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Pharmacotherapy 1 > 3 - Glucocorticoids > Flashcards

3 - Glucocorticoids Flashcards

1
Q

**Identify the factors controlling cortisol biosynthesis.

A

HPA axis!

stress–> hypothal–>CRH–>ant pituitary–>ACTH–>adrenal–> cortisol!

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2
Q

**Describe the general mechanism for steroid hormone receptor using the glucocorticoid receptor as a model.

A

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

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3
Q

**Explain the molecular model for the anti-inflammatory and immunosuppressive actions of glucocorticoids.

A

upregulate lipocortin –> decr eicosanoids

prevent NFkB from binding to response element –> suppressed transcription of cytokines

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4
Q

**Remember the relative potency and glucocorticoid/mineralocorticoid activity among various glucocorticoids

A

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

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5
Q

**Identify the modifications of the cortisol structure that are responsible for increased activity and increased glucocorticoid/mineralocorticoid activity.

A

1,2 double bond incr GR/MR ratio
6alpha methyl or F ncr Gr/MR ratio
9alphaF or Cl (incr both)

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6
Q

**Identify the adverse effects of glucocorticoid therapy.

A

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

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7
Q

**Explain the mechanism of the adverse effects of glucocorticoid therapy.

A

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

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8
Q

**Describe the desired properties of inhaled glucocorticoids.

A

high potency
minimal SEs
prolonged action

soln: high lipophilicity (prolong action)
low oral BA
rapid clearance (systemically)
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9
Q

**Identify the structural modifications that are responsible for increased lipophilicity and increased metabolism in inhaled glucocorticoids..

A

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

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10
Q

What are the fxns of gluco and mineralocorticoids?

A

gluco: stress hormones
incr ciruclating glucose conc
potent anti-inflamm

mineralo (ex ald):
regulate Na/K levels
controls BP

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11
Q

Describe the hypothalamic-pituitary-adrenal (HPA) axis .

A

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

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12
Q

Contrast the modes of action of epi and cortisol.

A

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.

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13
Q

What are the fxns of glucocorticoids for the liver?

A

incr gluconeogenesis

incr glycogen storage

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14
Q

What are the fxns of GCs for the muscle?

A

promote protein degrad
decr protein synth
decr sensitivity to insulin

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15
Q

What are the fxns of GCs for adipose tissue?

A

promote lipolysis

decr sensitivity to insulin

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16
Q

What are the fxns of GCs for immune system?

A

block synth of cytokines ==> immunosuppression

inhibit prod of eicosanoids –> anti-inflammx

17
Q

What do GCs upregulate?

A

enzymes for gluconeogenesis and anti-inflamm proteins.

**lipocortin I–suppresses phospholipase A2, which has critical role in eicosanoid synthesis.

18
Q

Describe how cytokine genes are turned on.

A

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.

19
Q

Describe the moa of immunosuppression by GCs.

A

activated GR binds to NFkB and prevents its binding to its response element

–> transcription of cytokine genes are suppressed.

20
Q

What are the needs when designing a glucocorticoid?

A

max anti-infamm
min MC activity (Na retention, HTN, edema)
prevent Cushing’s (hyperglycemia, hypocalecmia, fat reistribution, CNS)
prev Addisonian crisis upon withdrawl

21
Q

Describe Addisonian crisis.

A

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.

22
Q

What are the S-A relationship for GCs and MCs?

A

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

23
Q

Describe fludrocortisone in terms of S-A and use.

A

9alpha-F
-incr GC but also strong MC–> na retnetion–> edema

used in MC replacement therapy

24
Q

Describe prednisone/prednisolone in terms of S-A and use.

A

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

25
Q

Describe methylprednisolone in terms of S-A and use.

A

prednisolone + 6alpha-metyl group

potency similar to prednisolone

decr’d MC activity

26
Q

Describe triamcinolone in terms of S-A and use.

A

prenisolone + 9alphaF and 16 alpha OH

GC activity similar to prenisone
decr’d MC activity

incr hydrophilicity –> BA is poor

27
Q

Describe dexamethasone in terms of S-A and use.

A

triamcinolone but with 16alpha metyl instead of OH

incr lipophilicity –> incr R binding, stronger effect

**with betamethasone is strongest GC available

decr MC activity

28
Q

Describe betamethasone in terms of S-A and use.

A

enantiomer of dexamethasone at 16.

similar properties to dexamethasone (incr lipophilicity and R binding, decr MC activity)

**with dexamethasone is the strongest GC available

29
Q

What are the properties of 21-esters of acetate and butyrates?

A

incr’s lipophilicity

rolonged action upon Im or intraarticular inj

30
Q

What are the properites of 21-esters of phosphate?

A

incr’d solubility
rapid hydrolysis
optimal for IV or IM inj

31
Q

What are the properties of 21-esters of succinate?

A

soluble

slow hydrolysis

32
Q

What is the effect of a 1,2 double bond on GC activity?

A

5x enahcnement in GR/MR ratio

33
Q

What is the effect of the 11beta-OH on GC activity?

A

required for full GR/MR activity. more po for GR.

34
Q

What is the effect of 6alpha-CH3 or F on GC activity?

A

enhances GR/MR ratio

35
Q

What is the effect of a 9alpha F or Cl on GC activity?

A

enhances GR and MR potency

36
Q

What is the effect of 17-alpha O on GC activity?

A

req’d for GR activity; can be part of acetonide ring or ester

37
Q

What is the effect of 16-alpha or beta-CH3 r O subsitutnet on GC activity?

A

decreases MR activity

38
Q

What is the effect of 21-OH, F, or Cl on GC activity?

A

req’d for GR/MR activity; ester produt must be hydrolzed to OH for maximum activity

Pharmacotherapy 1 (26 decks)

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