Glucocorticoids/Antiallergic Pharmacology Flashcards
Where are mineralocorticoids and glucocorticoids produced
zona glomerulosa produces mineralocorticoids like aldosterone
zona fasciculata produces glucocorticoids like cortisol and corticosterone
These layers of the adrenal gland are physically close together and so disorders usually affect both
Explain the HPA axis
It controls cortisol and corticosterone release
stimuli = stress
- hypothalamus releases corticotropin releasing hormone
- anterior pituitary releases ACTH from propriomelanocortin (POMC)
- acts on adrenal gland which releases cortisol
There is negative feedback from
- ACTH acting on the anterior pituitary
- cortisol acting on the hypothalamus and anterior pituitary
How do exogenous corticoids affect the HPA axis
They cause negative feedback which results in atrophy of the adrenal gland
Must wean off slowly
How is aldosterone produced
RAAS
What is addisons disease? What are the main abnormalities?
hypoadrenocorticism
lack of aldosterone
hyponatremia and hyperkalemia
Explain steroidogenesis
- cholesterol
- pregnenolone
- progesterone
- makes cortisol - corticosterone
- aldosterone
Where are glucocorticoid receptors and what occurs after activation?
In the cytoplasm of cells
Once bound they will translocate to the nucleus and bind glucocorticoid response elements = gene transcription
- can also interact with other transcription factors to affect gene expression
takes time
There are fast effects
- inhibiting arachidonic acid release from damaged cells
- inhibiting lymphocyte activation through altering Ca channels
What are 2 main features of a stress leukogram
neutrophilia and lymphopenia
List 9 effects of glucocortioids
anti-inflammatory
immunosuppressive
vasoconstriction
positive inotrope
postiive chronotrope
bronchodilator
catabolic (increased glucose production from amino acids)
fluid homeostasis
neuroprotective
What mechanisms do glucocorticoids use to have a immunosuppressive/anti-inflammatory effect
only at supratherapeutic doses
causes eosinophilia/lymphopenia/neutrophilia
- appear like stress leukogram
- induce lymphoid apoptosis
inhibit arachidonic acid production
reduce histamine production
all along with the same adverse effects as NSAID but stronger
What mechanisms give glucocorticoids catabolic effects
increase lipolysis
increase gluconeogenesis (glucose from amino acids)
- only in monogastrics
- ruminants will not be impacted by this
increase blood glucose and antagonize insulin
inhibit bone formation and enhance bone loss
How do glucocorticoids maintain fluid homeostasis
Increase salt and water retention by targeting Na transporter in the kidney and inhibiting ADH release
result in PU/PD
- loss of renal medullary concentration gradient
- increased plasma volume
all glucocorticoids have some mineralocorticoid effect
What mechanisms do glucocorticoids use to have an effect on the vasculo-respiratory system? What species should this be noted in, why?
reduce vasopermeability and increase vasoconstriction
increase the number and sensitivity of beta adrenergic receptors
- beta 2 agonist impacts are enhanced (bronchodilation)
chronic glucocorticoid use in cats increase the risk of CHF due to increased blood volume and hypertension
How do glucocorticoids have a neuroprotective effect
Protect against hypoxic/ischemic damage
What are the consequences of glucocorticoid deficiency
hypotension
hypoglycemia
anorexia/weight loss
vomit/diarrhea
muscular weakness
increased stress
reduced ability to maintain endothelial integrity and vascular tone
potentially hyponatremia and polyuria
What are the 3 main structures of glucocorticoids and how do they impact the effect
steroid structure + side chains
glucocorticoid esters
free ester = short, routinely used, PO
phosphate/succinate = short, rapid onset, IV/IM
acetate/acetonide = long acting (poorly soluble) when IV
- topical
- interarticular in horses
- intralesional in dogs
- most risk of HPA suppression
What 4 factors can the structure of the glucocorticoid have an effect on
pharmacokinetics (duration in the body/absorption)
active (metabolite vs actual drug)
selectivity for receptor
potency = affinity for receptor
List 4 commonly used glucocorticoid drugs
prednisone
prednisolone
dexamethasone
fluticasone
What are the routes of administration you may use for glucocorticoids
IV
IM
SC
PO
local
inhale
topical
Compare prednisone and prednisolone
prednisone is the non active form of prednisolone
metabolism by CYP450 is needed to turn predisone to prednisolone
- therefore predisone cannot be used topically or by cats or horses
The dose given of either is equivalent
In what animals must you use prednisolone
cats and horses
In what animals is dexamethasone used
small and large animals
common in large animals because it is higher potency and so you need less
In what animals is fluticasone used and how is it administered?
