Block 3 Glucocorticoids Flashcards
What is the most common adrenal enzyme deficiency?
CYP21 (90% of CAH)
Where is cholesterol obtained?
1) intracellular cholesterol esters in diet
2) synthesized de novo in adrenals
What is the function of aldosterone?
- retain 3 Na, lose 2 K
- - produces HTN
Describe protein-binding transport of cortisol.
90% bound
- 80% to CBG/transcortin (hi affinity, lo capacity)
- 10% bound to albumin (lo affinity, high capacity)
What is the half-life of cortisol?
100 min
How is cortisol metabolized?
extrahepatic:
– 4-5 reduction (inactive)
hepatic:
– 4-5 reduction (inactive)
– 3-keto reduction (THC)
How are cortisol metabolites excreted?
urine
How is THC metabolized?
3-glucuronide or sulfate conjugation
How are synthetic glucocorticoids metabolized?
hepatic
- 3A4, 2C9, 2C19 hydroxylation
- conjugation
- biliary/renal excretion
How are glucocorticoids modified to enhance potency or selectivity?
1) 1-2 double bond
2) C6 methyl
3) C16 OH/methyl
4) C9 F
Synthetic addition of double bond at C1 - C2 produces:
1) 4-5x potency increase
2) slower metabolism
Synthetic addition of C6 methyl produces:
1) 1-2x potency increase
2) 1/2 mineralocorticoid potency
Synthetic addition of OH or methyl at C16 produces:
1) 2.5x potency increase
2) elimination of mineralocorticoid
Synthetic addition of F to C9 produces:
1) 10x potency increase
2) 125x mineralocorticoid potency increase
Synthetic combo of 1-2 desaturation, C9 F and C16 OH/methyl produces:
1) potent glucocorticoid
2) elimination of mineralocorticoid activity
What modifications does fludrocortisone have?
C9 F
What modifications do triamcinolone, betamethasone, dexamethasone have?
1,2-ene, C16-Me, 9-F
What modifications does methylprednisolone have?
1,2-ene, C6-Me
What modifications does prednisolone have?
1,2-ene
Rate metabolism of the synthetic glucocorticoids.
Short: cortisol Intermediate: -- prednisolone -- methylprednisolone -- tramcinolone -- fludrocortisone Long: -- betamethasone -- dexamethasone
Rate glucocorticoid potency of synthetic glucocorticoids.
Low:
- cortisol
- prednisone
- methylprednisolone = triamcinolone
- fludrocortisone
- betamethasone = dexamethasone
Rate mineralocorticoid potency of synthetic glucocorticoids.
Low
- tri=beta=dexa
- methylpred
- pred
- cortisol
- fludro
Where does cortisol act for feedback inhibition?
AP and HT
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
What effect does the GR receptor dimer have?
after 4-12h delay…
1) increase or decrease transcription of GRE genes
2) +/- HDAC activation
What are the required structural features of glucocorticoids?
1) C3 ketone
2) 4,5-ene
3) C11-OH (cortisone contains ketone here)
Why are 11-ketone glucocorticoids not used for topical application?
11-ketone must be reduced to 11-OH by Type 1 11bHSD in liver
When are 11-ketone glucocorticoids contraindicated?
11-bHSD-1 deficiency
topical use
liver dysfunction
What is the purpose of 11bHSD-2?
- -prevent cortisol from binding MR
- -gives aldosterone a chance
- -cortisol much greater than aldosterone in circulation
What are the events that occur when steroid binds GR?
1) release of HSPs
2) dimerization
3) nuclear localization signal triggers translocation
Where does licorice exert a physiological effect?
- 11bHSD-2 inhibitor
- - produces apparent mineralocorticoid excess (HTN)
Describe relative affinity for cortisol vs. aldosterone on MR and GR.
Equal at MR
GR much more selective for cortisol
What is the exact mechanism of CYP11B2?
oxidize C18 Me to aldehyde
What are the effects of glucocorticoids on metabolism?
1) gluconeogenesis
2) peripheral lipolysis
3) peripheral proteolysis
How is CYP21 deficiency diagnosed?
17-OH-progesterone accumulation
How is CYP11B1 deficiency treated?
HC
What is the 2nd most common cause of CAH?
11b1 deficiency
What defects cause CLAH?
1) 3bHSD
2) StAR
3) CYP11A1
How is CYP17 diagnosed?
failure to reach maturity at puberty
How is CYP17 deficiency treated?
1) HC
2) sex steroids
3) surgery
What is CYPOR?
cyp450 reductase, an electron transfer protein to CYP21 and CYP17 (21 and 17 don’t function)
What is CYPOR deficiency called?
Antley-Bixler syndrome
What are the effects of Antley Bixler syndrome?
1) elevated pregnenolone
2) elevated progesterone
3) genital ambiguity
4) total loss = fatality
How is acute adrenal insufficiency treated?
IV HC + glucose
- 100mg bolus
- once normal cortisol, then 50-100mg q8h
What causes acute adrenal insufficiency?
1) bilateral adrenal injury
2) pituitary injury
3) glucocorticoid withdrawal
What causes chronic adrenal insufficiency?
1) most common = autoimmune
2) TB
3) AIDS, metastasis
4) anterior pituitary lesions
How does androgen deficiency in females present?
loss of axillary and pubic hair
What stressors induce CRH release?
1) physical stress
2) emotional stress
3) hypoglycemia
4) cold exposure
5) pain
How is adrenal insufficiency diagnosed?
cosyntropin test
– an ACTH analog IV or IM
or, measure plasma [ACTH]
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
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
How do you know if aldosterone is deficient?
rening and AngII increased
What are MSH’s effects?
pigmentation of distal extremities and normally unpigmented skin
Where is ACTH formed?
