Steroid Pharmacology

Question 1

What are the major metabolic effects of glucocorticoids? What about effects on immune functioning? Does cortisol have mineralocorticoid effects? Given that cortisol binds the aldosterone receptor (AR) with the same affinity as aldosterone, and that cortisol levels are nearly 2000X greater than than those of aldosterone, how does aldosterone ever exert tissue specific effects?

Answer 1

Increase gluconeogenesis, Release amino acids (for glucose production) through muscle catabolism, Inhibit peripheral glucose uptake, Stimulate lipolysis –> All to increase blood glucose levels, especially to maintain adequate glucose supply to the brain under situations of stress. Glucocorticoids have potent anti-inflammatory and immunosuppressive effects. Cortisol has weak mineralocorticoid effects. In aldosterone-responsive cells, cortisol binding to AR prevented by 11B-hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone, which has no affinity for AR.

Question 2

What is the MOA of glucocorticoids? What are the general uses? What are important side effects?

Answer 2

Glucocorticoids: Binds GR, which regulates expression of genes with many effects on carbohydrate metabolism and immune function. Uses: Establish diagnosis and cause of Cushing’s, treat adrenal insufficiency and CAH, treat inflammatory/allergic/immunoloical disorders in supraphysiological doses. Side effects: Cushing’s, glucocorticoid-induced osteoporosis, iatrogenic adrenal insufficiency.

Question 3

Cortisol

Answer 3

RelAnti-Inflam: 1; RelMin: 1; DoA: 8- 12 hours

Question 4

Cortisone acetate

Answer 4

RelAnti-Inflam: 0.8; RelMin: 0.8; DoA: 8-12 hours

Question 5

Hydrocortisone

Answer 5

RelAnti-Inflam: 1; RelMin: 1; DoA: 8- 12 hours

Question 6

Prednisone

Answer 6

RelAnti-Inflam: 4; RelMin: 0.8; DoA: 12-36 hours; 1/4 dose of cortisol

Question 7

Prednisolone

Answer 7

RelAnti-Inflam: 4; RelMin: 0.8; DoA: 12-36 hours; 1/4 dose of cortisol

Question 8

Methylprednisolone

Answer 8

RelAnti-Inflam: 5; RelMin: 0.5; DoA: 12-36 hours; 1/5 dose of cortisol

Question 9

Triamcinolone

Answer 9

RelAnti-Inflam: 5; RelMin: 0; DoA: 12-36 hours; 1/5 dose of cortisol

Question 10

Dexamethasone

Answer 10

RelAnti-Inflam: 30; RelMin: 0; DoA: 8-12 hours; <1/20 dose of cortisol

Question 11

What is the only synthetic mineralocorticoid? MOA? Use? Side effects? Give “stats.”

Answer 11

Fludrocortisone: Binds aldosterone receptor (AR) which increases Na+K+ATPase expression and increase epithelial sodium channel expression. Use: Chronic primary adrenal insufficiency (maintenance), CAH. Side effects: Primary aldosteronism. RelAnti-Inflam: 10; RelMin: 125; DoA: 12-36 hours, very small dose.

Question 12

How is Cushing’s Syndrome diagnosed?

Answer 12

ACTH, 24-hr urine free cortisol excretion, low-dose (1mg) overnight dexamethasone suppression test (<1.8-5 normal), midnight salivary cortisol level (cortisol value over 2.0 ng/dL). Diagnosis requires that at least two of these tests are positive. Also – High ACTH and High Cortisol: ACTH dependent process. Low ACTH and High Cortisol: ACTH independent process.

Question 13

How is Cushing’s Syndrome treated? For each drug, give MOA & side effects if given.

Answer 13

Aminoglutethide: Blocks conversion of cholesterol to pregnenolone. Ketoconazole: Anti-fungal imidazole derivitive – Potent, nonselective inhibitor of adrenal and gonadal steroid synthesis. Mitotane: DDT insecticide
relative – Nonselective cytotoxic action on adrenal cortex, Very bad side effect profile. Metyrapone: Relatively selective inhibitor of 11- hydroxylation (interferes with cortisol and corticosterone synthesis). Metyrapone can be used diagnostically to test anterior pituitary (“Metyrapone Test” – ACTH & 11-DOC should rise in compensatory response to decreased cortisol and corticosterone). Mifepristone (RU-486): Progesterone receptor antagonist with glucocorticoid receptor antagonism at high concentrations (and will not bind to mineralocorticoid receptor). Also indicated to control hyperglycemia secondary to hypercortisolism and for rapid treatment of cortisol-induced psychosis. Side effects: Fatigue, nausea, headache, arthralgias, edema and endometrial thickening, adrenal insufficiency (so ACTH and cortisol cannot be used to measure efficacy or adrenal insufficiency, treat with withdrawal +/- high-dose dexamethasone), mod-severe hypokalemia (high levels not inactivated by 11B-HSD2). Pasireotide somatostatin analog: Specifically for Cushing’s disease. Binds to somatostatin receptor and blocks release of ACTH from corticotropes. Side effects: Hyperglycemia, GI problems.

