Pharmacology 1 - Anti-inflammatory Agents Corticosteroids

Question 1

What are the two different corticosteroids and what is their funcioin?

Answer 1

Glucocorticoids - anti-inflammatory/immunosuppressive effects
Mineralcorticoids - regulation of Na/K balance

Question 2

Why are glucocorticoids considered to be one of the most consistently effective drugs

Answer 2

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

Question 3

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

Answer 3

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

Question 4

Explain how glucocorticoids will be able to be activated

Answer 4

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

Question 5

Why is it that glucocorticoids can have such a widespread effect?

Answer 5

it acts on the DNA

Question 6

How are glucocorticoids able to diffuse across the cell?

Answer 6

Unionized and lipophilic

Question 7

What two things do glucocorticoids once activated and bound to DNA cause?

Answer 7

transactivation of anti-inflammatory genes and transpression of pro-inflammatory genes

Question 8

Why is it important to know the mechanism of action of a glucocorticoid?

Answer 8

-affects almost every cell
-very powerful anti-inflammatory and immunosuppressive genes
-need to balance clinical effects against the adverse effects and side effects

Question 9

Which two main cell types do glucocorticoids act on and what are examples of each?

Answer 9

inflammatory cells - neutrophils, eosinophils, T cells, mast cells, macrophages, dendritic cells
structural cells - epithelial, endothelial, smooth muscle, mucus glands

Question 10

What are the factors you should consider when choosing a glucocorticoid?

Answer 10

glucocorticoid activity vs mineralcorticoid activity since many have both
potency
duration of action
route of admin and formulation
species differences

Question 11

In what instance would you want a drug with mineralcorticoid activity

Answer 11

adrenocortical insufficiency (Addison’s)

Question 12

Why is potency important when choosing a glucocorticoid?

Answer 12

related to affinity of the drug for the glucocorticoid activity

Question 13

If a drug had a high affinity to the receptor what effect would it have on duration?

Answer 13

longer lasting

Question 14

If a drug had a high relative potency what would the dose be compared to that of a drug with lesser relative potency?

Answer 14

lower

Question 15

What three variables is duration of drug activity related to?

Answer 15

receptor affinity, drug, and formulation

Question 16

What is half life measured in vs effects?

Answer 16

half life is measured in minutes
effects measured in hours

Question 17

Hydrocortisone is _____ acting while dexamethasone is _______acting

Answer 17

short acting
long acting

Question 18

Hydrocortisone’s relative potency is 1, would its dose be high or low? How long would it act?

Answer 18

high
short

Question 19

Route of administration affects what?

Answer 19

formulation choice

Question 20

Formulation choice affects duration of activity except in what two cases?

Answer 20

oral administration
topical that becomes oral

Question 21

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?

Answer 21

highly soluble
suitable for IV admin
rapid onset
ER situations

Question 22

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?

Answer 22

poorly soluble
suitable for IM, SC, or IA admin
onset days to weeks

Question 23

How would a drug base compare to in an acetonide ester?

Answer 23

base would have lower potency and lesser duration while in an in an ester would have a higher potency and longer duration

Question 24

How quickly are aqueous suspensions absorbed and which routes of used?

Answer 24

rapid absorption after IM or SC admin

Question 25

What are some solutions of drugs and what route is used?

Answer 25

polyethylene glycol or alcohol vehicles with IV or IM administration

Question 26

Why should you use caution with polyethylene glycol in cats such as Dexamethasone?

Answer 26

Cats cannot metabolize this so giving multiple doses can lead to polyethylene glycol buildup and toxicity

Question 27

Prednisone is a ______ and therefore is converted to ________

Answer 27

Prodrug prednisolone

Question 28

Define prodrug

Answer 28

meds or compounds that after administration are metabolized in the liver to an active drug

Question 29

Which species have a low bioavailabiltiy of prednisone and therefore cannot readily metabolize it into prednisolone?

Answer 29

cats and horses

Question 30

What the the prodrug for cortisol?