POMC: ACTH + MSH
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
How is HC dosed for addison’s?
15-20 mg/day (bid or tid)
– largest dose in am to replicate diurnal variation
What are p450 inducers?
phenytoin, barbs, rifampin
How do you evaluate glucocorticoid replacement therapy?
1) am plasma ACTH level
2) normal pigmentation and electrolytes
3) sense of well-being
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
What are symptoms of hypocortisolism?
1) hairy, greasy skin, acne
2) irregular periods
3) tiredness, fatigue
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
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
How is mild CAH diagnosed in adults?
1) childhood sxs
2) syncope
3) short compared to parents
4) hypotension (21)
5) HTN (11bHSD)
How is mild CAH diagnosed in women?
1) clitoromegaly
2) poorly developed labia
3) hirsutism
4) infertility
5) PCOS
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
What does lipocortin do?
inhibits PLA2 to block arachidonic release from plasma membrane
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)
What is the duration of action of cortisol?
8-12 h
What is the duration of action of triamcinolone?
12-36h
What is the duration of action of betamethasone?
36-72h
What is the relative anti-inflammatory potency of cortisol, triamcinolone, and betamethasone?
cortisol 1
triamcinolone 5
betamethasone 25
What is the best strategy for long-term oral steroid use?
every other day with intermediate-acting
– methylpred
Why aren’t steroids used on the face?
1) perioral dermatitis
2) rosacea
What are concerns of glucocorticoid use in the eye?
1) may mask underlying infection
2) increase IOP (monitor if use exceeds 2 weeks)
What is the mechanism of ketoconazole?
inhibits CYP17
– at hi-doses, also inhibits 11A1 and 11B1
What are ADRs of ketoconazole?
1) p450 inhibitor
2) HA, sedation, n/v
3) gynecomastia, decreased libido, impotence
4) teratogen, hepatotoxic
What is the mechanism of metyrapone?
inhibits 11B1, synergy with ketoconazole
– at hi-dose, blocks aldosterone synthesis
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
What is the mechanism of mitotane?
adrenocorticolytic mitochondrial toxin
- related to DDT
- induces atrophy of zona fasciculata + reticularis
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
When is mitotane used?
only in adrenal carcinoma when surgery/radiation isn’t possible
What is the mechanism of mifepristone?
glucocorticoid receptor antagonist
What is the mechanism of pasireotide?
somatostatin analog to decrease ACTH
– given with cabergoline to further reduce
What are the ADRs of mifepristone?
1) abortofacient
2) nausea
3) peripheral edema
4) dizziness
5) loss of appetite
When is mifepristone used?
Cushings + T2DM/hyperglycemia when surgery isn’t feasible
What are the ADRs of pasireotide?
1) hyperglycemia
2) diarrhea
3) nausea
4) decreases BP and LDL
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
How is Cushing’s diagnosed?
1) urinary cortisol levels
or, 2) CRH stimulation test
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
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
What effects of fluid and electrolyte imbalance are NOT mediated by MR?
HTN and edema
How glucocorticoid induced hyperglycemia managed?
diet and insulin
What are the results of glucocorticoid induced immunosuppression?
infection, peptic ulcer (esp with NSAIDs)
Describe the mood changes seen in glucocorticoid therapy?
anxiety, insomnia, psychosis, suicidal
– previous psychiatric illness is not predictive
Where is glucocorticoid-induced osteonecrosis most common?
femoral head, humoral head, distal femur
- hip, shoulder, knee pain
- chronic or acute therapy
When is glucocorticoid-induced myopathy seen most?
- acute and chronic therapy, doesn’t matter
- twice as common in women
- most common with fluorinated
How does glucocorticoid induced myopathy manifest and how is it managed?
proximal limb weakness
termination (slow/incomplete recovery)
How are posterior sub-capsular cataracts managed?
1) regular eye exams if chronic (not reversible)
2) children more susceptible
What is the result of glucocorticoid withdrawal?
1) fever
2) muscle and joint pain
3) increased intracranial pressure
How is adrenal suppression managed?
taper over 1-2 weeks
note signs of insufficiency or withdrawal
How is ketoconazole’s efficacy monitored?
1) serum cortisol
or 2) 24h urinary cortisol
What bisphosphonates are indicated for glucocorticoid-induced osteoporosis?
alendronate
risendronate
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
What percentage of chronic glucocorticoid-treated patients develop fx’s? Where is most common?
30-50%
ribs, vertebrae
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
When does glucocorticoid-induced bone loss start?
first six months
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
How does growth suppression manifest?
slowing of prepubertal growth
- only in first 2 years, non-cumulative
- 1.2cm deficit
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)
What is familial cushings?
inherited tendency to develop cortisol-secreting endocrine gland tumors
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
How are glucocorticoids used in infection?
1) PCP with hypoxia in AIDS
2) H.flu, Bmeningitidis in infnats
3) early-stage septic shock
Why are glucocorticoids used in cancer?
anti-lymphocytic in ALL and lymphomas
Why are glucocorticoids used in SCI?
reduce neuro defects
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
T/F: steroids effective in head injury trauma
false
Effect of steroids in PCP hypoxia + AIDS?
decrease pulmonary inflammation
Effect of steroids in Hflu type B meningitis in infants?
reduce neuro impairment
Effect of steroids in septic shock?
reduce cytokine release
T/F: Steroids are good for asthma and COPD.
yes, but less effective for COPD
