Glucocorticoids

• Department of Pharmacology
• JianZhao Wu
• 股骨头


  femoral head
• 骨坏死


  osteonecrosis of the femoral head
• N. Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2021436
• 肾上腺皮质激素药物


  Adrenocortical hormone drugs: natural and synthetic adrenocortical hormones and their antagonists. Corticosteroids commonly used in clinic are mainly glucocorticoids (GCs).
• 肾上腺皮质激素


  Adrenocortical hormone
• 体内过程：产生


  1. Medulla: release adrenaline and NA

  2. Reticular: Sex hormones

  3. Fascicular: Glucocorticoids: hydrocortisone cortisone

  4. Globular: mineralocorticoids: aldosterone
• 体内过程：调控


  Hypothalamus pituitary adrenal axis - Under normal physiological conditions, the production of adrenocortical hormone is regulated. Stimulation and signals will act on the hypothalamus to make the hypothalamus secrete corticotropin releasing hormone (CRH), which promotes the release of adrenocorticotropic hormone (ACTH) in the anterior pituitary. ACTH release into the blood further regulates the release of GCs from the adrenal cortex. The concentration of glucocorticoid also has a negative feedback effect on the release of ACTH and CRH.
• 体内过程：昼夜节律


  Glucocorticoid concentration reach a trough at night and peak around 8 o'clock. The change of circadian rhythm is closely related to the time of administration. Generally, the time of high-dose glucocorticoid shock will be selected in the morning. Combined with higher concentration of physiological GC, it can not only produce better effect, but also maintain the change of circadian rhythm, so as to reduce the impact on normal hormone secretion axis.
• Basic chemical structure
• Absorption


  Both injection and oral administration can be absorbed. The plasma concentration of cortisone or hydrocortisone reached the peak 1 ~ 2 hours after oral administration
• Distribution


  More than 90% of hydrocortisone binds reversibly to plasma proteins after entering the blood, of which about 80% binds to corticosteroid binding globin (CBG) and 10% binds to albumin. Not easy to enter the cells after binding, so it has no biological activity; The free type with activity accounts for about 10%.
• Metabolism and Excretion


  Mainly metabolized in the liver, combined with glucuronic acid or sulfuric acid, and discharged from the urine together with the unbound part. Liver and kidney dysfunction, T 1 / 2 prolongation; Hyperthyroidism, accelerated liver inactivation, T 1 / 2 shortening; Cortisone and prednisone must be converted into hydrocortisone and prednisolone respectively in the liver. Patients with severe liver dysfunction only use hydrocortisone and prednisolone.
• 根据糖皮质激素 t ½ 的长短


  • Short acting: t ½ 90 minutes, hydrocortisone
  • Medium acting: t ½ > 200 minutes, prednisone, prednisolone
  • Long acting: t ½ > 300 minutes, dexamethasone, betamethasone
• Pharmacological action and mechanism


  GCs have a wide range of effects and are closely related to dose. At physiological doses, GCs mainly affect material metabolic processes, such as glucose metabolism, protein metabolism, fat metabolism, nucleic acid metabolism and water-electrolyte metabolism, etc. Supraphysiological doses of GCs have important pharmacological effects, such as anti-inflammation, immuno-suppression and anti-shock. Supraphysiological doses of GCs could cause many adverse reaction due to the effects of GCs on the metabolism of substances in the body.
• Glucose metabolism


  1. Increases liver and muscle glycogen content and elevates blood glucose

  2. Promotes gluconeogenesis, using amino acids and intermediate metabolites in protein metabolism as raw materials to synthesize glycogen

  3. Reduce glucose utilization, while increasing intermediate metabolites such as pyruvate and lactate, and synthesize glucose in the liver and kidney, and increase the source of blood glucose
• Lipid metabolism


  Short term use of GCs has no significant effect on fat metabolism. Long-term use with high doses can increase plasma cholesterol, activate the subcutaneous lipase of limbs, promote the decomposition of subcutaneous fat. Redistribute fat on the face, chest, back and buttocks, and form centripetal obesity, which is manifested as "full moon face, buffalo back", showing a special shape of round face, thick back, fat trunk and thin limbs.
• Protein metabolism


  1. Accelerate the protein catabolism of thymus, muscle, bone and other tissues, increase the excretion of nitrogen in urine, and cause negative nitrogen balance; High dose of GCs inhibit protein synthesis.

