Endocrine Pharmacology - Corticosteroids

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of adrenal gland.

Classification:

1. Glucocorticoids:
   • Short acting: Hydrocortisone (Cortisol)
   • Intermediate acting: Prednisolone, Methyl prednisolone, Triamcinolone, Deflazacort
   • Long acting: Dexamethasone, Betamethasone
2. Mineralocorticoids: Desoxycorticosterone acetate (DOCA), Fludrocortisone, Aldosterone

Regulation of synthesis and secretion of corticosteroids:

The Glucocoticoids is released by the zona fasciculata of adrenal cortex of the adrenal gland. The adrenal cortex is stimulated by the adrenocorticotropic hormone (ACTH) released by the Anterior pitiuitary, which inturn is stimulated by the corticotropin-releasing factor (CRF), released by the hypothalamus.

The Mineralocorticoid release is controlled by the Renin-angiotensin system.

Mechanism of action:

Coticosteroids enters the cells of target orgon → Binds to specific receptors in cytoplasm → Steroid receptor complex is activated → The complex enters the nucleus → Binds to specific site on DNA → Regulate protein synthesis → Response

Pharmacological Actions:

Glucocorticoids, primarily cortisol in humans, are involved in regulating metabolism, immune response, and stress. Synthetic glucocorticoids like prednisone and dexamethasone are commonly used in medicine.

• Metabolic Effects:
  • Carbohydrate Metabolism: Increase gluconeogenesis (glucose production) in the liver, stimulate glycogen deposition in the liver and decrease glucose uptake by cells, leading to increased blood glucose levels.
  • Protein Metabolism: Promote protein breakdown (catabolism) in muscles, lymphoid tissue, skin, bone, etc to provide amino acids for gluconeogenesis, which can lead to muscle wasting, lympholysis, thinning of skin, osteoporosis (Loss of bone matrix) in long-term use.
  • Fat Metabolism: Redistribute fat in the body (leading to central obesity) and promote lipolysis (fat breakdown) in some areas.
• Anti-Inflammatory Effects:
  • Inhibit the production of inflammatory mediators such as prostaglandins and leukotrienes by blocking phospholipase A₂ by lipocortin induced by the glucocorticoids.
  • Decrease synthesis of cytokines (IL-1, IL-6 and TNF-α), which reduces the recruitment and activity of immune cells like macrophages and T-cells.
  • Stabilize cell membranes, reducing the release of inflammatory enzymes.
  • Chemotaxis is suppressed
• Immunosuppressive Effects: Suppress T-lymphocyte activation and proliferation, leading to a reduced immune response. Inhibit antibody production, thus reducing immune-mediated inflammation. They inhibit both B-cell and T-cell lymphocye functions and this results in impairment of humoral and cell mediated immunity. Reduce the migration of white blood cells to sites of inflammation, which helps in managing autoimmune diseases.
• Cardiovascular Effects: Increase vascular responsiveness to catecholamines, which helps in maintaining blood pressure. In excessive doses, they can cause hypertension due to sodium and water retention, despite glucocorticoids having less effect on sodium balance than mineralocorticoids.
• Effects on Central Nervous System: Can alter mood and behavior; high doses can lead to euphoria, psychosis, or depression. Contribute to stress response, helping the body cope with physiological stress.
• Bone and Calcium Metabolism: Inhibit osteoblast activity (Bone forming cells) and calcium absorption in the intestines, which can lead to osteoporosis with prolonged use. They promote osteoclast activity that increase's bone resorption, which further contributes to the risk of osteoporosis.
• Skeletal muscle: Prolonged use of glucocorticoids may cause muscle wasting & weakness (Steroid myopathy).
• Gastrointestinal tract: Glucocorticoids inhibit prostaglandins, which increase gastric acid and pepsin secretion: which may cause peptic ulcer. They decrease local immune response against Helicobacter pylori
• Effects on Blood cells:
  1. After formation of neutrophils, the glucocorticoids promote the movement of neutophils from bone marrow to blood. Prolonged use can cause neutrophilia.
  2. After formation of Lymphocytes, the glucocorticoids inhibit the movement of lymphocytes from bone marrow to blood. Prolonged use can cause Lymphopenia.

Mineralocorticoids, primarily aldosterone, play a vital role in regulating electrolyte and water balance in the body.

• Regulation of Sodium and Water Balance: Promote sodium reabsorption in the distal tubules and collecting ducts of the kidneys, leading to increased blood sodium levels. Increase water reabsorption indirectly (water follows sodium), which increases blood volume and contributes to maintaining blood pressure.
• Potassium and Hydrogen Ion Excretion: Stimulate potassium excretion in the kidneys, which helps maintain potassium balance in the body. Increase hydrogen ion excretion, contributing to acid-base balance.
• Cardiovascular Effects: By increasing blood volume, they help maintain blood pressure. However, excessive mineralocorticoid activity can lead to hypertension. High levels of aldosterone are linked to cardiac remodeling, potentially leading to heart issues with long-term elevation.
• Interaction with Renin-Angiotensin-Aldosterone System (RAAS): Aldosterone secretion is stimulated by angiotensin II (as part of the RAAS) and by high potassium levels, making it crucial in the body’s response to low blood pressure or low blood sodium.

