Pharmacology - Adrenal Glands

1. Terminology
a. Corticosteroid refers to both glucocorticoids and
mineralocorticoids
b. Glucocorticoid - Class of steroid hormone characterized by
the ability to bind w/ glucocorticoid receptor and trigger
glucose metabolism
c. Mineralocorticoid - Class of steroid hormones characterized
by their similarity to aldosterone and their influence on Na+
and water balance
d. Cosyntropin Stimulation Test
i. Cosyntropin = Synthetic ACTH used to assess for
adrenal insufficiency
ii. If peak cortisol is >18 → not adrenal insufficient
iii. If peak cortisol is <18 → Adrenal Insufficiency
2. Glucocorticoids
a. Mechanism of Action
i. Bind to cytosolic glucocorticoid receptor → receptor translocates into nucleus + binds to
Glucocorticoid Response Elements (GRE) → transactivation or transrepression (via AP-1 or NF-kB)
1. Note: aldosterone and cortisol have similar affinity to mineralocorticoid R in kidney.
a. Glucocorticoids circulate at 100x levels of mineralocorticoids
b. 11-β hydroxysteroid DH metabolizes glucocorticoids – prevents overstimulation
c. Chronic consumption of inhibitor (licorice)  pseudohyperaldosteronism
ii. Stimulates gluconeogenesis, mobilizes amino acids from extrahepatic tissues, inhibits glucose
uptake in muscle + adipose tissue (insulin resistance), stimulates fat breakdown in adipose
iii. Main goal: maintain normal concentrations of glucose in the blood in the fasted state
b. Pharmacology
i. Natural and synthetic glucocorticoids can be used for both endocrine and non-endocrine disorders
1. In endocrine practice:
a. Establish the diagnosis and cause of Cushing's syndrome (dexamethasone)
b. For treatment of adrenal insufficiency and congenital adrenal hyperplasia
2. Others: inflammatory, allergic, immunological disorders, organ transplant etc.
ii. All have same chemical skeleton but different side chains and different effects on the body
iii. Short-to-Medium Acting: Hydrocortisone (Cortisol), Cortisone, Prednisone
1. Anti-inflammatory: cortisol (minimal)  prednisolone, methylprednisolone (most)
2. Salt-retaining: methylprednisolone (least)  cortisol (most)
c. Side Effects
i. All forms of steroid absorbed to some extent → can suppress H-P-A axis
1. Atrophy of hypothalamic and pituitary cells  decreased CRH and ACTH
2. Likely:
a. >20 mg prednisone/day for >3wks
b. In anyone with bedtime or evening dose for >3wks
c. Patient with cushingoid appearance
3. Unlikely: any dose for <3wks or patients on alternate day steroid dose
4. Intermediate group - 10-20mg of prednisone/day for more >3 weeks
a. Do not need testing unless therapy must be discontinued or patient has acute
stress (e.g. surgery)
ii. Iatrogenic Cushing’s (most to least common)– obesity (90%), high BP (85%), impotence and
decreased libido (85%), neuropsych (85%), thin bones, menstrual pain, weakness, purple striae
iii. Chronic oral therapy should not be stopped abruptly (ACTH suppression) + must taper
1. Relatively high doses can be used for short periods of time w/o adrenal suppression
a. Rationale behind “medrol dose-packs”— 7 days of steroids, tapering off to 1 pill
b. For chronic use, alternate day oral therapy is sometimes employed when possible
iv. Others: hyperglycemia, fat shifts, muscle wasting, weakening of bones and osteoporosis, Na +
retention, edema, HTN, psychosis, ulcers, cataracts, immune system
v. Absorption of topically administered glucocorticoids varies depending on the area of the body,
contents of vehicle, inflammation/desquamation, and age
d. Goal of Glucocorticoid Tx - Obtain maximal benefit with minimal adverse SE (exercise, Ca 2+, Vit D,
bisphosphonates and estrogen treatment in postmenopausal women can decrease side effects)
3. Mineralocorticoids - Fludrocortisone
a. Mechanism of Action
i. Involved in retention of Na+ - primary endogenous mineralocorticoid is aldosterone
ii. Act on the distal tubules of the kidney→ enhance reabsorption of Na+ ions from tubular fluid→
increase urinary excretion of both K+ and H+ ions
iii. Increased blood pressure
b. Adverse Effects: Edema, HTN, hypokalemia
c. Monitoring: limit Na+ intake, check lying + standing BP (also pulse, edema, serum K+, and plasma renin)
i. Renin is used to measure fludrocortisone efficacy
d. Clinical Use
i. Replacement therapy for Primary Adrenal Insufficiency
ii. Salt-losing Adrenogenital Syndrome
iii. Idiopathic orthostatic hypotension
iv. Hypoaldosteronism
4. Adrenal Androgens – DHEA-S
a. Mechanism of Action: Major source of androgens for women (men get androgens from testicles)
b. Clinical Use: Limited effect in women who have Primary Adrenal Insufficiency who are still not feeling
better (libido) after optimizing glucocorticoids and mineralocorticoids
c. Adverse Effects: none
5. Overall: Treatment of Adrenal Insufficiency
a. Use smallest doses possible
b. Hydrocortisone (AM and PM) or Prednisone (once/day)
i. During stress or illness, dose should be doubled or tripled
