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PHS 933 > Block 3 Glucocorticoids > Flashcards

Block 3 Glucocorticoids Flashcards

1
Q

What is the most common adrenal enzyme deficiency?

A

CYP21 (90% of CAH)

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2
Q

Where is cholesterol obtained?

A

1) intracellular cholesterol esters in diet

2) synthesized de novo in adrenals

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3
Q

What is the function of aldosterone?

A
    • retain 3 Na, lose 2 K

- - produces HTN

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4
Q

Describe protein-binding transport of cortisol.

A

90% bound

    • 80% to CBG/transcortin (hi affinity, lo capacity)
    • 10% bound to albumin (lo affinity, high capacity)
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5
Q

What is the half-life of cortisol?

A

100 min

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6
Q

How is cortisol metabolized?

A

extrahepatic:
– 4-5 reduction (inactive)
hepatic:
– 4-5 reduction (inactive)
– 3-keto reduction (THC)

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7
Q

How are cortisol metabolites excreted?

A

urine

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8
Q

How is THC metabolized?

A

3-glucuronide or sulfate conjugation

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9
Q

How are synthetic glucocorticoids metabolized?

A

hepatic

    • 3A4, 2C9, 2C19 hydroxylation
    • conjugation
    • biliary/renal excretion
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10
Q

How are glucocorticoids modified to enhance potency or selectivity?

A

1) 1-2 double bond
2) C6 methyl
3) C16 OH/methyl
4) C9 F

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11
Q

Synthetic addition of double bond at C1 - C2 produces:

A

1) 4-5x potency increase

2) slower metabolism

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12
Q

Synthetic addition of C6 methyl produces:

A

1) 1-2x potency increase

2) 1/2 mineralocorticoid potency

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13
Q

Synthetic addition of OH or methyl at C16 produces:

A

1) 2.5x potency increase

2) elimination of mineralocorticoid

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14
Q

Synthetic addition of F to C9 produces:

A

1) 10x potency increase

2) 125x mineralocorticoid potency increase

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15
Q

Synthetic combo of 1-2 desaturation, C9 F and C16 OH/methyl produces:

A

1) potent glucocorticoid

2) elimination of mineralocorticoid activity

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16
Q

What modifications does fludrocortisone have?

A

C9 F

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17
Q

What modifications do triamcinolone, betamethasone, dexamethasone have?

A

1,2-ene, C16-Me, 9-F

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18
Q

What modifications does methylprednisolone have?

A

1,2-ene, C6-Me

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19
Q

What modifications does prednisolone have?

A

1,2-ene

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20
Q

Rate metabolism of the synthetic glucocorticoids.

A 
Short: cortisol
Intermediate:
-- prednisolone
-- methylprednisolone
-- tramcinolone
-- fludrocortisone
Long:
-- betamethasone
-- dexamethasone
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21
Q

Rate glucocorticoid potency of synthetic glucocorticoids.

A

Low:

    • cortisol
    • prednisone
    • methylprednisolone = triamcinolone
    • fludrocortisone
    • betamethasone = dexamethasone
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22
Q

Rate mineralocorticoid potency of synthetic glucocorticoids.

A

Low

    • tri=beta=dexa
    • methylpred
    • pred
    • cortisol
    • fludro
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23
Q

Where does cortisol act for feedback inhibition?

A

AP and HT

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24
Q

How is CYP21 deficiency treated?

A
    • mild-severe: hydrocortisone replacement to restore normal cortisol and ACTH
    • severe: mineralocorticoid supplement (indicated by elevated renin)
    • for infants, give table salt to maintain Na
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25
Q

What effect does the GR receptor dimer have?

A

after 4-12h delay…

1) increase or decrease transcription of GRE genes
2) +/- HDAC activation

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26
Q

What are the required structural features of glucocorticoids?

A

1) C3 ketone
2) 4,5-ene
3) C11-OH (cortisone contains ketone here)

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27
Q

Why are 11-ketone glucocorticoids not used for topical application?

A

11-ketone must be reduced to 11-OH by Type 1 11bHSD in liver

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28
Q

When are 11-ketone glucocorticoids contraindicated?

A

11-bHSD-1 deficiency
topical use
liver dysfunction

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29
Q

What is the purpose of 11bHSD-2?

A
  • -prevent cortisol from binding MR
  • -gives aldosterone a chance
  • -cortisol much greater than aldosterone in circulation
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30
Q

What are the events that occur when steroid binds GR?

A

1) release of HSPs
2) dimerization
3) nuclear localization signal triggers translocation

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31
Q

Where does licorice exert a physiological effect?