Question 14

How can suspected adrenal insufficiency be confirmed?

Answer 14

Cosyntropin IV (synthetic ACTH): Normal response is cortisol > 18 ug/dl.

Question 15

How is chronic primary adrenal insufficiency treated? What if this individual has a minor febrile illness? Severe stress? Hospitalized illness or surgery?

Answer 15

Glucocorticoid replacement: “Classically,” Hydrocortisone 15-20 mg on awakening + 5-10 mg in early afternoon. Mineralocorticoid replacement: Fludricortisone 0.05-0.2 mg orally daily, Liberal salt intake, Monitor orthostatic BP, pulse, edema, serum K+ & renin. Minor Febrile Illness: Increase glucocorticoid dose 2-3X, do not increase mineralocorticoid. Severe stress: Inject prefilled dexamethasone (4mg) syringe IM. Hospital: Hydrocortisone 50 mg PO BID or IV (moderate), 100 mg IV Q8 (severe). Moderately stressful procedure: 100 mg IV right before. Major surgery: 100 mg IV before anestheia and then Q8 for first day.

Question 16

How is an adrenal crisis treated?

Answer 16

Patients require support with large amounts of IV fluids (0.9% NaCl solution or 50 g/L (5%) dextrose in 0.9% NaCl solution). 1 – 3 Liters in first 12-24 hours – Hypotonic saline will worsen hyponatremia!! Also: Give high-dose intravenous glucocorticoid – Dexamethasone 4mg IV every 12-24 hours if no previous dx of adrenal insufficiency, Hydrocortisone 100mg IV every 6 hrs until patient stable. Gradual tapering to maintenance dose.

Question 17

How is primary aldosteronism tested for? How is it treated?

Answer 17

Plasma aldosterone concentration. Plasma renin activity.
PAC/PRA ratio of >20ng/dL per ng/mL means further investigation required. 24-hr urine collection for aldosterone and sodium. Treatment: Spironolactone or Eplerenone (more specific, less antiandrogenic effects).

Question 18

How is CAH (late-onset) tested for? Treatment?

Answer 18

Increased response of plasma 17-hydroxyprogesterone to ACTH (cortrosyn) stimulation. (Cosyntropin stimulation test). Treatment: Steroids – usually dexamethasone, prednisone or hydrocortisone. In salt-wasting, need fludrocortisone as well. Treat whatever degree of glucocorticoid and mineralocorticoid deficiency exists.
Giving steroids suppresses ACTH production and reduces overproduction of androgens.

Question 19

What are acute side effects of corticosteroids? What happens in the long-run? How much is needed? Patients on long-term therapy should be assumed to have? What happens to these patients with abrupt withdrawal? Does this occur in the setting of normal cortisol levels? Again, what does this suggest? Can this happen during treated C’s syndrome? How can we avoid this?

Answer 19

Unusual to have serious adverse effects if used for less than 2 weeks. Acute side effects: Insomnia, Behavior changes (hypomania, acute psychosis). Acute peptic ulcers. Acute pancreatitis (rare, high dose). In the long-run, iatrogenic Cushing’s syndrome occurs, usually requiring at least 100 mg hydrocortisone or more for 2+ weeks. On long-term therapy, patients should be assumed to have adrenal suppression. With abrupt withdrawal: Glucocorticoid Withdrawal Syndrome – anorexia, nausea or vomiting, weight loss, lethargy, headache, fever, joint or muscle pain, postural hypotension. Can occur in setting of normal or even high plasma cortisol levels. Suggests glucocorticoid dependence. Can happen during withdrawal or in setting of treated Cushing’s Syndrome. To stop therapy and avoid withdrawal, must taper very slowly – can take 2-12 months for return of acceptable HPA axis function & another 6-9 months for fully normal function. During recovery from HPA suppression, hypothalamic pituitary function returns before adrenocortical function. Always remain concerned of an adrenal crisis.