2013: sa242: glucocorticoids: what, where, when, why and how?

Western Veterinary Conference 2013

Butch KuKanich, DVM, PhD, Dipl. ACVCP
Kansas State University
Manhattan, KS, USA

Glucocorticoids, mechanisms of action
Glucocorticoids (GCs) increase the circulating pool of mature neutrophils (PMNs) due to
release of PMNs from the marginal pool which decreases migration into inflamed tissues. The
effect is due to decreased expression of adhesion molecules, reduced adhesion to the
vascular epithelium, and reduced movement through the vasculature into the tissues. Anti-
inflammatory doses of GCs affect PMN trafficking more than function as minimal effects on
phagocytosis and lysosomal stability occur. GCs decrease the circulating pool of lymphocytes,
monocytes, eosinophils, and basophils primarily due to their movement from the vasculature to
the lymphoid tissues. GCs alter the function of macrophages and other antigen presenting
cells by reducing the cells ability to respond to antigens. The ability of macrophages to engulf
and kill microorganisms is markedly inhibited. The production of cytokines such as TNF-α,
interleukin-1 (IL-1), metalloproteinases, and plasminogen activator by macrophages are also
markedly inhibited. GCs also decrease the production of IL-12 and interferon-γ by lymphocytes
and macrophages which are important inducers of T-helper cell activity and cellular immunity.
T-cells are more affected by GCs then B-cells with minimal effects on B-cell production of
immunoglobulins at anti-inflammatory doses. However, high doses of GCs can decrease
immunoglobulin production.
GCs also reduce the production of prostaglandins and leukotrienes by the arachidonic acid
pathway. The primary effect on the arachidonic acid pathway is thought to be through inhibition
of phospholipase A2, but some effects on cyclooxygenase-2 (COX-2) may also occur. GCs
also have a variety of effects on blood vessels. GCs improve the microvascular integrity and
circulation, and decrease vessel permeability. It is unclear as to the precise mechanisms by
which these effects occur, but may be due to inhibition of vasoactive substances such as
histamine, serotonin, and prostaglandins among others. The vascular effects have not been
identified as a clinical benefit.
Glucocorticoids, adverse effects
Adverse effects are expected with both short-term and long-term administration of GCs. The
most common adverse effects with administration include the polyuria, polydipsia, and
polyphagia. Other effects with GC administration include osteoporosis, myopathy, inhibition of
fibroblast activity, decreased intestinal calcium absorption, pancreatitis, gastric ulceration /
perforation, colonic ulceration / perforation, sodium retention, fluid retention, hyperlipidemia,
lipolysis, protein catabolism, fatty infiltration of the liver, steroid hepatopathy, anti-insulin
effects, decreased thyroid hormone production, increased parathyroid production, decreased
host response to bacterial infections, and increased rates of cystitis. Case reports have been
published detailing acute episodes of congestive heart failure after GC administration to
animals with subclinical and undiagnosed cardiac disease which is probably due to fluid and
sodium retention and hypertension. A study examining the effects of shock doses of
methylprednisolone sodium succinate on animals presenting for spinal surgery resulted in
36/40 animals being identified as having GIT bleeding despite administration of cimetidine, sucralfate, or misoprostol. Therefore it is not unreasonable to expect GIT injury with administration of shock doses of GC for spinal injury. Shock doses of corticosteroids produce euphoria in human patients. The euphoric effect is probably the reason most animals “look better” after administration of shock doses of corticosteroids and typically is not an indication that the shock doses are beneficial. Opioid administration can also produce euphoric effects and make animals “look better” with less adverse effects than shock doses of GCs. Specific glucocorticoids
Prednisolone is the active form of the glucocorticoid whereas prednisone is inactive and must
be metabolized to prednisolone to elicit an effect. In dogs, prednisone is well metabolized to
prednisolone after administration and as such prednisone is a very good choice for oral
glucocorticoid therapy. In contrast, cats do not appear to metabolize prednisone to
prednisolone well and as such have variable and inconsistent effects from oral prednisone.
Prednisolone is a better choice than prednisone for oral administration to cats. In comparing
prednisone / prednisolone to dexamethasone, dexamethasone is approximately 7-10 times
more potent meaning an equivalent dose of dexamethasone should be 1/7th to 1/10th the dose
of prednisone. Prednisolone and prednisone produce some mineralocorticoid effects (sodium
and water retention) and therefore can exacerbate conditions of fluid retention like congestive
heart failure with pulmonary edema. In contrast, dexamethasone has minimal effects of sodium
and fluid retention and may be a better choice if fluid retention is contraindicated.
