EXAM 3 Adrenocorticosteroids and Adrenocortical antagonists Dr. Pond Flashcards
What is a Corticosteroid?
-A steroid that is released by the adrenal cortex or a steroid that is related to steroids synthesized by adrenal cortex
Cortico - adrenal cortex
steroid - steroid based molecule derived from cholesterol
Which molecules are produced by the cortex (outer part of the adrenal gland)?
produces steroid-based hormones
Which part of the adrenal gland produces NE and epinephrine?
the adrenal medulla (inner part)
-synthesis and secretion of NE and epinephrine in response to sympathetic signals
What are the 3 classes of steroid-based hormones?
-Glucocorticoids
-Mineralcorticoids
-Gonadocorticoids
Which class of molecules do Glucocorticoids refer to?
Cortisol
-> affecting glucose metabolism
(GLUCOse + CORTex + sterOID)
Which class of molecules do Mineralcorticoids refer to?
Aldosterone
-> affect salt and water balance (MINERAL + CORTex +
sterOID)
Which class of molecules do Gonadocorticoids refer to?
Steroid hormones
-> produced by the adrenal cortex that affects sexual function -> similar to those of the gonads
(GONAD + CORTex + sterOID)
What are the 3 layers of the adrenal cortex (outer part) and what do they secrete?
-Zona glomerulosa -> mineralcorticoids
-Zona fasciculata -> glucocorticoids
-Zona reticularis -> sex steroids (gonadocorticoids)
Go find Rex - make good sex
Hypothalamus-anterior pituitary-adrenal cortex Axis
- Hypothalamus -> CRH (corticotrophin-releasing hormone)
- CRH on anterior pituitary -> ACTH (adrenocorticotropic hormone)
- ACTH on adrenal cortex -> Cortisol
What are the main steroids produced by the adrenal cortex?
-Glucocorticoid: Cortisol
-mineralcorticoid: Aldesterone
-Gonadocorticoid: Dehydroepiadrosterone (DHEA), a weak androgen -> can be converted to testosterone or estradiol (stronger sex hormones)
Which hormone is primarily secreted by the adrenal gland?
Cortisol
-aldosterone (mineralocorticoid) is more regulated by the RAAS system, as well as sodium and potassium level
-the amount of sex hormones released from adrenal gland is minor (more from the gonads)
FYI: post-menopausal women mainly produce their sex hormones form the adrenal gland
What triggers CRH release from the Hypothalamus?
-Circadian rhytm
-Stress
Negative feedback in the HPA axis
-high cortisol -> negatively back to the anterior pituitary and hypothalamus
-high ACTH -> back to the hypothalamus
Where does Cortisol bind to in the plasma?
90% bound to corticosteroid-binding globulin (CBG)
-the remainder is free or closely bound to albumin
When do we see an increased level of free Cortisol and the plasma?
when plasma levels exceed 20-30 μg/dL
-> CBG is saturated
What may cause high levels of Cortisol in the plasma?
-severe stress
-Cushings disease
Where is cortisol metabolized?
-mostly in the liver -> activated from cortisone to cortisol
Kidney (also placenta)
-20% converted to cortisone - inactive
(by 11-hydroxysteroid DH 2)
-1% excreted unchanged
Which enzyme in the kidney converts Cortisol to Cortisone?
11-hydroxysteroid DH 2
Which receptor solely binds to Cortisol?
Glucocorticoid receptor (GR)
Which receptor does Cortisol and aldosterone bind to?
Mineralocorticoid receptor (MR)
How does the body steer Cortisol to bind to Glucocorticoid receptors (GR) rather than mineralcorticoid receptors (MR)?
with the enzyme 11-hydroxysteroid DH 2
by converting Cortisol into Cortisone in the kidney
-> Cortisone is inactive and won’t bind to GR or MR
anything that does bind to GR will be converted to cortisone, to prevent effects that come from MR???
What is the MOA cortisol?
-regulates gene transcription in the nucleus
-first bound to CBG in the plasma -> crosses the membrane and binds to Glucocorticoid receptors -> enters the nucleus and activates transcription in the GRE glucocorticoid response element (promotor region)
-long process -> so onset is delayed: 8-12hr
Other MOA
cortisol binds to GR and forms a complex with other transcription factors and regulates non-GRE-containing promotors
What is the effect of glucocorticoids in the plasma?
CATABOLIC EFFECTS
increase glucose in the plasma at the expense of proteins
-protein catabolism in bone, lymph, muscle, and elsewhere -> to make GLUCOSE
-more liver uptake of AS to make GLUCOSE (gluconeogenesis)
-it tries to keep blood glucose levels high -> so it breaks down things to keep it high (maintenance)
-triglycerides catabolism in adipose tissue -> release of glycerol and fatty acids into the blood - this effect is different in different body parts -> Cushings disease
Why do we see fat storage in Cushings disease?
release of Insuilin promotes fat storage in the stomach region
What are the consequences of the catabolic activity of Glucocorticoids?
