Corticosteroids: Pathophysiology & Pharmacology

• Corticosteroids are discussed with respect to Pathophysiology and Pharmacology

Adrenal Gland Anatomy and Function

• The paired adrenal glands sit atop the kidneys.
• Each adrenal region secretes different hormones.
• The adrenal cortex secretes steroid hormones.
• The adrenal medulla secretes catecholamines.

Adrenal Cortex Regions and Secretions

• Zona Glomerulosa: Secretes mineralocorticoids, primarily aldosterone.
• Zona Fasciculata: Secretes glucocorticoids.

Steroid Hormone Synthesis

• Cholesterol is the precursor for all steroid hormones.
• Key enzymes involved include 21-hydroxylase and 11-hydroxylase.
• Deficiencies in these enzymes can shift hormone production towards gonadal hormones (estrogen, testosterone).

Adrenal Cortex Hormones

• The adrenal cortex produces three main types of steroid hormones: glucocorticoids, mineralocorticoids, and sex hormones.
• Glucocorticoids (Cortisol):
  • Regulate metabolic functions.
  • Control inflammatory response which enables survival in stressful conditions.
• Mineralocorticoids (Aldosterone):
  • Regulate sodium, potassium, and water balance.
• Sex Hormones (Androgens).

Cortisol Overview

• Cortisol is the main glucocorticoid and is essential for human life.
• Secretion is controlled by the hypothalamic-pituitary-adrenal (HPA) pathway and follows a continuous, diurnal rhythm.
• Cortisol levels fluctuate throughout the day, therefore they aren't used as a reliable diagnostic criteria
• Cortisol is important in mediating long-term stress.
• It protects against hypoglycemia through a permissive effect involving glucagon and catecholamines.

HPA Regulation of Cortisol

• The HPA pathway regulates glucocorticoid levels through:
  • The hypothalamus releasing CRH
  • the anterior pituitary releasing ACTH
  • the adrenal cortex releasing Cortisol
• Cortisol acts as a long-loop negative feedback on the hypothalamus and pituitary.
• The Glucocorticoid receptors are widely distributed throughout the body.
• Mineralocorticoid receptors are confined to excretory organs, salivary glands and sweat glands.
• Suppression of the HPA axis occurs with higher doses of corticosteroids used for 2 weeks or longer.
• Chronic synthetic glucocorticoid treatment can interfere with negative feedback.
• CBG (corticosteroid-binding globulin) transports cortisol in the bloodstream.

Glucocorticoid Action

• Free cortisol enters the cell and binds to its receptor (R).
• Heat shock proteins (Hsp90) keep the receptor inactive when cortisol is absent.
• The steroid-receptor complex enters the nucleus as a dimer.
• It binds to the glucocorticoid response element (GRE) on the gene.
• This binding regulates gene transcription, leading to the production of proteins that mediate the hormone response.

Cortisol Effects Explained

• Cortisol origin is is in the adrenal cortex and it is a steroid.
• It is made from demand from cholesterol, and not stored.
• It travels in the circulation using corticosteroid-binding globulin.
• Circadian rhythm of tonic secretion and stress enhances it's release.
• It is regulated via CRH (hypothalamus) to ACTH (anterior pituitary) resulting release of cortisol (adrental cortex).
• The target cell is is most tissues.
• Has an intracellular receptor.
• Main action, is permissive for glucagon and catecholamines which activates immune activity and increases plasma glucose.
• Second action is Blocks cytokine production by immune cells, increasing gluconeogenesis and protein catabolism, suppressing inflammatory response.
• It initiates transcription, translation, and new protein synthesis.
• Negative feedback to the anterior pituitary and hypothalamus.

Cortisol Physiological Action

• Glucose metabolism stimulated resulting in gluconeogenesis, decrease glucose usage, and increase plasma protein levels.
• Protein metabolism is broken down resulting in an increase to plasma protein levels
• This results in a Fat metabolism increase of mobilization and usage of fatty acids.
• Stabilizes lysosomal membranes of inflammatory cells.
• Decreases capillary permeability.
• Depresses phagocytosis by lowering white blood cells.
• Suppresses immune response and causes atrophy of lymphoid tissue.
• Reduces fever and decreases antibody formation.
• Inhibits fibroblast activity.
• Facilitates tissue response to humoral and neural influences.

Mineralocorticoids

• Mineralocorticoids, like aldosterone, are released in high stress enviornments.

Aldosterone Actions

• Aldosterone promotes renal sodium reabsorption and potassium secretion.
• Originates in the adrenal cortex
• This increases water retention and blood pressure.
• It is released due to high plasma [K+] and low blood pressure.
• Increases Na+ reabsorption and K+ secretion
• Aldosterone increases synthesis of these new channels and activity of exiting pumps.
• This is done by acting on principal cells of the renal collecting duct:
  • Which stimulates proteins to modulate exiting channesl and pumps
  • And also starts translation and protein synthesis

Mineralocorticoid Deficiency

• Elevated aldosterone levels may cause alkalosis and hypokalemia, retention of sodium and water.
• Low sodium levels can be treated with hyperaldosteronism, and aldosterone antagonists.
• The primary action of aldosterone is renal sodium reabsorption.

