Glucocorticoids and anti-allergics Flashcards
What zone of the adrenal medulla produces glucocorticoids (cortisol, corticosterone, cortisone)
zona fasiculata
what zone of the adrenal medulla produces mineralocorticoids (aldosterone)
zona glomerulosa
Why is it rare to have a spontaneous adrenal-origin glucocorticoid deficiency without a concomitant mineralocorticoid deficiency
Because of the proximity of the two zones that produce them
What axis controls the release of cortisol from the adrenal cortex?
Hypothalamic-pituitary-adrenal (HPA) axis
describe the HPA axis
CRH produced by the hypothalamus -> CRH acts on the anterior pituitary -> POMC is converted into ACTH in the anterior pituitary -> ACTH enters blood stream and acts on adrenal cortex -> ACTH stimulates the release of cortisol
What is POMC
Proopiomelanocortin. POMC is a precursor protein with multiple cleavage sites, in which post translational modification gives rise to ACTH, beta-endorphin, and alpha-MSH.
What molecule, belonging to the HPA axis, is an important aspect of pituitary pars intermedia dysfunction (PPID) in horses
POMC
What is the main stimulus for cortisol release?
stress (like this exam amiright)
What two parts of the HPA exhibit negative feedback?
Cortisol inhibits both CRH and ACTH.
ACTH inhibits itself.
What is the primary mineralocorticoid?
aldosterone
How do exogenous glucocorticoids/corticosteroids decrease cortisol production?
exogenous glucocorticoids also give negative feedback to the hypothalamus and pituitary, inhibiting the release of CRH and ACTH
What stimulates the release of aldosterone?
Aldosterone is the final production of activation of the RAAS system in response to decreased renal blood pressure. Its secretion is stimulated by angiotensin II
Describe the RAAS system (im so sorry)
decreased blood pressure -> renin converts angiotensinogen in the liver into angiotensin I -> angiotensin converting enzyme (ACE), produced in the lungs, converts angiotensin 1 into angiotensin II -> angiotensin II results in aldosterone production from the zona glomerulosa
What are the four “emia”s caused by a lack of aldosterone (eg hypoadrenocorticism/Addison’s)
hyponatremia, hypochloremia, hyperkalemia, and hypovolemia
What does aldosterone do
increases sodium and water retention and increases potassium excretion
What is the precursor for all steroid hormones
cholesterol
What are the predominant glucocorticoids of mammals
cortisol, corticosterone
Adrenal steroidogenesis of cortisol
cholesterol -> pregnenolone ->progesterone -> cortisol
adrenal steroidogenesis of aldosterone
cholesterol -> pregnenolone -> progesterone -> corticosterone -> aldosterone
Where are glucocorticoid receptors found
in cell membrane and cytoplasm
when bound, a cytoplasmic glucocorticoid receptor translocates to the _____ to affect _____
nucleus, gene transcription
What are the 7 effects of glucocorticoids
-antiinflammatory
-immunosuppressive
- vasoconstrictor/positive inotrope/chronotrope
-bronchodilator
-catabolic (increase glucose production from amino acids)
- maintain fluid homeostasis
-neuroprotective
What two affects of glucocorticoids only occur at supraphysiological doses?
anti-inflammation and immunosuppression
what cell type do glucocorticoids act on?
ALMOST EVERY CELL TYPE/BODY SYSTEM
How are glucocorticoids anti-inflammatory
inhibition of arachidonic acid by inhibiting phospholipases. This reduces both the COX and lipoxygenase pathways products that are inflammatory mediators.
They also decrease histamine production and antagonize kinins and toxins.
Which negative affects are greater and why:
NSAIDS or glucocorticoids?
Glucocorticoids. They act higher up in the arachidonic acid pathway
How are glucocorticoids catabolic
promote fat utilization (lipolysis), promotes glucose production from amino acids (gluconeogenesis), antagonizes insulin (increases blood glucose), and inhibits bone formation/promotes bone loss
What does glucocorticoids deficiencies lead to in terms of blood glucose?
hypoglycemia. Glucocorticoids increase blood glucose by antagonizing insulin, so if they are deficient, insulin will take up all the glucose from the blood.
how do glucocorticoids maintain fluid homeostasis
promote salt and water retention due to the fact that they have some mineralocorticoid activity
What causes the classic PU/PD seen with glucocorticoids?
increased sodium and glucose levels, plus retention of more water than sodium, leads to increased plasma volume and lost of the renal medullary concentration gradient
How are glucocorticoids immunosuppressive
they alter leukocyte numbers.
(Think about a stress leukogram - the acronym I use to remember is SMiLEd -> segmented neutrophils and monocytes are increased, lymphocytes and eosinophils are decreased)
What are the cardiorespiratory affects of glucocorticoids
They block increased capillary permeability induced by acute inflammation (this ties into their immunosuppressive properties), enhance vasoconstriction, are slight positive inotropes, and increases B-2 affects (bronchodilation)
What does a glucocorticoids deficiency lead to in terms of blood pressure?
glucocorticoid deficiencies lead to hypotension. This is because glucocorticoids enhance vasoconstriction, and if this is impaired, blood pressure drops.
What is chronic glucocorticoid use associated with in cats, particularly those with pre-existing disease?