-osteoporosis in the bone (collagen = protein used for glucogeonesis)
-glucocorticoids inhibit the vitamin D effect -> block the absorption of calcium and phosphate from the gut -> less mineralization of the bone
-reduce growth in children
-decreases what is considered unnecessary in a stress situation: things like growth and fertility
Anti-inflammatory and immunosuppressive effects of glucocorticoids
-decreases of function of peripheral leukocytes
-Inhibition of prostaglandin and leukotriene synthesis and cytokines
-inhibits macrophages and other antigen-presenting cells (activating the induced immune responses)
-decreases capillary permeability by reducing
histamine release via basophils and mast cells
-> so leukocytes cant move to the site of infection readily
What is one of the important anti-inflammatory proteins that is stimulated by glucocorticoids?
Annexin A1
-inhibits prostaglandin synthesis
-decreaseing function of neutrophils
-> anti-inflammatory, anti-immune effect
Other effects of Corticosteroids
CNS:
increased mood first, later depression
also can contribute to psychosis at high doses
GI:
immune-repressive -> so increases peptic ulcers (H. pylori)
inhibits Vitamin D and Ca2+ absorption from the gut -> decreased bone mass
increase in appetite and weight gain
Blood:
increase in RBC, decrease in WBC
Endocrine:
chronically used: suppresses CRH, ACTH, GH, TSH, LH
Lungs:
increases development of fetal lungs by increasing absorption of surfactants
What are the major effects of Aldosterone?
Na+ and water retention at expense of potassium (excreted)
-> increases extracellular fluid (ECF) and blood volume -> increase in BP
Factors that regulate Aldosterone release
-RAS system
-directly via Na+/K+
-ANF (atrial natriuretic factor)
-ACTH
RAAS system
Renin converts Angiotensionogen to Angiotensin I
Angiotensin I to Angiotensin II by ACE
Angiotensin II ->
increases aldosterone release -> inc BP
acts as a vasoconstrictor -> inc BP
How do Na+ and K+ levels affect Aldosterone synthesis?
stimulated by
low Na+
high K+
since Aldosterone cause Na+ retention and K+ loss
How does ANF affect Aldosterone synthesis?
stretch of the atria -> caused by high blood volume
-> release of ANF -> decreases aldosterone since blood volume and BP is already high
What is Addison’s disease?
Chronic adrenocortical insufficiency
-too little glucocorticoids
-too little mineralcorticoids
(gonadocorticoids is also low, but there is not much production from the adrenal glands anyway)
How does Aldosterone cause Na+ retention/K+ excretion?
-synthesis of Na+/K+ transporter on the interstitial site and Na+ transporter on the lumen side of kidneys (reasborption)
-aldosterone binds to mineralocorticoid receptors (MR) reguate genes that encode for these transporter proteins
-Cortisol also binds to MR but we want to limit it -> conversion to inactive Cortisone via 11ßHSD2
Effects of Addison’s disease
low plasma sodium, high potassium
low blood pressure
-> since Aldosterone is low (low in Na+/K+ transporter)
-muscle weakness, fatigue
-vomitig, loss of appetite, dehydration (weight loss)
-hyperpigmentation in some patients
-blood glucose cannot be maintained during fasting - due to low levels of glucocorticoid
How is hyperpigmentation in Addison’s disease explained?
low levels of Cortisol we lose negative feedback to ACTH (anterior pituitary) and CRH (hypothalamus), also low level increases ACTH and CRH???
->high levels of ACTH
-the proprotein pro-opiomelanocortin of ACTH also contains MSH (melanocyte-stimulatiing hormone)
-> high melanin production
What is Cushing’s disease?
Excessive glucocorticoids
-might be due to an adrenal tumor (zona fasciculata)
-pituitary tumor - too much ACTH -> too much cortisol
-or ectopic (somewhere else) ACTH-producing tumor
Presentation
-upper body obesity (thin arms and legs)
-fat deposits between the shoulder blades (buffalo hump)
-moon face
Symptoms Cushings disease
-Euphoria (initially)
-HTN (sometimes with high cortisol due to binding to MR and causing Na+ retention)
-redistribution of fat
-infections
Protein wasting symptoms in Cushing’s disease
-muscle wasting
-thin skin with strae (failure of collagen production in the skin)
-bruising
.poor wound healing
-fragile bones/osteoporosis
Which of the steroid receptors have anti-inflammatory and which one has salt retention activity?
-glucocorticoid receptor (GR): anti-inflammatory
-mineralocorticoid receptor (MR): salt retention
Which steroid drug is short-acting with anti-inflammatory activity?
-Prednisone (prodrug) 4:0.3
-Prednisolone 5:0.3
-Methylprednisolone 5:0.25
Cortisone is inactive 0.8:0.8
Hydrocortison (cortisol) binds to both receptors 1:1
Which steroid drug is long-acting with anti-inflammatory activity?
