:L 25-26

Short-to Medium-Acting Glucocorticoids

  1. Hydrocortisone (Cortaid®)

  2. Prednisone (Intensol®)

  3. Methylprednisolone (Medrol®)

Intermediate-Acting Glucocorticoids

  1. Triamcinolone (Nasacort®)

Long-Acting Glucocorticoids

  1. Dexamethasone (Baycadron®)

Glucocorticoid Synthesis Inhibitors and Antagonists

  1. Metyrapone (Metopirone®)

  2. Ketoconazole (Nizoral®) - Antifungal

Mineralocorticoids

Agonists

  1. Fludrocortisone

Mineralocorticoid Antagonists

  1. Spironolactone (Aldactone)

Pharmacodynamics and Pharmacokinetics of Adrenocorticosteroids

Regulation of Adrenocortical Hormone Secretion

  • The pituitary gland releases ACTH (adrenocorticotropic hormone), which is a small peptide cleaved from a larger protein called proopiomelanocortin (POMC).

  • There is a corticotropin-releasing hormone (CRH) released from the hypothalamus due to different stressors. This hormone reaches the pituitary through the portal system and triggers the release of ACTH.

  • Notably, there is a circadian rhythm present in ACTH secretion. This is part of the HPA axis (hypothalamic-pituitary-adrenal axis).

  • The adrenal cortex consists of three zones:

    • Glomerulosa – Produces Aldosterone (Mineralocorticoid)

    • Fasciculata - Produces Cortisol (Glucocorticoid)

    • Reticularis - Produces Androgens

  • The adrenal medulla produces Epinephrine.

Biosynthesis of Cortisol

  • When ACTH reaches the adrenals, it interacts with a receptor known as MCR2, which activates a signaling pathway.

  • In this pathway, cholesterol is metabolized in the mitochondria, which is crucial to remember due to the interaction with P450 enzymes.

  • The metabolic process proceeds as follows:

    • Cholesterol → Pregnenolone (rate-limiting step).

    • If processed in the Zona Glomerulosa, results in Aldosterone (mineralocorticoid pathway).

    • If processed in the Zona Fasciculata, results in Cortisol.

  • Glucocorticoids are metabolized in the liver and excreted in the kidneys, with 90% of 17-hydroxysteroids (17-OH) excreted in urine, measurable via assays.

  • ACTH exhibits a circadian rhythm, predominantly released between 4:00 - 6:00 AM and is highly potent, capable of releasing 1 microgram of cortisol per picogram of ACTH.

  • Cortisol circulates bound to a protein called CBG (corticosteroid-binding globulin); a small fraction is free and loosely bound to albumin for cellular entry.

  • The half-life of cortisol is between 1-2 hours.

Molecular Mechanism of Action of Adrenocortical Hormones

  • Cells have receptors for both glucocorticoids and mineralocorticoids, collectively called corticosteroids.

  • Upon entry into a cell (due to their lipid solubility), steroids bind to a large receptor that includes heat shock proteins. These proteins must detach before the receptor can enter the nucleus to bind with GREs (glucocorticoid response elements).

  • This process leads to transcriptional changes, affecting gene expression by stimulating some and inhibiting others.

Physiological Effects of Glucocorticoids and Mineralocorticoids

Intermediary Metabolism

  1. Carbohydrate, protein, and fat metabolism are influenced by glucocorticoids.

  2. They increase glucose production through gluconeogenesis, stimulating the liver for enhanced glucose production.

  3. There is a decrease in peripheral glucose utilization leading to insulin resistance.

  4. Glucocorticoids increase proteolysis, resulting in amino acid release, especially in muscle and skin.

  5. They also promote lipolysis.

  • Net Result: Ensures adequate glucose supply to the brain. Excessive use can lead to muscle breakdown.

Water and Electrolyte Balance

  • Aldosterone (mineralocorticoid) affects cation excretion; all corticosteroids promote Na+ reabsorption but increase K+ and H+ excretion, which is problematic for patients with hypertension.

Cardiovascular and Blood Cell Effects

  1. Glucocorticoids support cardiovascular structure and function.

  2. They potentiate the vasoconstrictor effects in the skin and may suppress the degranulation of mast cells, which reduces histamine release and swelling.