A
    • 11bHSD-2 inhibitor

- - produces apparent mineralocorticoid excess (HTN)

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32
Q

Describe relative affinity for cortisol vs. aldosterone on MR and GR.

A

Equal at MR

GR much more selective for cortisol

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33
Q

What is the exact mechanism of CYP11B2?

A

oxidize C18 Me to aldehyde

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34
Q

What are the effects of glucocorticoids on metabolism?

A

1) gluconeogenesis
2) peripheral lipolysis
3) peripheral proteolysis

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35
Q

How is CYP21 deficiency diagnosed?

A

17-OH-progesterone accumulation

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36
Q

How is CYP11B1 deficiency treated?

A

HC

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37
Q

What is the 2nd most common cause of CAH?

A

11b1 deficiency

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38
Q

What defects cause CLAH?

A

1) 3bHSD
2) StAR
3) CYP11A1

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39
Q

How is CYP17 diagnosed?

A

failure to reach maturity at puberty

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40
Q

How is CYP17 deficiency treated?

A

1) HC
2) sex steroids
3) surgery

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41
Q

What is CYPOR?

A

cyp450 reductase, an electron transfer protein to CYP21 and CYP17 (21 and 17 don’t function)

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42
Q

What is CYPOR deficiency called?

A

Antley-Bixler syndrome

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43
Q

What are the effects of Antley Bixler syndrome?

A

1) elevated pregnenolone
2) elevated progesterone
3) genital ambiguity
4) total loss = fatality

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44
Q

How is acute adrenal insufficiency treated?

A

IV HC + glucose

    • 100mg bolus
    • once normal cortisol, then 50-100mg q8h
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45
Q

What causes acute adrenal insufficiency?

A

1) bilateral adrenal injury
2) pituitary injury
3) glucocorticoid withdrawal

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46
Q

What causes chronic adrenal insufficiency?

A

1) most common = autoimmune
2) TB
3) AIDS, metastasis
4) anterior pituitary lesions

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47
Q

How does androgen deficiency in females present?

A

loss of axillary and pubic hair

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48
Q

What stressors induce CRH release?

A

1) physical stress
2) emotional stress
3) hypoglycemia
4) cold exposure
5) pain

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49
Q

How is adrenal insufficiency diagnosed?

A

cosyntropin test
– an ACTH analog IV or IM
or, measure plasma [ACTH]

50
Q

What are the symptoms of acute adrenal insufficiency?

A

1) n/v
2) dehydration
3) hypoNa, hyperK = hypotension, orthostasis
4) lethargy
5) poor stressor response
6) back and leg pain

51
Q

What are the symptoms of chronic adrenal deficiency?

A

1) n/v, dehydration, hypoNa/hyperK, lethargy, poor stress response
2) excessive MSH
3) no axillary/pubic hair in females

52
Q

How do you know if aldosterone is deficient?

A

rening and AngII increased

53
Q

What are MSH’s effects?

A

pigmentation of distal extremities and normally unpigmented skin

54
Q

Where is ACTH formed?

A

POMC: ACTH + MSH

55
Q

how is chronic adrenal insufficiency treated?

A

1) HC, pred, or dexa
2) liberal salt intake
3) ? mineralocorticoid (can use fludro instead)
4) adjust for p450 inducers, stressors, n/v
5) wear id bracelet

56
Q

How is HC dosed for addison’s?

A

15-20 mg/day (bid or tid)

– largest dose in am to replicate diurnal variation

57
Q

What are p450 inducers?

A

phenytoin, barbs, rifampin

58
Q

How do you evaluate glucocorticoid replacement therapy?

A

1) am plasma ACTH level
2) normal pigmentation and electrolytes
3) sense of well-being

59
Q

What are symptoms of Cushings?

A

1) appetite, weight gain
2) muscle weakness, osteoporosis (rib and vertebrae)
3) diabetes, HTN
4) upper body obesity; thin arms and legs; moon face
5) thin skin, easy bruising, abdomen/thigh striae
6) irritability, anxiety, depression
7) hirsutism
8) menstrual irregularity
9) loss of libido

60
Q

What are symptoms of hypocortisolism?

A

1) hairy, greasy skin, acne
2) irregular periods
3) tiredness, fatigue

61
Q

How is prenatal CAH treated?

A 
in utero hi-dose dexamethasone daily
must begin prior to 10 weeks gestation
stopped if:
-- one wild-type CYP21 allele
-- male sex
62
Q

How is mild CAH diagnosed in children?

