Adrenal Hormones (Canvas)

University:
West Coast University
Course:
PHAR 742 | IPC Endocrine
Academic year:

2024
Views:

454

Pages:

50
Author:

Asal A.

Adrenal Hormones Fred Farris, PhD Adrenal Glands Adrenal Glands Adrenal medulla • Modified sympathetic ganglion (Neural tissue) • Innervated via cholinergic preganglionic fibers • On stimulation releases • Epinephrine • Norepinephrine Adrenal Gland Cortex • Mesodermal origin • Zona glomerulosa • Mineralocorticoids • Zona fasciculata • Glucocorticoids • Zona reticularis • Androgens • All hormones are steroidal Asteroids from Adrenal Glands Adrenal Hormones Overview of Corticosteroids (Mineralocorticoids) • Mineralocorticoids (Aldosterone) • Promote sodium reabsorption in transporting epithelia of kidneys, salivary glands, and large intestines • Sodium reabsorption is followed by passive water reabsorption • Circulating aldosterone concentrations rise in response to: • Low blood volume or low sodium depletion • Under control of reninangiotensin system (RAS) Overview of Corticosteroids (Glucocorticoids) • Glucocorticoids (Cortisol) • Regulate metabolic activity, immune function, and behavior • Target cells include almost all tissues of the body • Circulating glucocorticoid levels increase in response to • Sleep-wake cycles • Stressors under control of Hypothalamic-pituitaryadrenal (HPA) axis Steroid biosynthesis • Cholesterol and pregnenolone: Common precursors • Mineralocorticoid pathway: “sterone” suffix • Corticosterone and aldosterone both have mineralocorticoid activity but are not used therapeutically Steroid Biosynthesis: Pregnenolone Formation • In the adrenal glands, cholesterol is converted enzymatically to pregnenolone • Serves as a biosynthetic precursor to the adrenocorticoids • Cholesterol side cleavage enzyme is activated in response to ACTH Rate-Limiting Step in Pregnenolone Synthesis • • • • Conversion of 27-carbon cholesterol to 21-carbon pregnenolone Catalyzed by P450 side-chain cleavage enzyme (P450ssc) Catalyzes 3 sequential reactions shown Rate of steroid biosynthesis is determined by rate at which cholesterol is presented to P450scc Regulation of Endogenous Levels of Cortisol Hypothalamic-Pituitary-Adrenal (HPA) Axis • Low plasma cortisol stimulates release of • CRH from hypothalamus • ACTH from pituitary • ACTH stimulates adrenal cortex to synthesize and release cortisol • P450scc is the target for ACTH • High plasma levels of cortisol suppress HPA axis activity • Results in decreased cortisol Diurnal Levels of Cortisol • Cortisol levels peak in the 3045 minutes immediately after waking • To prepare the body to take on the stresses of the day • Circadian rhythm • Shift work • Lark versus night owl • Evening naps • Dawn Phenomenon • Increase in blood glucose levels in the morning after waking • Normal in most humans • Relevance in diabetes Glucocorticoid Signaling Metabolic Effects • Glucocorticoids act through glucocorticoid receptors • Nuclear receptor superfamily • Transcription factors • Physiologic effects of cortisol • Carbohydrate metabolism • Protein metabolism • Lipid metabolism • Calcium metabolism • Skeletal muscles • Water excretion • Cardiovascular effects • Stomach • CNS • Inflammatory response • Immunological and allergic responses • Lymphoid tissue and blood cells CBG – corticosteroid binding globulin Hsp – heat shock proteins GRE – glucocorticoid response element Carbohydrate and Protein Metabolism • Glucocorticoids worsen glycemic control in patients with over diabetes • Precipitate the onset of hyperglycemia in patients who are otherwise predisposed Anti-inflammatory and Immunosuppressive Actions of Glucocorticoids • Glucocorticoids dramatically reduce inflammation • Reduce numbers and change function of peripheral leukocytes • Suppress release of inflammatory cytokines • Inhibit interactions between endothelial cells and white cells • Inhibits Phospholipase A2 and reduces release of arachidonic acid • Single dose of short-acting glucocorticoid • Neutrophils in circulation increase • Inflammatory cells in circulation decrease • Effect peaks at 6 hr and dissipates in 24 hr Immune Modulation by GCs • Suppress activation of