Lecture 17 - Adrenal Hormones Flashcards
Where are adrenocorticoids synthesized?
adrenal cortex
Where are sex steroids synthesized?
ovaries, testes
Steroid secretion is generally controlled by peptides secreted form the: ______ and ______
hypothalamus and pituitary
Glucocorticoids:
-modulation of _____ metabolism
carbohydrate
Glucocorticoids:
-increase levels of ____ in the liver and circulating glucose
glycogen
Glucocorticoids:
-early effects stimulate ____ system
immune
Glucocorticoids:
-prolonged secretion leads to immune _____ and cell death
suppression
Glucocorticoids:
-basal rhythmic secretion increased during periods of ______
stress
Mineralocorticoids:
-modulation of ??
water balance, promotion of Na+/K+ transport
Mineralocorticoids:
-promotes ___ uptake in tubular epithelial cells
Na+
Mineralocorticoids:
-modulates ___ ion transport
K+
Mineralocorticoids:
-control of _____ reabsorption
water
Mineralocorticoids:
-secreted only during periods of _____
stress
Secretion of ____ during stress is essential for life
cortisol
see diagram on slide 6
okay
when do cortisol levels peak?
in the morning
What does cortisol do in response to stress?
- stops the release of stuff (???) from the pituitary and hypothalamus
- stops the inflammatory and immune response
- HELPS YOU LIVE MAN
Cortisol levels increased by ??
- stress
- hypothyroidism
- liver disease
________ binds about 90% of circulating cortisol. The remainder is free or loosely bound to albumin and is available to exert its effect on target cells
corticosteroid-binding globulin (CBG)
What causes increased transcription?
- Lipocortin-1
- B2 adrenoceptors
- secretory leucocyte inhibitory protein
- IkB-alpha (inhibitor of NF-kB)
- MKP1 (inhibits MAPK pathways)
- glucocorticoid inducible leucine zipper (GILZ)
- anti-inflammatory or inhibitory cytokines: IL-10, IL-12, IL-1 receptor antagonist
What does cortisol do?
cortisol goes to nucleus and increases IL and beta receptors (increases opening of airways) glucocorticoids good for asthma because anti-inflammatory and opens airways
What causes decreased transcription?
- Inflammatory cytokines: Only know about TNF-alpha
- Chemokines:
- Inflammatory enzymes: COX-2
- Inflammatory proteins
- Mediator receptors
- Adhesion molecules
What do chemokines do?
decreases inflammation and entire immune regulation
benefit of a COX-2 selective inhibitor?
won’t cause ulcers because COX-1 is present in stomach
List the steroids that we have to know
Cortisone Cortisol Prednisone Methylprednisolone Dexamethasone Betamethasone Fluticasone- Primary inhaled steroid for people with allergic asthma or serious rhinitis, local tissue as a steroid to knock down inflammatory pathways
Betamethasone is a ______ potency steroid
medium
Hydrocortisone is a ____ potency steroid
low
Describe the potency scale of topical corticosteroids for dermatologic use
1 = ultra high 2-3 = high 4-5 = medium 6-7 = low
Topical corticosteroids:
AE?
topical side effects only (striae, skin atrophy); higher potency formulations can cause systemic side effects if used on large areas and/or for prolonged periods
Topical corticosteroids:
_____ can increase or decrease potency level
Vehicles
ex. ointments are considered higher potency than their cream or lotion equivalent
The ______ have widespread effects because they influence the function of most cells in the body.
*everything in the body changes so huge numbers of side effects, not specific at all
glucocorticoids
Glucocorticosteroids:
Some important effects are the result of homeostatic responses by ______ and ______
insulin and glucagon
Glucocorticosteroids:
Describe the different effects (4)
1) Metabolic
2) Catabolic and anti-anabolic
3) Anti-inflammatory and immunosuppressive
4) Others
Glucocorticosteroids:
Metabolic:
Stimulate ____ and ______ synthesis in the fasting state
gluconeogensis and glycogen
*Overall effect is to increase glucose production, increase insulin secretion - can make you drug dependent diabetic because insulin system can’t keep up with the amount of glucose, increases chance of getting type 2 later in life
Glucocorticosteroids:
Metabolic Effects:
Increase serum ____ levels which increase ______ release and decrease glucose uptake by muscle cells
glucose
insulin
Glucocorticosteroids:
Metabolic Effects:
Increase _____ secretion which increases lipogenesis and to a lesser degree decreases lipolysis
insulin
Glucocorticosteroids:
Catabolic and anti-anabolic effects:
In what tissues?
In lymphoid and connective tissue, muscle, peripheral fat and skin:
-decreases muscle mass, weakness and thinning of the skin
On bone:
- cause of osteoporosis in Cushing’s syndrome and impose a major limitation in the long-term therapeutic use of glucocorticoids
- Reduce growth in children
Glucocorticosteroids:
Anti-inflammatory and Immunosuppressive Effects:
Describe these effects
Profound effects on the concentration, distribution, and function of peripheral leukocytes and on their suppressive effects on the inflammatory cytokines, chemokines and other mediators of inflammation
- increase neutrophiles
- decrease lymphocytes (T and B cells)
- decrease monocytes
- decrease eosinophils
- decrease basophils
Glucocorticosteroids:
Anti-inflammatory and Immunosuppressive Effects:
How do glucocorticosteroids suppress the immune system?
