Glucocorticoid is a steroid hormone secreted by the adrenal cortex that regulates the biosynthesis and metabolism of sugar, fat, and protein, and also has anti-inflammatory effects, and is called “glucocorticoid” because its activity in regulating sugar metabolism was first recognized. It is called “glucocorticoid” because its activity in regulating glucose metabolism was first recognized by people. Han Shujun, Department of Neurology, Weifang Municipal Hospital
The basic structural features of glucocorticoids include the C3 carbonyl group, Δ4 and 17β ketone alcohol side chains of adrenocorticotropic hormones, as well as the 17α-OH and 11β-OH that are unique to glucocorticoids.
At present, the concept of glucocorticoids not only includes endogenous substances with the above characteristics and activities, but also includes many synthetic drugs with similar structures and activities after structural optimization.
1.Mechanism of action
Physiological origin and secretion regulation.
Glucocorticoid is a metabolic regulating hormone secreted by the middlemost fasciculus of the adrenal cortex.
The secretion of glucocorticoids in the body is mainly regulated by the hypothalamic-anterior pituitary-adrenal cortex axis. Adrenocorticotropin-releasing hormone (CRH) secreted by the hypothalamus enters the anterior pituitary and promotes the secretion of adrenocorticotropic hormone (ACTH), which in turn promotes the secretion of cortisol. In turn, the increase of glucocorticoid concentration in blood can inhibit the secretion of CRH and ACTH by the hypothalamus and anterior pituitary gland, thus reducing the secretion of glucocorticoids, and the increase of ACTH content can also inhibit the secretion of CRH by the hypothalamus, which is a negative feedback process to ensure the balance of glucocorticoid content in the body.
The secretion of endogenous glucocorticoids has a circadian rhythm, with the lowest level at midnight and the highest level in the early morning. In addition, when the body is under stress, the secretion of endogenous glucocorticoids will surge to about 10 times of the usual level.
2. Physiological effects
Promote gluconeogenesis, reduce the uptake and utilization of glucose by peripheral tissues, raise blood sugar, and also increase the synthesis of hepatic glycogen myoglycogen.
Promote protein metabolism in extrahepatic tissues, reduce protein synthesis, and increase amino acid content and urea nitrogen excretion in serum.
Promotes lipolysis and decreases anabolism, increasing glycerol and fatty acid content in blood, and consequently increasing cholesterol content in blood, thus activating the activity of subcutaneous lipase in limbs, breaking down subcutaneous fat in limbs and redistributing it to face, chest, abdomen, back and buttocks, causing centripetal obesity.
There is a weak salt corticosteroid-like effect, and can show the effect of potassium discharge and sodium retention.
3.Pharmacological effects
Anti-inflammatory effect: This mainly comes from increasing vascular collection s force, reducing vascular isotonicity, antagonizing histamine and other inflammatory mediators on vasodilatation, reducing local congestion, reducing leukocyte and body fluid exudation stabilizing the lysosomal membrane, reducing tissue protease and hydrolase release due to lysosomal rupture, reducing tissue decomposition and inflammatory mediator release.
Inhibits the recruitment of neutrophils, monocytes and macrophages to inflammatory sites.
Inhibits phospholipase A2 activity and reduces the conversion of membrane phospholipids to arachidonic acid, which is the biosynthetic precursor of many inflammatory mediators such as prostaglandins, leukotriene, and platelet-activating factor.
It inhibits the synthesis and release of interleukins, tumor necrosis factor, interferon and other cytokines related to immune response.
Inhibits fibroblast DNA synthesis and capillary proliferation, impedes collagen deposition, and inhibits granulation tissue formation.
Immunosuppressive effects: In addition to the immune system-related effects mentioned in the anti-inflammatory effects, glucocorticoids can also inhibit the conversion of B cells to plasma cells and reduce antibody production; inhibit humoral immunity and reduce the release of aggressive substances caused after antigen-antibody reactions.
Antitoxic effect: Although glucocorticoids have no effect on bacterial exotoxins, they have a powerful anti-bacterial endotoxic effect, reduce the release of endogenous pyrogenic substances, have a good antipyretic effect and a great improvement of toxic symptoms.
Anti-shock effect: This is the result of the combination of anti-inflammatory immunosuppressive and anti-endotoxic effects. Glucocorticoids can inhibit the vasoconstrictive effects of adrenaline, norepinephrine, pressin, angiotensin, 5-HT, and other transmitters and improve microcirculation, and their stabilizing effect of lysosomes can effectively reduce the release of myocardial inhibitory factors, thus maintaining normal cardiac output and maintaining the blood circulation of internal K from vasoconstriction. systolic effects.
Affects the hematopoietic system: increases the production of red blood cells and hemoglobin, increases platelets and fibrinogen, increases the amount of neutrophilic leukocytes entering the circulation, and decreases monocyte lymphocyte eosinophilic and basophilic leukocytes.
Central excitatory effects: Decreases the amount of inhibitory resistance to GABA in the brain, causing central excitation and producing symptoms such as euphoria, agitation, and insomnia.
Promotes gastric acid secretion.
Inhibits the secretion of pineal melatonin.
Reduce the uptake of iodine ion clearance and conversion by the thyroid gland.