1. Maximum glucocorticoid activity - Dexamethasone
2. Maximum mineralocorticoid activity - Aldosterone
3. Glucocorticoid has maximum mineralocorticoid activity - Hydrocortisone (Cortisol)
4. Mineralocorticoid has maximum glucocorticoid activity - Fludrocortisoe
5. Selective glucocorticoid - Dexamethasone, Betamethasone, Paramethasone, Triamcinolone
6. Selective mineralocorticoid - Desoxycorticosterone acetate (DOCA)

Adverse Effects:

While glucocorticoids are effective in managing inflammation and autoimmune responses, they can cause a variety of side effects, especially with prolonged use or at high doses.

• Hyperglycemia and Diabetes: Increases blood glucose levels, which can lead to or worsen diabetes.
• Weight Gain and Obesity: Causes fat redistribution, leading to a characteristic "moon face," "buffalo hump" (fat deposits on the back of the neck), and central obesity.

• Osteoporosis: Inhibits bone formation and increases bone resorption, making bones brittle and more susceptible to fractures.
• Muscle Wasting: Can lead to muscle weakness due to protein breakdown (catabolism), especially in long-term use.

• Hypertension: Can raise blood pressure by increasing vascular sensitivity to catecholamines and causing fluid retention.
• Increased Risk of Atherosclerosis: Long-term use may increase the risk of heart disease and stroke.

• Increased Risk of Infection: Suppresses immune function, making individuals more susceptible to bacterial, viral, and fungal infections.
• Poor Wound Healing: Delays tissue repair and healing processes.

• Peptic Ulcers: Increases gastric acid secretion and decreases mucus protection in the stomach, which can lead to ulcers and gastrointestinal bleeding.
• Pancreatitis: Rarely, glucocorticoids can cause inflammation of the pancreas.

• Mood Changes: Can cause mood swings, anxiety, euphoria, or depression.
• Psychosis: At high doses, glucocorticoids may lead to hallucinations or delirium.

• Thin, Fragile Skin: Skin may become more prone to bruising and tearing.
• Striae (Stretch Marks): Often seen on the abdomen, thighs, and arms, due to weakened skin structure.

• Adrenal Suppression: Long-term use suppresses natural cortisol production by the adrenal glands, which can lead to adrenal insufficiency if the glucocorticoid therapy is stopped abruptly.
• Cushingoid Appearance: Characteristic appearance due to prolonged high-dose use, including "moon face," "buffalo hump," and central obesity.

Mineralocorticoids, primarily aldosterone or synthetic forms like fludrocortisone, also have side effects, especially related to fluid and electrolyte imbalances.

• Sodium Retention and Hypernatremia: Causes excess sodium retention, which can lead to high sodium levels in the blood.
• Hypokalemia: Promotes potassium excretion, leading to low potassium levels, which can cause muscle weakness, cramps, and even arrhythmias.

• Edema: Fluid retention can cause swelling in the extremities and face.
• Weight Gain: Increased water retention can lead to noticeable weight gain.

• Hypertension: Increased blood volume due to sodium and water retention raises blood pressure, potentially leading to or worsening hypertension.
• Heart Failure: Prolonged fluid retention can strain the heart, leading to or worsening heart failure, particularly in those with pre-existing cardiovascular conditions.

• Acid-Base Imbalance: Increased excretion of hydrogen ions can lead to metabolic alkalosis, characterized by an elevated blood pH, which may cause muscle twitching, nausea, and irritability.

Therapeutic Uses:

Glucocorticoids are widely used for their anti-inflammatory, immunosuppressive, and metabolic effects. Common glucocorticoids include prednisone, dexamethasone, and hydrocortisone.

• Rheumatoid Arthritis: Reduces joint inflammation and pain.
• Systemic Lupus Erythematosus (SLE): Helps manage systemic inflammation and autoimmune reactions.
• Inflammatory Bowel Disease (IBD): Used in Crohn’s disease and ulcerative colitis to reduce gut inflammation.

• Asthma: Inhaled glucocorticoids reduce inflammation in the airways and prevent asthma attacks.
• Severe Allergic Reactions: Useful in anaphylaxis, angioedema, and other severe allergic responses by suppressing inflammation.
• Skin Allergies: Topical glucocorticoids treat eczema, dermatitis, and other inflammatory skin conditions.

• Organ Transplantation: Suppresses immune response to prevent organ rejection after a transplant.

• Leukemias and Lymphomas: Used to manage certain cancers by reducing immune activity and inflammation.
• Reduce Side Effects of Cancer Treatment: Helps manage nausea and inflammation due to chemotherapy and radiation therapy.

• Chronic Obstructive Pulmonary Disease (COPD): Reduces inflammation in airways to improve breathing.
• Croup in Children: Reduces airway swelling and eases symptoms in this viral respiratory condition.

• Addison’s Disease: Replaces deficient cortisol in people with adrenal insufficiency.
• Congenital Adrenal Hyperplasia: Manages hormone imbalances in individuals with this genetic condition.

• Multiple Sclerosis (MS): Used to manage flare-ups and reduce nerve inflammation.
• Cerebral Edema: Reduces brain swelling in cases of trauma, brain surgery, or tumors.

Mineralocorticoids, primarily in the form of fludrocortisone, are used for their effects on electrolyte and fluid balance, specifically in conditions that cause mineralocorticoid deficiency.

• Primary Adrenal Insufficiency: Used to replace aldosterone in patients whose adrenal glands do not produce enough of this hormone, helping to maintain sodium and potassium balance.

• Salt-Wasting CAH: Fludrocortisone is used to manage electrolyte imbalances and prevent dehydration in patients with this condition, which affects cortisol and aldosterone production.

• Blood Pressure Regulation: Occasionally used to help maintain blood pressure in patients with orthostatic hypotension (a drop in blood pressure when standing up), by increasing blood volume.

Last modified on: 03/11/2024