CH 39 Table: Corticosteroids & Antagonists

Primary endogenous glucocorticoid hormone?

cortisol

Glucocorticoid agonist?

Prednisone

What is the MOA of Prednisone?

activation of glucocorticoid receptor alters gene transcription

Clinical applications of Glucocorticoid agonists?

1. many inflammatory conditions

2. organ transplantation

3. hematologic cancers

Pharmacokinetics of glucocorticoid agonists?

duration of activity is longer than pharmacokinetic half-life of drug owing to gene transcription effects

Toxicities/Drug Interactions of glucocorticoid agonists?

1. adrenal suppression

2. growth inhibition

3. muscle wasting

4. osteoporosis

5. salt retention

6. glucose intolerance

7. behavioral changes

Mineralocorticoid agonist?

Fludrocortisone

MOA of Fludrocortisone?

1. strong agonist at mineralocorticoid receptors

2. moderate activation of glucocorticoid receptors

Clinical applications of mineralocorticoid agonists?

adrenal insufficiency (Addison's disease)

Pharmacokinetics of Mineralocorticoid agonists?

long duration of action

Toxicities/drug Ix of mineralocorticoid agonists?

1. salt & fluid retention

2. CHF

3. signs & symptoms of glucocorticoid excess

Glucocorticoid receptor antagonist?

Mifepristone

MOA of Mifepristone?

1. antagonist of glucocorticoid receptors

2. antagonist of progesterone receptors

Clinical applications of glucocorticoid receptor antagonists?

1. medical abortion

2. Cushing's syndrome (rare)

Pharmacokinetics of glucocorticoid receptor antagonists?

oral administration

Toxicities/Drug Ix of glucocorticoid receptor antagonists?

1. vaginal bleeding in women

2. abdominal pain

3. GI upset

4. diarrhea

5. headache

Mineralocorticoid receptor antagonists?

1. Spironolactone

2. Eplerenone

MOA of Spironolactone/Eplerenone?

1. pharmacological antagonist of mineralocorticoid receptor

2. weak antagonism of androgen receptors

More selective for mineralocorticoid receptor?

Eplerenone

Clinical applications of Mineralocorticoid receptor antagonists?

1. aldosteronism from any cause

2. hypokalemia due to other diuretics

3. post-myocardial infarction

Pharmacokinetics of Mineralocorticoid receptor antagonists?

1. slow onset & offset effect

2. duration: 24-48 hours

Toxicities/Drug Ix of Mineralocorticoid receptor antagonists?

1. hyperkalemia

2. gynecomastia (spironolactone)

3. additive interaction with other K-retaining drugs

Adrenocorticosteroid synthesis inhibitors?

1. Ketoconazole

2. Aminoglutethimide

3. Metyrapone

4. Etomidate

MOA of Ketoconazole/other Adrenocorticosteroid synthesis inhibitors?

blocks fungal & mammalian CYP450 enzymes

Clinical applications of Adrenocorticosteroid synthesis inhibitors?

1. inhibits mammalian steroid hormone synthesis

2. inhibits fungal ergosterol synthesis

Pharmacokinetics of Adrenocorticosteroid synthesis inhibitors?

1. oral administration

2. topical administration

Toxicities/Drug Ix of Adrenocorticosteroid synthesis inhibitors?

1. hepatic dysfunction

2. many drug-drug CYP450 interactions