Adrenocortical Steroids and Antagonists Quiz

Adrenocortical Steroids and Antagonists

• Glucocorticoids: Key function is regulating metabolism, especially glucose. Cortisol is a primary example. Also involved in immune function.
• Mineralocorticoids: Aldosterone is the main mineralocorticoid, responsible for salt and water retention.
• Weak Androgens and Estrogens: Dehydroepiandrosterone (DHEA), androstenedione, and androstenediol are weak androgens and androstenedione can be converted into testosterone and then estradiol. DHEA is a major source of estrogen in post-menopausal females.

Steroid Synthesis Pathway

• Cholesterol is the precursor for all steroid hormones.
• Enzymes like desmolase, 17α-hydroxylase, 21-hydroxylase, and 11β-hydroxylase catalyze various steps in the conversion to different steroid hormones like pregnenolone, progesterone, deoxycorticosterone, corticosterone, cortisol, and aldosterone.
• Androstenedione is also a product in the pathway.

Cortisol (Hydrocortisone)

• Involved in metabolic effects like growth, cardiovascular function, and immunity.
• Cortisol levels are tightly regulated through a negative feedback mechanism.
• Secretion follows a circadian rhythm, peaking in the morning and lowering at night.
• Bound to corticosteroid-binding globulin (CBG) in the blood.
• CBG levels are influenced by pregnancy, estrogen administration, and hyperthyroidism.

Cortisol - Diurnal Trend

• Cortisol levels in saliva exhibit a typical diurnal pattern.
• Levels are highest shortly after waking up and decline throughout the day.

Mechanism of Glucocorticoid Action

• Glucocorticoid receptors (GR) are primarily intracellular.
• They are activated by binding to cortisol and dimerize.
• Enter the nucleus and regulate gene expression.
• Influence various metabolic processes.

Metabolic Effects of Glucocorticoids

• Carbohydrate Metabolism: Gluconeogenesis, glycogenolysis, elevating blood glucose.
• Protein Metabolism: Muscle breakdown, reduced protein synthesis.
• Fat Metabolism: Stimulation of lipolysis and fat redistribution.

Important Roles of Glucocorticoids

• Stress Response: Important in the stress response, maintaining adequate glucose supply to the brain and heart.
• Surfactant Production: Critical for near-term babies to support lung function.

Immune System Effects

• Powerful anti-inflammatory effects: Reduce leukocyte and other immune cell activity.
• Reduce prostaglandins and leukotrienes, impacting inflammatory responses.
• Inhibit histamine release from basophils, reducing capillary permeability.

Nervous System Effects

• Central Nervous System: Insomnia, euphoria, and depression, especially with chronic use.

High-Dose Effects

• Peptic Ulcer Disease (PUD): Possible ulcer development due to reducing protection from stomach acid.
• Fat Distribution: Abnormal fat distribution, potential for increased appetite.
• Vitamin D Metabolism: Inhibition of vitamin D-mediated calcium absorption.

Uses and Indications of Adrenocortical Agents

• Diagnosis and treatment of disturbed adrenal function: Essential in Addison's disease (chronic insufficiency), and congenital adrenal hyperplasia.
• Stress Response: Increase doses during stressful periods (trauma, infections).
• Congenital Adrenal Hyperplasia: Treatment of hormonal imbalances.
• Cushing's Syndrome: Used in cases of tumor-related hypercortisolism.

Glucocorticoid Resistance

• Can affect fetus lung maturation, in situations like premature deliveries.
• Cause arthritis like conditions in bones and joints and various GI conditions.
• Related to various other autoimmune diseases.

Dosage Forms and Pharmacokinetics of Glucocorticoids

• Available through oral, topical, intravenous, intramuscular, inhalation, and nasal routes.
• Demonstrates good oral bioavailability and is often highly bound to plasma proteins.
• Metabolized predominantly in the liver and excreted by the kidneys, mostly in conjugated forms.

Synthetic Glucocorticoids

• Medium to Short Acting: examples include Hydrocortisone (Cortef), Cortisone (Cortone).
• Intermediate Acting: examples include Triamcinolone (Aristocort), and others.
• Long Acting: examples include Betamethasone (Diprosone) and Dexamethasone (Maxidex).

Locally Acting Agents (for asthma)

• Typically inhaled corticosteroids that are designed for localized action in respiratory system conditions.
• Examples include Beclomethasone, Budesonide, Ciclesonide, Flunisolide, Fluticasone, and others.

Adverse Effects of Glucocorticoids

• Cushing's syndrome (excessive cortisol).
• Increased blood glucose and blood pressure.
• Muscle weakness and wasting.
• Abnormal fat distribution.
• Thinning skin.
• Reduced wound healing.
• Increased susceptibility to infection.
• Osteoporosis.
• Adrenal suppression.

Contraindications

• Peptic ulcer disease (PUD).
• Hypertension (HTN).
• Heart failure.
• Infections.
• Psychosis.
• Diabetes mellitus.
• Osteoporosis.
• Glaucoma.

Mineralocorticoids

• Aldosterone. Primary regulator of salt and water balance; promotes sodium reabsorption and potassium excretion in the kidneys.
• Deoxycorticosterone. Another mineralocorticoid.
• Fludrocortisone. Synthetic mineralocorticoid; often used in Addison's disease to treat mineralocorticoid deficiency.

Mineralocorticoid Receptor Antagonists

• Spironolactone and Eplerenone. Block aldosterone receptors to reduce sodium retention and promote potassium excretion.

Adrenocortical Synthesis Inhibitors

• Aminoglutethimide (Cytadren). Blocks conversion from cholesterol to pregnenolone.
• Ketoconazole. Inhibits synthesis of most adrenocortical steroids.
• Abiraterone. Inhibits steroidogenesis, preventing the production of cortisol and other related hormones.

Mifepristone (Korlym, RU-486)

• GR antagonist and progesterone receptor antagonist. Used for hyperglycemia in Cushing's syndrome and, controversially, for pregnancy termination. Teratogenic.