Dexamethasone 30:0
Bethametasone 25-40:0
Which steroid drug is long-acting with salt-retaining activity?
Fludrocortisone 10:250
so 10x than cortisol (which has 1)
but very potent for MR so we use a small dose (2mg) to minimize anti-inflammatory activity from GR
Treatment approach Addison’s Disease
since too little cortisol and aldosterone
-> treat with glucocorticoids and Fludrocortisone (MR activity)
Drug targets in Cushing’s disease
too much glucocorticoids
Pituitary gland:
-Cabergoline
-Pasereotide
Glucocorticoid receptor antagonist:
-Mifepristone
Adrenal gland:
-Ketoconazole
-Metyrapone
-Mitotane
-Surgery: remove the tumor that is causing the overproduction
MOA of Ketocanozole
in Cushing’s disease
inhibits the production of corticosteroids (adrenal steroidogenesis), inhibits multiple enzymes involved in the synthesis -> decrease in cortisol
-since cortisol will be decreased we expect ACTH and CRH to go up (loss of negative feedback)
-but we don’t see an increase in ACTH - not understood, it somehow also blocks ACTH
ADE of Ketocanole
-potential impact on gonads (especially testes)
-> Hypogonadism
-> Gynecomastia
What is the BBW for Ketocanozole?
-Hepatoxicity
-DDIs: dysrhytmia risk
MOA of Metyrapone
inhibits the final step in the corticoid synthesis pathway
by blocking the enzyme 11ß-hydroxylase
ADE: adrenal insufficiency
MOA of Mitotane
Adrenolytic: destroys adrenal cells by disruption of mitochondrial cristae -> mitochondrial swelling -> lysis
Adrenostatic: inhibtis multiple enzymes involved in the production of cortisol
What is the BBW for Mitotane
Adrenal insufficiency
bc it literally destroys cells of the adrenal gland
ADE: Neurotoxicity -> ataxia, somnolence, anorexia, vertigo, parashetsia, dizziness, parkinsonian syndrome
MOA of Mifepristone
Glucocorticoid receptor antagonist
(also prgesterone receptor antagonist RU-486 for pregnancy termination)
ADE: HTN, periperhal edema, fatigue, hyperkalemia, reduced appetite, N/V, dizziness, headache, hypertrophy of endometrium (progesterone receptor-related)
Where is 11ßHSD2 expressed during pregnancy affecting and affecting fetal lung development?
in the placenta
->in the late phase of pregnancy the maternal corticosol goes up, so that enough crosses the placenta to overcome 11ßHSD2 and increases fetal lung development
Which drug may be used at the late stage of pregnancy for fetal development in case of early delivery?
Betamethasone or Dexamethasone
->they have high potency of glucocorticoid receptors and they are not affected by 11ßHSD2 metabolism
-given to the mother if there is risk for early delivery
ADE with long-term ADE of corticosteroids
Cushings-like symptoms
-redristribution of fats
-poor wound healing
-breakdown of skin and other places to build glucose
-growth suppression in kids
-short-term (<2 weeks):
-insomnia
-psychosis (with large doses)
-acute peptic ulces (H. pylori, or due to increased gastric secretion)
What are the effects of binding to mineralocorticoid receptors?
-Na+ and flutid retention
-hypokalemia
What are signs of corticoid withdrawal?
-fewer
-headache, fatigue
-joint pain, muscle plain
-low BP
-N/V
-> must taper therapy to restore HPA axis function,
patients would have adrenal insufficiency
How is water solubility achieved in corticosteroid formulation?
as esters or salts (only salts are soluble enough for injections
-topical (creams)
-inhaled for asthma
-nasal sprays for allergic
-rhinitis, IM, IV, oral
Which drugs bind to Mineralocorticoid receptors?
-Spironolactone
-Eplerenone
-Drospirenone
Which of the Mineralocorticoid antagonists also bind to androgen receptors (AR)?
Spironolactone
Indication of Spironolactone
-treatment of aldosteronism
->the adrenal glands produce too much aldosterone
-diuretic: heart failure, HTN
Patient presentation in aldosteronism
-hypertension
-muscle weakness
-tetany
-hypokalemia
Adverse effects of Spironolactone
-hyperkalemia (blocking Na+/K+ transporter synthesis), cardiac arrhythmias!!!
-sedation
-headache
-GI disturbances
-rash
androgen receptor-specific ADEs
-menstrual abnormalities (in women)
-gynecomastia (in men)
Indication of Drospirenone
progestin in oral contraceptives
-> also has diuretic effects due to binding to MR
ADE: hyperkalemia
Indication for Finerenone
used for chronic kidney disease in patients with T2DM
-High potency and selectivity for the MR
ADE:
(blocking Na+/K+ transporter synthesis)
-hyponatremia
-hyperkalemia
-hypotension
