coated cells by its effect
on Fc receptors of splenic macrophages (Ruiz et al, 1991). In
healthy cats, dexamethasone showed a greater diabetogenic effect
than equipotent doses of prednisolone (Lowe et al, 2009).
Galenic Formulations and Steroid Esters
Water solubility of glucocorticoids is generally low and can be
altered by pharmaceutical manipulations. Esterification and the
kind of ester at C-21 of the glucocorticoid base determine to a
large extent the lipid/water solubility ratio and the duration of
action (Ferguson et al, 2009). The ester moiety also determines if
the drug can be given intravenously, intramuscularly, or topically
(Fig. 14-7; Table 14-3). Glucocorticoid preparations for oral use
are either free alcohols or they are esterified; however, in this case,
esterification does not impair bioavailability.
For parenteral application, three galenic formulations are
available.
Water-Soluble Ester (Aqueous Solutions)
The most commonly used esters are succinate, hemisuccinate,
and phosphate; common formulations are hydrocortisone sodium
succinate, prednisolone sodium succinate, prednisolone sodium
phosphate, methylprednisolone sodium phosphate, and dexa-
methasone sodium phosphate. Those esters are hydrolyzed within
minutes, resulting in immediate availability of the glucocorticoid.
They can be administered intravenously, as well as intramuscularly
and subcutaneously. These characteristics render them ideal for
emergency situations. The duration of action of these esterified
glucocorticoids is equivalent to that of the unmodified glucocor-
ticoid (Cohn, 2010).
Free Alcohol Solutions
These preparations are unique to veterinary medicine as dexa-
methasone solutions. Dexamethasone is poorly soluble in water,
but it is available as an injectable preparation in solution with
polyethylene glycol. The glucocorticoid is released within minutes
to a few hours. Free alcohol solutions can be administered intra-
muscularly as well as intravenously. IV application, however, may
be associated with CNS side effects. If IV application of larger
doses is required, water soluble esters should be used.
 CHAPTER 14 |   Glucocorticoid Therapy 567

O O
C CH2 CH2 C O Na Sodium succinate
O
P O Na
Sodium phosphate
O
CH2O Na
C O O
CH3 Acetate
OH OH C CH3
CH3
CH3 O CH3
Acetonide FIGURE 14-7 Esters of glucocorticoids. Gluco-
C CH2 C CH3
corticoid structure illustrating various esters that
O CH3
may bind to C-21.

TABLE 14-3   D
 URATION OF ACTION OF VARIOUS STEROID ESTERS AFTER
INTRAMUSCULAR ADMINISTRATION

ABSORPTION FOLLOWING
STEROID ESTER INTRAMUSCULAR APPLICATION DURATION OF ACTION MOST COMMONLY USED GLUCOCORTICOID BASES
Sodium succinate Minutes to hours Hours Hydrocortisone, prednisolone, prednisone, methylprednisolone,
dexamethasone, betamethasone
Sodium phosphate
Acetate Days to weeks Days to weeks Methylprednisolone, triamcinolone, betamethasone
Diacetate
Acetonide Weeks Weeks Triamcinolone
Dipropionate
Pivalate

Insoluble Steroid Ester (Suspensions)
Suspensions can be administered intramuscularly, intra-articu-
larly, and intralesionally. They are not to be given intravenously.
They are used as depot preparation because of their slow release
of the active glucocorticoid from the site of administration.
They provide long-term, low level therapy and are not indi-
cated in situations in which a quick effect and high blood lev-
els are needed (Feldman and Nelson, 2004). The duration of
action depends on the extent of water-solubility. Water solubil-
ity of acetate and diacetate esters is moderate and duration of
action ranges from days to weeks. Pivalate, dipropionate, and
acetonide esters are the least water soluble and have duration
of actions of several weeks. It is of utmost importance to real-
ize that glucocorticoid preparations esterified with those esters
do not compare with the native base with regard to duration
of effect. For instance, the duration of effect of methylpred-
nisolone is 12 to 36 hours; the duration of methylprednisolone
acetate, however, is 3 to 6 weeks (Cohn et al, 2010). The major
advantage of the suspensions is convenience of administration.
However, they have major disadvantages, such as unpredictabil-
ity of blood concentrations, long-term suppression of the HPA
axis (may be up to several months after a single dose), pos-
sible induction of glucocorticoid resistance, and the fact that
the drug cannot be withdrawn in case adverse reactions occur
(Boothe and Mealey, 2012). Steroid suspensions should be
handled with care, and the guidelines of the manufacturer with
regard to storage temperature and shelf life should be followed.
The steroid suspensions represent some of the most abused and
overused drugs in veterinary medicine. Other than for intra-
lesional and intra-articular therapy, those long-acting prepa-
rations are hardly ever needed. The exceptions are fractious
cats and cats that live outdoors and are only seen occasion-
ally by their owners. The same anti-inflammatory effects can
be achieved with much shorter acting oral preparations. Use
of short-acting drugs allows the dose to be altered as needed
and helps to minimize HPA axis suppression and other adverse
effects (Feldman and Nelson, 2004).
Combination Products
Combination products between glucocorticoids and other phar-
maceutical products (e.g., antibiotics) are available. However, their
use is associated with various problems, such as dose discrepancies
and variable duration of effects of the constituent drugs. Dose
discrepancy means that administrations based on recommended
dose for one of the drugs may result in underdosing or overdos-
ing of the other drug in the product. The use of those drugs is
discouraged.
THERAPEUTIC APPLICATION AND CLASSES OF
GLUCOCORTICOID USAGE
Goals and General Guidelines
Except in case of physiological replacement, therapy with gluco-
corticoids is not directed at the inciting agent. Glucocorticoids
are used to reduce the processes that are activated in response to
a disease (Boothe and Mealey, 2012). Oftentimes, glucocorti-
coids are applied, although there is no indication or even a clear
contraindication in higher than recommended doses and/or as
depot preparations that lead to long-term suppression of the
HPA axis. The goal is to bring the disease process under control
568 SECTION 4    THE ADRENAL GLAND
with the lowest dose necessary. In serious conditions, initial IV
application may be required. For this purpose, water-soluble
ester preparations should be used. Thereafter, treatment should
be continued with oral glucocorticoids (e.g., prednisolone). Par-
enteral use of depot preparations (insoluble steroid esters) should
only be used in exceptional cases (i.e., if application of shorter
acting steroids is not possible [fractious cats]). After achieving
disease remission, the latter should be maintained with the low-
est possible dose; alternate-day regimens using oral predniso-
lone should be used whenever indicated. Cats have fewer GRs
than dogs and require higher doses. For the discussion on the
preferred use of prednisolone over prednisone, see the Route of
Administration section.
