1
Q
Adrenal cortex produces?
A
CORTICOSTEROIDS
- mineralocorticoids (Aldosterone)
- glucocorticoids (hydrocortisone)
- androgens
2
Q
Adrenal medulla produces?
A
CATECHOLAMINES
- E
- NE
3
Q
Mineralocorticoid (aldosterone) actions:
A
- inc Na reabsorption at renal collecting tubule –> regulates blood pressure
- Inc excretion of K
4
Q
GLucocorticoids (cortisol/hydrocortisone) actions:
A
- restore homeostasis after exposure to physical/emotional stresses
- inc blood glucose levels + other metabolic effects
- works with E and NE responses
5
Q
Androgens actions
A
(dehydroepiandrosterone (DHEA) and androstenedione)
- weak -converted to testosterone
- major source of female androgens
6
Q
Major drug target enzymes in corticosteroid synthesis?
A
- Cholesterol desmolase
- 17alpha-hydroxylase
- 11beta-hydroxylase
7
Q
- What is signal for inc steroid synthesis by adrenals?
- Exact effects on adrenals?
A
-inc corticotropin releasing hormone (CRH) from hypothalamus –> inc adrenal corticotropic hormone (ACTH) from anterior pituitary –> stimulates steroid synthesis by adrenals
- increased import of cholesterol
- inc transcription of cholesterol desmolase and other enzymes involved in steroid synthesis
- growth of adrenal cortex
8
Q
Role of hypothalamus in hypothalamus-pituitary-adrenal (HPA) axis?
A
-inc corticotropin releasing hormone (CRH) from hypothalamus
(–> inc adrenal corticotropic hormone (ACTH) from anterior pituitary –> stimulates steroid synthesis by adrenals)
9
Q
Role of anterior pituitary in hypothalamus-pituitary-adrenal (HPA) axis?
A
-CRH binds G-proteins on anterior pit = rapid release of preformed ACTH and slow inc in synth of ACTH precurson
10
Q
Role of adrenal cortex in hypothalamus-pituitary-adrenal (HPA) axis?
A
- ACTH binds G-protein (GPCR), melanocortin 2 receptor (MC2R) on surface of adrenals
- inc steroidogenic enzyme expression and synthesis + secretion of cortical steroids (++CORTISOL AND ++ADRENAL ANDROGENS)
11
Q
ACTH and aldosterone synthesis?
A
(ACTH give base synthesis of aldosterone. aldosterone synthesis by adrenal cortex stimulated by angiotensin2 more so)
12
Q
What is the feedback control in hypothalamus-pituitary-adrenal axis?
A
Circulating cortisol neg inhibits ant pit and hypothalamus
13
Q
How do cortcosteroids exert their effect on cell?
A
- bind glucocorticoid receptor or mineralocorticoid receptor in the cytoplasm
- go to nucleus to increase or decrease trascription
14
Q
How do cortisol and aldosterone regulate if cortisol levels are usually way hgiher than aldosterone?
A
-enzyme type 2 isoform of 11beta-hydroxysteroid dehydrogenase converts cortisol to cortisone with does not bind the mineralocorticoid receptor so aldosterone can have its efefct to
15
Q
Side effects of high glucocorticoids on the nervous system?
A
psychiatric disorders
16
Q
Side effects of high glucocorticoids on the cardiovascular system?
A
cardiovascular disease
17
Q
Side effects of high glucocorticoids on the musculoskeletal system?
A
osteoporosis
18
Q
Side effects of high glucocorticoids on the visual system?
A
glaucoma
19
Q
Side effects of high glucocorticoids on glucose and liver metabolism?
A
obesity and hyperglycemia
20
Q
Side effects of high glucocorticoids on the reproductive system?
A
gonadal virtzation
21
Q
What is the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-hydroxylase type 2 - 11beta-HSD2) used for?