small animals and horses
inhale
What are the adverse effects of glucocorticoids
immunosuppression
- stress leukogram
- increased infection risk
GI ulcers
increased liver enzymes/steroid hepatopathy
- glucocorticoid inducible increased ALP
- secondary liver enzyme increase due to glycogen accumulation
PU/PD (inconvenient for owners)
iatrogenic hyperadrenococrticism
HPA axis suppression
polyphagia
reduced wound healing
behaviour change
muscle atrophy
induce birth (if late parturition)
hyperglycemia
insulin resistance
How does cat vs dog dosing of glucocorticoids compare
cats usually need higher dose because they have fewer receptors and lower affinity than dogs
usually have less adverse effects compared to dogs
What are 4 common uses of glucocorticoids
physiologic replacement therapy (tx hypoadrenocorticism)
anti-inflammation/anti-allergic
immunosuppressive (tx autoimmune dz)
- higher dose and for many months
chronic palliative
How much endogenous glucocorticoids are produced daily? How does this influence their replacement dose?
1mg/kg endogenous per day
usually replacement dose is less because the drugs are more potent
ex. dogs, prednisone = 0.1/0.2mg/kg/d
timing of administration is not important
- not influenced by circadian rhythm
Which glucocorticoids are commonly used to treat allergy in small and large animals
small
- prednisone/prednisolone
large
- dexamethasone
When would you use glucocorticoids for chronic palliative care
chronic inflammation like OA that is non responsive to NSAID
Are glucocorticoids used for treating septic shock
sometimes - not good evidence
may be helpful in patients with critical illness related corticosteroid insufficiency
but also cause immunosuppression
only if not responsive to medical management (abx/fluid/vasopressin)
What should you consider before giving glucocorticoids
dont give with NSAID
careful if combining with K wasting diuretic
suppress HPA axis
not curative - will control clinical signs
How and when to taper glucocorticoids
After 2 weeks of therapy
can usually reduce dose to every other day
- except if replacing the physiologic amount
taper even with the use of chronic topical
- to prevent rebound inflammation
- ex. equine recurrent uveitis
What 3 diseases indicate the use of glucocorticoids (non-replacement)
atopic dermatitis
- pruritis/alopecia
- use for anti-inflam effects
IMHA
- lethargy/anemia/icterus
- use for immunosuppressive effects
lymphoma
- large LN/v/d/dyspnea
- immunosuppressive effects (induce lymphocyte apoptosis)
- palliative
What 4 conditions are contraindications for glucocorticoid use
systemic fungal disease
laminitis
concurrent infection
corneal ulcer
What is ciclesonide’s mechanism of action? How is it administered
inhaled
It is a prodrug that is converted to desisobutyryl-ciclesonide in the lungs (has higher affinity for receptors)
It has similar effect as PO dexamethasone with less impact on HPA/adverse
What is a soft drug? Give an example
ciclesonide
low adverse effects
low bioavailability if PO
increased clearance = less exposure to active metabolite
soft mist of small particles = higher efficacy
What is the pathogenesis of hyperadrenocorticism
increased secretion of glucocorticoids
either
adrenal dependent = increased cortisol = adrenal neoplasia
pituitary dependent = increased ACTH = adenoma
- more common (dog/horse)
What 2 mechanisms are used to treat hyperadrenocorticism
suppress ACTH
- target pituitary
suppress cortisol
- target adrenal
Provide 2 examples for hyperadrenocorticism drugs that target the pituitary and adrenal
pituitary
- selegine
- pergolide mesylate
adrenal
- trilostane
- mitotane
What is the mechanism of action of trilostane
blocks pregnenolone conversion to progesterone by inhibiting 3beta hydroxysteroid dehydrogenase
- target adrenal
70% effective
most commonly used
What are the adverse effects associated with trilostane
vomit
diarrhea
anorexia
lethargy
can have mineralocorticoid disruption
What is the mechanism of action of mitotane
blocks conversion of cholesterol to pregnenolone and pregnenolone to progesterone by inhibiting CYP450 side chain cleavage enzymes
- target adrenal
What are the adverse effects of mitotane
severe progressive necrosis of the zona fasciculata and reticularis
- high doses can cause destruction and lifelong monitoring/supplementation
addisonian crisis
What are the common adverse effects of hypoadrenocorticism
lethargy
vomit
diarrhea
anorexia
weakness
hyponatremia
hyperkalemia
What is the mechanism of action of selegine
dopamine agonist results in feedback inhibition of ACTH