Generally, given dose ranges should be regarded as approxi-
mate guidelines, because glucocorticoid sensitivity differs
between individuals. Frequent reevaluations of patients treated
with glucocorticoids are of utmost importance. It is the predom-
inant opinion that cats require higher doses of glucocorticoids
than dogs. This belief is supported by a study demonstrating
that cats have approximately half the density of GRs in skin
and liver as compared to dogs, and the receptors have lower
binding affinity (van den Broek and Stafford, 1992; Lowe et al,
2008a). Physiological effects of glucocorticoids occur at much
lower doses than do anti-inflammatory and immunosuppressive
doses (see Dose Equivalents of Glucocorticoids). Before initiat-
ing glucocorticoid therapy, the clinician should identify the goal
(e.g., physiological replacement, suppression of inflammation,
suppression of the immune system, or other actions like in neu-
rological or neoplastic disorders) (Cohn, 2010). Other questions
that should be answered prior to glucocorticoid therapy are (Fer-
guson et al, 2009):
  
• Has an exact diagnosis been made and specific treatment been
initiated?
• Have other types of treatment been explored to minimize glu-
cocorticoid dose and side effects?
• Are there contraindications or known risk factors?
• How serious is the disease?
• What is the anticipated length of glucocorticoid therapy?
Physiological Replacement Therapy
Animals with primary or secondary adrenocortical insufficiency
require replacement of glucocorticoids. In case of primary
disease (Addison's disease), the majority of patients also need
mineralocorticoid replacement. Replacement means to provide
glucocorticoids in amounts similar to those of the naturally
produced glucocorticoids (mainly cortisol). Ideal replacement
mimics the hormonal output of the adrenal gland under basal
conditions, which is roughly 1 mg/kg cortisol per day in dogs
and cats. Dose increase is needed in times of stress (Ferguson
et al, 2009). A perfect replacement is difficult to reach because
of the dynamic function of the adrenal gland with minute-to-
minute adaption of cortisol secretion according to the actual
requirement. Prednisolone is the glucocorticoid preparation
most commonly used for replacement therapy in a dose of
0.1 to 0.25 mg/kg once daily. Glucocorticoid sensitivity varies
widely between individuals, and therefore, replacement doses
have to be curtailed to the patient's need. In some dogs in
which the mineralocorticoid deficiency is replaced by fludro-
cortisone (which also has glucocorticoid activity), additional
prednisolone may not be required under normal conditions.
During times of stress, the need for glucocorticoid activity
increases. As a rough guideline, the replacement dose should be
increased two to five times in case of moderate stress, and five
to twenty times in case of severe stress (e.g., surgery) (Ferguson
et al, 2009). See Chapter 12 for more details.
Anti-Inflammatory Therapy
Inflammatory and allergic disorders are the most common rea-
sons for the use of glucocorticoids. If no specific treatment can
be initiated or is insufficient, glucocorticoids can help to com-
bat the clinical signs. However, there is a great potential for
misuse in this category. If an infectious disease goes unnoticed,
the use of glucocorticoids may have deleterious effects because
the disease can progress and the outcome can potentially be
fatal. Due to the general effects of glucocorticoids (e.g., reduc-
tion of fever, stimulation of appetite, feeling of euphoria, and
suppression of the clinical signs of inflammation), the clini-
cian may have the impression of improvement, while in fact
the disease is worsening (Cohn, 2010). Calvert and Cornelius
(1990b) described this as, “When glucocorticoids are mis-
used, the patient may walk all the way to the necropsy labora-
tory.” There are a few exceptions, as in some infectious diseases
(e.g., bacterial or Malassezia-induced otitis externa or severe
ehrlichiosis), the concurrent administration of glucocorticoids
may have beneficial effects. It is understood that in the latter
disease the application should be limited to a few days (2 to 7
days) (Cohn, 2003; Rougier et al, 2005; Bensignor and Gran-
demange, 2006). Generally, before using glucocorticoids for
their anti-inflammatory effects, information regarding specific
conditions should be reviewed.
Except in emergency cases (e.g., acute bronchial disease)
in which IV administration of sodium succinate or sodium
phosphate esters of prednisolone or methylprednisolone is
indicated, oral prednisolone is usually the treatment of choice.
In dogs, the anti-inflammatory dose of prednisolone is 0.5 to
1.0 mg/kg per day. In cats, it is usually recommended to give
twice the dose of dogs (e.g., 1.0 to 2.0 mg/kg) (Lowe et al,
2008a; Cohn, 2010). As soon as clinical signs of inflammation
are under control, the dose should be reduced to the lowest
necessary concentration. The induction period usually ranges
between 5 and 7 days (Behrend and Kemppainen, 1997). Pred-
nisolone (or methylprednisolone) enables accurate dose titra-
tion and the possibility of withdrawal in case of adverse effect.
It is also the glucocorticoid that can be most appropriately used
every other day after remission is achieved, thereby allowing
the HPA axis to recover to a certain extent (Boothe and Mealey,
2012). There is some controversy as to whether the daily dose
of prednisolone should be given at once or divided twice daily.
As studies supporting either frequency are lacking, once-daily
dosing seems reasonable—in particular in animals that are dif-
ficult to medicate (Lowe et al, 2008a).
Topical instead of systemic glucocorticoids may be use-
ful in inflammatory conditions of the eye, skin, respiratory
tract, gastrointestinal tract, and joints. Topical steroids reduce
inflammation by their local activity while minimizing systemic
effects. Newer generation glucocorticoids (also called “soft
glucocorticoids”) were designed specifically for topical use in
humans, and some of them have also been investigated in small
animals. Inhalant glucocorticoids are used in nebulizers or
metered dose inhaler (MDI) in patients with chronic inflam-
matory airway inflammation. They have relatively low systemic
bioavailability because of their poor absorption and extensive
first-pass metabolism in the liver into inactive metabolites.
Examples are fluticasone and budesonide; their local potencies

are extremely high. In the case of budesonide, the potency
compared to cortisol is 60, that of fluticasone is 540 (Viviano,
2013). Both have been successfully used as inhaled glucocor-
ticoids in dogs and cats (Bexfield et al, 2006; Padrid, 2006;
Cohn et al, 2010; Galler et al, 2013). Budesonide is also avail-
able as an oral drug and exerts its inflammatory action locally
in the intestinal tract. It is mainly used to treat IBD in dogs
(Dye et al, 2013; Pietra et al, 2013). Mometasone is a potent
topical glucocorticoid with low systemic effects designed for
use in dermatological diseases; it is 25 times more potent than
cortisol (Mendelsohn, 2009).
