3 - Glucocorticoids Flashcards
**Identify the factors controlling cortisol biosynthesis.
HPA axis!
stress–> hypothal–>CRH–>ant pituitary–>ACTH–>adrenal–> cortisol!
**Describe the general mechanism for steroid hormone receptor using the glucocorticoid receptor as a model.
penetrate cell membrane. IC receptor. binds to HR and mves into the nuclear and imerizes. binds to specific region on DNA. regulates gene transcription.
TAKES TIME.
HREs–> upstream of steroid responsive genes. binding alters rate of transcription.
**GCs upregulate gluconeogeneis and anti-inflamm proteins
**Explain the molecular model for the anti-inflammatory and immunosuppressive actions of glucocorticoids.
upregulate lipocortin –> decr eicosanoids
prevent NFkB from binding to response element –> suppressed transcription of cytokines
**Remember the relative potency and glucocorticoid/mineralocorticoid activity among various glucocorticoids
coritsol and cortisone: low potency, short-acting
prednisolone/nisolone: incr’d GC, decr MC, intermed doa
methylprednisolone and triamcinolone: incr’d GC, no MC, intermed doa
dexamethasone/betamethasone: long doa, high GC, no MC
fludrocortisone: incr’d GC but more incr’d MC, short-acting
**Identify the modifications of the cortisol structure that are responsible for increased activity and increased glucocorticoid/mineralocorticoid activity.
1,2 double bond incr GR/MR ratio
6alpha methyl or F ncr Gr/MR ratio
9alphaF or Cl (incr both)
**Identify the adverse effects of glucocorticoid therapy.
crossover MC activity
-sodium and water retetnion
HTN
correctable w selective synthetic GCs
metabolic (incr glucose prod)
- steroid myopathy–wasting of proximal muscles w high doses ove time
- reduced long bone growth in children
- osteoporosis–inhib osteoblasts. can be prevented w bisphosphonate
Cushing’s-like fat redistribution
-moon face
buffalohump
imp’d glucose tolerance
-hyperglycemia
decr insulin response (may unmask DM)
suppress imm sys: incr infx, imp healing
GI: incr ulcer risk
CNS: euphoria, depression
cataracts
**Explain the mechanism of the adverse effects of glucocorticoid therapy.
crossover MC activity
-sodium and water retetnion
HTN
correctable w selective synthetic GCs
metabolic (incr glucose prod)
- steroid myopathy–wasting of proximal muscles w high doses ove time
- reduced long bone growth in children
- osteoporosis–inhib osteoblasts. can be prevented w bisphosphonate
Cushing’s-like fat redistribution
-moon face
buffalohump
imp’d glucose tolerance
-hyperglycemia
decr insulin response (may unmask DM)
suppress imm sys: incr infx, imp healing
GI: incr ulcer risk
CNS: euphoria, depression
cataracts
**Describe the desired properties of inhaled glucocorticoids.
high potency
minimal SEs
prolonged action
soln: high lipophilicity (prolong action) low oral BA rapid clearance (systemically)
**Identify the structural modifications that are responsible for increased lipophilicity and increased metabolism in inhaled glucocorticoids..
acetonide (triamcinolone acetonide, flunisolide) resistant to hydrolysis –> lipophilic –> local
diproprionate (beclemethasone diproprionate)–converted rapidly to monoproprionate by hydrolysis
flunisolide–6alpha F, acetonide
–> rapid abs, met’d by liver (first pass)
budesonide: butylacetal epimer mixture, faster topical uptake, low PO BA, extensive first-pass
mometasone: potent, rapid ooa, rapid systemic metab
fluticasone: inactivated by hydrolysis of thioester (rapid first pass)
hihgly lipophilic d/t F groups, ester
What are the fxns of gluco and mineralocorticoids?
gluco: stress hormones
incr ciruclating glucose conc
potent anti-inflamm
mineralo (ex ald):
regulate Na/K levels
controls BP
Describe the hypothalamic-pituitary-adrenal (HPA) axis .
stress cuases the hypothalmus to release CRH (corticotropin-releasing) –> ant pituitary to release ACTH (adrenocorticotrpic) –> adrenal to release cortisol
cortisol causes response and feeds back
Contrast the modes of action of epi and cortisol.
epi: binds to beta-adrenergic R (GPCR)
signal transduction
immediate response
breaks down glycoge and release glucose
cortisol:
binds GCR (nuclear hormone R)
–> reg gene transcription–> translation–> protein prod
induces long-term, perisitent biological response
–induces gluconeogenic enzymes.