A

1) hyperpigmentation (esp. genitals)
2) recurrent sinus/pulmonary infection
3) severe acne
4) tall for age
5) early-onset puberty

63
Q

How is mild CAH diagnosed in adults?

A

1) childhood sxs
2) syncope
3) short compared to parents
4) hypotension (21)
5) HTN (11bHSD)

64
Q

How is mild CAH diagnosed in women?

A

1) clitoromegaly
2) poorly developed labia
3) hirsutism
4) infertility
5) PCOS

65
Q

How does the GR exert anti-inflammatory effects?

A

1) induce lipocortin expression
2) suppress cytokine transcription (by interacting with NF-kB and AP1)
3) inhibit leukotrine and prostaglandin synthesis

66
Q

What does lipocortin do?

A

inhibits PLA2 to block arachidonic release from plasma membrane

67
Q

What are ADRs of topical steroid use?

A

1) telangectasia
2) fine hair growth
3) bruising
4) hypopigmentation
5) striae
6) on thin skinned areas: dermal atrophy (genitals, face, flexures)

68
Q

What is the duration of action of cortisol?

A

8-12 h

69
Q

What is the duration of action of triamcinolone?

A

12-36h

70
Q

What is the duration of action of betamethasone?

A

36-72h

71
Q

What is the relative anti-inflammatory potency of cortisol, triamcinolone, and betamethasone?

A

cortisol 1
triamcinolone 5
betamethasone 25

72
Q

What is the best strategy for long-term oral steroid use?

A

every other day with intermediate-acting

– methylpred

73
Q

Why aren’t steroids used on the face?

A

1) perioral dermatitis

2) rosacea

74
Q

What are concerns of glucocorticoid use in the eye?

A

1) may mask underlying infection

2) increase IOP (monitor if use exceeds 2 weeks)

75
Q

What is the mechanism of ketoconazole?

A

inhibits CYP17

– at hi-doses, also inhibits 11A1 and 11B1

76
Q

What are ADRs of ketoconazole?

A

1) p450 inhibitor
2) HA, sedation, n/v
3) gynecomastia, decreased libido, impotence
4) teratogen, hepatotoxic

77
Q

What is the mechanism of metyrapone?

A

inhibits 11B1, synergy with ketoconazole

– at hi-dose, blocks aldosterone synthesis

78
Q

What are ADRs of metyrapone?

A

1) p450 inhibitor
2) HA, sedation, dizziness
3) n/v, abdominal pain
4) androgen and aldosterone increase
5) at hi-doses, hypotension

79
Q

What is the mechanism of mitotane?

A

adrenocorticolytic mitochondrial toxin

    • related to DDT
    • induces atrophy of zona fasciculata + reticularis
80
Q

What are ADRs of mitotane?

A

1) nausea (give QHS)
2) will kill the tissue
3) long-lasting (lipophilic)
4) 3A4 inducer
5) anorexia, depression, lethargy

81
Q

When is mitotane used?

A

only in adrenal carcinoma when surgery/radiation isn’t possible

82
Q

What is the mechanism of mifepristone?

A

glucocorticoid receptor antagonist

83
Q

What is the mechanism of pasireotide?

A

somatostatin analog to decrease ACTH

– given with cabergoline to further reduce

84
Q

What are the ADRs of mifepristone?

A

1) abortofacient
2) nausea
3) peripheral edema
4) dizziness
5) loss of appetite

85
Q

When is mifepristone used?

A

Cushings + T2DM/hyperglycemia when surgery isn’t feasible

86
Q

What are the ADRs of pasireotide?

A

1) hyperglycemia
2) diarrhea
3) nausea
4) decreases BP and LDL

87
Q

What are the treatments for hypercortisolism?

A

SURGERY!!! use drugs before surgery or when surgery isn’t possible

1) ketoconazole
2) ketoconazole + metyrapone
3) mitotane
4) mifepristone
5) pasireotide + cabergoline

88
Q

How is Cushing’s diagnosed?

A

1) urinary cortisol levels

or, 2) CRH stimulation test

89
Q

What is the CRH stimulation test?

A

give CRH

    • if pituitary adenoma, expect increased ACTH and cortisol
    • if ectopic/adrenal tumor, ACTH/cortisol won’t increase
90
Q

What are the main ADRs of glucocorticoid therapy?

A

CORTICOmyopathy

Change in mood
Osteoporosis/necrosis
Retardation of growth in kids
T2dm
Immunosuppression
Cataracts
Oedema/electrolyte
Myopathy
91
Q

What effects of fluid and electrolyte imbalance are NOT mediated by MR?

