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VETM 443 Pharmacology > Glucocorticoids/Antiallergic Pharmacology > Flashcards

Glucocorticoids/Antiallergic Pharmacology Flashcards

1
Q

Where are mineralocorticoids and glucocorticoids produced

A

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

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2
Q

Explain the HPA axis

A

It controls cortisol and corticosterone release

stimuli = stress

  1. hypothalamus releases corticotropin releasing hormone
  2. anterior pituitary releases ACTH from propriomelanocortin (POMC)
  3. 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

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3
Q

How do exogenous corticoids affect the HPA axis

A

They cause negative feedback which results in atrophy of the adrenal gland

Must wean off slowly

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4
Q

How is aldosterone produced

A

RAAS

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5
Q

What is addisons disease? What are the main abnormalities?

A

hypoadrenocorticism

lack of aldosterone

hyponatremia and hyperkalemia

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6
Q

Explain steroidogenesis

A
  1. cholesterol
  2. pregnenolone
  3. progesterone
    - makes cortisol
  4. corticosterone
  5. aldosterone
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7
Q

Where are glucocorticoid receptors and what occurs after activation?

A

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

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8
Q

What are 2 main features of a stress leukogram

A

neutrophilia and lymphopenia

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9
Q

List 9 effects of glucocortioids

A

anti-inflammatory

immunosuppressive

vasoconstriction

positive inotrope

postiive chronotrope

bronchodilator

catabolic (increased glucose production from amino acids)

fluid homeostasis

neuroprotective

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10
Q

What mechanisms do glucocorticoids use to have a immunosuppressive/anti-inflammatory effect

A

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

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11
Q

What mechanisms give glucocorticoids catabolic effects

A

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

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12
Q

How do glucocorticoids maintain fluid homeostasis

A

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

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13
Q

What mechanisms do glucocorticoids use to have an effect on the vasculo-respiratory system? What species should this be noted in, why?

A

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

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14
Q

How do glucocorticoids have a neuroprotective effect

A

Protect against hypoxic/ischemic damage

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15
Q

What are the consequences of glucocorticoid deficiency

A

hypotension

hypoglycemia

anorexia/weight loss

vomit/diarrhea

muscular weakness

increased stress

reduced ability to maintain endothelial integrity and vascular tone

potentially hyponatremia and polyuria

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16
Q

What are the 3 main structures of glucocorticoids and how do they impact the effect

A

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

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17
Q

What 4 factors can the structure of the glucocorticoid have an effect on

A

pharmacokinetics (duration in the body/absorption)

active (metabolite vs actual drug)

selectivity for receptor

potency = affinity for receptor

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18
Q

List 4 commonly used glucocorticoid drugs

A

prednisone

prednisolone

dexamethasone

fluticasone

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19
Q

What are the routes of administration you may use for glucocorticoids

A

IV
IM
SC
PO
local
inhale
topical

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20
Q

Compare prednisone and prednisolone

A

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

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21
Q

In what animals must you use prednisolone

A

cats and horses

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22
Q

In what animals is dexamethasone used

A

small and large animals

common in large animals because it is higher potency and so you need less

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23
Q

In what animals is fluticasone used and how is it administered?

A

small animals and horses

inhale

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24
Q

What are the adverse effects of glucocorticoids

A

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

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25
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
26
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
27
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
28
Which glucocorticoids are commonly used to treat allergy in small and large animals
small - prednisone/prednisolone large - dexamethasone
29
When would you use glucocorticoids for chronic palliative care
chronic inflammation like OA that is non responsive to NSAID
30
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)
31
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
32
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
33
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
34
What 4 conditions are contraindications for glucocorticoid use
systemic fungal disease laminitis concurrent infection corneal ulcer
35
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
36
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
37
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)
38
What 2 mechanisms are used to treat hyperadrenocorticism
suppress ACTH - target pituitary suppress cortisol - target adrenal
39
Provide 2 examples for hyperadrenocorticism drugs that target the pituitary and adrenal
pituitary - selegine - pergolide mesylate adrenal - trilostane - mitotane
40
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
41
What are the adverse effects associated with trilostane
vomit diarrhea anorexia lethargy can have mineralocorticoid disruption
42
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
43
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
44
What are the common adverse effects of hypoadrenocorticism
lethargy vomit diarrhea anorexia weakness hyponatremia hyperkalemia
45
What is the mechanism of action of selegine
dopamine agonist results in feedback inhibition of ACTH monoamine oxidase inhibitor (caution with SSRI = seratonin syndrome)
46
When is selegine used
in dogs usually after theyve tried trilostane and mitotane
47
What is the mechanism of action of pergolide mesylate
dopamine agonist resulting in feedback inhibition of ACTH inhibit production of POMC-derived hormones
48
When is pergolide mesylate used
PPID horse standard tx
49
What is hypoadrenocorticism
immune mediated reduction of gluco and mineralocorticoids
50
What is the standard treatment for hypoadrenocorticism
mineralocorticoid then glucocorticoid if needed
51
List 3 potential treatment options for hypoadrenocorticism
desoxycorticosterone pivalate - mineralocorticoid replacement fludrocortisone acetate - mineralo and glucocorticoid replacement dexamethasone - glucocorticoid replacement
52
How is desoxycorticosterone pivalate administered
usually 1 injection lasts 25d titrate to lowest dose may need to add glucocorticoid supplementation too
53
How is fludrocortisone acetate administered
PO q24h
54
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
55
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
56
List 2 examples of antihistamines
diphenhydramine (benadryl) hydoxyzine minimal effect
57
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
58
When are antihistamines contraindicated
Dont give with other CNS depressants or monoamine oxidase inhibitors
59
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
60
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
61
How is oclacitinib administered
PO BID for 2 weeks then SID
62
What is oclacitinib mainly used for
canine atopic dermatitis
63
What contraindications are there for oclacitinib
dont give if the animal has an active infection not labelled for animals <12mo but safe long term
64
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
65
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
66
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
67
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
68
How is cyclosporine administered
PO 1-2h after meal
69
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
70
What are 2 brand name cyclosporine products
atopica - ultramicronized sandimmune - not ultramicronized - not absorbed as well as atopica
71
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
72
What is the brand name for Lokivetmab? What is its mechanism of action
cytopoint monoclonal Ig against IL31
73
How is lokivetmab administered
dogs SC q3-4 weeks
74
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
75
What are the adverse effects of lokivetmab
very safe can use in pregnant and lactating - unlike librela (frunevetmab)

VETM 443 Pharmacology (23 decks)

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