Lecture 23 4/23/24

Question 1

Which molecule serves as the basis for all hormones of the adrenal cortex?

Answer 1

cholesterol

Question 2

What are the main products of the adrenal cortex?

Answer 2

C21 and C19 steroids

Question 3

What are the C21 steroids with a two-carbon side chain at position 17 categorized as?

Answer 3

-mineralocorticoids
-glucocorticoids

Question 4

What are the results of chemical modification of the cortisol molecule?

Answer 4

-increased glucocorticoid activity
-decreased mineralocorticoid activity
-altered protein binding
-hepatic metabolism

Question 5

What is anti-inflammatory activity associated with?

Answer 5

glucocorticoid activity

Question 6

How does prednisone/prednisolone differ from cortisol?

Answer 6

-introduction of a double bond between C1 and C2
-increased anti-inflammatory activity
-reduced mineralocorticoid activity

Question 7

What are the characteristics of prednisone?

Answer 7

-originally an inactive compound
-must be converted into active form in the liver

Question 8

What change converts prednisolone into methylprednisolone?

Answer 8

addition of a methyl group at the C6alpha position

Question 9

What change converts prednisolone into triamcinolone?

Answer 9

insertion of a 16alpha hydroxyl group

Question 10

How do methylprednisolone and triamcinolone differ from prednisolone in terms of activity?

Answer 10

-higher anti-inflammatory effect
-decreased mineralocorticoid activity

Question 11

What are the characteristics of dexamethasone and betamethasone?

Answer 11

most potent anti-inflammatory glucocorticoids
-added C9a fluorine atom increases glucocorticoid activity
-added C16 methyl group decreases mineralocorticoid activity

Question 12

What is D ring manipulation?

Answer 12

changes made to the D ring to produce “soft” glucocorticoids that have increased topical and/or inhalational absorption

Question 13

What are the steps of glucocorticoid binding to its receptor?

Answer 13

-GCs passively diffuse into cells
-bind to cytoplasmic glucocorticoids receptor
-GC-GR complex translocates into nucleus for gene regulation

Question 14

What are the direct actions of activated glucocorticoid receptors?

Answer 14

-inhibit pro-inflammatory transcription factors
-actively suppress transcription of inflammatory genes
-induce transcription of immunosuppressive genes

Question 15

Why are glucocorticoids-induced biological responses slow?

Answer 15

time is required before RNA and protein levels of target gene are fully degraded

Question 16

Which effects of glucocorticoids are induced rapidly?

Answer 16

-effects on transmembrane currents
-effects on signal transduction
-effects on second messenger cascades and intracellular Ca2+ mobilization

Question 17

What are the characteristics of glucocorticoid suppression of inflammatory and immune-mediated responses?

Answer 17

-rapid action mediated by nongenomic mechanisms
-affects only seen when supraphysiological doses are given

Question 18

Why is glucocorticoid therapy dangerous?

Answer 18

can mask severity and progression of disease and any serious side effects that may occur

Question 19

Which cells are primarily effected by glucocorticoids?

Answer 19

leukocytes

Question 20

What is plasma half life?

Answer 20

the amount of time required for 50% of the drug’s concentration to disappear from plasma

Question 21

What is biological half life?

Answer 21

-refers to duration of effects
-varies because biological effect is due to alterations in genetic regulation of protein production
-must be considered when establishing treatment protocol

Question 22

What influences duration of action for a drug?

Answer 22

-route of administration
-preparation used
-patient health
-concurrent use of other drugs

Question 23

What are the three classifications for biological half life?

Answer 23

-short-acting
-intermediate-acting
-long-acting
–all are based on duration of HPA axis suppression

Question 24

What are the advantages of oral administration?

Answer 24

-GCs are orally effective
-preferred route for systemic application
-safest route
-most convenient
-most economical

Question 25

What are the disadvantages of oral administration?

Answer 25

-vomiting -variable absorption -cooperation of the pet

Question 26

How does oral bioavailability differ for glucocorticoids?

Answer 26

-high: cortisol, prednisolone, methylprednisolone -low: dexamethasone -very low: triamcinolone, budesonide

Question 27

Why must the prednisone dose be 3-5 times higher than the prednisolone dose?

Answer 27

prednisone is the inactive form that needs to be activated; must account for losses of the inactive drug

Question 28

What are the characteristics of parenteral glucocorticoid administration?

Answer 28

-more predictable absorption than oral -more expensive than oral -glucocorticoids are synthesized as glucocorticoid esters -IV admin. allows for rapid high concentrations -IM admin. allows for prolonged effects

Question 29

What are the possible forms of topical/inhalable GCs?

Answer 29

-ointments -creams -gels -solutions -shampoos/rinses -eye drops -crystal suspensions -aerosols

Question 30

What is the advantage of topical GCs?

Answer 30

provides high conc. of GC in a specific site; should reduce systemic effects

Question 31

What are the disadvantages of topical GCs?

Answer 31

-all forms can still have adverse systemic effects -absorption is variable

Question 32

How is dose equivalency expressed for GCs?

Answer 32

-cortisol is assigned a value of 1 for both glucocorticoid and mineralocorticoid potency -numbers higher than 1 indicate increased potency -numbers lower than 1 indicate decreased potency

Question 33

How do the doses for prednisolone and dexamethasone differ?

Answer 33

-prednisolone dose is 1 mg/kg -dexamethasone dose is 0.14 mg/kg

Question 34

What are the characteristics of steroid esters?

Answer 34

-GCs typically have low water solubility -esterification can alter the lipid/water solubility ratio and duration of action -ester also determines route of administration for drug

Question 35

What are the characteristics of water-soluble esters?

Answer 35

-esters include succinate and phosphate -given IV, IM, or SC -ideal for emergency -duration of action equal to unmodified GC

Question 36

What are the characteristics of free alcohol solutions?

Answer 36

-unique to vet med -dexa polyethylene glycol has increased water solubility -injectable solution -IM and IV admin. -possible CNS side effects

Question 37

What are the characteristics of insoluble steroid esters?

Answer 37

-esters from acetate to pivalate -IM, IA, and intralesional admin -NO IV admin. -depot preparation/slow release

Question 38

What is the advantage of insoluble steroid esters?

Answer 38

convenience of admin.

Question 39

What are the disadvantages of insoluble steroid esters?

Answer 39

-unpredictability of blood conc. -long-term suppression of HPA axis -possible induction of GC resistance -cannot withdraw drug in case of adverse reactions