monoamine oxidase inhibitor (caution with SSRI = seratonin syndrome)
When is selegine used
in dogs
usually after theyve tried trilostane and mitotane
What is the mechanism of action of pergolide mesylate
dopamine agonist resulting in feedback inhibition of ACTH
inhibit production of POMC-derived hormones
When is pergolide mesylate used
PPID horse
standard tx
What is hypoadrenocorticism
immune mediated reduction of gluco and mineralocorticoids
What is the standard treatment for hypoadrenocorticism
mineralocorticoid then glucocorticoid if needed
List 3 potential treatment options for hypoadrenocorticism
desoxycorticosterone pivalate
- mineralocorticoid replacement
fludrocortisone acetate
- mineralo and glucocorticoid replacement
dexamethasone
- glucocorticoid replacement
How is desoxycorticosterone pivalate administered
usually 1 injection lasts 25d
titrate to lowest dose
may need to add glucocorticoid supplementation too
How is fludrocortisone acetate administered
PO q24h
How is dexamethasone used for treating hypoadrenocorticism
glucocorticoid replacement
acute use
- use pred long term
less reactivity with cortisol assays so you can use it before diagnostic testing
What are the 2 main mechanisms of atopic dermatitis
associated with a skin barrier defect
mast cell degranulation
- Th2 cells trigger B cell release of IgE
- sensitize mast cells
- histamine release
- vasodilation/vascular leak/smooth muscle spasm
- anaphylaxis if systemic
cytokine dystregulation
- IL31 = pruritis - due to Th2
- also IFNy/TNFa - due to Th1
List 2 examples of antihistamines
diphenhydramine (benadryl)
hydoxyzine
minimal effect
What are the adverse effects associated with H1 antagonist
antihistamines
mild
- CNS depression/drowsy
- GI
- anticholinergic
- drug interactions - synergistic with omega 3 and 6, may interact with ketoconazole
When are antihistamines contraindicated
Dont give with other CNS depressants or monoamine oxidase inhibitors
Explain the JAK-STAT pathway
JAK =janus kinase
STAT = signal transducer and activator of transcription
JAK binds cytokine receptor and phosphorylates tyrosine residue
- will phosphorylate STAT
- result in gene transcription
many types of JAK with many functions
What is the mechanism of action of oclacitinib? What is the brand name?
apoquel
It is a JAK 1 inhibitor
It blocks IL (IL31) associated B cell IgE production
How is oclacitinib administered
PO BID for 2 weeks
then
SID
What is oclacitinib mainly used for
canine atopic dermatitis
What contraindications are there for oclacitinib
dont give if the animal has an active infection
not labelled for animals <12mo
but safe long term
What are the pharmacokinetics of oclacitinib
it is rapidly absorbed and reached T max in 1h
it has minimal binding to CYP450 so there are few drug interactions
What are the adverse effects associated with oclacitinib
GI - vomit/diarrhea/anorexia
immunosuppression and increased risk of secondary infection
- otitis
- UTI
-pyoderma
worsen pre-existing tumors
What is the mechanism of action of cyclosporine
It is immunosuppressive
inhibits calcineurin in T cells resulting in reduced cytokine (IL2, 4) transcription
It binds RBC
What are the pharmocokinetic properties of cyclosporine
it is large and lipophilic
more absorption if it is ultramicronized
- absorbed in small intestine
binds RBC - use whole blood for monitoring
CYP450 metabolism
biliary excretion
How is cyclosporine administered
PO 1-2h after meal
What is cyclosporine primarily used for
atopic dermatitis in dogs after other treatments have failed
- because strong immunosuppressant and expensive
also IBD cats/lupus/perianal fistula
What are 2 brand name cyclosporine products
atopica
- ultramicronized
sandimmune
- not ultramicronized
- not absorbed as well as atopica
What are the adverse effects associated with cyclosporine
GI upset
- common but usually decreases over time
drug interactions (lots)
- if giving with ketoconazole (a CYP450 inhibitor) it will reduce the amount of cyclosporine you need
gingival hyperplasia
hypertrichosis
diabetes mellitus
papillomatosis
neoplasia risk after long term use
rare = hepatotoxic/thromboembolism
What is the brand name for Lokivetmab? What is its mechanism of action
cytopoint
monoclonal Ig against IL31
How is lokivetmab administered
dogs
SC q3-4 weeks
How is lokivetmab metabolized
It uses protein degradation pathway
does not use conjugation/CYP450
- not affected by liver or kidney disease
long half life - max effect is 3d post injection
What are the adverse effects of lokivetmab
very safe
can use in pregnant and lactating
- unlike librela (frunevetmab)