Immunosuppressive Therapy
Glucocorticoids are considered the initial first-line therapy in
various immune-mediated diseases, including immune-medi-
ated hemolytic anemia, immune-mediated thrombocytopenia,
immune-mediated polyarthritis, systemic lupus erythematosus,
and pemphigus complex. They are also used to prevent organ
rejection after transplantation and to reduce immunological
reactions associated with some infectious diseases, such as feline
infectious peritonitis (FIP) and ehrlichiosis (Cohn, 2003; Greg-
ory et al, 2006; Case et al, 2007; Addie et al, 2009; Hopper et al,
2012). It should be noted, however, that treatment protocols for
small animals are mostly empirical and adapted from human
medicine. Rigorous evaluations by randomized double-blinded
placebo-controlled trials have not been performed (Whitley and
Day, 2011).
The goal of immune-suppressive therapy is to achieve disease
remission quickly, which usually requires high doses; thereafter,
the dose is tapered slowly to the lowest level that will maintain
remission. Oral application of prednisolone is the preferred
modality. In acute or emergency situations, IV application of
water-soluble esters of prednisolone or methylprednisolone may
be indicated. Depot preparations do not allow dose adjustments
and should not be used. The initial oral dose of prednisolone
typically is 2 to 4 mg/kg in dogs and 2 to 8 mg/kg in cats per
day (Cohn, 1997; 2010; Lowe et al, 2008a). The dose is usu-
ally divided twice daily, based on the belief that this division
will decrease gastrointestinal side effects. Generally, larger dogs
should be treated with the lower end of the dose range (Cohn,
2010). In the opinion of the author, the high-end dose in cats
should be used with great caution. The recommendation may
in part be based on the frequent use of prednisone instead of
prednisolone. As mentioned earlier, it is now known that only
a small part of oral prednisone appears as prednisolone in the
systemic circulation in cats (Graham-Mize and Rosser, 2004).
Some clinicians prefer to use dexamethasone for the first few
doses and thereafter switch to oral prednisolone. There are no
controlled clinical studies to confirm any advantage of this
approach. In one experimental study, dexamethasone was more
effective than prednisone and cortisol in inhibiting the clearance
of IgG-coated cells (Ruiz et al, 1991) (see Dose Equivalents of
Glucocorticoids).
If dexamethasone is used, equipotent doses have to be calcu-
lated (e.g., 2 mg/kg prednisolone equals approximately 0.3 mg/kg
dexamethasone). High doses of prednisolone are continued for
several days after remission is achieved; usually, high doses are
needed for 1 to 4 weeks.
Thereafter, the dose should be tapered slowly over many weeks
to months (see Glucocorticoid Reduction Protocol). Adverse
effects are commonly seen with immunosuppressive doses, and
the owner has to be warned about them. The addition of other
CHAPTER 14 |   Glucocorticoid Therapy 569
immunosuppressive agents may have steroid-sparing effects and
may allow disease control at lower glucocorticoid doses and faster
tapering of the dose (Cohn, 2010).
Antineoplastic Therapy
Prednisolone is often included in combination chemotherapy
protocols for their cytotoxic activity. Additional desired effects
of prednisolone are reduction of edema and inflammation,
appetite-stimulations, and decrease of nausea and vomiting.
Oral prednisolone is also used for alleviation of chronic cancer
pain; the recommended dose in dogs is 0.25 to 1.0 mg/kg, and
for cats it is 0.5 to 1.0 mg/kg (Mealey et al, 2003; Lascelles,
2013). Interestingly, in dogs with multicentric lymphoma
using a multidrug protocol, the benefit of prednisolone with
regard to outcome was recently questioned (Zandvliet et al,
2013). In case of financial or other restrictions, prednisone/
prednisolone (initial dose, 2 mg/kg) is sometimes used as a
single agent in lymphoma cases with a possible tumor control
of 1 to 2 months. Besides the short remission period, other dis-
advantages include serious side effects and the potential induc-
tion of multidrug resistance. The latter would limit the success
of more aggressive drug therapy in case the owner changes his
or her mind (Chun, 2009; Vail et al, 2013). Besides the poten-
tial risk of decreased response to later chemotherapy, glucocor-
ticoids induce apoptosis of neoplastic lymphocytes and may
interfere with the diagnosis; they should therefore only be used
after the diagnosis has been made.
Glucocorticoids may also be used in patients with hypercalce-
mia of malignancy (see Chapter 15) and to increase blood glucose
concentrations in cases with insulinoma (see Chapter 9).
Shock
The use of high-dose glucocorticoid therapy for shock has fallen
repeatedly in and out of favor (Cohn, 2010). Different from the
past, high-dose glucocorticoids are nowadays mentioned only in
the treatment protocols of anaphylactic shock. In humans, epi-
nephrine is the first line treatment with a rapid onset of action;
and although glucocorticoids are often used, their onset of action
is considered quite slow (Lieberman, 2014). A systemic review
of databases failed to identify adequately designed studies, and
no relevant evidence for the use of glucocorticoids was found.
The authors were therefore unable to make any recommenda-
tions for the use of glucocorticoids in the treatment of anaphy-
laxis in humans (Choo et al, 2013). Similarly, in dogs and cats,
epinephrine is the drug of choice for treatment of anaphylaxis
(Shmuel and Cortes, 2013). Glucocorticoids continue to be fre-
quently used in small animals with anaphylaxis; however, as in
humans, no studies support their benefit. Of note, glucocorticoids
themselves may cause allergic reaction and even anaphylaxis. The
application of methylprednisolone sodium succinate 30 mg/kg
intravenously is commonly mentioned for cases with anaphylactic
shock (Dowling, 2009).
