Glucocorticoids Flashcards
why is it rare to have spontaneous glucocorticoid deficiency without a concomitant mineralocorticoid deficiency
glucocorticoid production site, the zona fasciculata, is very close to mineralocorticoid production site, the zona glomerulosa
where are mineralocorticoids produced and what is an example this hormone type
zona glomerulosa of adrenal cortex; eg. aldosterone
where are glucocorticoids produced and what is an example this hormone type
zona fasciculata of adrenal cortex; cortisol, corticosterone, cortisone are examples
this hormone is released from the adrenal cortex in response to stress due to the action of the hypothalamic-pituitary-adrenal axis
cortisol
what is the effect of a LACK of aldosterone on calcium levels? how does this occur?
a lack of aldosterone decreases calcium excretion which can lead to hypercalcemia
what is the effect of aldosterone on blood pressure? how does this occur?
increased blood pressure: aldosterone causes retention of sodium and water by the kidney so increases blood volume, which increases blood pressure. also increases excretion of potassium by kidney into lumen in exchange for sodium uptake
name 7 effects of glucocorticoids
anti-inflammatory, immunosuppressive, vasoconstrictor/ positive ionotrope/ chronotrope, bronchodilator, catabolic (increased glucose production from amino acids), maintain fluid homeostasis, neuroprotective
which 2 effects of glucocorticoids only occur at supra physiological doses
anti-inflammatory and immunosuppressive effects
what do glucocorticoids inhibit
conversion of cell membrane phospholipids to arachidonic acid by phospholipase
why are the negative effects of NSAIDs also seen with glucocorticoids, but to a greater extent
glucocorticoids act earlier in the arachidonic acid pathway that NSAIDs, so there is no opportunity for glucocorticoids to be COX2 selective
what is the effect of a glucocorticoid deficiency on blood glucose
hypoglycemia (glucocorticoids increase blood glucose and antagonize insulin)
name 4 catabolic effects of glucocorticoids
promote lipolysis, promote gluconeogenesis, increase blood glucose and antagonize insulin, inhibit bone formation and promote bone loss
name 2 ways glucocorticoids maintain fluid homeostasis
mineralocorticoid activity to promote salt and water retention; inhibit LDH release leading to PU/PD
changes in WBC induced by glucocorticoids are consistent with what changes you would see on a CBC
consistent with stress leukogram changes
name 4 immunosuppressive effects of glucocorticoids
eosinopenia; lymphopenia; neutrophilia; reduced functionality of macrophages, monocytes, and eosinophils
what is the effect of a glucocorticoid deficiency on vasoconstriction
hypotension (glucocorticoids enhance vasoconstriction)
how do glucocorticoids lead to bronchodilation
increase beta-adrenergic receptor number and sensitivity, increasing effects of beta-2 agonists on bronchiolar smooth muscle
chronic glucocorticoid use increase the risk of this condition in cats, especially those with pre-existing disease, (hint: likely due to sodium/water retention in the kidney and resulting blood volume/hypertension)
congestive heart failure
how do glucocorticoids protect against hypoxic/ischemic brain damage
possibly by decreasing basal energy requirements of availability of energy substrates
name at least 5 effects of glucocorticoid deficiency
hypotension, hypoglycemia, anorexia, vomiting, diarrhea, weight loss, muscular weakness, increased susceptibility to stress, inability to maintain endothelial integrity and vascular tone, +/- hyponatremia, =/- polyuria
what is the difference between short-acting, intermediate-acting, and long-acting corticosteroids?
the glucocorticoids length of duration of action is based on the biological half-life of the parent compound (not the same as T1/2). short-acting formulations have a duration of action of under 12 hours, intermediate-acting 12-36 hours, and long-acting over 36 hours
how long do prednisone and prednisolone act for?
biologic half-life of 12-36 hours. they are intermediate acting corticosteroids (from Plumb’s)
are glucocorticoids such as prednisone and prednisolone more likely to cause adverse effect in the short term or in the long term
long term! there are many adverse effects associated with chronic use (from Plumb’s).