c. Add a mineralocorticoid (fludrocortisone) daily in pts with Primary Adrenal Insufficiency
i. Not necessary for Secondary Adrenal Insufficiency
ii. Monitor BP and Renin
d. Add DHEA for patients
e. Patient education is key
i. Can deteriorate acutely (esp. Primary Adrenal Insufficiency): educate patient about the disease,
how to manage minor illnesses and major stresses and how to inject dexamethasone IM
ii. Emergency precautions - Medic-Alert bracelet, medical information card
iii. Prefilled syringes hydrocortisone or dexamethasone
6. Cushing’s: Symptoms of EXCESS Cortisol
a. Indications:
i. When surgery is contraindicated
ii. Control hypercortisolism in preparation for surgery or while waiting for effect of pituitary
radiation (ACTH-Dependent Pituitary Cushing's)
iii. Persistence or recurrence of hypercortisolism after surgery
iv. Treatment of ectopic ACTH syndrome
b. Mitotane
i. Mechanism of Action
1. Adrenocorticolytic drug – medical adrenalectomy during or after pituitary irradiation and
inhibits cortisol synthesis (11-β hydroxylase, cholesterol side-chain cleavage)
2. Spares zona glomerulosa
ii. Side Effects
1. Highly toxic: Nausea, vomiting, anorexia, diarrhea, rash, gynecomastia, ataxia, arthralgias,
leukopenia, hypercholesterolemia, hepatotoxicity
2. Start with low dose at bedtime and add additional doses at meals as tolerated
iii. Clinical use: Reserved for Adrenal Carcinoma because of toxicity (but can be used for Cushings)
c. Ketoconazole
i. Mechanism of Action - azole derived antifungal that inhibits first step in cortisol biosynthesis
(cholesterol desmolase) + inhibits ACTH and testosterone production.
ii. Pharmacokinetics
1. Doses used to treat Cushings are MUCH higher than those for fungal infections
2. Must monitor urinary cortisol levels→ adjust dose as needed
iii. Side Effects
1. Headache, sedation, nausea, vomiting, gynecomastia, decreased libido and impotence
2. Reversible Hepatotoxicity → must monitor liver function
iv. Clinical Uses - First line for Cushings
d. Metyrapone - Inhibits 11-B-hydroxylase
 e. Etomidate - Imidazole derivative used to sedate pts on mechanical ventilation that inhibits adrenal
enzymes involved in cortisol synthesis - not widely used
f. Pasireotide
i. Mechanism of Action
1. Somatostatin analog: binds to somatostatin receptors → blocks release of ACTH from
corticotrophs in pituitary or pituitary corticotroph tumor
2. SubQ injection 2x/day → Reduces mean 24h cortisol by 48%
ii. Side Effect - Severe hyperglycemia
g. Mifepristone
i. Mechanism of Action:
1. Anti-progesterone receptor drug - antagonizes glucocorticoid receptors → decreases
excess cortisol symptoms and blocks exogenous glucocorticoids
2. If adrenal Insufficiency were to develop, cortisol does not help
ii. Clinical Use - Not widely used
1. Control hyperglycemia secondary to hypercortisolism in adults w/ endogenous Cushing’s
2. T2DM or glucose intolerance who have failed surgery or are not candidates for surgery
7. Medical Management of Hyperaldosteronism
a. Symptoms: Low renin + hypokalemia and hypernatremia + HTN
b. Aldosterone Antagonists are treatment of choice
i. Spironolactone
1. MOA: Aldosterone + progesterone + androgen receptor antagonist
2. Side Effects
a. Men: gynecomastia, impotence, decreased libido
b. Women: breast tenderness and menstrual irregularities
3. Clinical Use
a. PCOS in women
b. Hyperaldosteronism
ii. Eplerenone: Highly selective mineralocorticoid receptor antagonist. No sex hormone effects.
8. Medical Management of Pheochromocytoma and Paraganglioma
a. Combined α- and β blockade→ control BP and prevent intraoperative hypertensive crises
i. 10 to 14 days preoperatively:
1. α-adrenergic blocker – normalize BP and expand the contracted blood volume
2. Phenoxybenzamine: preferred drug for preoperative preparation to control BP and
arrhythmia - irreversible, long-acting, nonspecific alpha-adrenergic blocking agent
ii. 2nd or 3rd day day of alpha-adrenergic blockade:
1. Patients encouraged to start high sodium diet (>5000 mg daily) bc of catecholamine-
induced volume contraction and the orthostasis associated with alpha-adrenergic blockade
2. May be contraindicated in patients with congestive heart failure or renal insufficiency
iii. After α-adrenergic blockade achieved (typically 2-3 days preoperatively):
1. β-adrenergic blockade is initiated
2. β blocker should never be started first - blockade of vasodilatory peripheral β-adrenergic
receptors with unopposed α-adrenergic receptor stimulation  elevation in BP
iv. Although perioperative alpha-adrenergic blockade is widely recommended, a second regimen that
has been utilized involves the administration of a calcium channel blocker
b. Metyrosine
i. MOA: Inhibits
catecholamine synthesis –
may provide smoother
pre-op course compared to
patients who just received
phenoxybenzamine alone
ii. Side Effects: Sedation,
depression, diarrhea,
anxiety, nightmares,
crystalluria, urolithiasis,
galactorrhea