adrenal pharmacology Flashcards
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
- Discuss the structure-activity relationship of the following adrenocorticosteroids: hydrocortisone (Solu-Cortef®), prednisone-prednisolone, Dexamethasone (Decadron®), and fludrocortisone (Florinef®).
- 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
- 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)
- 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
- preoperative aldosterone antagonists (spironolactone and eplerenone). 2. Adrenalectomy
Treatment of idiopathic hyperaldosteronism
- 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
- 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
- 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
Nicardipine
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
- Replace deficient steroids (GC +/-MC). 2. Minimize excess androgen production. 3. Avoid GC excess
Dosing of glucocorticoids for anti-inflammatory use
- 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
- 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
- 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
- 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
- osteoporosis. 2. posterior capsular cataracts- esp prolonged asthma treatment. 3. skin atrophy. 4. growth retardation in kids. 5. peptic ulceration
