Pharmacology 1 - Anti-inflammatory Agents Corticosteroids Flashcards
What are the two different corticosteroids and what is their funcioin?
Glucocorticoids - anti-inflammatory/immunosuppressive effects
Mineralcorticoids - regulation of Na/K balance
Why are glucocorticoids considered to be one of the most consistently effective drugs
Used to treat a wide variety of inflammatory/immune conditions
such as respiratory dx, dermatologic dx, GI dx, Ophthalmic dx, musculoskeletal dx, neurologic dx, immune-mediated and autoimmune dx
Explain the classic arachidonic acid pathway that occurs with inflammation and then explain how glucocorticoids would act on this pathway to prevent inflammation from being too much
If inflammation is present, the body will produce phospholipase A2 which will break down membrane phospholipids of the cell into arachidonic acid. Enzymes will act on arachidonic acid to break it down into prostaglandin H2 and leukotrienes which will magnify inflammation. Glucocorticoids act on the pathway very early on, blocking phospholipase A which will block the pathway and prevent inflammation from occurring
Explain how glucocorticoids will be able to be activated
Glucocorticoid receptors in the body will be normally inactive with the presence of hsp90. if there is inflammation or an exogenous glucocorticoid detected in the body, the receptor will activate and that will be able to translocate into the nucleus of the cell and bind to the DNA and turn on the glucocorticoid response element to activate anti-inflammatory genes and repress pro-inflammatory genes
Why is it that glucocorticoids can have such a widespread effect?
it acts on the DNA
How are glucocorticoids able to diffuse across the cell?
Unionized and lipophilic
What two things do glucocorticoids once activated and bound to DNA cause?
transactivation of anti-inflammatory genes and transpression of pro-inflammatory genes
Why is it important to know the mechanism of action of a glucocorticoid?
-affects almost every cell
-very powerful anti-inflammatory and immunosuppressive genes
-need to balance clinical effects against the adverse effects and side effects
Which two main cell types do glucocorticoids act on and what are examples of each?
inflammatory cells - neutrophils, eosinophils, T cells, mast cells, macrophages, dendritic cells
structural cells - epithelial, endothelial, smooth muscle, mucus glands
What are the factors you should consider when choosing a glucocorticoid?
glucocorticoid activity vs mineralcorticoid activity since many have both
potency
duration of action
route of admin and formulation
species differences
In what instance would you want a drug with mineralcorticoid activity
adrenocortical insufficiency (Addison’s)
Why is potency important when choosing a glucocorticoid?
related to affinity of the drug for the glucocorticoid activity
If a drug had a high affinity to the receptor what effect would it have on duration?
longer lasting
If a drug had a high relative potency what would the dose be compared to that of a drug with lesser relative potency?
lower
What three variables is duration of drug activity related to?
receptor affinity, drug, and formulation
What is half life measured in vs effects?
half life is measured in minutes
effects measured in hours
Hydrocortisone is _____ acting while dexamethasone is _______acting
short acting
long acting
Hydrocortisone’s relative potency is 1, would its dose be high or low? How long would it act?
high
short
Route of administration affects what?
formulation choice
Formulation choice affects duration of activity except in what two cases?
oral administration
topical that becomes oral
What is the solubility of phosphate and succinate esters? What route is it suitable for? What is its onset of action? What instances would you use these drugs?
highly soluble
suitable for IV admin
rapid onset
ER situations
What is the solubility of acetate and acetonide esters? What route is it suitable for? What is its onset of action? What instances would you use these drugs?
poorly soluble
suitable for IM, SC, or IA admin
onset days to weeks
How would a drug base compare to in an acetonide ester?
base would have lower potency and lesser duration while in an in an ester would have a higher potency and longer duration
How quickly are aqueous suspensions absorbed and which routes of used?
rapid absorption after IM or SC admin
What are some solutions of drugs and what route is used?
polyethylene glycol or alcohol vehicles with IV or IM administration
Why should you use caution with polyethylene glycol in cats such as Dexamethasone?