In humans with septic shock, relative adrenal insufficiency
may be present and low-dose glucocorticoid therapy for a few
days appeared to be safe and may have some benefit for shock
reversal and short-term survival (Annane et al, 2009; Sligl et al,
2009). Although relative adrenal insufficiency may also exist in
dogs and cats, no clinical studies have investigated the use of low-
dose glucocorticoid therapy in cases with septic shock. The results
of one experimental study using low-dose corticosteroids showed
beneficial effects in dogs with severe sepsis; however, results also
570 SECTION 4    THE ADRENAL GLAND

pointed to reduced bacterial clearance even with short term treat- TABLE 14-4   POTENTIAL DRUG
ment (Hicks et al, 2012). Therefore, no recommendation can be INTERACTIONS OF
made for the application of glucocorticoids in septic shock. They GLUCOCORTICOIDS
should only be used at low doses, if at all, under close monitoring
of the patient. DRUG POTENTIAL INTERACTION
Antacids Reduced oral glucocorticoid absorption
Neurological Diseases Anticholinesterase agents Muscle weakness
Previously, glucocorticoids were advocated for the treatment of Aspirin (salicylates) Reduced salicylate blood levels
traumatic brain injury on the basis that they decreased brain Cyclophosphamide Inhibition of hepatic metabolism of
edema. However, in humans, high-dose methylprednisolone was cyclophosphamide
associated with an increase in mortality. Their use in humans
as well as in small animals with brain injury is no longer rec- Cyclosporine Increase blood levels of each, by inhibiting
ommended (DiFazio and Fletcher, 2013). In acute spinal cord hepatic metabolism of each other
injury, methylprednisolone is considered to reveal free radical- Digoxin Secondary to hypokalemia, increased risk
scavenging effects, which other glucocorticoids are lacking. It is for arrhythmias
suggested that methylprednisolone has a positive effect if admin- Diuretics (furosemide, Increased risk of hypokalemia
istered within 8 hours of the time of insult. Suggested initial thiazides)
dose of methylprednisolone sodium succinate is 30 mg/kg fol-
Ephedrine Increased metabolism of glucocorticoids
lowed by repeated boluses of 15 mg/kg at 2 and 6 hours, then
every 8 hours up to 48 hours after the trauma (Park et al, 2012). Estrogens Potentiation of glucocorticoid effect
However, these doses are enormous and have the potential of Insulin Decreased insulin effect
serious side effects (e.g., gastrointestinal ulceration, immuno- Ketoconazole Decreased metabolism of glucocorticoids
suppression, and impaired wound healing). Sound data to sup-
port the use of this protocol is lacking in small animals, and its Macrolide antibiotics (eryth- Decreased metabolism of glucocorticoids
use in acute spinal cord injury is currently controversial (Park romycin, clarithromycin)
et al, 2012). Nonsteroidal anti-­ Increased risk of gastric ulceration
inflammatory drugs
(NSAIDs)
ADVERSE EFFECTS
Phenobarbital Increased metabolism of glucocorticoids
Adverse effects are common with glucocorticoid therapy, in
Phenytoin Increased metabolism of glucocorticoids
particular if the protocol includes high doses and/or long-term
application. Severely reduced quality of life and even fatal out- Rifampin Increased metabolism of glucocorticoids
comes are possible. On the other hand, glucocorticoids may be Vaccines Immunosuppressive doses of glucocorti-
life-saving and have major therapeutic benefits when used ade- coids may augment virus replication,
quately. As with any therapy, benefits must be weighed against avoid live-attenuated vaccines
potential adverse effects. Glucocorticoids can also alter the effec-
tiveness or toxicity of other drugs. One of the most important Modified from Plumb DC, editor: Plumb’s veterinary drug handbook, ed 7, Ames, IA, 2011,
Wiley-Blackwell.
examples is the substantially increased risk of gastric ulceration
when glucocorticoids are co-administered with non-steroidal
anti-inflammatory agents (Table 14-4). Numerous adverse effects be seen either as a short- or long-term effect. Resolution of
may occur; the most important ones are discussed in the follow- those signs takes considerably longer than cessation of polyuria,
ing section. polydipsia, polyphagia, and panting. Improvement may be seen
within a few weeks; however, depending on severity, resolution
Iatrogenic Hyperadrenocorticism may take up to 6 months or longer. Resolution may not always
be complete; for instance, persistence of calcinosis cutis and of
In a significant percentage of dogs with hyperadrenocorticism, pulmonary mineralization has been reported, and there may be
the disease is in fact caused by exogenous glucocorticoids. Clini- color change in new hair growth (Huang et al, 1999; Blois et al,
cal signs and laboratory abnormalities of iatrogenic hyperadre- 2009). Exogenous glucocorticoids lead to atrophy of the adrenal
nocorticism are identical to those of the endogenous form of the glands, which may be seen ultrasonographically as reduction in
disease. Polyuria, polydipsia, polyphagia, and panting usually length and height of the cranial and caudal pole. The decrease in
manifest within the first 1 to 2 weeks of therapy in dogs (e.g., size is progressive during therapy and percentage change varies
with oral prednisolone in anti-inflammatory or immunosup- between dogs (Pey et al, 2012). Generally, there is a large indi-
pressive doses). These signs may even occur within hours after vidual variation with regard to glucocorticoid sensitivity. The
the first dose. They dissipate as the dose is tapered or discon- same dose may be tolerated well in one dog, whereas substantial
tinued (Feldman and Nelson, 2004). More severe signs such side effects are seen in another dog. Even low doses (e.g., sug-
as cutaneous lesions (thin hair coat, alopecia, hyperpigmenta- gested for physiological replacement) may induce side effects in
tion, pyoderma, calcinosis cutis, and thin skin), poor wound sensitive dogs. In particular, large breed dogs may develop pro-
healing, muscle weakness and atrophy, hepatomegaly due to found weakness and paraparesis when treated with high doses of
steroid hepatopathy, pendulous abdomen, urinary tract infec- glucocorticoids.
tion, and myotonia usually require a longer time and develop Cats are considered to be more resistant than dogs toward the
within weeks to months (Behrend and Kemppainen, 1997; development of iatrogenic hyperadrenocorticism. Associated
Huang et al, 1999; Feldman and Nelson, 2004). Lethargy may signs occur most often after repeated injections of long-acting

glucocorticoid preparations; however, occurrence of signs (e.g.,
polyphagia and weight gain) have also been reported after a
single injection of methylprednisolone acetate (Ferasin, 2001).
