Dexamethason

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Sicherheit

  P201：Vor Gebrauch besondere Anweisungen einholen.

  P202：Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P308+P313：BEI Exposition oder falls betroffen: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P405：Unter Verschluss aufbewahren.

  P501：Inhalt/Behälter ... (Entsorgungsvorschriften vom Hersteller anzugeben) zuführen.

Dexamethasone Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R43:Sensibilisierung durch Hautkontakt möglich.
  R40:Verdacht auf krebserzeugende Wirkung.
  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
  R20/21/22:Gesundheitsschädlich beim Einatmen,Verschlucken und Berührung mit der Haut.

• S-Sätze Betriebsanweisung:

  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S22:Staub nicht einatmen.

• Beschreibung

  The activity of dexamethasone, as measured by glycogen deposition, is 20 times greater than that of hydrocortisone. It has five times the anti-inflammatory activity of prednisolone. Clinical data indicate that this compound has seven times the antirheumatic potency of prednisolone. It is roughly 30 times more potent than hydrocortisone. Its pharmacokinetics are presented in Table 33.3. Routes of metabolism for dexamethasone are similar to those for prednisolone, with its primary 6β-hydroxy metabolite being recovered in urine. Dexamethasone sodium phosphate is the water-soluble sodium salt of the 21-phosphate ester, with an IV half-life of less than 10 minutes because of rapid hydrolysis by plasma phosphatases. Peak plasma levels for dexamethasone usually are attained in approximately 10 to 20 minutes following its IV administered dose. A similar reaction occurs when the phosphate ester is applied topically or by inhalation.

• Chemische Eigenschaften

  White or almost white, crystalline powder.

• Originator

  Dexacen,Central,US,1977

• History

  A group of chemists at Merck discovered dexamethasone, a steroid hormone, in 1958 as an anti-inflammatory steroid. Merck marketed dexamethasone with a brand name Decadron in 1959.
  Since its emergence on the market in 1959, dexamethasone has become one of the two most popular orally bioavailable corticosteroids. The other one is prednisone. Having been on the market for over sixty years, dexamethasone has been tried with certain degree of success for many indications, making it seem like a panacea. For instance, it has been found to have efficacy for rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, and along with antibiotics in tuberculosis. Doctors are very familiar with dexamethasone’s pharmacological properties. Therefore, they have been using this drug on severe COVID patients "off label" to relieve their pneumonia symptoms.

• Verwenden

  Dexamethasone is used for the same indications as all corticosteroids; however, it exhibits a significantly more powerful anti-inflammatory and anti-allergic action. It is used for circulatory collapse—shock during or after surgical operations, trauma, blood loss, myocardial infarction, and burns. It is also used in severe infections—toxemia, vascular collapse in meningococcosis, septicemia, diphtheria, typhoid fever, and peritonitis. It is used in severe allergic conditions—asthmatic status, laryngeal edema, severe anaphylactic reactions to medicinal drugs, and pyrogenic reactions.

• Verwenden

  Anti-inflammatory glucocorticoidDexamethasone is used to treat inflammatory and autoimmune conditions such as rheumatoid arthritis and bronchospasm. It is useful to study apoptosis, cell signaling pathways and gene expression. It is associated with marbofloxacin and clotrimazole and finds application in veterinary medicine to treat difficult ear infections in dogs. It is also used to treat horses with swelling of of distal limbs and general bruising in combination with trichlormethiazide. It is also an anti-inflammatory glucocorticoid.

• Indications

  Cushing’s disease is defined as hypercortisolism due to chronic overproduction of corticotrophin by a corticotroph adenoma. Cortisol’s lack of suppressibility during the administration of low doses of dexamethasone but suppressibility during high-dose dexamethasone is the key diagnostic finding in 99% of the patients with Cushing’s disease. This contrasts with the lack of glucocorticoid suppressibility typically found in patients with corticotrophin-independent hypercortisolism (Cushing’s syndrome). A judicious selection of the available tests may be necessary to obtain an accurate diagnosis in patients with Cushing’s syndrome.

• Definition

  ChEBI: Dexamethasone is a fluorinated steroid that is 9-fluoropregna-1,4-diene substituted by hydroxy groups at positions 11, 17 and 21, a methyl group at position 16 and oxo groups at positions 3 and 20. It is a synthetic member of the class of glucocorticoids. It has a role as an adrenergic agent, an antiemetic, an antineoplastic agent, an environmental contaminant, a xenobiotic, an immunosuppressive agent and an anti-inflammatory drug. It is a fluorinated steroid, a 3-oxo-Delta(1),Delta(4)-steroid, a glucocorticoid, a 20-oxo steroid, an 11beta-hydroxy steroid, a 17alpha-hydroxy steroid and a 21-hydroxy steroid. It derives from a hydride of a pregnane.

• Manufacturing Process

  The preparation of dexamethasone acetate is described in US Patent 3,007,923 as follows. 1.5 cc of dimethylformamide and 1.5 cc of anhydrous hydrofluoric acid are admixed and treated with 480 mg of 9β,11β-epoxy-17αhydroxy-21-acetoxy-16α-methyl-1,4-pregnadiene-3,20-dione (prepared according to E.P. Oliveto et al, J. Am. Chem. Soc., 80, 44331, 1958). The steroid dissolves in about 15 minutes. The reaction mixture is shaken for two hours at a temperature between 0 and +5°C, and then poured into 75 cc of
  water containing in suspension, 7.5 grams of sodium bicarbonate. The mixture is vacuum filtered, the filter cake washed and then dried at 100°C, yielding 460 mg of crude hexadecadrol contaminated with a small amount of the starting material. A single recrystallization from methylene chloride yields 370 mg of the pure product having a melting point of 170°C and 229°C. The mother liquor yields 62 mg of the starting material, and a remainder constituting a mixture of starting and final materials with little other contamination.

