adrenal pharmacology

Question 1

Metabolic effects of glucocorticoids on carbs, protein, fat and the consequence of excess cortisol

Answer 1

Carbs: increased gluconeogenesis and increased blood glucose. Excess causes diabetes like state. Protein: decreased protein synthesis and increased conversion of aa to glucose. Excess causes muscle wasting, skin-CT atrophy. Fat: increased peripheral lipolysis and increased free fatty acids. Excess causes lipogenesis (via insulin) and central obesity

Question 2

Effects of aldosterone and consequences of excess

Answer 2

Increase Na reabsorption at kidney leading to increased blood volume and BP. Excess causes fluid retention, hypertension and hypokalemia

Question 3

Antiinflammatory actions of glucocorticoids

Answer 3

GC block T cell activation, cytokine production, mast cell mediator release and eosinophil mediator release. Also blocks COX-1, COX-2 preventing formation of prostaglandins and blocks phospholipase A2 from developing arachidonic acid

Question 4

discuss separation of mineralcorticoid, glucocorticoid and anti-inflammatory properties of adrenocorticoid agents

Answer 4

Can separate MC actions from GCC actions ( dexamethasone) but can NOT separate anti-inflammatory from GCC actions

Question 5

List adrenocorticoid agents and their relative mineralcorticoid and glucocorticoid action

Answer 5

Cortisol- GC: MC. Prednisone- 4 GC : 0.3 MC. Dexamethasone- 30GC : 0 MC. Fludrocortisone- 10 GC: 125-250 MC

Question 6

2. Discuss the structure-activity relationship of the following adrenocorticosteroids: hydrocortisone (Solu-Cortef®), prednisone-prednisolone, Dexamethasone (Decadron®), and fludrocortisone (Florinef®).

Answer 6

1. hydrocortisone: 11-keto form is inactive. 2. Prednisone: 11-keto form is inactive. 3. Prednisolone: C1-C2 double bond increases anti-inflammatory/glucocorticoid actions. 4. Dexamethasone: C16 methyl group eliminates mineralcorticoid activity. 5. Fludrocortisone: C9 fluoro group increases mineralcorticoid activity

Question 7

Inactivation of glucocorticoids

Answer 7

1. liver- inactivation via conjugation to glucuronide. 2. Kidney- 11B-hydroxysteroid dehydrogenase II converts cortisol to cortisone (inactive)

Question 8

Activation of glucocorticoids

Answer 8

In liver, 11-B-hydroxysteroid dehydrogenase I can convert cortisone back to cortisol

Question 9

Glucocorticoids in the fetus

Answer 9

•Placental 11b-HSD2 is active, but not 11b-HSD1 as fetal liver is not functional, so you can treat mother with GCs without affecting the fetus. The placental enzyme can convert the active drug back to prodrug (ie. prednisolone to prednisone). To treat fetus with GCs, can use betamethasone which is a poor substrate for 11B-HSDII

Question 10

Prednisone topical activity

Answer 10

none- Prednisone is inactive until hepatic conversion to prednisolone

Question 11

Treatment of chronic adrenal insufficiency (Addisons dz)

Answer 11

1. glucocorticoid replacement: oral hydrocortisone to mimic diurnal rhythm, or long acting dexamethasone or prednisone. 2. mineralocorticoid replacement: fludrocortisone if needed 3. DHEA replacement in women for mood and well being

Question 12

Treatment of acute Addisons dz

Answer 12

During acute attack- adrenal crisis: electrolyte abnormalities (hyponatremia and hyperkalemia) and plasma volume depletion. 1. saline to replenish volume. 2. IV hydrocortisone (large amounts) if previously diagnosed. 3. Dexamethasone if NOT previously diagnosed
During acute attack- adrenal crisis: electrolyte abnormalities (hyponatremia and hyperkalemia) and plasma volume depletion. 1. saline to replenish volume. 2. IV hydrocortisone (large amounts) if previously diagnosed. 3. Dexamethasone if NOT previously diagnosed
During acute attack- adrenal crisis: electrolyte abnormalities (hyponatremia and hyperkalemia) and plasma volume depletion. 1. saline to replenish volume. 2. IV hydrocortisone (large amounts) if previously diagnosed. 3. Dexamethasone if NOT previously diagnosed

Question 13

Treatment of aldosterone producing adenoma

Answer 13

1. preoperative aldosterone antagonists (spironolactone and eplerenone). 2. Adrenalectomy

Question 14

Treatment of idiopathic hyperaldosteronism

Answer 14

1. Aldosterone antagonists (spironolactone, eplerenone). 2. PLUS BP meds (ca channel blocker, ACEI, ARB). Goal is to normalize hypokalemia and BP

Question 15

compare Ca channel blockers used for idiopathic hyperaldosteronism

Answer 15

The dihydropyridines (nifedipine) have greater ratio of vascular (dilation) to cardiac (rate-conduction-contractility) effects. Verapamil and diltiazem have prominent effects at cardiac nodal tissue and cardiac muscle in addition to vascular dilation.