It is often assumed that polyuria and polydipsia do not occur
in cats until diabetes mellitus is induced by exogenous glu-
cocorticoids. Although this may be true for the majority of
cases, polyuria and polydipsia have also been reported in cats
without diabetes (Lien et al, 2006; Lowe et al, 2008a). Other
signs of iatrogenic hyperadrenocorticism are similar to those
seen in dogs. Unique to the cat is the development of spon-
taneous tearing and sloughing of the skin and, in rare cases,
medial curling of the pinnae (Scott et al, 1982; Lowe et al,
2008a; 2008b). Steroid hepatopathy does occur in cats, but is
considered to be less common than in dogs (Schaer and Ginn,
1999). Of note, signs of iatrogenic hyperadrenocorticism may
not only occur with oral or parenteral application but also with
topical treatment. Exceptions are the newer generations of top-
ical glucocorticoids (budesonide, fluticasone), which seem to
have minimal side effects. There is no treatment for iatrogenic
hyperadrenocorticism. The only measure consists in cessation
of glucocorticoid therapy. Because the HPA axis is usually sup-
pressed, adrenocortical insufficiency may develop if therapy is
abruptly stopped (see later and Glucocorticoid Reduction Pro-
tocol section).
Alteration of the Hypothalamic Pituitary Adrenal Axis
Closely related to the development of clinical signs of gluco-
corticoid excess is the suppression of the HPA axis. Of note,
however, suppression of the HPA axis may be present without
the animal displaying clinical signs of hyperadrenocorticism.
All synthetic glucocorticoids suppress CRH and ACTH secre-
tion, but their effects are not equivalent. Generally, the greater
the anti-inflammatory potency, the greater is the capacity to
suppress the HPA axis. Over time, the glucocorticoid-produc-
ing cells of the two inner zones of the adrenal cortex atrophy
and the responsiveness of the HPA axis decrease progressively
(Behrend and Kemppainen, 1997). Animals with suppression
of the HPA lack the ability to secrete cortisol sufficiently in
response to stress and may develop signs of acute adrenocortical
insufficiency. The zona glomerulosa and its function are pre-
served, and therefore, electrolyte abnormalities associated with
mineralocorticoid deficiency are not seen. Suppression of the
HPA axis may occur quite soon after the onset of glucocorticoid
therapy.
Oral, parenteral, and topical administration all lead to
HPA axis suppression, which is most serious and prolonged
after repeated injection of long-acting preparations (water-
insoluble esters). In experimental dogs, a single dose of
methylprednisolone acetate (2.5 mg/kg IM) suppressed the
HPA axis, as demonstrated by reduced response of cortisol
after ACTH, for at least 5 weeks (Kemppainen et al, 1981).
A dog that was treated for pruritus with a similar single dose
of methylprednisolone acetate experienced HPA axis sup-
pression for 7 weeks (Meyer, 1982). A single dose of triam-
cinolone acetonide (0.22 mg/kg IM) suppressed the HPA axis
for 2 to 4 weeks (Kemppainen et al, 1982). Single IV doses
of 0.01 mg/kg and 0.1 mg/kg dexamethasone (as free alco-
hol) resulted in reduced cortisol response after ACTH for
16 to 24 hours and 32 hours, respectively. Dexametha-
sone sodium phosphate was associated with a somewhat
shorter suppression compared with the free alcohol with
the 0.01 mg/kg dose (Kemppainen and Sartin, 1984). A single
CHAPTER 14 |   Glucocorticoid Therapy 571
dose of prednisone (2.2 mg/kg IM) did not result in adre-
nocortical suppression (Kemppainen et al, 1982). How-
ever, even prednisone/prednisolone given at physiological
doses can suppress the HPA axis when given for some
time. Oral application of 0.22 mg/kg (physiological dose) or
0.55 mg/kg per day led to a significantly depressed cortisol after
ACTH stimulation after 1 week. Administration of 1 mg/kg
prednisone daily resulted in HPA axis suppression within 2
weeks; administration of 1 mg/kg prednisolone every other
day was associated with HPA axis suppression after 3 weeks
(Chastain and Graham, 1979; Moore and Hoenig, 1992). Cats
are more resistant to the development of clinical signs of iat-
rogenic hyperadrenocorticism; however, they experience HPA
suppression similar to dogs (Behrend and Kemppainen, 1997).
The application of a single dose of methylprednisolone acetate
(20 mg IM) to healthy cats led to a reduced cortisol response
after ACTH within 1 week (Scott et al, 1979). In a cat treated
with subcutaneous (SC) methylprednisolone acetate (20 mg)
weekly for 4 weeks, complete suppression of the HPA axis was
still seen 1 month after the last injection (Ferasin, 2001). Daily
oral administration of prednisolone (2 mg/kg) resulted in HPA
axis suppression after 1 week and was more pronounced after 2
weeks of daily therapy (Middleton et al, 1987). Similarly, daily
oral methylprednisolone (4 mg/kg) was associated with HPA
axis suppression within 1 week (Crager et al, 1994).
Any topically applied glucocorticoid can suppress the HPA
axis. Application of triamcinolone, fluocinonide, and beta-
methasone valerate on the skin of healthy dogs (once daily for
5 days) resulted in decreased cortisol after stimulation with
ACTH within 5 days. The HPA axis remained suppressed for 3
to 4 weeks after the last treatment (Zenoble and Kemppainen,
1987). Ophthalmic instillation of 1% prednisolone acetate or
0.1% dexamethasone four times daily in both eyes resulted in
HPA axis suppression within 2 weeks, intensifying throughout
the treatment period (Roberts et al, 1984; Glaze et al, 1988).
Ototopical administration of therapeutic doses of dexametha-
sone-containing ointment daily to healthy dogs resulted in HPA
axis suppression within 11 days (Abraham et al, 2005). The new
generation of topical steroids cause minimal signs of iatrogenic
hyperadrenocorticism but are associated with HPA axis sup-
pression. Oral budesonide in dogs with IBD resulted in signifi-
cantly lower post-ACTH cortisol concentrations after 30 days
of therapy (Tumulty et al, 2004). Inhalant budesonide in cats
with chronic bronchial disease resulted in HPA axis suppression
in three of 15 cases (Galler et al, 2013). Inhaled fluticasone in
healthy dogs and inhaled flunisolide in healthy cats suppressed
the HPA axis within 2 to 3 weeks (Reinero et al, 2006; Cohn
et al, 2008).
Diagnosis of HPA axis suppression is made by performing an
ACTH stimulation test. Depending on the severity, post-ACTH
cortisol concentrations can be below the detection limit of the
cortisol assay, low (e.g., 2 to 5 μg/dL, 55 to 138 nmol/L) or low-
normal. Animals with undetectable or low concentrations are at
risk for signs of adrenal insufficiency, in particular when encoun-
tering a stressful situation. Potentially lethal situations may arise.
