Pharmacological effects of dexamethasone

Introduction

Dexamethasone (DXMS for short) was first synthesized in 1957 and is listed in the WHO Model List of Essential Medicines as one of the essential medicines for the basic public health system. On June 16, 2020, the WHO stated that preliminary clinical trial results in the United Kingdom showed that dexamethasone can save the lives of patients with severe new coronary pneumonia, and for patients on ventilators, it can reduce the mortality rate by about one third. Patients receiving oxygen alone can reduce their mortality by about one-fifth. In October 2020, the World Health Organization announced that the results of the latest research on drugs involving new coronary pneumonia showed that remdesivir and others had little effect in preventing the death of patients with new coronary pneumonia or shortening the length of hospitalization, and dexamethasone was still the only one in severe patients with new coronary pneumonia. effective medicine[1].

Picture 1 The Dexamethasone injection

Dexamethasone is inexpensive, usually costing less than $25 a month in the United States. In India, a session of preterm labor costs only $0.50. Dexamethasone is readily available in most countries. Dexamethasone is a synthetic corticosteroid used to treat a variety of conditions, including rheumatic diseases, certain skin conditions, severe allergies, asthma, chronic obstructive pulmonary disease, prosthetic laryngitis, cerebral edema, and possibly Combined with antibiotics for tuberculosis patients. In the United States, the pregnancy classification of this product is C, and it needs to be evaluated that the efficacy of the drug is greater than the side effects before it can be administered; in Australia, it is rated as A, which means that this product is commonly used in pregnant women, and there is no evidence that it will cause harm to the fetus.

The preparation method of dexamethasone

A novel production process method for dexamethasone 21-hydroxy compound, the intermediate 21-acetate is used as a substrate, an appropriate amount of methanol containing 0-10% chloroform is used as a solvent to semi-dissolve the substrate, and an alkali is used as a catalyst Carry out hydrolysis reaction, neutralize with acetic acid after the reaction is complete, concentrate the reaction solution under reduced pressure to an appropriate volume, cool the temperature, filter, rinse the filter cake with water, and dry to obtain 21-hydroxyl compound. The process can shorten the production cycle, improve the quality and yield of 21-hydroxyl compounds, and reduce the content of impurities in 21-hydroxyl compounds.

Development of dexamethasone

In 1958, Arth and Oliveto synthesized dexamethasone respectively. In 1960, Merck & Co. produced dexamethasone sodium phosphate, and more than 12 kinds of dexamethasone derivatives were listed on the market. The chemical structure of dexamethasone is the introduction of a fluorine atom at the 9α position of the B ring of prednisolone, and the introduction of a methyl group at the 16α ​​position of the D ring; both the 9α fluorine and the 16α ​​methyl group significantly enhance the anti-inflammatory activity, while the 16α ​​methyl group significantly Decreased sodium and water retention side effects of dexamethasone. The clinical bioequivalent dose ratio of dexamethasone to prednisolone is 0.75:5, the biological half-life is 36-54 hours, and it is classified as a long-acting glucocorticoid.

Like other glucocorticoids, dexamethasone has pharmacological effects such as anti-inflammatory, anti-endotoxin, immunosuppression, anti-shock and enhancement of stress response, so it is widely used in various departments to treat various diseases, such as autoimmune diseases, allergies, inflammation, asthma and dermatology, eye diseases. Dexamethasone Sodium Phosphate Injection is an indispensable first aid drug for the rescue of dying patients. In the past ten years, clinicians have used Dexamethasone Sodium Phosphate to treat and prevent drug allergies caused by various Chinese and Western medicines, and to treat fever caused by viral colds, etc. The clinical dosage of dexamethasone has increased year by year, and China has become the largest dexamethasone market in the world.

Pharmacological effects of dexamethasone

Dexamethasone, also known as flumethasone, flumethicone, and dexamethasone, is a glucocorticoid. Its derivatives include hydrocortisone, prednisone, etc., and its pharmacological effects are mainly anti-inflammatory, anti-toxic, anti-allergic and anti-rheumatic, and are widely used in clinical practice. It is easily absorbed from the digestive tract. Its plasma T1/2 is 190 minutes, and its tissue T1/2 is 3 days. After intramuscular injection of dexamethasone sodium phosphate or dexamethasone acetate, the peak plasma concentration is reached in 1 hour and 8 hours, respectively. . The plasma protein binding rate of this product is lower than that of other corticosteroids. The anti-inflammatory activity of 0.75mg of this product is equivalent to 5mg of prednisolone. Adrenal cortical hormone drugs have stronger anti-inflammatory, anti-allergic and anti-toxic effects than prednisone, and have less water and sodium retention and promotion of potassium excretion.

Anti-inflammatory effects of dexamethasone

Dexamethasone reduces and prevents the tissue response to inflammation, thereby reducing the manifestations of inflammation. Hormones inhibit the accumulation of inflammatory cells, including macrophages and leukocytes, at sites of inflammation, and inhibit phagocytosis, the release of lysosomal enzymes, and the synthesis and release of inflammatory chemical mediators.

Immunosuppressive effects of dexamethasone

Dexamethasone includes preventing or inhibiting cell-mediated immune responses, delayed allergic reactions, reducing the number of T lymphocytes, monocytes, and eosinophils, reducing the binding capacity of immunoglobulins to cell surface receptors, and inhibiting The synthesis and release of interleukins, thereby reducing the transformation of T lymphocytes to lymphoblasts, and reducing the expansion of the primary immune response. It can reduce the passage of immune complexes through the basement membrane, and can reduce the concentration of complement components and immunoglobulins. This product is easily absorbed from the gastrointestinal tract. Its plasma T1/2 is 190 minutes, and its tissue T1/2 is 3 days. After intramuscular injection of dexamethasone sodium phosphate or dexamethasone acetate, it reaches the blood level in 1 hour and 8 hours, respectively. peak concentration. The plasma protein binding rate of this product is lower than that of other corticosteroids, and the anti-inflammatory activity of 0.75mg of this product is equivalent to 5mg of prednisolone.

Pharmacokinetics of dexamethasone

Dexamethasone is easily absorbed from the digestive tract and can also be absorbed through the skin. After intramuscular injection of dexamethasone sodium phosphate or dexamethasone acetate, the peak blood concentration is reached after 1h and 8h, respectively. The plasma protein binding rate is lower than that of other corticosteroids, about 77%, and it is easy to pass through the placenta without being inactivated. The biological half-life of dexamethasone is about 190 minutes, and the tissue half-life is about 3 days. More than 65% of the drug is excreted from the urine within 24 hours, mainly inactive metabolites.

Reference

1 Lammers T, Sofias A M, Van der Meel R, et al. Dexamethasone nanomedicines for COVID-19[J]. Nature nanotechnology, 2020, 15(8): 622-624.