corticosteroids Flashcards
1
Q
Glucocorticoids are produced where?
A
adrenal gland, adrenal cortex, zona fasiculata
2
Q
biosynthesis of adrenal steroids
A
- cholesterol is the common source from which all adrenal steroids are formed **
- cortisol: one pathway of cortisol synthesis involves progesterone, one pathway from 17-hydroxyprogesterone
- aldosterone: from progesterone
- androgens: from 17-hydroxyprogesterone or 17-hydroxypregnenolone
3
Q
double negative feedback loop regulation of corticosteroid release
A
- hypothalamus releases CRF
- CRF stimulates anterior pituitary to release ACTH into the bloodstream
- ACTH stimulates the release of cortisol from the adrenal cortex
- high blood levels of cortisol inhibits both (1) hypothalamus release of CRF and (2) ant. pituitary release of ACTH
4
Q
circadian rhythm
A
- the result of fluctuating levels of circulating cortisol caused by dbl negative feedback loop regulation
- diurnal peak at about 8am daily, assuming hours of wakefulness from 6a-10p
- affected by travel, sleep patterns, light cycle, exogenous cortisol intake, stress
5
Q
effect of stress on adrenal steroids
A
- causes release of catecholamines to maximize utilization of energy
- causes release of glucocorticoids to maximize availability of energy
- catecholamines and glucocorticoids work in concert
6
Q
mechanism of action of glucocorticoids
A
- ligand binds to receptor in the interior of the cell (widely distributed in the cytosol)
- ligand/receptor complex moves into the nucleus and binds to DNA where protein production can be activated or inhibited
- influence on DNA transcription of several proteins may take place simultaneously
- this mechanism accounts for the slow onset of action of glucocorticoids
7
Q
general effects of glucocorticoids (list of 10)
A
- increases sensitivity to adrinergic drugs
- direct vascular effects (from dyslipidemia and htn)
- anti-inflammatory effects (decreased leukotriene and prostaglandin production, reduced macrophage recruitment); limits the damage associated with spinal cord injury due to inflammation
- inhibits wound healing (inhibits fibrin, inhibits collagen deposition)
- increased bone catabolism / brittle bone syndrome; antagonize effects of vitamin D on calcium absorption
- required for production of surfactant (effect on fetal growth)
- destruction of lymphocytes in lymph nodes
- inhibits mitosis by transformed lymphoblasts
- anabolic in the liver (leads to enlarged liver) / catabolic everywhere else
- anti-insulin effects: increases glucose and fatty acid availability for energy (gluconeogenesis, glycogenesis, lipid breakdown to free fatty acids); overall: increased amino acids, fatty acids, glycerol delivery to liver for glucose/glycogen production
8
Q
simplified arachidonic acid cascade
A
- phospholipase A2 causes release of free arachidonic acid from cell membranes (this initial step is blocked by glucocorticoids)
- 2 pathways for metabolism of free arachidonic acid: cyclooxygenase pathway, lipoxygenase pathway
- lipoxygenase pathway: produces leukotrienes
- cyclooxygenase pathway: produces prostaglandins and thromboxane A2 (this pathway blocked by NSAIDS this accounts for anti-inflammatory effects (less prostaglandins) and impaired clotting (less thromboxane A2))
9
Q
inflammatory mediators
A
- release is stimulated by prostaglandins
- histamine, serotonin, bradykinin, substance P, lipid mediators
- prostaglandins also cause change in pH of local tissue
10
Q
lipid mediators (list)
A
prostaglandins thromboxane A2 HETE leukotrienes platelet activating factor activated complement components lysosomal enzymes autoantibodies cytokines
11
Q
prostaglandin D2
A
- cyclooxygenase metabolite
- causes vasodilation, destabilization of basophils, hyperalgesia, *bronchoconstriction
12
Q
prostaglandin E2
A
- cyclooxygenase metabolite
- causes vasodilation, increased vascular permeability (swelling), release of calcium from bone, hyperalgesia, *elevated body temp by action on hypothalamus, *maintain renal blood flow and sodium excretion during low flow (inhibiting causes serum hyperkalemia), *protection of GI tract mucosal layer
13
Q
prostaglandin F2alpha
A
- cyclooxygenase metabolite
- causes *bronchoconstriction, *dysmennorhea, *uterine contractions, hyperalgesia
14
Q
prostaglandin I2
A
- cyclooxygenase metabolite
- causes release of calcium from bone, vasodilation, *inhibits platelet aggregation
15
Q
thromboxane A2
A
- cyclooxygenase metabolite
- involved in regulation of platelet function
16
Q
5-HETE
A
- lipoxygenase metabolite
- causes chemotaxis
17
Q
leukotrienes B4
A
- lipoxygenase metabolite
- causes chemotaxis