If clinical signs (e.g., lethargy, anorexia, or vomiting) develop
after cessation of steroids, prednisolone administrations should be
instituted. The dose is somewhat arbitrary and depends on the
clinical situation. If severity of signs and extent of stress are mod-
erate, prednisolone doses between 0.5 to 1 mg/kg/day may be suf-
ficient; doses up to 2 to 4 mg/kg/day may be needed temporarily
in life-threatening situations. The prednisolone dose should then
be tapered slowly. Generally, glucocorticoids should be reduced
572 SECTION 4    THE ADRENAL GLAND
slowly after a longer period of glucocorticoid administration (e.g.,
> 2 weeks). Suppression of the HPA axis is usually reversible. The
length of time required for full axis recovery depends on duration,
dose, preparation, and frequency of application of the steroid.
Single doses of triamcinolone acetonide or methylprednisolone
acetate can suppress adrenal responsiveness for up to 5 weeks (see
earlier). Multiple injections of long-acting preparations will aggra-
vate the suppressive effect, and HPA axis malfunction may persist
for months. Oral administration of shorter-acting or less-potent
preparations may result in quicker normalization (Behrend and
Kemppainen, 1997).
Abrupt cessation of glucocorticoids may result in a so-called
glucocorticoid withdrawal syndrome (Greco and Behrend,
1995). Several subgroups are known in humans; one of them
is attributed to the sudden lack of the high concentration of
steroids. In this situation, the body perceives the glucocorticoid
withdrawal as a relative deficiency. The signs are vague and can
easily be mistaken with those of true adrenal insufficiency. The
syndrome has been poorly characterized in dogs and cats. In
questionable cases, an ACTH stimulation test should be per-
formed to differentiate between absolute or relative adrenal
insufficiency. Prednisolone administration may be needed in
either situation.
Diabetes Mellitus
Glucocorticoids may exert diabetogenic properties thereby induc-
ing hyperglycemia in previously normoglycemic patients, as well
as worsening glycemic control in patients already known to have
diabetes mellitus. Glucocorticoids increase insulin resistance in
peripheral tissues (muscle, fat) and increase hepatic glucose produc-
tion, and they may also inhibit insulin release from the β cells. In
humans, overt diabetes or impaired glucose tolerance is seen in 14%
to 28% of individuals receiving long-term glucocorticoids. Preva-
lence of diabetes induced by exogenous glucocorticoids has not been
systematically studied in dogs and cats. It is well known that cats
are more susceptible to the diabetogenic effects of glucocorticoids
than dogs. Approximately 80% of cats with endogenous hyperad-
renocorticism are diabetic, whereas in dogs, the prevalence is only
about 10%. Steroid diabetes can occur after oral or parenteral, as
well as after topical administration of any of the traditional gluco-
corticoids, but it has not been reported with the newer class of topi-
cal drugs (budesonide, fluticasone). Glucocorticoid sensitivity varies
between individuals and therefore dose, duration, and frequency of
application that will ultimately lead to hyperglycemia cannot be
predicted. Experimental studies have shown that abnormalities may
already become apparent after short-term therapy. Administration
of 2 mg/kg prednisolone once daily for 8 days resulted in reduced
glucose tolerance after an IV glucose load in all six cats, and three
of the six cats developed hyperglycemia (Middleton and Watson,
1985). Weekly injections of 20 mg methylprednisolone subcutane-
ously lead to hyperglycemia within 4 weeks in the two cats stud-
ied (Scott et al, 1982). Within 1 month of daily administration of
immunosuppressive doses of prednisolone or dexamethasone, 29%
and 71% of cats developed glucosuria (Lowe et al, 2009). The later
study points to a greater diabetogenic effect of dexamethasone than
equipotent doses of prednisolone. Steroid-induced diabetes is also
seen in dogs but with much lower frequency than in cats (Camp-
bell and Latimer, 1984; Jeffers et al, 1991). Administration of anti-
inflammatory/immunosuppressive doses of prednisone (1.1 mg/kg/
day) or prednisolone (1 to 2 mg/kg/day) for 28 days to normal dogs
has not produced hyperglycemia, glucose intolerance, or insulin
resistance (Wolfsheimer et al, 1986; Moore and Hoenig, 1993).
Diagnosis of steroid-induced diabetes should result in cessation
of glucocorticoid therapy whenever possible; depending on the dis-
ease, alternative drugs (e.g., cyclosporine) or topical use of the new
generation of glucocorticoids should be considered. In cats, steroid-
induced diabetes often goes into remission, provided that the glu-
cocorticoid application is ceased immediately and insulin treatment
is initiated. In dogs, diabetic remission has been seen; however, too
few data have been published to make a general statement. In a
dog or cat with known diabetes, glycemic control usually worsens
when glucocorticoids are administered. Diabetes mellitus should
not be regarded as an absolute contraindication for glucocorticoids,
because in some diseases they may be life-saving. The glucocorti-
coid dose should be as low as possible to control the disease. In
short-term glucocorticoid therapy (1 to 2 weeks), the insulin dose
may be maintained while awaiting the withdrawal of the drug. If
long-term glucocorticoid therapy is needed, an increase in the daily
insulin doses is usually necessary to maintain control over the dia-
betic state. The amount of increase is variable and should follow
the guidelines discussed in Chapters 6 and 7. Careful monitoring
of blood glucose levels is important. After the effect of the gluco-
corticoid on insulin sensitivity wears off, the insulin requirement
decreases, resulting in the need to also decrease the insulin dose.
Remission may fail to appear if treatment is inadequate or if the cat
has substantial islet pathology. If glucocorticoid therapy cannot be
terminated and no alternative drug can be used, the insulin dose
has to be adjusted based on the severity of the insulin resistance. In
those cases, glycemic control oftentimes remains difficult.
Gastrointestinal Hemorrhage and Ulceration
In the physiological state, glucocorticoids exert protective effects for
the gastrointestinal integrity by various mechanisms. The adminis-
tration of glucocorticoids in pharmacological doses may alter muco-
sal defense mechanisms in many ways (e.g., by decreasing mucus
production, altering the biochemical structure of mucus, decreas-
ing mucosal cell turnover, increasing acid output, and impairing
mucosal blood flow). Other mechanisms are decreased healing rate
and promotion of bacterial colonization of ulcers (Hanson et al,
1997; Rohrer et al, 1999a; Feldman and Nelson, 2004). In most
situations, it is unlikely that glucocorticoids are the sole factor for
gastrointestinal problems. The exception may be when extremely
high doses of steroids are used. The application of methylpredniso-
lone sodium succinate (30 mg/kg initially, and then 15 mg/kg 2
and 6 hours later and every 6 hours thereafter for 48 hours) was
associated with gastric hemorrhage in all of the 10 dogs and was
severe in nine of them (Rohrer et al, 1999a). Similarly, the applica-
tion of extremely high doses of dexamethasone (4.4 mg/kg/day for
8 days) or prednisone (8.8 mg/kg/day for 7 days) to experimental
dogs did result in endoscopic evidence of hemorrhage but not in
ulcers (Sorjonen et al, 1983; Behrend and Kemppainen, 1997).