  3. Corticosteroids decrease capillary permeability, reducing histamine release from basophils/mast cells.

  4. They help control blood volume through sodium retention.

  5. Glucocorticoids increase the numbers of neutrophils, leukocytes, and total white blood cells (WBCs).

  6. Side effects include a reduction in eosinophils, basophils, monocytes, and lymphocytes, which are crucial components of the immune system.

Immune System Effects

  1. Glucocorticoids inhibit the production of prostaglandins and leukotrienes by blocking phospholipase A2, the enzyme that cleaves arachidonic acid from membrane phospholipids, thus preventing inflammation.

  2. They effectively reduce inflammation and suppress immune-related cytokines and chemokines.

Central Nervous System Effects

  1. The role of glucocorticoids in the CNS is not fully defined.

  2. Corticosteroids can enter the brain (due to lipid solubility) and potentially affect mood, sleep, and EEG activity.

  3. Adrenal insufficiency can be associated with mood changes such as depression.

Skeletal Muscle Effects

  1. Glucocorticoids are necessary for maintaining skeletal strength; however, excessive amounts can lead to proteolysis and subsequent muscle weakness.

Stress Response

  • Cortisol secretion is elevated during stress.

Non-Endocrine Uses of Glucocorticoids

  • Glucocorticoids are used in pharmacological doses to treat various inflammatory, allergic, and immunological disorders, chronic diseases.

  • Treatment of Allergic Disorders:

    • Drugs include: Prednisone, Methylprednisolone, Triamcinolone, and Dexamethasone.

  • Cerebral Edema:

    • Prednisone is utilized.

  • Bacterial Meningitis:

    • TNF-alpha and IL-1β response to Gram-negative bacterial layers can cause meningitis inflammation; steroids reduce TNF and IL-1. Dexamethasone is used.

  • Collagen Disorders:

    • Can be treated with: Prednisone, Methylprednisolone, Triamcinolone, and Dexamethasone for systemic lupus, polymyalgia rheumatica, and other autoimmune conditions.

  • Hematological Disorders:

    • Prednisone, Triamcinolone, and Dexamethasone can treat autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura (ITP).

  • Hepatic Disorders:

    • Prednisone is used to treat subacute hepatic necrosis and autoimmune chronic hepatitis.

  • Renal Disease:

    • Methylprednisolone is effective in idiopathic nephrotic syndrome.

  • Respiratory Disorders:

    • Prednisone treats pulmonary sarcoidosis, while Dexamethasone is given for respiratory distress syndrome in premature births.

Adverse Effects of Glucocorticoids

  • Chronic glucocorticoid use should be avoided due to associated adverse effects, which correlate with dosage, frequency, route of administration, duration, age, and comorbidities.

  • An analysis of risk versus benefits is essential, as some effects are merely displeasing while others can prove life-threatening.

  • Gastrointestinal Reactions:

    • Increase gastric acid and reduce the mucus barrier, potentially causing ulcers and bleeding. Occult blood may be present, and there is a synergistic effect when combined with NSAIDs, increasing GI risks.

  • Edema:

    • Fluid retention is common; this is significant for patients with heart or kidney diseases. Dietary sodium restriction is advisable due to enhanced mineralocorticoid activity in the body.

  • Carbohydrate and Lipid Metabolism:

    • Hyperglycemia can occur due to heightened gluconeogenesis in the liver, potentially aggravating diabetes.

    • Increased serum triglycerides may lead to atherosclerotic vascular diseases.

  • Hypokalemia:

    • High doses can induce hypokalemia and metabolic alkalosis, which can lead to phenomena such as asthenia, paralysis, or arrhythmias.

  • Hypophosphatemia:

    • Although rare, it can result in severe muscle weakness and hemolysis, requiring monitoring.

  • Osteonecrosis:

    • Long-term high-dose use (12-24 months) can cause osteonecrosis, usually affecting the femoral head.

  • Negative Nitrogen Balance:

    • Resulting from excessive proteolysis, potentially corrected by increasing protein intake.

  • CNS Edema:

    • Being lipid-soluble, high doses can cross into the brain, causing changes in behavior or personality, such as euphoria, within days to two weeks; effects cease upon discontinuation.

  • Growth Suppression:

    • Prolonged glucocorticoid use can suppress growth in children, who should ideally be under alternate day therapy.