4.Adverse effects
From the above mechanism of action, it is easy to see that the adverse reactions of glucocorticoids are
Medically induced hyperadrenocorticism: a series of symptoms caused by the high level of glucocorticoids in the body due to long-term high dose application of glucocorticoids, including muscle atrophy (caused by long-term negative nitrogen balance) occurring mostly in the large muscle groups of the limbs; thinning of the skin; centripetal obesity; acne; increased body hair; hypertension; hyperlipidemia; hypokalemia (will be combined with muscle atrophy to cause muscle weakness); elevated urine sugar; bone Osteoporosis.
Inducing or aggravating infections or metastasizing potential infections in the body: This is mainly because glucocorticoids have only anti-inflammatory effects and do not really kill the pathogens that cause infections.
Causes peptic ulcers: Glucocorticoids have the effect of stimulating the secretion of gastric acid and pepsin, which will reduce the resistance of gastric mucosa to digestive juices and can induce or aggravate gastric or duodenal ulcers, called steroid hormone ulcers. The characteristics of steroid hormone ulcers are: superficial, multiple, easy to occur in the anterior pyloric sinus, less insidious symptoms, and high rate of bleeding and perforation.
Induction of pancreatitis and fatty liver
The use in the first trimester of pregnancy can cause fetal developmental malformations, and high doses in the second trimester can suppress the fetal hypothalamus-pituitary anterior lobe, causing atrophy of the adrenal cortex and symptoms of postpartum cortical insufficiency.
Medically induced adrenocortical insufficiency: Due to the negative feedback mechanism of hypothalamic-pituitary-adrenocortical axis caused by prolonged use, the secretion of endogenous adrenocorticotropic hormone will be inhibited, and the rebound phenomenon and withdrawal reaction will occur after sudden discontinuation of the drug. Hypoglycemia, hypotension, shock, etc.
Schizophrenia and epilepsy may be induced.
[edit] History of development
The physiological effects and clinical applications of adrenocorticotropic hormones have been studied since 1855. The existence of adrenocorticotropic hormones was demonstrated in 1927 when Rogoff and Stewart used adrenal homogenate extracts to survive intravenous administration to dogs with adrenal glands removed, and it was hypothesized from this experiment that the biological activity of the extracts was caused by a single substance, but later people from 47 compounds were isolated from the extracts, including the endogenous glucocorticoids hydrocortisone and cortisone.
Early glucocorticoids were derived from homogenized extracts of animal organs, which were expensive to produce, and later, with the development of steroid chemistry and organic synthesis, total synthesis of steroid hormones was achieved, and any kind of steroid hormone could be synthesized from the simplest organic compounds, but considering the cost of actual production, people generally used diosgenin glycosides as the starting material for synthesis, and diosgenin was obtained from Dioscoreaceae ( Dioscoreaceae (Dioscorea) Diosgenin is a glycoside of terpenoids extracted from the tuberous roots of plants such as yam and pierogi, which is less expensive, and the use of diosgenin greatly reduces the production cost.
Based on the synthesis of hydrocortisone people continued to study the structural optimization of glucocorticoids, and a steroidal compound trenbolone with 16α-hydroxyl groups was extracted from the urine of a kidney cancer patient, which was found to have good glucocorticoid properties without causing sodium retention as hydrocortisone does.
By studying the metabolic process of hydrocortisone in vivo, dexamethasone with better stability, better anti-inflammatory activity and lower sodium retention was discovered in 1958.
On the basis of dexamethasone, people have developed betamethasone, beclomethasone, fludrocortisone and other drugs by introducing methyl, halogen and other structures on the parent ring of steroid.
5.Clinical application
Treatment of acute or chronic hyperaldosteronism.
When severe acute infection, toxic infection with shock or inflammatory symptoms caused by infection pose a threat to the patient’s life, glucocorticoids are used to suppress inflammatory symptoms and enable the patient to pass the dangerous period.
Anti-shock: These drugs have beneficial effects on all types of shock.
They can be used to treat rheumatoid diseases, systemic lupus erythematosus, myasthenia gravis, etc. In addition, they can be used to suppress rejection after organ transplantation to ensure the safe survival of the transplanted organ.
Preventing inflammation and seizure marks in vital organs: Inflammation and seizure marks in vital organs such as meninges, pleura, peritoneum, pericardium, joints, and eyes can have serious consequences, and glucocorticoids can reduce such damage when used in the early stages of infection.
Glucocorticoids can also treat blood disorders including acute lymphoblastic leukemia, aplastic anemia, granulocytopenia, thrombocytopenia, and allergic purpura.
The anti-inflammatory effect of glucocorticoids can be used in the topical treatment of some skin diseases, such as topical treatment of contact dermatitis, eczema, and psoriasis.
Rational use of glucocorticosteroids.
Because glucocorticoids can rapidly suppress some inflammatory reactions in the short term and can receive good “curative effect”, some doctors often use glucocorticoids to treat infections in order to have good therapeutic effect, but in fact this is not helpful to the patients’ healing. This is obvious from the mechanism of action of glucocorticoids described above. Therefore, glucocorticoids should be used with caution, and only when the inflammatory reaction caused by the infection is so severe that it threatens the patient’s life, glucocorticoids should be used in large doses for a short period of time to relieve symptoms.
Under normal circumstances, the concentration of corticosteroids in the human body can reach a maximum of four times the minimum in the early morning. Taking glucocorticoids in the early morning can synchronize the changes of exogenous and endogenous corticosteroids in the blood, reduce the impact on the hypothalamic-anterior pituitary-adrenal cortical axis and reduce feedback inhibition of the hypothalamic-anterior pituitary.