A
converts cortisol to cortisone with does not bind the mineralocorticoid receptor so aldosterone can have its effect to regulate since cortisol levels are so much higher it gives aldo a chance
22
Q
Physiological effect/Uses of glucocorticoids on the nervous system?
A
- physiological homestasis
- response to stressors
23
Q
Physiological effects/Uses of glucocorticoids on the cardiovascular system?
A
- anti-inflammatory
- cardiomyocyte survival
- homeostasis of blood pressure and vascular tone
- ant-angigenesis
24
Q
Physiological effects/Uses of glucocorticoids on the immune system:
A
- suppression of proinflammatory cytokines
- regulation of immune cell maturation, migration, and apoptosis
25
Physiological effects/Uses of glucocorticoids on the musculoskeletal system?
- anti-inflammatory
- muscle anabolism and catabolism
- insulin resistance
- osteoblast apoptosis
- osteoclastogenesis
26
Physiological effects/Uses of glucocorticoids on the visual system
- anti-inflammatory
- anti-angiogenesis
- photoreceptor survival
27
Physiological effects/Uses of glucocorticoids on the respiratory system?
-suppression of cytokines, chemokines, and cell adhesion molecules
28
Physiological effects/Uses of glucocorticoids on glucose and liver metabolism?
- glucose regulation
| - lipid homeostasis
29
Physiological effects/Uses of glucocorticoids on the reproductive system
- gonadal function in males and females
| - fetal organ development and maturation
30
Physiological effects/Uses of glucocorticoids on the integumentary system?
- anti-inflammatory
- delayed wound healing
- regulate epithelial integrity
31
Glucocorticoids on development of a fetus?
-in babies who are going to be premies the glucocorticoids are given to speed up development of the lungs
32
Cortisol and E/NE functions?
- cortisol inc glycogen synthesis in the liver so that there can be increase glycogenolysis induced by E/NE (inc blood glucose)
- cortisol ==> ++ upreg of receptors for E/NE (vascular tone reg - potentially hypotension if low cortisol levels)
- cortisol inc expression of enzyme that converts NE into E in adrenal medulla
33
- Mineralocorticoid vs glucocorticoid use?
| - mineralocorticoid fludrocortisone + a GC is used for?
- glucocorticoids for almost anything while mineralos for replacement therapy
- replacement therapy in adrenal insufficiency
34
MOA for anti-inflammatory effects of corticosteroids?
1) inh of phospholipase A2 > dec production of lipd mediators (PG, leukotrienes, platelet activating factor)
2) Inh COX induction > dec PG synthesis
3) inh NO synthase induction > dec NO production
4) inh cytokine production > suppress cell-mediated inflam
5) inh mast cell activity and #s > fewer mast cell inflam mediators (his and 5HT)
6) vasoconstriction > dec local blood flow
35
glucocorticoid effect on neurtrophils:
inc blood count
36
glucocorticoid effect on macrophages and monocytes:
dec number and activity
37
glucocorticoid effect on lymphocytes
dec blood count
38
glucocorticoid effect on eosinophils
dec blood count
39
glucocorticoid effect on basophils
dec blood count
40
which corticosteroid is used as a mineralocorticoid?
Fludrocortisone
41
Which corticosteroid as the most salt retaining potnecy?
fludrocortisone - mineralocorticoids retain salt
42
Which glucocorticoids are pro-drugs?
Which enzyme converts?
cortisone --> cortisol
prednisone --> prednisolone
11beta- HSD type 1
43
Topical gucocorticoid
| -uses/effects?
- reduce inflam and inh immune function for skin disorders (atopic dermatitis, psoriasis...etc)
- antiproliferative qualities
- MANY DIFFERENT POTENCIES
44
Topical Corticosteroid side effects:
- atrophy
- acne
- enhanced fungal infection
- retard wound healing
- contact dermatitis
- glaucoma
- cataracts
Systemic side-effects: hyopothalamus pit adrenal axis suppression; cushings syndrome; growth retardation
45
Topical corticosteroid therapy principles:
- start with low potency to try to control disease
- avoid prolonged use --> use low potency if you have to
- low potency on face (thin skin)
- high potency on palms and soles (thicker skin)
- do not use high potency in children - high surface area to body mass ratio
- alternate day application to avoid tachyphylaxis (diminished benefit)
46
How are glucocorticoids transported through the blood?