Immunosuppresion:
- down regulates T lymphocyte proliferation
- inhibits T-lymphocyte activation
- down regulation of plasma cells
- inhibits inflammatory cell migration
- inhibition of antigen phagocytosis by macrophages
- suppression of antibody production
Glucocorticosteroids:
Anti-inflammatory and Immunosuppressive Effects:
How do glucocorticoids inhibit the functions of tissue macrophages?
Decrease:
- response to antigens and mitogens
- phagocytosis and kill microorganisms
- cytokines
- metalloproteinase
- plasminogen activator
*just know it inhibits macrophages in every way it can
Glucocorticosteroids:
Anti-inflammatory and Immunosuppressive Effects:
What else do glucocorticoids inhibit ?
Inhibit phospholipase A2:
- decrease synthesis of arachidonic acid
- decrease prostaglandins
- decrease leukotrienes
- decrease platelet-activating factor (decreased chance of blood clots)
Reduce expression of COX-2:
-decrease prostaglandins
Depress mast cell and basophil secretion:
- vasoconstriction (topical)
- decrease capillary permeability (histamine?)
- decrease response to allergens can get dry eye/mucous membranes
Glucocorticosteroids:
Other effects:
Marked slowing of the alpha rhythm of the electroencephalogram and is associated with _____
depression
Glucocorticosteroids:
Other effects:
Behavioral disturbances:
- initially insomnia
- euphora
- subsequently depression
Glucocorticosteroids:
Other effects:
Can cause ____ ulcers
peptic
Glucocorticosteroids:
Other effects:
Chronic glucocorticoids decrease the pituitary release of:
??
- ACTH
- growth hormone
- thyroid-stimulating hormone
- leuteinizing hormone
Glucocorticosteroids:
Other effects:
Increase fat redistribution in the body:
??
- increase of visceral fat
- increase of facial fat
- increase of supraclavicular fat
- centrepetal obesity
Glucocorticosteroids:
Other effects:
Hematopoietic:
- increase platelets
- increase red blood cells
Glucocorticosteroids:
Other effects:
Production of _____ surfactant near term
*given specifically for preterm babies without right surfactant in their lungs so can’t open and close properly, cortisol induces this to increase the surfactants
fetal
What are some uses of exogenous glucocorticoids?
1) Appropriate dose in each case is determined by trial and error
2) Therapeutic concentrations must exceed endogenous levels
3) Single dose of glucocorticosteroid is virtually without harmful effect
4) A few days of usage is unlikely to produce harmful effects except at extreme doses
5) Prolongation of treatment increases the incidence of disabling or life threatening effects
6) Corticosteroids are neither specific or curative treatment:
- pathological processes continue
- clinical manifestations
- suppressed
- primarily useful where host response causes disease manifestations
* THEY DON’T TREAT ANYTHING, ONLY HELP WITH SYMPTOMS
7) Abrupt cessation of prolonged high dose treatment may induce adrenal insufficiency serious enough to be life threatening (CAN’T SUDDENLY STOP TAKING - HAVE TO TAPER OFF)
List some conditions that can be treated with exogenous glucocorticoids
-shock (ex. septic shock)
-cerebral edema
-increased intracranial pressure
-allergies
-arthritis
-asthma
-rheumatic carditis
-renal disease
-collagen disease
certain malignancies
-ulcerative colitis
-Chrohn’s disease
-organ transplants
-anaemias, thrombocytopenias
-renal disease
-oral ulcerations
-fetal lung maturation (<34 weeks gestation)
*see slide for 28/29 for ones that we can be tested on
List some adverse effects of glucocorticoids
- Decrease resistance to infections (systemic & local)
- CNS effects
- Hyperglycemia/glycosuria
- Electrolyte imbalance
- Suppression of growth, amenorrhea
- Peptic ulcer, ocular effects (Increase IOP, cataracts)
- Suppression of pituitary-adrenal function (1-2 yr recovery - supplemental corticosteroids)
- Alterations in appearance (long term therapy) - moonfaced and buffalo hump, central obesity
- Muscle weakness and atrophy
- Osteoporosis/osteonecrosis
- Poor wound healing
- Acne, hirsutism, skin thinning, hypertension
*see slide 30 for ones in yellow (testable ones)
What is Mifepristone?
Glucocorticoid Antagonist
Mifepristone:
MOA
- Blocks cortisol binding
- Reduces excess cortisol effects in Cushing’s
- Inhibits prostaglandin dehydrogenase - increase uterine contraction
- Used with mifepristone to induce abortion
Metyrapone and Ketoconazole are ??
corticosteroid biosynthesis inhibitors
Metyrapone:
MOA
inhibits 11B-hydroxylation reaction
diagnosis hypothalamus - pituitary malfunction
Ketoconazole:
MOA
blocks cholesterol side chain cleavage in the adrenal
Cushing’s syndrome
One adverse effect of glucocorticoids is hyperadrenocorticism aka ??
Cushing’s syndrome
making too much cortisol
What is Addison’s disease?
-decreased secretion of glucocorticoids and sometimes aldosterone
Symptoms:
- fatigue
- syncope
- GI upset
- CNS effects
- joint/muscle pain
- hyperpigmentation
Describe Addison’s crisis/adrenal crisis
Severe adrenal insufficiency:
- pain in the legs, lower back and/or abdomen
- severe gastric upset
- dehydration
- hypotension
- syncope
- hypoglycemia
- confusion, psychosis, slurred speech
- lethargy
- hyponatremia
- hyperkalemia
- hypercalcemia
- convulsions
- fever
- death