What are the fxns of glucocorticoids for the liver?
incr gluconeogenesis
incr glycogen storage
What are the fxns of GCs for the muscle?
promote protein degrad
decr protein synth
decr sensitivity to insulin
What are the fxns of GCs for adipose tissue?
promote lipolysis
decr sensitivity to insulin
What are the fxns of GCs for immune system?
block synth of cytokines ==> immunosuppression
inhibit prod of eicosanoids –> anti-inflammx
What do GCs upregulate?
enzymes for gluconeogenesis and anti-inflamm proteins.
**lipocortin I–suppresses phospholipase A2, which has critical role in eicosanoid synthesis.
Describe how cytokine genes are turned on.
Nuclear factor kappa B (NFKB) forms a heterodimer w inhibitor protein IkB. immune cell activation removes IkB inhibition of NFkB and NFkB moves to the nucleus, to turn on transcription of cytokine genes.
Describe the moa of immunosuppression by GCs.
activated GR binds to NFkB and prevents its binding to its response element
–> transcription of cytokine genes are suppressed.
What are the needs when designing a glucocorticoid?
max anti-infamm
min MC activity (Na retention, HTN, edema)
prevent Cushing’s (hyperglycemia, hypocalecmia, fat reistribution, CNS)
prev Addisonian crisis upon withdrawl
Describe Addisonian crisis.
can’t product enough GCs when drug stopped (adrenal insuff), resulting in drop in BP, tachycardia, chills, pain, rashes, etc.)
d/t negative feedback
delayed recov of hyothal and ituitary
depressed ACTH release and adrenal response to ACTH
Why we need to taper GCs.directly related to dose and duration of therapy.
What are the S-A relationship for GCs and MCs?
4,5 double bond required for GC/MC activity
C3 ketone required for both
11-beta hydroxyl is required for GC, less po for MC
C17 hydroxyl is required for GC, not req’d for MC
Describe fludrocortisone in terms of S-A and use.
9alpha-F
-incr GC but also strong MC–> na retnetion–> edema
used in MC replacement therapy
Describe prednisone/prednisolone in terms of S-A and use.
extra double bond between C1 and C2.
more potent GC (stronger binding)
decr’d MC activity
prednisone is not actue int he body–11 ketone is converted to hydroxyl (prenisolone)
–> must use prednisolone is liver problems or topical
Describe methylprednisolone in terms of S-A and use.
prednisolone + 6alpha-metyl group
potency similar to prednisolone
decr’d MC activity
Describe triamcinolone in terms of S-A and use.
prenisolone + 9alphaF and 16 alpha OH
GC activity similar to prenisone
decr’d MC activity
incr hydrophilicity –> BA is poor
Describe dexamethasone in terms of S-A and use.
triamcinolone but with 16alpha metyl instead of OH
incr lipophilicity –> incr R binding, stronger effect
**with betamethasone is strongest GC available
decr MC activity
Describe betamethasone in terms of S-A and use.
enantiomer of dexamethasone at 16.
similar properties to dexamethasone (incr lipophilicity and R binding, decr MC activity)
**with dexamethasone is the strongest GC available
What are the properties of 21-esters of acetate and butyrates?
incr’s lipophilicity
rolonged action upon Im or intraarticular inj
What are the properites of 21-esters of phosphate?
incr’d solubility
rapid hydrolysis
optimal for IV or IM inj
What are the properties of 21-esters of succinate?
soluble
slow hydrolysis
What is the effect of a 1,2 double bond on GC activity?
5x enahcnement in GR/MR ratio
What is the effect of the 11beta-OH on GC activity?
required for full GR/MR activity. more po for GR.
What is the effect of 6alpha-CH3 or F on GC activity?
enhances GR/MR ratio
What is the effect of a 9alpha F or Cl on GC activity?
enhances GR and MR potency
What is the effect of 17-alpha O on GC activity?
req’d for GR activity; can be part of acetonide ring or ester
What is the effect of 16-alpha or beta-CH3 r O subsitutnet on GC activity?
decreases MR activity
What is the effect of 21-OH, F, or Cl on GC activity?
req’d for GR/MR activity; ester produt must be hydrolzed to OH for maximum activity