90% bound to albumin or corticosteroid binding protein (CBP) --> remaining unbound is ACTIVE FRACTION
47
glucocorticoids in people with liver issues?
-they have low serum proteins ==> less steroids will be bound = need to give smaller doses
48
Glucocorticoid metabolism and excretion?
liver met and kidney excretion
49
Glucocorticoid drug interaction-
- dec effects of steroid?
- inc effects of steroid?
- DEC-drugs that inc expression of P450s in liver should be avoided or youre going to lose effective therapeutic level of drug (barbs, carbamazepines, rafampin)
- INC-drugs like estrogens and androgens compete for metabolism so INC active level of drug in circulation
50
How do glucocorticoids increase Na retention and inc K secretion?
When they bind to mineralocorticoid receptors in renal collecting duct
51
Glucocorticoid drug interacion-
| -what happens with NSAIDS?
-inc risk of stomach ulcers
52
Glucocorticoid drug interacion-
| -glucocorticoids reduce effects of which types of drugs?
- hypoglycemics
- BP meds
- glaucoma meds
53
Adverse effects - glucocorticoids
| -2 weeks or less of therapy:
- even with high doses not major AEs
- insomnia
- hypomania
* *-acute peptic ulcers
54
Adverse effects - glucocorticoids
| -more than 2 weeks of therapy:
- iatrogenic Cushings
- metabolic
- myopathy
- mast bacterial infections
- sodium and fluid retention (11beta-HSD2 saturated)
- hgih BP
* *-HPA axis suppression (for up to 12 mo after stopping)
* *-gastric acid and pepsin production (large doses) == + peptic ulcers
* *-OSTEOPOROSIS - stim bone reabsorption inc osteoclast activity
55
How to take a patient off of glucocorticoids?
must taper off slowly! - helps HPA axis come back online and other stuff..?
56
Primary adrenal insufficiency
- other name for disease?
- most common cause US vs OUS
- what is it/what happens?
- tx?
-Addison's disease
-US=autoimmune vs OUS=TB
-deficiency in cortisol, aldosterone and androgens
-ACTH and CRH are elevated bc no negative feedback
==> hypotension bc unresponsiveness of vascular smooth muscle to catecholamines
-TX= oral cortisol and fludrocortisone
57
Secondary adrenal insufficiency
- cause?
- describe types?
- what is Tx?
1) pituitary disease or hypothalamic disorders
2) a) pituitary
- decrease ACTH levels --> decreased cortisol levels (CRH levels inc bc dec cortisol induced neg feedback at hypothalamus) == basically pituitary is broken so hypothalamus pumps out CRH
b) hypothalamic disorder
- decrease CRH production --> dec ACTH and cortisol == bascially hypothalamus is broken so CRH is down and pituitary isnt making ACTH bc its not getting an CRH
* -oral cortisol NO NEED FOR FLUDROCORTISONE bc aldosterone levels are normal*
58
Do Primary or secondary adrenal insufficiency patients have normal aldosterone levels?
-Secondary have normal aldosterone levels = dont need fludrocortisone bc Na and K levels are ok-ish
59
Congenital adrenal hyperplasia
- what is the issue?
- what happens?
- tx?
-most common issue is 21-hydroxylase deficiency
=dec cortisol and aldosterone
=inc ACTH (hyperplasia of adrenal cortex)
=inc androgens (**build up of products is shunted toward testosterone production since aldosterone and cortisol production is broken**) leading to virilization (sex changes due to hormones)
-tx: oral cortisol and fludrocortisone if needed
60
21-hydroxylase
- what does this enzyme do?