Question 16

Treatment of Cushings Syndrome

Answer 16

1. Surgery. 2. ACTH secretion inhibitors: Cabergoline, Pasireotide. 3. Cortisol synthesis inhibitors: Ketoconazole, Metyrapone, Etomidate. 4. Adrenolytic agents: mitotane. 5. Cortisol receptor blockers: mifepristone

Question 17

Which cortisol synthesis inhibitors affect early vs late steps in steroid biosynthesis

Answer 17

early: mitotane, ketoconazole. Late: metyrapone.

Question 18

ketoconazole MOA and adverse rxns

Answer 18

Inhibits desmolase. SE: headache, n/v, gynecomastia-impotence, reversible hepatotoxicity

Question 19

Metyrapone MOA and adverse rxns

Answer 19

Used as an add on to ketoconazole. Inhibits 11B-hydroxylase and can increase adrenal androgen production. SE: hirsutism in women, Na retention and HTN

Question 20

Mifepristone uses

Answer 20

Approved to control hyperglycemia secondary to Cushings.

Question 21

Pheochromocytoma treatment

Answer 21

1. pre-operative: alpha blocker first (vasodilation) then beta blocker (rate control), OR Ca channel blocker. 2. Adrenalectomy. 3. If inoperable, Metyrosine

Question 22

List alpha blockers used in pheochromocytoma and their selectivities

Answer 22

Phenoxybenzamine (irreversible a1-a2 antagonist), prazosin, terazosin (reversible a1 antagonist), doxazosin (reversible a1 antagonist).

Question 23

List beta blockers used in pheochromocytoma and selectivities

Answer 23

Metoprolol (B1 blocker). Labetalol (a1-B1-B2 blocker)

Question 24

List Ca channel blockers used in pheochromocytoma

Answer 24

Nicardipine

Question 25

MOA of Metyrosine

Answer 25

Catecholamine synthesis inhibitor- inhibits rate limiting enzyme for NE-epi synthesis (tyrosine hydroxylase)

Question 26

Why should you avoid beta blockers before alpha blockers in pheochromocytoma

Answer 26

Block of B2 mediated vasodilation will result in severe HTN

Question 27

Congenital adrenal hyperplasia

Answer 27

Incrased ACTH due to loss of feedback inhibition leads to adrenal hyperplasia and diminished cortisol synthesis. Mineralcorticoids and androgens may be decreased OR elevated

Question 28

Congenital adrenal hyperplasia treatment

Answer 28

1. Replace deficient steroids (GC +/-MC). 2. Minimize excess androgen production. 3. Avoid GC excess

Question 29

Dosing of glucocorticoids for anti-inflammatory use

Answer 29

1. large dose with shorter acting agent and less MC activity. 2. alternate day schedule to minimize adrenal suppression. 3. terminate gradually over 7-28 days.

Question 30

Glucocorticoid administration

Answer 30

1. oral- used when systemic actions desired. Also IV or IM used for this purpose. 2. topical: systemic effects are possible if potent steroids used for long periods, occlusive dressing or used on large areas. 3. ophthalmic. 4. Intra-articular: RA. 5. Enemas: ulcerative colitis. 6. inhalants: asthma- decreased systemic effects. 7. nasal sprays- allergic rhinitis

Question 31

Possible side effects of acute systemic steroid use

Answer 31

1. Mineralocorticoid effects: Salt and water retention > edema > increased blood pressure, hypokalemia. 2. Glucocorticoid effects: Glucose intolerance in diabetics, mood changes (up or down), insomnia, GI upset

Question 32

Side effects of high dose sustained steroid use

Answer 32

1. iatrogenic Cushings: hyperglycemia, protein wasting, weight gain, diabetes like state. 2. hypo-pituitary-adrenal axis suppression. 3. Mood disturbance. 4. impaired wound healing. 5. susceptibility to infection

Question 33

Side effects of large cumulative doses of steroids

Answer 33

1. osteoporosis. 2. posterior capsular cataracts- esp prolonged asthma treatment. 3. skin atrophy. 4. growth retardation in kids. 5. peptic ulceration