Answer 30

cortisone

Question 31

In what instance would you consider giving a dog prednisolone despite its high cost?

Answer 31

if dog has liver issues

Question 32

Cats require a _____ dose compared to a dog for the _____ effect

Answer 32

higher same

Question 33

Why is it that cats require a higher dose of glucocorticoids than dogs do?

Answer 33

fewer GRs lower affinity to GRs

Question 34

How are cats able to get a higher dose of glucocorticoids than dogs?

Answer 34

more resistant to adverse effects

Question 35

What are the commonly used systemic GCs used in each of the species below? Dogs Cats Horses Cattle, swine

Answer 35

Dogs - prednisone, prednisolone Cats - prednisolone Horses - prednisolone, dexamethasone Cattle, swine - dexamethasone

Question 36

Why is dexamethasone often used in horses, cattle, and swine?

Answer 36

Convenient, cheaper, smaller dose than pred, works really well

Question 37

What effect do glucocorticoids have on leukocytes?

Answer 37

affect number of circulating immune cells - increases neutrophils and monocytes and decreases lymphocytes, eosinophils, and basophils affect function - decreased release of inflammatory cytokines

Question 38

What can high doses of corticosteroids lead to?

Answer 38

immunosuppressive dose

Question 39

Define immunosuppression

Answer 39

inability to mount immune response, inability to fight infection

Question 40

True or False: Immunosuppression can be related to dose and/or duration of dosing

Answer 40

TRUE

Question 41

Is immunosuppression good or bad?

Answer 41

BOTH can lead to an inability to mount of an immune response OR treat an overactive immune response

Question 42

Explain the metabolic effects of glucocorticoids

Answer 42

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

Question 43

Explain the effect glucocorticoids have on blood vessels

Answer 43

stabilize membranes and decrease vascular permeability leading to a decrease in inflammation in CNS

Question 44

Explain the endocrine effect of glucocorticoid use

Answer 44

can lead to diabetes mellitus in cats due to gluconeogenic and antagonism of insulin

Question 45

Explain how glucocorticoid use can lead to hyper and hypoadrenocorticism

Answer 45

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

Question 46

How can glucocorticoids result in heptatopathy or hepatomegaly?

Answer 46

GC stimulates production of the steroid specific isoenzyme of alkaline phosphate (ALP) in dogs

Question 47

How do GC lead to GI ulceration?

Answer 47

slow turnover of enterocytes, inhibition of protective prostaglandins

Question 48

What happens if glucocorticoids alter fluid and electrolyte balance?

Answer 48

sodium and fluid retention and hypokalemic alkalosis leading to PU/PD with glucosuria and behavioral changes

Question 49

Explain the relation between laminitis and horses with the use of glucocorticoids

Answer 49

likely related to genetic predisposition or metabolism issues related to obese and cresty neck horses

Question 50

Glucocorticoid adverse effects are often said to be "not if, but when" so what is an important aspect of managing this?

Answer 50

minimize not prevent

Question 51

Explain how alternate day glucocorticoid therapy works and why

Answer 51

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

Question 52

What are examples of intermediate acting glucocorticoids you would want to use alternate day therapy with?

Answer 52

prednisone, prednisolone, and methylprednisolone

Question 53

Why is tapering the dose important and when is it used as a way to minimize adverse effects?

Answer 53

Used when discontinuing treatment to prevent signs of hypoadrenocorticism after long-term GC therapy >2 weeks

Question 54

What should be the rule of thumb when you cant discontinue the drug completely?

Answer 54

lowest possible dose at the longest possible dosing interval

Question 55

Explain the timing of the dose (i.e. what time of the day should it be administered?

Answer 55

morning - when body normally produces it

Question 56

If not looking to systemically exposure the body to a glucocorticoid what is an alternative route of administration?

Answer 56

intra-articular inhalant topical such as ocular or on skin

Question 57

When are IMHA IMTP drugs used? What are the significant adverse effects associated with it?

Answer 57

used in cases that dont respond to GCs alone myelosuppression is adverse effect