corticosteroids

Question 1

Glucocorticoids are produced where?

Answer 1

adrenal gland, adrenal cortex, zona fasiculata

Question 2

biosynthesis of adrenal steroids

Answer 2

• 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

Question 3

double negative feedback loop regulation of corticosteroid release

Answer 3

• 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

Question 4

circadian rhythm

Answer 4

• 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

Question 5

effect of stress on adrenal steroids

Answer 5

• causes release of catecholamines to maximize utilization of energy
• causes release of glucocorticoids to maximize availability of energy
• catecholamines and glucocorticoids work in concert

Question 6

mechanism of action of glucocorticoids

Answer 6

• 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

Question 7

general effects of glucocorticoids (list of 10)

Answer 7

• 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

Question 8

simplified arachidonic acid cascade

Answer 8

• 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))

Question 9

inflammatory mediators

Answer 9

• release is stimulated by prostaglandins
• histamine, serotonin, bradykinin, substance P, lipid mediators
• prostaglandins also cause change in pH of local tissue

Question 10

lipid mediators (list)

Answer 10

prostaglandins
thromboxane A2
HETE
leukotrienes
platelet activating factor
activated complement components
lysosomal enzymes
autoantibodies
cytokines

Question 11

prostaglandin D2

Answer 11

• cyclooxygenase metabolite

- causes vasodilation, destabilization of basophils, hyperalgesia, *bronchoconstriction

Question 12

prostaglandin E2

Answer 12

• 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

Question 13

prostaglandin F2alpha

Answer 13

• cyclooxygenase metabolite

- causes *bronchoconstriction, *dysmennorhea, *uterine contractions, hyperalgesia

Question 14

prostaglandin I2

Answer 14

• cyclooxygenase metabolite

- causes release of calcium from bone, vasodilation, *inhibits platelet aggregation

Question 15

thromboxane A2

Answer 15

• cyclooxygenase metabolite

- involved in regulation of platelet function

Question 16

5-HETE

Answer 16

• lipoxygenase metabolite

- causes chemotaxis

Question 17

leukotrienes B4

Answer 17

• lipoxygenase metabolite

- causes chemotaxis

Question 18

leukotrienes C4,D4,E4

Answer 18

• lipoxygenase metabolite

- causes vasoconstriction, bronchospasm, increased vascular permeability, neutrophil activation

Question 19

pharmacokinetics

Answer 19

• 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

Question 20

short-acting glucocorticoids

Answer 20

cortisone
hydrocortisone

• plasma half life: 30-75 min
• *biological half-life: 8-12 hrs
• mineralocorticoid potency is 2x compared to anti-inflammatory potency

Question 21

intermediate-acting glucocorticoids

Answer 21

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

Question 22

long-acting glucocorticoids

Answer 22

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

Question 23

therapeutic uses of glucocorticoids (8)

Answer 23

• 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

Question 24

adverse effects: adrenal suppression

Answer 24

• 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

Question 25

adverse effects

Answer 25

• 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

Question 26

more adverse effects

Answer 26

• 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

Question 27

and even more adverse effects

Answer 27

• 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

Question 28

Cushing syndrome

Answer 28

• 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

Question 29

Addison’s disease

Answer 29

• 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)

Question 30

causes of adrenal insufficiency

Answer 30

• primary adrenal insuff: Addison’s, tuberculosis, surgical removal adrenal gland(s)
• secondary adrenal insuff: ACTH insuff, abrupt withdrawal of exogenous glucocorticoid therapy