Lecture 23 4/23/24 Flashcards
Which molecule serves as the basis for all hormones of the adrenal cortex?
cholesterol
What are the main products of the adrenal cortex?
C21 and C19 steroids
What are the C21 steroids with a two-carbon side chain at position 17 categorized as?
-mineralocorticoids
-glucocorticoids
What are the results of chemical modification of the cortisol molecule?
-increased glucocorticoid activity
-decreased mineralocorticoid activity
-altered protein binding
-hepatic metabolism
What is anti-inflammatory activity associated with?
glucocorticoid activity
How does prednisone/prednisolone differ from cortisol?
-introduction of a double bond between C1 and C2
-increased anti-inflammatory activity
-reduced mineralocorticoid activity
What are the characteristics of prednisone?
-originally an inactive compound
-must be converted into active form in the liver
What change converts prednisolone into methylprednisolone?
addition of a methyl group at the C6alpha position
What change converts prednisolone into triamcinolone?
insertion of a 16alpha hydroxyl group
How do methylprednisolone and triamcinolone differ from prednisolone in terms of activity?
-higher anti-inflammatory effect
-decreased mineralocorticoid activity
What are the characteristics of dexamethasone and betamethasone?
most potent anti-inflammatory glucocorticoids
-added C9a fluorine atom increases glucocorticoid activity
-added C16 methyl group decreases mineralocorticoid activity
What is D ring manipulation?
changes made to the D ring to produce “soft” glucocorticoids that have increased topical and/or inhalational absorption
What are the steps of glucocorticoid binding to its receptor?
-GCs passively diffuse into cells
-bind to cytoplasmic glucocorticoids receptor
-GC-GR complex translocates into nucleus for gene regulation
What are the direct actions of activated glucocorticoid receptors?
-inhibit pro-inflammatory transcription factors
-actively suppress transcription of inflammatory genes
-induce transcription of immunosuppressive genes
Why are glucocorticoids-induced biological responses slow?
time is required before RNA and protein levels of target gene are fully degraded
Which effects of glucocorticoids are induced rapidly?
-effects on transmembrane currents
-effects on signal transduction
-effects on second messenger cascades and intracellular Ca2+ mobilization
What are the characteristics of glucocorticoid suppression of inflammatory and immune-mediated responses?
-rapid action mediated by nongenomic mechanisms
-affects only seen when supraphysiological doses are given
Why is glucocorticoid therapy dangerous?
can mask severity and progression of disease and any serious side effects that may occur
Which cells are primarily effected by glucocorticoids?
leukocytes
What is plasma half life?
the amount of time required for 50% of the drug’s concentration to disappear from plasma
What is biological half life?
-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
What influences duration of action for a drug?
-route of administration
-preparation used
-patient health
-concurrent use of other drugs
What are the three classifications for biological half life?
-short-acting
-intermediate-acting
-long-acting
–all are based on duration of HPA axis suppression
What are the advantages of oral administration?
-GCs are orally effective
-preferred route for systemic application
-safest route
-most convenient
-most economical
What are the disadvantages of oral administration?
-vomiting
-variable absorption
-cooperation of the pet
How does oral bioavailability differ for glucocorticoids?
-high: cortisol, prednisolone, methylprednisolone
-low: dexamethasone
-very low: triamcinolone, budesonide
Why must the prednisone dose be 3-5 times higher than the prednisolone dose?
prednisone is the inactive form that needs to be activated; must account for losses of the inactive drug
What are the characteristics of parenteral glucocorticoid administration?
-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
What are the possible forms of topical/inhalable GCs?
-ointments
-creams
-gels
-solutions
-shampoos/rinses
-eye drops
-crystal suspensions
-aerosols
What is the advantage of topical GCs?
provides high conc. of GC in a specific site; should reduce systemic effects
What are the disadvantages of topical GCs?
-all forms can still have adverse systemic effects
-absorption is variable
How is dose equivalency expressed for GCs?
-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
How do the doses for prednisolone and dexamethasone differ?
-prednisolone dose is 1 mg/kg
-dexamethasone dose is 0.14 mg/kg
What are the characteristics of steroid esters?
-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
What are the characteristics of water-soluble esters?
-esters include succinate and phosphate
-given IV, IM, or SC
-ideal for emergency
-duration of action equal to unmodified GC
What are the characteristics of free alcohol solutions?
-unique to vet med
-dexa polyethylene glycol has increased water solubility
-injectable solution
-IM and IV admin.
-possible CNS side effects
What are the characteristics of insoluble steroid esters?
-esters from acetate to pivalate
-IM, IA, and intralesional admin
-NO IV admin.
-depot preparation/slow release
What is the advantage of insoluble steroid esters?
convenience of admin.
What are the disadvantages of insoluble steroid esters?
-unpredictability of blood conc.
-long-term suppression of HPA axis
-possible induction of GC resistance
-cannot withdraw drug in case of adverse reactions