why should you NOT use prednisone in horses or cats
do not metabolize prednisone well. use prednisolone instead. (Plumb’s notes that it is poorly absorbed after oral use in horses and is not readily converted to prednisolone in cats)
all glucocorticoids used clinically are modifications of this basic steroid structure
cortisol
what structural changes are made to cortisol in different synthetic glucocorticoids
pharmacokinetics (residence in body, species differences in absorption), active vs inactive, affinity for GR receptor (affects potency) selectivity for GR and AR), interaction with GR (affects duration of activation)
when do the acetate and acetonide esters (types of glucocorticoid esters) have long-acting formulations
when parenteral
what is the active metabolite of prednisone? how much more potent is the active metabolite?
prednisolone. 4x as potent
is prednisone suitable for topical administration
no. not in any species.
name 4 adverse effects of glucocorticoid drugs
stress leukogram, elevation in liver enzymes or steroid-induced hepatopathy, GI ulcers, PU/PD (not important to animal, but challenging for owner management), HPA axis suppression were all emphasized in class. also iatrogenic hyperadrenocorticism, polyphagia, poor wound healing, behaviour changes, muscel atrophy, hyperglycemias/insulin resistance, induction of parturition, possibly laminitis in horses.
which glucocorticoids are most commonly used for anti-inflammatory and anti-allergic effects in large animals
prednisone (except in cats) or prednisolone (ok in cats) are most commonly used
which glucocorticoid is most commonly used for anti-inflammatory and anti-allergic effects in large animal
dexamethasone most commonly used
HPA acts suppression occurs in dogs after 2 weeks of glucocorticoid therapy. how can this suppression be reduced
alternate day therapy, although this would be inappropriate in replacement treatment programs. can taper withdrawal if have had chronic administrate
can you co-administer an NSAID and steroid? why or why not?
no. GI lesions and renal abnormalities may occur
name 4 diseases that often require treatment with glucocorticoids
atopic dermatitis, immune-mediated hemolytic anemia, lymphoma, equine or feline asthma
name 4 contraindications for providing glucocorticoids
systemic fungal disease, laminitis in horses, concurrent infection, corneal ulcers
there are many drug interactions, reported and theoretical, with prednisolone and prednisone. name 4 drugs with interactions
vaccines, especially live attenuated viral vaccines, rifampin, phenytoin, phenobarbital, NSAIDS, mitotane, ketoconazole, insulin, estrogens, ephedrine, potassium-wasting diuretics (furosemide, thazides), digoxin, cyclosporine, cyclophosphamide, aspirin (from Plumb’s)
name 3 laboratory effects you might see after administering glucocorticoids such as prednisone and prednisolone
increase serum cholesterol levels, increase serum urine glucose levels, decrease serum potassium, suppress release of TSH and reduce T3 and T4 values, reactions to skin tests may be suppressed, false negative results of the nitro blue tetrazolium test for systemic bacterial infections (from Plumb’s)
should you go read Plumb’s entries on prednisolone, prednisone, fluticasone, and dexamethasone
yes. we have to know detailed information about these drugs
what glucocorticoid is used most commonly in vet med as an inhaled aerosol, often for treating feline asthma, chronic cough dogs, recurrent airway obstruction or inflammatory airway disease in horses
fluticasone (from Plumb’s)
how is fluticasone metabolized
cytochrome P450 pathway to a metabolite with negligible pharmacologic activity (Plumb’s)
when is fluticasone contraindicated
during acute bronchospasm or when patients are sensitive to it (Plumb’s)
should you use fluticasone in pregnant animals? why or why not?