  2. Muscle wasting, osteoporosis, skin thinning and delayed wound healing. In nephrotic patients with severe protein loss or other diseases affecting protein metabolism, protein assimilation hormones must be combined with GCs (especially long-term treatment).
• Water-electrolyte metabolism


  1. Act on mineralocorticoid receptors and produce weak mineralocorticoid like effects, sodium retention and potassium excretion

  2. Increase glomerular filtration rate, antagonize the effect of antidiuretic hormone and reduce the reabsorption of water by renal tubules, so it has diuretic effect;

  3. Bone decalcification, which may be related to reducing the absorption of calcium by small intestine, inhibiting the reabsorption of calcium by renal tubules and promoting urinary calcium excretion.
• Permissive action


  No direct effect on some tissues, but it can create favorable conditions for the role of other hormones; Enhance the vasoconstriction of catecholamine and the hyperglycemic effect of glucagon.
• Anti-inflammatory effect


  Inflammation is a protective response on the body, involving defense mechanism and tissue repair. Inflammation is too powerful, it will cause excessive tissue damage and functional disorder, and even endanger life. GCs have a powerful effect against inflammation a significant inhibitory effect on all stages of inflammation.
• Diuretic effect


  Increase glomerular filtration rate, antagonize the effect of antidiuretic hormone and reduce the reabsorption of water by renal tubules
• Bone decalcification


  Reducing the absorption of calcium by small intestine, inhibiting the reabsorption of calcium by renal tubules and promoting urinary calcium excretion
• Permissive action


  No direct effect on some tissues, but it can create favorable conditions for the role of other hormones
• Permissive action


  Enhance the vasoconstriction of catecholamine and the hyperglycemic effect of glucagon
• Anti-inflammatory effect


  Inflammation is a protective response on the body, involving defense mechanism and tissue repair. If inflammation is too powerful, it will cause excessive tissue damage and functional disorder, and even endanger life
• Anti-inflammatory effect


  • Powerful effect against inflammation, a significant inhibitory effect on all stages of inflammation, rapid, powerful and non-specific anti-inflammatory effect
• Anti-inflammatory effect in early stage of inflammation


  Reduce exudation, edema, capillary dilation, leukocyte infiltration and phagocytosis, relieve symptoms such as redness, swelling, heat and pain
• Anti-inflammatory effect in late stage of inflammation


  Inhibit proliferation of capillaries and fibroblasts, formation of granulation tissue, adhesion and scar formation, sequelae
• Anti-inflammatory effect


  Double edged sword: inflammatory signs, body's defense function. The spread of infection and delayed wound healing
• Mechanism of anti-inflammatory effect


  Combination of GCs and glucocorticoid receptor (GR); genes involved in inflammation; some inflammatory process; cytokines, inflammatory mediators and nitric oxide synthase; cell apoptosis
• Mechanism of anti-inflammatory effect


  Effects on inflammatory inhibitory proteins and some target enzymes: chain reaction of arachidonic acid metabolism; inducible nitric oxide synthase and cyclooxygenase-2; inflammatory mediators
• Mechanism of anti-inflammatory effect


  Effects on cytokines and adhesion molecules: inflammatory cytokines; expression of adhesion molecules
• Role of cytokines in inflammation

  Aggravating, repairing or slowing the inflammatory response; interleukin 1 (IL1), IL3, IL4, Il5, IL6 and IL8, tumor necrosis factor (TNF ), macrophage colony stimulating factor (GM-CSF), etc.
• Mechanism of anti-inflammatory effect of GCs


  Permeability and chemotaxis of microvascular wall; vascular endothelial adhesion to leukocytes; inflammatory activation; proliferation and differentiation of fibroblasts and lymphocytes; production of cytokines; number of their receptors
• Mechanism of anti-inflammatory effect of GCs


  Inhibit transcription of IL1, IL3, TNF α and GM-CSF; Increase the rupture of mRNA, so as to reduce the production of IL1, IL3 and GM-CSF; Inhibit the synthesis of IL2 receptor; Reverse the activation regulation of activator protein-1 (AP-1), or directly interact with it to exert the anti-inflammatory effect of cytokines
• Mechanism of anti-inflammatory effect of GCs


  GR mediates gene transcription changes, and finally activates caspase and specific endonuclease, resulting in cell apoptosis
• Immunosuppressive effect


  GCs inhibit immune process; Low dose mainly inhibit cellular immunity; High dose inhibit the transformation of B cells into plasma cells, antibody production and inhibit humoral immunity
• Mechanism of immunosuppressive effect


  Induce lymphocyte DNA degradation: only occurs in lymphoid tissue and has GC specificity; Affect the material metabolism of lymphocytes: reduce the activity of RNA polymerase and the production of ATP in lymphocytes; Induce lymphocyte apoptosis: mainly immature lymphocytes with CD4 / CD8 double positive