Dexamethasone produces a longer duration of effect, at least 32 hours of adrenal suppression,
after a single dose in dogs compared to <24 hours for prednisone/prednisolone.
Dexamethasone also appears to be more likely to cause GI adverse effects than prednisone /
Glucocorticoids, dose-dependent effects
Glucocorticoid dosages depend on the condition that is being treated. Glucocorticoid dosages
can be classified as physiologic replacement, anti-inflammatory, immunosuppressive, and
shock doses.
Physiologic dosages are designed to supplement or replace the amount of endogenous
cortisol produced in a 24-hour period. Prednisone or prednisolone is administered at 0.2
mg/kg/d for replacement therapy. Anti-inflammatory dosages of glucocorticoids are commonly
administered for conditions such as atopy, angioedema, and urticaria. The anti-inflammatory
dosages of prednisone / prednisolone in dogs is 1-2 mg/kg/d and for dexamethasone 0.1-0.2
mg/kg/d. The anti-inflammatory dose in cats is approximately twice that of dogs.
Immunosuppressive dosages are administered for conditions such as autoimmune hemolytic
anemia and immune mediated thrombocytopenia. Prednisone administered at 2-6 mg/kg/d and
dexamethasone 0.3-1 mg/kg/d are immunosuppressive dosages. Most animals respond to the
lower end of the dosages for immunosuppression therapy. The shock dosage of
methylprednisolone sodium succinate is 30 mg/kg IV. There currently no indications (no clinical
benefits demonstrated) for shock doses of dexamethasone in dogs or cats (see below).
Efficacy of shock doses of glucocorticoids
Head trauma. A recent study in humans demonstrated an increased mortality rate in patients
receiving shock doses of methylprednisolone sodium succinate as compared to groups that did
not receive GCs. There are no large studies in animals assessing the effects of GCs on head
trauma, but extrapolation from human data indicate GCs are NOT indicated in the acute
management of head trauma in animals.
Spinal trauma. There are conflicting opinions on the benefit of shock doses and GC use in
spinal trauma. A study in 1990 indicated a benefit to shock dose methylprednisolone sodium
succinate (MPSS) in spinal trauma, but criticisms of the study soon followed as to its
applicability and limitations. Experimental models have produced positive results for GC use in
spinal trauma, but doses were administered prior to experimental injury or within a short period
of time following injury. Clinical cases of IVDD in dogs, pre or postoperative
administration of glucocorticoids provided no benefit compared to animals not treated
with GC’s
, but increased adverse effects were seen in GC treated dogs. There is conflicting
data supporting the use of GC in spinal trauma, although they are widely used. Currently, most
people recommend shock doses of Solu Medrol only within 8 hours of spinal trauma.
Generalized trauma / Heat Stroke. There is no data supporting the use of GC in generalized
trauma (i.e. hit by car, dog fights, etc.) or heat stroke. In fact GC may increase morbidity and
mortality due to the numerous adverse effects. Supportive care such as crystalloids and
colloids, pain management with opioids, and body temperature are the primary
recommendations along with stabilization of blood loss and fractures. Antimicrobials may also
be indicated.
Sepsis / endotoxemia. Most studies investigating the use of GC in sepsis and endotoxin
models are poorly translated into clinical practice. Most of the models have administered GCs
prior to exposure or immediately following exposure. Shock doses GCs may increase the
morbidity and mortality in sepsis due to the immunosuppressive effects and beneficial effects
have not been demonstrated clinically. Shock doses in endotoxemia also do not result in
decreased mortality or morbidity, however physiologic doses may be beneficial (i.e. 0.2 mg/kg
methylprednisolone), but there is not a consensus on their use.
Anaphylaxis. GCs are indicated for the treatment of anaphylactic reactions. However
immunosuppressive doses are recommended (i.e. 2-6 mg/kg IV MPSS OR 0.3-1 mg/kg
dexamethasone), not shock doses. If cardiovascular collapse is present administration of
epinephrine (2.5-5 mcg/kg {0.0025-0.005 mg/kg} IV) will provide immediate cardiac stimulant
and vasopressor effects.
Addison’s Crisis. GCs are recommended for the treatment of animals in an Addison’s
(hypoadrenocorticism) crisis, although immunosuppressive dosages are recommended
initially (2-6 mg/kg MPSS). The primary focus in stabilizing animals is to correct the
hyperkalemia and hyponatremia. Normal saline is the fluid of choice for dehydrated animals
with hyperkalemia and hyponatremia.
Disclaimer: References available on request. The information is accurate to the best of the author’s knowledge. However recommendations change as new data become available and errors are possible. The author recommends double checking the accuracy of all information including dosages.

Source: http://www.wvc.org/images/session_notes_2013/2013_SA242.pdf


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