Pathophysiology of Adrenal Disorders

• Addison's Disease: Characterized by reduced cortisol levels.
  • Involves primary destructive disease of the adrenal cortex.
  • Characterized by volume depletion and hypotension
  • It stimulates more CRH production
• Cushing's Syndrome: Characterized by excess glucocorticoid levels.
  • Due to a tumor in the anterior pituitary, nodular hyperplasia or excessive steroid use.

Addison´s Disease

• Addison's disease shows low cortisol levels, hyperpigmentation, hypoglycemia, cardiac insufficiency, and urinary losses.
• A loss of mineralocorticoid results in a decrease to control salt and water elimination.
• Low corticoid levles increase patients pain intolerance.

Corticosteroid Agonists Structures

• Steroidal ring structures with modifications dictate biological activity.
• Key functional groups at C11 and C17 determine activity.

Corticosteroid Potency

• Fludrocortisone, has the highest mineralocorticoid potency.
• Betamethasone and Dexamethasone have the highest Glucocorticoid potency.

Coriticosteroid Examples

• Short acting (1-12 hours)
• Cortisone
• Hydrocortisone
• Intermediate acting (12-36 hours)
• Methylprednisolone
• Prednisolone
• Prednisone
• Long Acting(36-55 hours)
• Betamethasone
• Dexamethasone

Fludrocortisone

• Fludrocortisone is a mineralocorticoid agonist.
• It has a good affinity for water molecules.
• Indicated for adrenal insufficiency (Addison's Disease)
• Main toxicities
• Salt and fluid retention, congestive heart failure.

Prednisone Characteristics

• Prednisone is a glucocorticoid agonist.
• Immuno-suppresant.
• Its many applications is against other inflammatory conditions, ect
• The toxicities is Adrenal suppression, growth inhibition, muscle wasting, osteoporosis, salt retention, glucose intolerance, behavioral changes

Dexamethosone

• Dexamethasone is a glucocorticoid agonist.
• Effects are similar to prednisone.
• It is a strong agonist of GR.

Causes of Pathophysiology

• Addison's or Cushing's disease are the result of a variety of disorders ranging from gland tumors to iatrogenic syndromes.
• Excess corticoid increase muscle weakness.
• Cortisol promotes high levels of glucose and the breakdown of muscle proteins.
• Improper levels influence brain function and causes mood swings.

Negative Cortisol Balance

• Cortisol can cause an improper calcium balance affecting small intestines, bones, and the kidneys.
• Resulting in extra cellular levels and loss in bone causing osteoporosis

Clinical Uses of Corticosteroids

• Replacement and diagnostic.
• Relief for inflammatory symptoms
• Treatment of allergies
• Corticosteroids may be used in various other treatments, such as inflammatory bowel disease and arthritis.

Clinical uses continued

• Prednisone used in pregnancy to mimimize the fetus effects.
• Betamethasone helps to accelerate the newborns lungs function to prevent respiratory destress.
• Spironolactone inhibits aldosterone synthesis and is for treatment resistant hypertesion

Adverse Effect of Corticoids

• The corticosteroids induce glaucoma, mood swings, increased risk of infection, and impaired wound healing
• Prolonged use of corticosteroids is linked to a loss of bone structure, increasing risk of fractures.

Topical therapy Side Effects

• Corticosteroids may retard bone growth.
• The also may result in glaucoma, increased appetitive or appetite loss.

Ways to Reduce systemic Steroid Risk

• Use a localized treatment, or dose, such as in a asthma inhaler where the drug goes local and stays in the lungs or an injected joint can also localize the treament.
• Alternate day dosing
• Use steroids with low systemic absorption

Steroid List

• Steroid list include the common steroids used, with the names of their inhibitors and common brand names. 1 Ketoconazole inhibits adrenal steroid hormone synthesis

2. Spironolactone competes and inhibits sodium reabsorption in the Kidney
3. Eplerenone binds to the mineral corticoid receptor and acts as an aldosterone antagonist

Glucocorticoid Receptor Antagonist

• Mifeptistrone is an antagonist for adrenals.
• It competes in binding for receptors to treat adrenal cancers.
• And has antagonist activity at the progesterone receptor.

An overview of corticosteroids, focusing on adrenal gland anatomy, hormone synthesis, and the roles of glucocorticoids and mineralocorticoids. It covers the adrenal cortex regions, including the zona glomerulosa and zona fasciculata. Key enzymes like 21-hydroxylase and 11-hydroxylase in steroid hormone synthesis are discussed.