In clinical patients, the most striking gastrointestinal side effects
have been reported in dogs with neurological disease. However,
because a neurological problem can result in gastrointestinal
lesions itself, it is difficult to say how much glucocorticoids con-
tributed to the development of the problems. In one study, 23
of 155 dogs with intervertebral disk herniation had gastrointes-
tinal problems, and 10 of them had not received glucocorticoids
(Moore and Withrow, 1982). More than 75% of dogs with acute
intervertebral disc disease treated with glucocorticoids had gastric
mucosal lesions as detected by endoscopy. In 8% of dogs, gastric
ulcers developed during the treatment period. Only 24% of the
dogs had clinical signs such as vomiting or melena (Neiger et al,
2000). The most catastrophic of the gastrointestinal complications

is colon perforation. Colonic perforation in 13 dogs treated with
glucocorticoids was uniformly fatal (Toombs et al, 1986). Ten of
the 13 dogs were neurosurgical patients, one was treated for head-
trauma and non-ambulatory paresis, and two others had under-
gone major surgery for other reasons. Dexamethasone was the
most frequently used steroid and was given in a mean cumulative
dose of 6.4 mg/kg/day over a period of 5 days. The most com-
mon clinical signs were depression, anorexia, and vomiting. Signs
became evident 3 to 8 days after surgery and preceded death by an
average of 22 hours (Toombs et al, 1986).
Because of the potential association between glucocorticoids
and gastrointestinal side effects, certain precautions should be
taken, in particular in patients with neurological disease. Non-
ambulatory patients certainly have an increased risk (Behrend and
Kemppainen, 1997). The following recommendations have been
made: to use prednisolone or methylprednisolone instead of the
more potent dexamethasone, limit treatment to the lowest pos-
sible dose and duration, avoid concurrent or successive use of
other drugs with known ulcerogenic potential (in particular non-
steroidal anti-inflammatory drugs), avoid urinary retention by
closed urine drainage, and correct fecal retention problems prior
to surgery (Toombs et al, 1986).
Misoprostol, cimetidine, or sucralfate were evaluated for their
potential preventative role for gastrointestinal hemorrhage but did
not show any effect (Hanson et al, 1997; Rohrer et al, 1999b).
Laboratory Abnormalities
The most common biochemical abnormalities in dogs receiving
exogenous glucocorticoids are elevation of liver enzymes. Any glu-
cocorticoid and any form of application (oral, parenteral, or topi-
cal) can lead to an increase of alkaline phosphatase (ALP), alanine
aminotransferase (ALT), and gamma glutamyl transferase (GGT).
However, there is a tremendous amount of variation between indi-
vidual dogs; in some, the elevation may reach several-fold of nor-
mal, whereas others only have minor increase or even no change.
In part, the changes may be dose-related. The administration of
1.1 mg/kg/day prednisone by mouth for 35 days did not result in
a significant increase of ALP and the glucocorticoid-induced ALP
isoenzyme. Only five of the 18 healthy dogs had ALP activities
above the reference range (Moore et al, 1992). A prednisone dose
of 4.4 mg/kg/day IM for 14 days was associated with a significant
increase in ALP activity within 2 days, in ALT activity within
3 days, and in GGT activity within 6 days. Six weeks after the end
of the study, the enzyme activities were still slightly to moderately
increased (Badylak and Van Vleet, 1981).
The application of other glucocorticoids, such as dexametha-
sone, methylprednisolone (acetate), and triamcinolone, has simi-
lar effects. The contributory role of the glucocorticoid induced
isoenzyme of ALP to the increase of total ALP activity seems to
be inconsistent. In the study of Moore and colleagues (1992), it
contributed only to a small extent to the total ALP activity. In a
study by Solter and colleagues (1994), the initial increase of ALP
was mainly due to the liver ALP isoenzyme, followed by the gluco-
corticoid and bone isoenzyme 7 and 10 days after initiating treat-
ment with prednisone. Serum bile acids may also increase during
glucocorticoid therapy, whereas ammonia tolerance test does not
seem to be affected (Meyer, 1982; DeNovo and Prasse, 1983;
Solter et al, 1994). For effects on blood glucose and lipase activity,
see the Diabetes Mellitus section and the Pancreatitis section. Otic
medications containing triamcinolone or dexamethasone were also
associated with an increase in ALP, ALT, and GGT (Meyer et al,
1990; Abraham et al, 2005). Increase in liver enzyme activities
CHAPTER 14 |   Glucocorticoid Therapy 573
may also be seen with the new generation of glucocorticoids. A
short term (30 days) oral application of budesonide was associated
with an increase in ALP activity in dogs, but the difference to pre-
treatment levels was not significant (Tumulty et al, 2004). Cats are
generally considered more resistant to the effects of glucocorticoids
and do not have a glucocorticoid induced isoenzyme. Increases in
liver enzyme activities after administration of glucocorticoids do
occur, and the most consistent increase is seen in ALT activity.
The ALP activity may also increase; however, it often still remains
within the normal range (Scott et al, 1982; Sharkey et al, 2007;
Lowe et al, 2008b). As in dogs, glucocorticoid administration in
cats may result in steroid (vacuolar) hepatopathy, although the fre-
quency is lower (Schaer and Ginn, 1999). Increase in serum lipids
(cholesterol, triglycerides) may be seen in both species.
Glucocorticoids also affect hematological parameters. In dogs
with iatrogenic hyperadrenocorticism, eosinopenia was seen in 18
out of 28 dogs and was the most frequent finding. Other constitu-
ents of the “stress leukogram” were also found, but to a lesser extent
(Huang et al, 1999). In 14 cats treated with glucocorticoids (4.4
mg/kg prednisolone or 0.55 mg/kg dexamethasone for 56 days),
neutrophils were significantly higher, and lymphocytes and eosino-
phils were significantly lower after treatment (Lowe et al, 2008b).
In this study, monocytes were also increased, which is usually con-
sidered not a typical finding in steroid-treated cats.