T lymphocytes • Suppress production of cytokines by activated T helper cells • Prevent mast cells, basophils, and eosinophils from releasing various chemical mediators of inflammation • Vasoconstriction • Decrease capillary permeability Susceptibility of infection is a potential adverse effect of long-term suppression of the inflammatory process Pathophysiology of Adrenal Disorders • Glucocorticoid Excess • Cushing’s Syndrome • Cushingoid symptoms • Glucocorticoid Deficiency • Addison’s disease • Adrenal cortex is selectively destroyed by T-cell mediated autoimmune reaction • Addisonian Crisis Therapeutic Overview of Adrenocorticoids • Glucocorticoids • Replacement therapy in adrenal insufficiencies • Anti-inflammatory and immunosuppressive action • Systemic steroids and locally administered steroids • Myeloproliferative diseases • Shock • Mineralocorticoids • Replacement therapy in primary adrenal insufficiencies • Hypoaldosteronism • Na+/H2O retention Therapeutic Indications for Glucocorticoids Glucocorticoid Structure-Activity Relationships: Insertion of Double Bonds • • Adding a double bond between positions 1 and 2 in hydrocortisone increases glucocorticoid activity of the product The Δ1-corticoids have a much longer half-life in plasma and tissues than hydrocortisone Tissue half-life for hydrocortisone = 8 to 12 hr Tissue half-life for prednisolone and methylprednisolone = 18 to 36 hr Glucocorticoid Structure-Activity Relationships: Insertion of α-CH3 Group • Insertion of a CH3 group at carbon 6, and 16 increases glucocorticoid activity • Methylprednisolone and dexamethasone are more potent than hydrocortisone Dexamethasone is much more potent than methylprednisolone • Glucocorticoid Structure-Activity Relationships: Insertion of α-F Groups • • The 9α-F group increases glucocorticoid activity by preventing metabolic oxidation of the 11β-OH group to a ketone 6α-F group also increases glucocorticoid activity • • Dexamethasone is about 30 time more potent than hydrocortisone Flumetasone is 420 times more potent than hycrocortisone Glucocorticoid Structure-Activity Relationships: Insertion of α-F Groups • The 12α-F group decreases glucocorticoid activity • Hydrogen bonding between the 12α-F and the 17α-OH groups renders the analogue inactive • A 21-F group increases both glucocorticoid and mineralocorticoids activity Glucocorticoid Structure-Activity Relationships: Insertion of Halogens at C-21 • • The hydroxyl (-OH) group ar C-21 can be replace with halogens (F>Cl>Br) leading to highly active glucocorticoids • • A 21-F group increase both glucocorticoid and mineralocorticoid acctivity Mineralocorticoid Structure-Activity Relationships Mineralocorticoid activity of adrenocorticoids (retention of sodium) is an action of major significance • • 17α-OH: Highly active, naturally occurring mineralocorticoids have no-OH function at position 17. This OH group reduces the sodium retaining activity of the steroid (not desired) • 9α-halogen: Substitution with 9α-F, 9αCl, or 9α-Br causes increased retention of urinary sodium (Order of activity is F>Cl>B Fludrocortisone • Fludrocortisone (9α-fluorocortisol or 9αfluorohydrocortisone) is a synthetic corticosteroid • Therapeutically used for mineralocorticoid activity • It possesses moderate glucocorticoid activity and much greater mineralocorticoid activity • Contains 17α-OH Mineralocorticoid Structure-Activity Relationships Mineralocorticoid activity of adrenocorticoids (retention of sodium) is an action of major significance • 21α-OH: Contributes to glucocorticoid activity, but also leads to improved mineralocorticoid activity • • Systemic Glucocorticoids Corticosteroids Used for Systemic Therapy Long-term Effects of Glucocorticoids • Lipid metabolism: Characteristic redistribution of fat • Peripheral wasting of adipose stores and central obesity • Excessive fat deposition occurs on back of neck (buffalo hump) and face (moon face) • Skeletal Muscle Wasting: Steroid Myopathy • Two Distinct Types: Acute and Chronic • Chronic/classic form occurs after prolonged use of GCs • Acute form (less common) associated with rhabdomyolysis and occurs abruptly with high dose corticosteroids (more frequent with dexamethasone and triamcinolone • Characterized by weakness of proximal limb muscles • Myopathy of respiratory muscles occurs in patients with asthma or COPD • Recovery from steroid myopathy is slow and incomplete • Bone: Long-term GC use → Osteoporosis • In children, chronic GC use → growth retardation Glucocorticoid-Induced Osteoporosis • Pharmacologic dosing of glucocorticoids inhibits the vitamin Dmediated absorption of calcium; resulting in secondary hyperparathyroidism • Increase in bone resorption • Glucocorticoids suppress osteoblast rebuilding and increase osteoclast reportion • Steroid-induced bone loss Cushing's Syndrome Glucocorticoid Excess • Cushing’s Syndrome • Cause: Adenoma (tumor) – surgery is TOC • Drug induced – excess GC dose or chronic high dose • Clinical features result from overstimulation of target organs Glucocorticoid Insufficiency • Addison’s Disease • Primary • Selective destruction of the adrenal cortex • Autoimmune disease • Treated with exogenous glucocorticoids and mineralocorticoids • Secondary • Insufficient release of ACTH • Treated with exogenous glucocorticoids Pathophysiology of Adrenal Crisis • Adrenal crisis or Addisonian crisis or acute adrenal insufficiency is a potentially life-threatening emergency • Symptoms Include: Sudden penetrating pain in lower back and legs, hypotension, hyponatremia, hyperkalemia, severe lethargy, confusion, slurred speech, severe vomiting and diarrhea leading to dehydration, fever, psychosis, convulsions • Patients with adrenal disorders • Addison’s, or Patients receiving chronic glucocorticoids • Inability of the cortex to respond to sudden increase in demand for cortisol • Triggered by stress (such as trauma) • Septic shock • Treated with IV hydrocortisone and fluids Adrenal Crisis Glucocorticoid Withdrawal and Tapper • Withdrawal Syndrome: • Flare-up of underlying diseases • Acute adrenal insufficiency • Exogenous GCs suppress ACTH, withdrawing GCs leave no stimulus for adrenals and no cortisol in the serum How about quick switching of oral to inhalation glucocorticoids? Cortisone-Cortisol Conversion • Hydrocortisone and cortisone are biochemically interconvertible • Cortisone (11-keto) reduced to hydrocortisone (11-OH) • 11-beta hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2 Pregnancy Adrenocorticosteroids: General SAR: Summary Common Features (GCs and MCs) • Pregnane Template (21 Carbon) • Carbonyl group at C3 • Δ4 double bond • -OH at C11 • Hydroxymethylketone (-CO-CH2-OH) Adrenocorticosteroids: General SAR: Summary Differences (glucocorticoids versus mineralocorticoids) • Glucocorticoids (hydrocortisone) has 17α-OH but mineralocorticoids (aldosterone) does not Adrenocorticosteroids: General SAR: Summary Increasing activity of GCs • Addition of Δ1 double bond – increases tissue and plasma half-life, and GC potency • Insertion of α-CH3 groups at C6 and C16 increase GC potency • Insertion of α-F groups at C6 and C9 increase GC potency • C9 αF group also protects 11-OH group from oxidation • Replacing C21-OH groups with halogen increases MC potency Glucocorticoids: Adverse Effects • Adrenocortical insufficiency: Suppression of HPA-GC withdrawal and adrenal crisis • Adrenocortical excess (Cushingoid symptoms): Moon face, buffalo hump • Hyperglycemia (Diabetes Mellitus) • Impaired wound healing • Osteoporosis, muscle weakness and atropy • Cardiovascular effects: Fluid retention, edema, hypertension • Cataract formation (GC-induced gene transcription events in lens epithelial cells, and also other intraocular or systemic cells) • CNS effects: psychological and behavioral changes; aggravation of pre-existing psychiatric disorders Contraindications The following are aggravated by GCs: • Peptic ulcer • Diabetes mellitus • Hypertension • Viral and fungal infections • TB and other infections • Herpes simplex keratitis • Psychosis • Epilepsy • CHF • Renal failure Corticosteroids Potency Acknowledgements ◦ The contents of many of the slides used in this presentation were adapted from material originally prepared by Dr. Gauri Sabnis – Many Thanks for her assistance

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