18
Q
leukotrienes C4,D4,E4
A
- lipoxygenase metabolite
- causes vasoconstriction, bronchospasm, increased vascular permeability, neutrophil activation
19
Q
pharmacokinetics
A
- 90% plasma bound: cortisol (Corticosteroid binding globulin, α2- globulin); synthetic corticosteroids (albumin)
- competitive interaction with other plasma bound drugs, will increase serum levels of those drugs (i.e. warfarin, aspirin)
- liver inactivation
20
Q
short-acting glucocorticoids
A
cortisone
hydrocortisone
- plasma half life: 30-75 min
- *biological half-life: 8-12 hrs
- mineralocorticoid potency is 2x compared to anti-inflammatory potency
21
Q
intermediate-acting glucocorticoids
A
prednisone
prednisolone
triamcinilone
methylprednisolone
- plasma half life: 1-4 hrs
- *biological half life: 18-36 hrs
- slight mineralocorticoid activity with prednisone, none with the rest
- anti-inflammatory potency is 4-5x compared to short-acting
22
Q
long-acting glucocorticoids
A
dexamethasone
betamethasone
- plasma half life: 2-5 hrs
- *biological half life: 36-54 hrs
- no mineralocorticoid activity
- anti-inflammatory potency is 25x compared to short-acting
significant s/e of long-actings: disruption of circadian rhythms, no diurnal cortisol peak bc cortisol levels remain consistently high due to long half life
23
Q
therapeutic uses of glucocorticoids (8)
A
- inflammatory diseases: eczema, dermatitis, arthritis, bursitis, inflammatory bowel disease
- respiratory diseases: asthma, COPD
- rheumatoid/collagen diseases: rheumatoid arthritis, lupus
- immune suppression: autoimmune diseases, organ transplant, acute allergic conditions (bee sting, drug hypersensitivity, angioedema)
- replacement therapy for Addison’s (cortisone)
- cerebral edema (dexamethasone)
- premature delivery (to increase surfactant; betamethasone)
- inhibit fibrosis in eye injury
24
Q
adverse effects: adrenal suppression
A
- adrenal cortex normally produces cortisol 30mg/day
- if exogenous cortisol given for an acute process (not replacement therapy), the artificially high levels of cortisol influence dbl negative feedback loop
- results in decrease of endogenous cortisol production if exogenous dose < 30 mg/day
- results in cessation of endogenous cortisol production if exogenous dose > 30 mg/day
- with abrupt discontinuation of exogenous dosing, the adrenal cortex will not have had time to respond, results in adrenal insufficiency
25
Q
adverse effects
A
- immunosuppression (can be therapeutic or adverse depending on context)
- fluid and electrolyte imbalance (due to mineralocorticoid activity of short-acting glucocorticoids)
- peptic ulcer disease (suppression of PGE1); abdominal pain/burning, bloody/black stools
- eye problems: with CHRONIC use only; sub capsular cataracts, increased intraocular pressure, eye redness, photophobia
- CNS: psych sx due to loss of diurnal rhythm/ difficulty sleeping, unusual tiredness/weakness
26
Q
more adverse effects
A
- osteoporosis/ brittle bone syndrome: decr bone formation, release of bone calcium, reduces protein matrix that bone builds on
- aseptic necrosis (esp head of femur)
- decreased wound healing (due to effects on collagen)
- loss of muscle mass (breakdown protein to amino acids for glucose/glycogen production in liver); muscle cramps/weakness
- increased circulating triglycerides (breakdown of adipose to free fatty acids for glucose/glycogen production in liver)
- decreased carbohydrate tolerance (hyperglycemia)
- redistribution of body fat (loss of body fat to hip and shoulder, truncal obesity, moon face, buffalo hump); rapid weight gain
27
Q
and even more adverse effects
A
- dysmennorhea
- pitting of skin at site of injection (must rotate sites with each injection)
- unusual bruising (inhibition of thromboxane A2)
- thin, fragile or shiny skin
- hirsutism
28
Q
Cushing syndrome
A
- over-administration of exogenous glucocorticoids
- over-secretion of ACTH (pituitary over-secretion or ectopic secretion)
- symptoms: acne, truncal obesity, moon face, buffalo hump, purple striae on abdomen, thin extremities
29
Q
Addison’s disease
A
- auto-immune mediated adrenal insufficiency
- symptoms: chronic fatigue, muscle weakness, loss of appetite
- treatment: chronic replacement therapy (either intermediate acting glucocorticoid with alternating day therapy but trending toward short-acting/cortisol given every morning to minimize disruption of circadian rhythm)
30
Q
causes of adrenal insufficiency
A
- primary adrenal insuff: Addison’s, tuberculosis, surgical removal adrenal gland(s)
- secondary adrenal insuff: ACTH insuff, abrupt withdrawal of exogenous glucocorticoid therapy