Pancreatitis
More than 500 drugs have been reported to the World Health
Organization (WHO) because they were suspected to induce
pancreatitis in humans. In many of them, evidence of causal-
ity is weak, and for only 31 of those drugs a definitive causality
has been established. Among them are steroids, but they do not
belong to the group of high risk drugs (Nitsche et al, 2010). Previ-
ously, glucocorticoids were also assumed to cause pancreatitis in
small animals. Much of the evidence regarding this association,
however, is related to an increased viscosity of pancreatic secretion
shown in rabbits. In dogs, increased viscosity of pancreatic secre-
tions has been shown only when isolated pancreases were perfused
with a huge dose of methylprednisolone (400 mg); a lower dose
(200 mg) did not change the viscosity (Kimura et al, 1979; Beh-
rend and Kemppainen, 1997). Pancreatitis has also been seen in
dogs treated with glucocorticoids. However, these were sporadic
cases, and the dogs suffered from intervertebral disc disease, which
may alone be a risk factor (Behrend and Kemppainen, 1997). The
administration of dexamethasone to healthy dogs in various doses
for up to 3 weeks did not cause pancreatitis. However, it increased
lipase activity without any histological damage to the pancreas
(Parent, 1982). In a more recent study, evaluating the canine pan-
creatic lipase immunoreactivity (cPLI), immunosuppressive doses
of prednisone (2.2 mg/kg once daily) given for 6 weeks did not
result in an increase in cPLI (Steiner et al, 2009).
In dogs and cats, the early concerns that glucocorticoids could
cause pancreatitis have now largely been dismissed. Steroids are
no longer included in the list of drugs suspected of being associ-
ated with pancreatitis (Armstrong and Williams, 2012; Mansfield,
2012). It is possible, however, that glucocorticoids are a contrib-
uting factor in sick animals or that only a subset of patients is
susceptible for steroid-induced pancreatitis.
Miscellaneous
Glucocorticoids may have numerous other adverse effects, includ-
ing growth retardation in young animals, induction or worsening
574 SECTION 4    THE ADRENAL GLAND

of hypertension, disposing the animal to infections due to immu-
nosuppression (e.g., urinary tract infection), interference with fer-
tility, induction of abortion, and behavior changes.
GLUCOCORTICOID REDUCTION PROTOCOL
There are various ways to taper an animal from glucocorticoids,
and there are no studies demonstrating that one way is better than
the other. Several principles, however, are widely accepted. Taper-
ing of the glucocorticoid dose should always be done if therapy
was longer than or equal to 2 weeks, or if high doses have been
used (> 1 mg/kg prednisolone/day or its equivalent) (Ferguson
et al, 2009). In the latter case (i.e., short duration of high dose),
tapering can be done quickly over a few days. Tapering of the ste-
roid dose should be started after the disease being addressed is
in remission (e.g., normalized hematocrit in immune-mediated
anemia, and/or absence of gastrointestinal signs in IBD). Inflam-
matory diseases usually require 5 to 7 days of induction therapy,
whereas immunosuppressive diseases may need 10 to 28 days
(Behrend and Kemppainen, 1997). Worsening of the disease soon
after the start of tapering suggests that the tapering was done too
fast. If an immune-mediated disease recrudesces, a second remis-
sion is more difficult to obtain than previously. If recrudescence
occurs, the glucocorticoid dose should be increased immediately
to a dose equivalent even higher than the initial dose. If remission
is lost in an inflammatory disease, the dose should be increased to
the last dose that kept the animal disease free (Behrend and Kemp-
painen, 1997). In general, the longer the induction phase and/or
the greater the induction dose, the more stepwise and longer the
period between dose reductions has to be. Glucocorticoids used
for life-threatening diseases should be tapered more slowly than
glucocorticoids used for other diseases (Cohn, 2010). Tapering
for immune-mediated disease can take several months; some cases
may even need life-long therapy.
The initial dose reduction step may be done by consolidating
the dose, thereby achieving longer dosing intervals; this might
spare the HPA axis suppression while the desired effects are main-
tained. For instance, if prednisolone is administered twice daily,
the daily dose is given at once (e.g., 10 mg prednisolone once
daily instead of 5 mg prednisolone twice daily). The daily dose
is then reduced incrementally (Cohn, 2010). Usually, when the
daily prednisolone dose has been reduced to 0.25 to 0.5 mg/kg/
day, the dose interval is switched to alternate-day therapy. The
latter should allow the HPA axis to recover on the “off-days” and
is assumed to provide greater safety than if therapy is suddenly
discontinued. Successful alternate-day therapy depends upon the
therapeutic effects lasting longer than the suppressive effects on
the HPA axis (Ferguson et al, 2009). Alternate-day therapy should
not be applied during the initial phase of glucocorticoid therapy
because it will not be effective to bring the disease under con-
trol. Prednisolone is the preferred glucocorticoid for alternate-day
therapy; the action of cortisol (hydrocortisone) is too short and
that of dexamethasone is too long for this approach. When chang-
ing to alternate-dose therapy, the same daily dose of prednisolone
can be given every other day (e.g., change from 5 mg every day to
5 mg every other day), which results in a 50% reduction of dose.
Alternatively, the same dose can be maintained by doubling the
dose on the “on-days” (e.g., change from 5 mg every day to 10 mg
every other day) (Behrend and Kemppainen, 1997). In case of
serious immune-mediated diseases, this latter approach for mov-
ing from daily to alternate-day therapy is preferred. If alternate-
dose therapy is successful to maintain the disease in remission,
further reduction to every third day can be attempted (Behrend
and Kemppainen, 1997).
Tapering of oral prednisolone used for immune-mediated dis-
ease in dogs could be done as follows (Behrend and Kemppainen,
1997):
Induction: 2.0 mg/kg divided b.i.d. for 10 to 28 days
Tapering: 1.5 mg/kg divided b.i.d. or once daily for
10 to 28 days
1.0 mg/kg divided b.i.d. or once daily for
10 to 28 days
0.5 mg/kg divided b.i.d. or once daily for
10 to 28 days
0.25 mg/kg once daily for 10 to 28 days
0.25 mg/kg every other day, for 21 days or more
It should be understood that the animal should be reevaluated
before every reduction step to ensure that the disease is still in
remission. The glucocorticoid dose used for induction in inflam-
matory diseases is substantially lower (0.5 to 1.0 mg/kg/day in
dogs) and the induction period is shorter (5 to 7 days). Tapering,
therefore, can be done faster, usually within 10 to 14 days. Taper-
ing of the higher anti-inflammatory and immune-suppressive
doses in cats should be done accordingly.

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