A

HTN and edema

92
Q

How glucocorticoid induced hyperglycemia managed?

A

diet and insulin

93
Q

What are the results of glucocorticoid induced immunosuppression?

A 
infection,
peptic ulcer (esp with NSAIDs)
94
Q

Describe the mood changes seen in glucocorticoid therapy?

A

anxiety, insomnia, psychosis, suicidal

– previous psychiatric illness is not predictive

95
Q

Where is glucocorticoid-induced osteonecrosis most common?

A

femoral head, humoral head, distal femur

    • hip, shoulder, knee pain
    • chronic or acute therapy
96
Q

When is glucocorticoid-induced myopathy seen most?

A
    • acute and chronic therapy, doesn’t matter
    • twice as common in women
    • most common with fluorinated
97
Q

How does glucocorticoid induced myopathy manifest and how is it managed?

A

proximal limb weakness

termination (slow/incomplete recovery)

98
Q

How are posterior sub-capsular cataracts managed?

A

1) regular eye exams if chronic (not reversible)

2) children more susceptible

99
Q

What is the result of glucocorticoid withdrawal?

A

1) fever
2) muscle and joint pain
3) increased intracranial pressure

100
Q

How is adrenal suppression managed?

A

taper over 1-2 weeks

note signs of insufficiency or withdrawal

101
Q

How is ketoconazole’s efficacy monitored?

A

1) serum cortisol

or 2) 24h urinary cortisol

102
Q

What bisphosphonates are indicated for glucocorticoid-induced osteoporosis?

A

alendronate

risendronate

103
Q

How is glucocorticoid-induced osteoporosis risk managed?

A

baseline bone scan if treatment longer than 6 months

1) hi Ca intake (1500mg/day)
2) Vit D (600 IU/day)
3) avoid loop diuretics (increase fx risk)
4) bisphosphonates
- - androgen/estrogen tx not effective to maintain bone

104
Q

What percentage of chronic glucocorticoid-treated patients develop fx’s? Where is most common?

A

30-50%

ribs, vertebrae

105
Q

How do glucocorticoids decrease bone density?

A

1) inhibit bone formation
- - suppressing osteoblasts, stimulating osteoclasts
2) suppress sex steroid hormone synthesis
3) decrease GI Ca absorption
- - via increase in PTH

106
Q

When does glucocorticoid-induced bone loss start?

A

first six months

107
Q

How is growth suppression in kids as a glucocorticoid ADR managed?

A

1) adjust to minimal effective dose
2) substitue cromolyns or antileukotrienes
- - although not as effective for SEVERE asthma

108
Q

How does growth suppression manifest?

A

slowing of prepubertal growth

    • only in first 2 years, non-cumulative
    • 1.2cm deficit
109
Q

What are the causes of Cushings?

A

1) pituitary adenoma (most common)
2) ectopic ACTH syndrome
3) adrenal tumor
4) familial cushings
5) drug-induced hypercortisolism (common)

110
Q

What is familial cushings?

A

inherited tendency to develop cortisol-secreting endocrine gland tumors

111
Q

What are the anti-inflammatory uses of glucocorticoids?

A

1) Chrons/UC
2) Sarcoidosis
3) asthma
4) Allergy
5) ocular
6) preterm labor
7) infection
8) cancer
9) cerebral edema from parasites and metastasis, SCI
10) transplant
a sac topicc

112
Q

How are glucocorticoids used in infection?

A

1) PCP with hypoxia in AIDS
2) H.flu, Bmeningitidis in infnats
3) early-stage septic shock

113
Q

Why are glucocorticoids used in cancer?

A

anti-lymphocytic in ALL and lymphomas

114
Q

Why are glucocorticoids used in SCI?

A

reduce neuro defects

115
Q

How are glucocorticoids used in preterm labor?

A

≤ 48h tx for moms

    • decrease preterm neonatal respiratory distress, intraventricular hemorrhage, and death
      • tocolytics = MgSO4, indomethacin will prevent birth
116
Q

T/F: steroids effective in head injury trauma

A

false

117
Q

Effect of steroids in PCP hypoxia + AIDS?

A

decrease pulmonary inflammation

118
Q

Effect of steroids in Hflu type B meningitis in infants?

A

reduce neuro impairment

119
Q

Effect of steroids in septic shock?

A

reduce cytokine release

120
Q

T/F: Steroids are good for asthma and COPD.

A

yes, but less effective for COPD

PHS 933 (14 decks)

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