Block 3 Glucocorticoids Flashcards Preview

PHS 933 > Block 3 Glucocorticoids > Flashcards

Flashcards in Block 3 Glucocorticoids Deck (120):
1

What is the most common adrenal enzyme deficiency?

CYP21 (90% of CAH)

2

Where is cholesterol obtained?

1) intracellular cholesterol esters in diet
2) synthesized de novo in adrenals

3

What is the function of aldosterone?

-- retain 3 Na, lose 2 K
-- produces HTN

4

Describe protein-binding transport of cortisol.

90% bound
-- 80% to CBG/transcortin (hi affinity, lo capacity)
-- 10% bound to albumin (lo affinity, high capacity)

5

What is the half-life of cortisol?

100 min

6

How is cortisol metabolized?

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

7

How are cortisol metabolites excreted?

urine

8

How is THC metabolized?

3-glucuronide or sulfate conjugation

9

How are synthetic glucocorticoids metabolized?

hepatic
-- 3A4, 2C9, 2C19 hydroxylation
-- conjugation
-- biliary/renal excretion

10

How are glucocorticoids modified to enhance potency or selectivity?

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

11

Synthetic addition of double bond at C1 - C2 produces:

1) 4-5x potency increase
2) slower metabolism

12

Synthetic addition of C6 methyl produces:

1) 1-2x potency increase
2) 1/2 mineralocorticoid potency

13

Synthetic addition of OH or methyl at C16 produces:

1) 2.5x potency increase
2) elimination of mineralocorticoid

14

Synthetic addition of F to C9 produces:

1) 10x potency increase
2) 125x mineralocorticoid potency increase

15

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

1) potent glucocorticoid
2) elimination of mineralocorticoid activity

16

What modifications does fludrocortisone have?

C9 F

17

What modifications do triamcinolone, betamethasone, dexamethasone have?

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

18

What modifications does methylprednisolone have?

1,2-ene, C6-Me

19

What modifications does prednisolone have?

1,2-ene

20

Rate metabolism of the synthetic glucocorticoids.

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

21

Rate glucocorticoid potency of synthetic glucocorticoids.

Low:
-- cortisol
-- prednisone
-- methylprednisolone = triamcinolone
-- fludrocortisone
-- betamethasone = dexamethasone

22

Rate mineralocorticoid potency of synthetic glucocorticoids.

Low
-- tri=beta=dexa
-- methylpred
-- pred
-- cortisol
-- fludro

23

Where does cortisol act for feedback inhibition?

AP and HT

24

How is CYP21 deficiency treated?

-- 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

25

What effect does the GR receptor dimer have?

after 4-12h delay...
1) increase or decrease transcription of GRE genes
2) +/- HDAC activation

26

What are the required structural features of glucocorticoids?

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

27

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

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

28

When are 11-ketone glucocorticoids contraindicated?

11-bHSD-1 deficiency
topical use
liver dysfunction

29

What is the purpose of 11bHSD-2?

--prevent cortisol from binding MR
--gives aldosterone a chance
--cortisol much greater than aldosterone in circulation

30

What are the events that occur when steroid binds GR?

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

31

Where does licorice exert a physiological effect?

-- 11bHSD-2 inhibitor
-- produces apparent mineralocorticoid excess (HTN)

32

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

Equal at MR
GR much more selective for cortisol

33

What is the exact mechanism of CYP11B2?

oxidize C18 Me to aldehyde

34

What are the effects of glucocorticoids on metabolism?

1) gluconeogenesis
2) peripheral lipolysis
3) peripheral proteolysis

35

How is CYP21 deficiency diagnosed?

17-OH-progesterone accumulation

36

How is CYP11B1 deficiency treated?

HC

37

What is the 2nd most common cause of CAH?

11b1 deficiency

38

What defects cause CLAH?

1) 3bHSD
2) StAR
3) CYP11A1

39

How is CYP17 diagnosed?

failure to reach maturity at puberty

40

How is CYP17 deficiency treated?

1) HC
2) sex steroids
3) surgery

41

What is CYPOR?

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

42

What is CYPOR deficiency called?

Antley-Bixler syndrome

43

What are the effects of Antley Bixler syndrome?

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

44

How is acute adrenal insufficiency treated?

IV HC + glucose
-- 100mg bolus
-- once normal cortisol, then 50-100mg q8h

45

What causes acute adrenal insufficiency?

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

46

What causes chronic adrenal insufficiency?

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

47

How does androgen deficiency in females present?

loss of axillary and pubic hair

48

What stressors induce CRH release?

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

49

How is adrenal insufficiency diagnosed?

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

50

What are the symptoms of acute adrenal insufficiency?

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

51

What are the symptoms of chronic adrenal deficiency?

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

52

How do you know if aldosterone is deficient?

rening and AngII increased

53

What are MSH's effects?

pigmentation of distal extremities and normally unpigmented skin

54

Where is ACTH formed?

POMC: ACTH + MSH

55

how is chronic adrenal insufficiency treated?

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

How is HC dosed for addison's?

15-20 mg/day (bid or tid)
-- largest dose in am to replicate diurnal variation

57

What are p450 inducers?

phenytoin, barbs, rifampin

58

How do you evaluate glucocorticoid replacement therapy?

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

59

What are symptoms of Cushings?