Chronic glucocorticoid use increases the risk of CHF in cats
How are glucocorticoids neuroprotective
they protect against hypoxic/ischemic brain damage
What is the (fricking long) list of the effects of glucocorticoid deficiency
Hypotension
hypoglycemia
anorexia
vomiting
diarrhea
weightloss
muscular weakness
increased susceptibility to stress
inability to maintain endothelial integrity and tone
+/- hyponatremia and +/- polyuria
Which is the active form: prednisone or prednisolone
prednisolone
What are the two forms of glucocorticoid esters
phosphate and succinate esters
acetate and acetonide esters
What do the ester forms of glucocorticoids affect in terms of pharmacokinetics
speed of onset and duration of action
Which esters have rapid onset:
phosphate and succinate esters or acetate and acetonide esters
phosphate and succinate esters. These are highly water soluble
Which esters have delayed onset:
phosphate and succinate esters or acetate and acetonide esters.
acetate and acetonide esters. These are poorly water soluble
What form of prednisone/prednisolone should be given to cats and horses? why
Prednisolone. Horses and cats don’t metabolize prednisone well because it is a CYP450 dependent process
What are the four most commonly used glucocorticoid drugs?
prednisone
prednisolone
dexamethasone
fluticasone
Which form (prednisone vs prednisolone) is not suitable for topical administration in any species, and why?
prednisone because it requires hepatic metabolism to get to its active form
Which typically require a higher glucocorticoid dose: cats or dogs
cats
glucocorticoid routes of administration
IV/IM/SQ/oral/local(intraarticular)/inhaled/topical
What are the top 3 adverse affects of glucocorticoids
immunosuppression
GI ulcers
Elevated liver enzymes/steroid-induced hepatopathy
What glucocorticoid is commonly used in SA for anti-inflammatory/antiallergic treatment
prednisone/prednisolone
What glucocorticoid is commonly used in LA for anti-inflammatory/antiallergic treatment
dexamethasone
Why should you taper glucocorticoid administration withdrawal if their was a chronic administration
HPA axis suppression often occurs, so quitting cold turkey will mean the animal wont produce any endogenous glucocorticoids
How can you reduce HPA axis suppression?
alternate day therapy
What happens if you co-administer an NSAID with a steroid
Because they act on the same arachidonic acid pathway, any adverse affects will be amplified/doubled. This includes things like GI lesions and renal abnormalities
What skin condition is commonly treated with glucocorticoids
atopic dermatitis
What blood condition of dogs is commonly treated with glucocorticoids
immune-mediated hemolytic anemia
What neoplasia is commonly treated with glucocorticoids
lymphoma
What respiratory condition is commonly treated with glucocorticoids
equine/feline asthma
What are contraindications/cautions for glucocorticoid use
systemic fungal disease
laminitis in horses
concurrent infection
corneal ulcers
What is ciclesonide
a new inhaled corticosteroid that was released and then pulled from the market.
What treatments for hyperadrenocorticism (PPID, cushing’s) target the adrenal gland
Trilostane and mitotane
MOA of trilostane
inhibits pregnenolone conversion into progesterone, preventing the production of cortisol in the adrenal gland
Mitotane MOA
inhibits the conversion of cholesterol into pregnenolone, and inhibits the conversion of pregnenolone into progesterone, preventing the production of cortisol in the adrenal gland
What are the adverse affects of trilostane and mitotane?
signs associated with HYPOadrenocorticism:
lethargy, vomiting, diarrhea, inappetance, weakness
What treatments for hyperadrenocorticism (PPID, cushings) target the pituitary
Selegiline and pergolide mesylate
What are selegiline and pergolide mesylates
dopamine agonists that reduce cortisol production at the level of the pituitary
What dopamine agonist is used to treat hyperadrenocorticism in dogs
selegiline, although it is only effective in 20% of dogs
What dopamine agonist is the standard treatment for PPID in horses
pergolide mesylate
Selegiline MOA
acts as a dopamine agonist to cause feedback inhibition to ACTH
Pergolide mesylate MOA
acts as a dopamine agonist and inhibits production of POMC derived hormones
What are the symptoms of hypoadrenocorticism (addisons)
lethargy, vomiting, diarrhea, inappetance, weakness
What mineralocorticoid replacements are used to treat addisons (hyopadrenocorticism)
Desoxycorticosterone pivalate (DOCP)
Fludrocortisone acetate
What glucocorticoid replacement is used to treat hypoadrenocorticism (addisons)
Dexamethosone for acute crises, pred for chronic
What are the two components of atopic dermatitis
IgE-mediated mast cell degranulation
Cytokine dysregulation
What type of T helper cells is most responsible for the initial response in atopic dermatitis
Th-2
What do Th-2 cells release
interleukins
what do Th-1 cells release
IFN-y, TNF-a
What are the two H1 antagonists used to treat atopic dermatitis (perhaps ineffectively)
Diphenhydramine (benadryl)
Hydroxyzine
What is the top adverse affect of antihistamines
CNS depression
What should you not give CNS depressants (like antihistamines) with
monoamine oxidase inhibitors
What is oclacitinib?
brand name Apoquel, is a JAK-1 selective inhibitor
How does oclacitinib work for atopic dermatitis
it blocks the action of IL-31, an interleukin specifically associated with pruritis
How is oclacitinib administered
typically orally
when should you not dive oclacitinib
during active infections, due to the immunomodulatory effects
What are the adverse effects of Oclacitinib
Mostly GI (diarrhea, anorexia, vomiting)
Immunosuppression
Possibly worsens pre-existing tumors
What is cyclosporine
an immunosuppressive drug used to treat a variety of conditions, includingg transplant rejection
what immunosuppresive drug can be used to treat atopic dermatitis
cyclosporine
What are the adverse affects of cyclosporine
Gi upset, but usually decreases with time
What is Lokivetmab
aka cytopoint, is a monoclonal antibody against IL-31
