Corticosteroids

Question 1

How does the hypothalamus and pituitary regulate biosynthesis of cortisol? (5)
glucocorticoid synthesis

Answer 1

1) Hypothalamus releases CRH
2) Pituitary releases ACTH
3) ACTH reaches bloodstream to get to adrenal cortex
4) Adrenal cortex produces cortisol
5) Cortisol reduces release of CRH and ACTH

Question 2

Regulation of mineralocorticoid synthesis

Answer 2

1) kidney releases renin
2) renin converts to angiotensin II
3) angiotensin II stimulates zona glomerulosa to produce aldosterone
4) K+ levels = stimulates aldosterone synthesis
5) inc aldosterone = Na+ and water retention, BP and BV rises, K+ excreted
6) kidneys signaled to reduce renin release

Question 3

What are the 2 different mechanisms of action of glucocorticoids?

Answer 3

1) Slow metabolism - changes gene expression
- binds to GR, turns genes on and off
2) Fast metabolism - no gene transcription
- interact with pathways, quick exchange

Question 4

What are the physiologic effects of glucocorticoids? (4)

Answer 4

1) Liver
- inc gluconeogenesis + glycogen storage
2) Muscle
- promote protein degradation
- dec protein synthesis + sensitivity to insulin
3) Adipose Tissue
- promote lipolysis
- dec sensitivity to insulin
4) Immune system
- block cytokine synthesis -> immunosup
- inhibit eicosanoid production -> anti-inflam

Question 5

Addison’s Disease

Answer 5

• hypoadrenalism
• dec secretion of steroid hormones
• cessation of long-term glucocorticoid therapy can lead to sx

Question 6

What are the causes of Addison’s Disease? (2)

Answer 6

1) destruction of cortex by tuberculosis or atrophy *primary
2) dec secretion of ACTH due to anterior pituitary diseases **NO HYPOALDOSTERISM

Question 7

What are the sx associated with Addison’s disease? (5)

Answer 7

• extreme weakness
• anorexia, anemia, N/V
• low BP *primary only
• hyperpigmentation *primary only
• depression

Question 8

Cushing’s Disease

Answer 8

• hyperadrenalism
• long term therapeutic use of systemic glucocorticoids can lead to sx

Question 9

What are the causes of Cushing’s Disease? (3)

Answer 9

1) tumors in adrenal cortex
2) increased ACTH production due to pituitary carcinoma
3) ectopic production of ACTH

Question 10

What are the sx of Cushing’s Disease? (4)

Answer 10

• weight gain, thing arms + legs, moon face
• inc protein catabolism (easy bruising, delayed wound healing, muscle wasting) and inc glucose levels
• osteoporosis
• opportunistic infections

Question 11

What are the 6 synthetic glucocorticoids?

Answer 11

• fludrocortisone
• prednisone/prednisolone
• methylprednisolone
• triamcinolone
• dexamethasone
• betamethasone

Question 12

Fludrocortisone

Answer 12

• 9a-F
• greater glucocorticoid activity
• strong mineralocorticoid activity (intense NA+ retention leading to edema)
• used in mineralocorticoid replacement therapy

Question 13

Prednisone/prednisolone

Answer 13

• extra double bond between C1 and 2
• more potent glucocorticoid activity
• reduced mineralocorticoid activity
• interconvertible by 11B-hydroxysteroid dehydrogenase

Question 14

Methylprednisolone

Answer 14

• 6a-methyl group
• potency similar to prednisone
• reduced mineralocorticoid activity

Question 15

Triamcinolone

Answer 15

• 9a-F and 16a-OH
• glucocorticoid activity similar to prednisone
• reduced mineralocorticoid activity
• inc hydrophilicity
• low oral bioavailability

Question 16

Dexamethasone

Answer 16

• 16a-methyl group
• increased lipophilicity (inc receptor binding = stronger effect)
• inc stability in human plasma
• reduced mineralocorticoid activity

Question 17

Betamethasone

Answer 17

• stereoisomer of dexamethasone at 16
• similar properties to dexamethasone

Question 18

21-esters (4)

Answer 18

Acetate (-COCH3)/ Butyrate (-COC3H7)
- inc lipophil, prolonged action in IM
Succinate (-COCH2CH2COO-)
- soluble, slow hydrolysis (30-45 min)
Phosphate (-PO2-)
- increased solubility, rapid hydrolysis (~10 min)

Question 19

What are the properties of inhaled glucocorticoids? (5)

Answer 19

• high potency
• minimal systemic effects
• prolonged action (high lipophilicity)
• low oral bioavailability
• rapid clearance

Question 20

What are the 6 inhaled glucocorticoids?

Answer 20

• triamcinolone acetonide
• beclomethasone dipropionate
• flunisolide
• budesonide
• mometasone furoate
• fluticasone propionate

Question 21

What are the properties of topical glucocorticoids? (3+2 tips)

Answer 21

• high lipophilicity (fast absorption)
• minimal systemic effect
• prolonged action
  halogenated analogues (Cl) = very potent
  low potency = safest for chronic

Question 22

What are the 8 topical glucocorticoids?

Answer 22

Acetonide/ester groups
- Triamcinolone acetonide (high potent)
- Fluocinonide (high potent)
- Betamethasone valerate (med potency)
21-Cl
- Clobetasol propionate (very high pot)
- Halobetasol propionate (very high pot)
- Halcinoide (high potency)
Weak
- Fluticasone propionate (med pot)
- Mometasone furoate (med pot)

Question 23

How much more potent is Triamcinolone Acetonide than Prednisolone?

Answer 23

8x

Question 24

How much more potent is Beclomethasone dipropionate than Dexamethasone?

Answer 24

14x

Question 25

Flunisolide

Answer 25

- rapid abs from nasal + lungs - rapid metabolism by liver (min systemic/high first pass)

Question 26

Budesonide

Answer 26

- faster topical uptake - extensive first pass metabolism

Question 27

Mometasone furoate

Answer 27

- highly potent - more rapid onset - rapid metabolism/low oral bioavailability

Question 28

Fluticasone propionate

Answer 28

- inactivated by hydrolysis of thioester - highly lipophilic + insoluble