Cats cannot metabolize this so giving multiple doses can lead to polyethylene glycol buildup and toxicity
Prednisone is a ______ and therefore is converted to ________
Prodrug
prednisolone
Define prodrug
meds or compounds that after administration are metabolized in the liver to an active drug
Which species have a low bioavailabiltiy of prednisone and therefore cannot readily metabolize it into prednisolone?
cats and horses
What the the prodrug for cortisol?
cortisone
In what instance would you consider giving a dog prednisolone despite its high cost?
if dog has liver issues
Cats require a _____ dose compared to a dog for the _____ effect
higher
same
Why is it that cats require a higher dose of glucocorticoids than dogs do?
fewer GRs
lower affinity to GRs
How are cats able to get a higher dose of glucocorticoids than dogs?
more resistant to adverse effects
What are the commonly used systemic GCs used in each of the species below?
Dogs
Cats
Horses
Cattle, swine
Dogs - prednisone, prednisolone
Cats - prednisolone
Horses - prednisolone, dexamethasone
Cattle, swine - dexamethasone
Why is dexamethasone often used in horses, cattle, and swine?
Convenient, cheaper, smaller dose than pred, works really well
What effect do glucocorticoids have on leukocytes?
affect number of circulating immune cells - increases neutrophils and monocytes and decreases lymphocytes, eosinophils, and basophils
affect function - decreased release of inflammatory cytokines
What can high doses of corticosteroids lead to?
immunosuppressive dose
Define immunosuppression
inability to mount immune response, inability to fight infection
True or False: Immunosuppression can be related to dose and/or duration of dosing
TRUE
Is immunosuppression good or bad?
BOTH
can lead to an inability to mount of an immune response
OR treat an overactive immune response
Explain the metabolic effects of glucocorticoids
can stimulate glucose and lipid production leading to hyperglycemia and increase in triglycerides and cholesterol
can mobilize amino acids from extrahepatic tissues leading to muscle breakdown
Explain the effect glucocorticoids have on blood vessels
stabilize membranes and decrease vascular permeability leading to a decrease in inflammation in CNS
Explain the endocrine effect of glucocorticoid use
can lead to diabetes mellitus in cats due to gluconeogenic and antagonism of insulin
Explain how glucocorticoid use can lead to hyper and hypoadrenocorticism
The body normally produces cortisol endogenously and if given exogenously for a long period of time the body will forget how to make cortisol endogenously so if it is stopped abruptly, the body will not make any cortisol leading to hypoadrenocorticism or Addison’s. If too much cortisol is being produced then the animal will have hypercorticism or Cushing’s
How can glucocorticoids result in heptatopathy or hepatomegaly?
GC stimulates production of the steroid specific isoenzyme of alkaline phosphate (ALP) in dogs
How do GC lead to GI ulceration?
slow turnover of enterocytes, inhibition of protective prostaglandins
What happens if glucocorticoids alter fluid and electrolyte balance?
sodium and fluid retention and hypokalemic alkalosis leading to PU/PD with glucosuria and behavioral changes
Explain the relation between laminitis and horses with the use of glucocorticoids
likely related to genetic predisposition or metabolism issues related to obese and cresty neck horses
Glucocorticoid adverse effects are often said to be “not if, but when” so what is an important aspect of managing this?
minimize not prevent
Explain how alternate day glucocorticoid therapy works and why
Higher doses every other day of intermediate acting glucocorticoids to allow the body to produce own cortisol on day off - gives HPAA chance to recover
What are examples of intermediate acting glucocorticoids you would want to use alternate day therapy with?
prednisone, prednisolone, and methylprednisolone
Why is tapering the dose important and when is it used as a way to minimize adverse effects?
Used when discontinuing treatment to prevent signs of hypoadrenocorticism after long-term GC therapy >2 weeks
What should be the rule of thumb when you cant discontinue the drug completely?
lowest possible dose at the longest possible dosing interval
Explain the timing of the dose (i.e. what time of the day should it be administered?
morning - when body normally produces it
If not looking to systemically exposure the body to a glucocorticoid what is an alternative route of administration?
intra-articular
inhalant
topical such as ocular or on skin
When are IMHA IMTP drugs used? What are the significant adverse effects associated with it?
used in cases that dont respond to GCs alone
myelosuppression is adverse effect