with caution. unknown if drug enters maternal milk and has teratogenic effects in lab animals (Plumb’s)
should you give prednisone or prednisolone to pregnant animals
with caution: can enter milk, can cause unwanted effects in offspring, can induce parturition especially in large animals in late stage pregnancy (Plumb’s)
name a drug interaction with fluticasone
use caution with drugs that inhibit CYP 3A4 isoenzymes such as ketoconazole (Plumb’s)
what are potential routes of administration for glucocorticoid drugs
IV, IM, SQ, oral, local (e.g intra-articular), inhaled, topical (skin, ears, eyes). note that prednisone cannot be given topically and that local administration will reduce systemic effects
what are some similarities and differences between adrenal-dependent and pituitary-dependent hyperadrenocorticism?
similarities: symptoms are related to excess of glucocorticoids, involves increased endogenous secretion. adrenal-dependent: more common type in large dogs, increased cortisol, adrenal neoplasia. pituitary-dependent: more common type in small dogs and horses, increased ACTH, adenomas.
what are the treatment target organs of hyperadenocorticism
pituitary (to suppress ACTH release), adrenal gland (suppress cortisol release)
what are 2 other names for hyperadrenocorticism
Cushing’s or in horses, PPID (pituitary pars intermedia dysfunction)
where does trilostane target in the hyperadrenocorticism pathway? what organ?
competitively inhibits the conversion of pregnenolone to progesterone, targeting the adrenal gland
where does mitotane target in the hyperadrenocorticism pathway? what organ?
inhibits conversion of cholesterol to pregnolone by inhibiting cytochrome P450 enzymes, as well as inhibiting conversion of prenenolone to progesterone. targets adrenal gland
trilostane and mitotane adverse effects are generally associated with what? name 5 adverse effects
hypoadrenocorticism. lethargy, vomiting, diarrhea, inappetence, weakness
what is the mechanism of action for selegiline in hyperadrenocorticism therapy? what organ does it target?
dopamine agonist, causes feedback inhibition of ACTH from pituitary. also a monoamine oxidase inhibitor. targets pituitary
what is the mechanism of action for pergolide mesylate in hyperadrenocorticism therapy? what organ does it target?
acts as dopamine agonist and inhibits production of POMC-derived hormones. targets pituitary
what drug is used to treat hyperadrenocorticism in dogs, but is only effective in 20% of patients, so would likely be used in dogs unable to tolerate trilostane or mitotane
selegiline
what is the standard treatment drug for pituitary pars intermedia dysfunction (PPID) in horses
pergolide mesylate
what are symptoms of hypoadrenocorticism or Addison’s disease
lethargy, vomiting, diarrhea, inappetence, weakness, PU/PD, electrolyte abnormalities
what is hypoadrenocorticism or Addison’s disease?
usually an autoimmune disease in dogs that causes both mineralocorticoid and glucocorticoid deficiency
should you treat hypoadrenocorticism with a mineralocorticoid or glucocorticoid first
mineralocorticoid first and add glucocorticoid if needed
oops! you gave your patient iatrogenic hypoadrenocorticism. why did this happen?
usually result of HPA axis inhibition due to glucocorticoid treatment and occurs when chronic glucose therapy is stopped to quickly
how can you prevent iatrogenic hypoadrenocorticism
if ending chronic glucocorticoid therapy, TAPER glucocorticoids
what drug(s) is used for glucocorticoid replacement for hypoadrenocorticism?
dexamethasone for acute crisis (rapid onset of action and less reactivity with cortisol assays so can be gives before testing in emergency), then prednisone or prednisolone
what drug is used for mineralocorticoid replacement in repository form (injection lasting 25 days) as the standard treatment for dog hypoadrenocorticism
DOCP, deoxycorticosterone pivalate
what hypoadrenocorticism drug has both mineralocorticoid and glucocorticoid activity and requires daily oral dosing
fludrocortisone acetate
how long is the half life of dexamethodone compared to its biological activity
half life is only 2-5 hours in dogs, but biologic activity can be over 48 hours (Plumb’s)
can dexamethasone be used alone for treatment of adrenal insufficiency
generally no. it has a negligible mineralocorticoid effects (Plumb’s)
is dexamethasone considered long-acting or short-acting
long-acting (Plumb’s)