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

What are symptoms of hypocortisolism?

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

61

How is prenatal CAH treated?

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

62

How is mild CAH diagnosed in children?

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

63

How is mild CAH diagnosed in adults?

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

64

How is mild CAH diagnosed in women?

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

65

How does the GR exert anti-inflammatory effects?

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

66

What does lipocortin do?

inhibits PLA2 to block arachidonic release from plasma membrane

67

What are ADRs of topical steroid use?

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

68

What is the duration of action of cortisol?

8-12 h

69

What is the duration of action of triamcinolone?

12-36h

70

What is the duration of action of betamethasone?

36-72h

71

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

cortisol 1
triamcinolone 5
betamethasone 25

72

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

every other day with intermediate-acting
-- methylpred

73

Why aren't steroids used on the face?

1) perioral dermatitis
2) rosacea

74

What are concerns of glucocorticoid use in the eye?

1) may mask underlying infection
2) increase IOP (monitor if use exceeds 2 weeks)

75

What is the mechanism of ketoconazole?

inhibits CYP17
-- at hi-doses, also inhibits 11A1 and 11B1

76

What are ADRs of ketoconazole?

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

77

What is the mechanism of metyrapone?

inhibits 11B1, synergy with ketoconazole
-- at hi-dose, blocks aldosterone synthesis

78

What are ADRs of metyrapone?

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

79

What is the mechanism of mitotane?

adrenocorticolytic mitochondrial toxin
-- related to DDT
-- induces atrophy of zona fasciculata + reticularis

80

What are ADRs of mitotane?

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

81

When is mitotane used?

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

82

What is the mechanism of mifepristone?

glucocorticoid receptor antagonist

83

What is the mechanism of pasireotide?

somatostatin analog to decrease ACTH
-- given with cabergoline to further reduce

84

What are the ADRs of mifepristone?

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

85

When is mifepristone used?

Cushings + T2DM/hyperglycemia when surgery isn't feasible

86

What are the ADRs of pasireotide?

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

87

What are the treatments for hypercortisolism?

SURGERY!!! use drugs before surgery or when surgery isn't possible
1) ketoconazole
2) ketoconazole + metyrapone
3) mitotane
4) mifepristone
5) pasireotide + cabergoline

88

How is Cushing's diagnosed?

1) urinary cortisol levels
or, 2) CRH stimulation test

89

What is the CRH stimulation test?

give CRH
-- if pituitary adenoma, expect increased ACTH and cortisol
-- if ectopic/adrenal tumor, ACTH/cortisol won't increase

90

What are the main ADRs of glucocorticoid therapy?

CORTICOmyopathy

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

91

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

HTN and edema

92

How glucocorticoid induced hyperglycemia managed?

diet and insulin

93

What are the results of glucocorticoid induced immunosuppression?

infection,
peptic ulcer (esp with NSAIDs)

94

Describe the mood changes seen in glucocorticoid therapy?

anxiety, insomnia, psychosis, suicidal
-- previous psychiatric illness is not predictive

95

Where is glucocorticoid-induced osteonecrosis most common?

femoral head, humoral head, distal femur
-- hip, shoulder, knee pain
-- chronic or acute therapy

96

When is glucocorticoid-induced myopathy seen most?

-- acute and chronic therapy, doesn't matter
-- twice as common in women
-- most common with fluorinated

97

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

proximal limb weakness
termination (slow/incomplete recovery)

98

How are posterior sub-capsular cataracts managed?

1) regular eye exams if chronic (not reversible)
2) children more susceptible

99

What is the result of glucocorticoid withdrawal?

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

100

How is adrenal suppression managed?

taper over 1-2 weeks
note signs of insufficiency or withdrawal

101

How is ketoconazole's efficacy monitored?

1) serum cortisol
or 2) 24h urinary cortisol

102

What bisphosphonates are indicated for glucocorticoid-induced osteoporosis?

alendronate
risendronate

103

How is glucocorticoid-induced osteoporosis risk managed?

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

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

30-50%
ribs, vertebrae

105

How do glucocorticoids decrease bone density?

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

106

When does glucocorticoid-induced bone loss start?

first six months

107

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

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

108

How does growth suppression manifest?

slowing of prepubertal growth
-- only in first 2 years, non-cumulative
-- 1.2cm deficit

109

What are the causes of Cushings?

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

110

What is familial cushings?

inherited tendency to develop cortisol-secreting endocrine gland tumors

111

What are the anti-inflammatory uses of glucocorticoids?

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

How are glucocorticoids used in infection?

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

113

Why are glucocorticoids used in cancer?

anti-lymphocytic in ALL and lymphomas

114

Why are glucocorticoids used in SCI?

reduce neuro defects

115

How are glucocorticoids used in preterm labor?

≤ 48h tx for moms
-- decrease preterm neonatal respiratory distress, intraventricular hemorrhage, and death
-- + tocolytics = MgSO4, indomethacin will prevent birth

116

T/F: steroids effective in head injury trauma

false

117

Effect of steroids in PCP hypoxia + AIDS?

decrease pulmonary inflammation

118

Effect of steroids in Hflu type B meningitis in infants?

reduce neuro impairment

119

Effect of steroids in septic shock?

reduce cytokine release

120

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

yes, but less effective for COPD