  • Myopathy:

    • Due to proteolytic effects, glucocorticoids can cause myopathy particularly in the upper and lower extremities; this condition is generally reversible and highly associated with Triamcinolone.

  • Skin and Soft Tissue Effects:

    • Long-term use can lead to skin conditions like purpura, non-melanoma skin cancers, acne, alopecia, and features consistent with Cushing’s syndrome such as a buffalo hump, skin thinning, and striae due to fat redistribution.

  • Ocular Effects:

    • Glucocorticoids can elevate intraocular pressure (IOP), decreasing aqueous outflow, leading to open-angle glaucoma. They can also increase susceptibility to infections by viruses (such as herpes).

    • Subscapular cataracts can form with prolonged use.

  • Infections:

    • Long-term glucocorticoid therapy decreases resistance to infections including bacterial, viral, fungal, and parasitic. An alternate day therapy (ADT) may mitigate these risks. Reactivation of latent tuberculosis (TB) is also a concern.

  • HPA Suppression:

    • Negative feedback can lead to suppression of the hypothalamic-pituitary-adrenal axis, proportional to dose, half-life, and duration of glucocorticoid therapy. Suppression can occur as soon as within one week.

Pregnancy and Lactation

  • Glucocorticoids such as Cortisol, Prednisone, and Dexamethasone can traverse the placenta, potentially causing fetal adrenal hypoplasia, hypoadrenalism, and cleft palate.

  • Classified as FDA Category C for pregnancy.

Mineralocorticoids

Overview of the Adrenal Cortex

  • The adrenal cortex has three zones (from outer to inner):

    • Glomerulosa – Produces Aldosterone (Mineralocorticoid)

    • Fasciculata - Produces Cortisol (Glucocorticoid)

    • Reticularis - Produces Androgens

Aldosterone: Physiological and Pharmacological Effects

  • Function: Aldosterone promotes sodium reabsorption, potassium excretion, and hydrogen ion excretion.

  • Excessive Aldosterone Levels: This may lead to hypokalemia, metabolic alkalosis, increased plasma volume, and hypertension. This is due to the increased expression of Na+/K+ ATPase and sodium channels.

Drug Selection

  • The primary agent is Fludrocortisone, which possesses both glucocorticoid and mineralocorticoid activities and is the most widely used mineralocorticoid for treating adrenal cortical insufficiencies involving mineralocorticoid deficiency.

Use of Corticosteroids in Endocrine Disorders

Hypersecretion of Adrenocortical Hormones

Cushing's Syndrome Types:

  1. ACTH Dependent (68%): Caused by pituitary adenomas or tumors.

  2. ACTH Independent (18%): Usually from benign adrenal adenomas.

  3. ACTH Dependent as a syndromic cause (12%): Associated with adrenal hyperplasia.

  • Patients exhibit elevated hormone levels consistently, lacking a circadian rhythm.

  • Clinical Features: Characterized by obesity, facial plethora (red cheeks), glucose intolerance, and myopathy.

Treatment for Adrenal Glucocorticoid Hypersecretion:

  • Initial treatment uses Ketoconazole, which inhibits all steroid biosynthesis effectively at early rate-limiting steps.

  • Once cortisol levels are managed, Metyrapone can be employed to selectively inhibit cortisol and aldosterone production since it acts at a later step in the metabolic pathway.

Hyperaldosteronism (Conn’s Syndrome)

  • Leads to decreased renin activity, hypokalemia, metabolic alkalosis, and hypertension, often resulting from adrenal adenomas or bilateral zona glomerulosa hyperplasia.

  • Treatment involves using Spironolactone (an aldosterone antagonist) before proceeding to surgical options.

Hypoaldosteronism

  • Characterized by low cortisol concentrations, often resulting from autoimmune diseases. To assess whether the issue pertains to the pituitary gland or the hypothalamus, a synthetic ACTH (Cosyntropin) is injected; if cortisol levels increase, it indicates that the pituitary is functioning normally (the adrenals respond).

  • Initial treatment consists of hydrocortisone and cortisone, which possess both glucocorticoid and moderate mineralocorticoid properties.

  • Fludrocortisone, known for its potent mineralocorticoid activity, is added for more comprehensive management.