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Flashcards in adrenal pharmacology Deck (33):

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

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


Effects of aldosterone and consequences of excess

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


Antiinflammatory actions of glucocorticoids

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


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

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


List adrenocorticoid agents and their relative mineralcorticoid and glucocorticoid action

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


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

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


Inactivation of glucocorticoids

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


Activation of glucocorticoids

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


Glucocorticoids in the fetus

•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


Prednisone topical activity

none- Prednisone is inactive until hepatic conversion to prednisolone


Treatment of chronic adrenal insufficiency (Addisons dz)

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


Treatment of acute Addisons dz

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


Treatment of aldosterone producing adenoma

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


Treatment of idiopathic hyperaldosteronism

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


compare Ca channel blockers used for idiopathic hyperaldosteronism

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.


Treatment of Cushings Syndrome

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


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

early: mitotane, ketoconazole. Late: metyrapone.


ketoconazole MOA and adverse rxns

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


Metyrapone MOA and adverse rxns

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


Mifepristone uses

Approved to control hyperglycemia secondary to Cushings.


Pheochromocytoma treatment

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


List alpha blockers used in pheochromocytoma and their selectivities

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


List beta blockers used in pheochromocytoma and selectivities

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


List Ca channel blockers used in pheochromocytoma



MOA of Metyrosine

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


Why should you avoid beta blockers before alpha blockers in pheochromocytoma

Block of B2 mediated vasodilation will result in severe HTN


Congenital adrenal hyperplasia

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


Congenital adrenal hyperplasia treatment

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


Dosing of glucocorticoids for anti-inflammatory use

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.


Glucocorticoid administration

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


Possible side effects of acute systemic steroid use

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


Side effects of high dose sustained steroid use

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


Side effects of large cumulative doses of steroids

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