- what does def cause? disease name?
- important step in both aldosterone AND cortisol production
- disease is called congenital adrenal hyperplasia = build up of mineralocorticoid (aldosterone product) and glucocorticoid (cortisol product) intermediates that get shunted to testosterone production
61
21-hydroxylase deficiency - what does baby have?
-usually a female with male genetalia
62
Dosing of glucocorticoids?
follow circadean pattern of body as with normal corticoid peaks and decreases .. so 2/3 dose given in morning and 1/3 dose given in afternoon
63
Cushings syndrome
* -what happens?
* -causes?
- affected indiv/issues?
* 1) chronic glucocorticoid excess
* 2) -chronic glucocorticoid therpy
- pituitary tumor with ACTH secretion
- extopic hypersection of ACTH by non pit tumor
- adrenal tumor with inc cortisol secretion
3) -adbominal and shoulder/back fat = buffalo hump
- moon face - lipids in the face
- thinning of the skin
- poor wound healing
64
Lab studies for Pit hypersecretion tumor
DEC CRH
INC ACTH
- pit tumor secretes a lot of ACTH
- ACTH stim adrenal cortex to make cortisol
- cortisol feedbacks to hypothalamus so low CRH levels
65
Lab studies for adrenal adenoma
DEC CRH
DEC ACTH
- adrenal cortex tumor secretes a lot of corticoids
- feedback to hypothal and pituitary to stop making CRH and ACTH
66
Lab studies Ectopic ACTH production
- DEC CRH
- INC ACTH
- some tumor somewhere secretes ACTH = more corticoids from adrenals
- feedback to hypothal and pit to stop making CRH and ACTH (but ACTH is still being made elsewhere)
67
Adrenocorticosteroid synthesis inhibitors-name the drugos:
- aminolutethimide
- metyrapone
- ketoconazole
68
Aminoglutethimide
- type?
- MOA?
- tx for?
- adrenocorticosteroid synthesis inh
- blocks conversion of cholesterol to pregnenolone (first step of mineralo, gluco-corticoid and androgen synthesis
- tx adrenocortal tumors and cushings syndrome
69
Ketoconazole
- type?
- MOA?
- used for?
- AE?
- adrenocorticosteroid synthesis inh -- ANTIFUNGAL
- inh 17alpha hydroxylase and 11beta hydroxylase at high levels (so conversion steps btw minceralos and glucocorts and glucocorts and androgens)
- used to tx cushings syndrome
- LIVER TOX
70
Metyrapone
- type?
- MOA?
- used for?
- AE?
- adrenocorticosteroid synthesis inh
- selectvie 11beta-hydroxylase inh (final step to make aldosterone and cortisol)
- for cushings syndrome
- build up of androgens and 11beta-deoxycorticosterone
- salt and water retention (HTN)
71
Mifepristone
- type?
- high dose use?
- other use?
- glucocorticoid receptor antagonist - ONLY AT HIGH DOSES
- anti progestin effects = terminate prego
- tx inoperable patients with ectopic ACTH secretion or adrenal carcinoma
72
Mineralocorticoid receptor antagonist?
- spironolactone
| - eplerenone
73
Spironolactone
- type? MOA?
- uses?
- AEs?
1) Mineralocorticoid receptor antagonist (ALSO ANDROGEN RECEPTOR ANTAGONIST)
2) *tx primary aldosteronism (adrenal cortex adenoma that secretes aldosterone)
- diuretic for HTN
- hirsutism in women (bc androgen receptor antagonist)
3) hyperkalemia - cardiac arrhythmias
- gynecomastia, skin rash, menstrual issues, GI issues
74
Eplerenone
- type?
- uses?
- AE?
1) Mineralocorticoid receptor antagonist (DOES NOT HIT ANDROGEN RECEPTOR)
2) Tx HTN
3) mild hyperkalemia