• Trademarks

  Aeroseb-Dex (Allergan); Decadron (Merck); Dexone (Solvay Pharmaceuticals); Hexadrol (Organon); Maxidex (Alcon); Mymethasone (Morton Grove).

• Therapeutic Function

  9-Fluoro-11β,17-dihydroxy-21-acetoxy-16α-methylpregna1,4-diene-3,20-dione

• Allgemeine Beschreibung

  Dexamethasone, 9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione,is the 16 -isomer of betamethasone.
  Dexamethasone acetate, USP (21-acetate)
  Dexamethasone sodium phosphate, USP (21-sodiumphosphate).

• Allgemeine Beschreibung

  Odorless white to off-white crystalline powder with a slightly bitter taste.

• Air & Water Reaktionen

  Insoluble in water.

• Reaktivität anzeigen

  Dexamethasone may be sensitive to prolonged exposure to light. Dexamethasone is incompatible with strong oxidizers, strong acids, acid chlorides and acid anhydrides. Oxidation may occur with bases.

• Brandgefahr

  Flash point data for Dexamethasone are not available; however, Dexamethasone is probably combustible.

• Biologische Aktivität

  Glucocorticoid; anti-inflammatory. Reduces levels of activated NF- κ B in immature dendritic cells (DCs) and inhibits differentiation into mature DCs.

• Biochem/physiol Actions

  Target IC50: 5 nM Inhibiting the expression of inducible but not constitutive nitric oxide synthase in vascular endothelial cells

• Pharmakologie

  Dexamethasone is a corticosteroid with high glucocorticoid activity and virtually no mineralocorticoid activity. I ts mechanism of action as an antiemetic is unknown, but it is possible that either direct genomic or indirect non-genomic effects on 5-HT3 and GABAA receptors contribute to its antiemetic activity. Many of the original studies were carried out using 8– 10mg of dexamethasone phosphate, but smaller doses (2.5–4mg) provide equal antiemetic efficacy with minimal risk of adverse effects. Concerns relating to adrenal suppression and other steroid-induced adverse effects (including increased risk of bleeding) after a single dose of dexamethasone remain largely unfounded. O ne of the most unpleasant adverse effects of dexamethasone involves intense perineal stimulation after rapid i.v. injection.

• Pharmakokinetik

  The activity of dexamethasone, as measured by glycogen deposition, is 20 times greater than that of hydrocortisone. It has five times the anti-inflammatory activity of prednisolone. Clinical data indicate that this compound has seven times the antirheumatic potency of prednisolone. It is roughly 30 times more potent than hydrocortisone. Its pharmacokinetics are presented in Table 33.3. Routes of metabolism for dexamethasone are similar to those for prednisolone, with its primary 6β-hydroxy metabolite being recovered in urine. Dexamethasone sodium phosphate is the water-soluble sodium salt of the 21-phosphate ester, with an IV half-life of less than 10 minutes because of rapid hydrolysis by plasma phosphatases. Peak plasma levels for dexamethasone usually are attained in approximately 10 to 20 minutes following its IV administered dose. A similar reaction occurs when the phosphate ester is applied topically or by inhalation.

• Clinical Use

  Corticosteroid:
  Cerebral oedema
  Bacterial meningitis (unlicensed indication)
  Suppression of inflammatory and allergic disorders
  Rheumatic disease
  Congenital adrenal hyperplasia
  Anti-emetic (unlicensed indication)

• Sicherheitsprofil

  Poison by intraperitoneal and subcutaneous routes. An experimental teratogen. Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits toxic fumes of F-.

• Synthese

  Dexamethasone, 9|á-fluoro-16|á-methyl-11|,17,21-trihydroxypregna- 1,4-dien-3,20-dione (27.1.51), or simply 9|á-fluoro-16|á-methylprednisolone. The distinctive characteristic of dexamethasone is the presence of a fluorine atom at C9 of the steroid ring.
  Dexamethasone is synthesized in a multistage process from 3|á-acetoxy-16-pregnen- 11,20-dione, which is reacted with methylmagnesium bromide in the presence of lithium bromide to give 3|á-hydroxy-16|á-methylpregnan-11,20-dione (27.1.39), after which a 17|á- hydroxyl group is added. This is done by a reaction with acetic anhydride in the presence of p-toluenesulfonic acid, forming the 3-acetoxy-17-enolacetate 27.1.40, which is epoxidized by perbenzoic acid 27.1.41, and the product is hydrolyzed by an alkali to give an oxyketone 27.1.42. Addition of another hydroxyl group at C21 is accomplished by subsequent bromination of a methyl group with molecular bromine, replacing the bromine atom with iodine, and reacting iodide with potassium acetate, which forms the corresponding acetoxyketone 27.1.43. The hydroxyl group at C3 is oxidized to a carbonyl by chromium(VI) oxide in pyridine, giving the 3,11,20-triketone 27.1.44, which again undergoes bromination by molecular bromine, but at position C4. Dehydrogenation of this compound is accomplished using semicarbazide, which results in the formation of an unsaturated triketone 27.1.45. In order to avoid formation of semicarbazones at the keto-groups at C3 and C20, the final product is treated with pyruvic acid. Semicarbazones are then specially formed at the keto-groups of C3 and C20, and the keto-group at C11 that does not take part in semicarbazone formation is reduced to hydroxyl group using sodium borohydride. After removing the protective semicarbzone groups, 21-O-acetoxy-16|-methylhydrocortisone (27.1.46) is formed. This is reacted with potassium acetate and transformed to the epoxide 27.1.49. Reacting this with hydrofluoric acid results in an opening of the epoxide ring, during which the fluorohydrin 27.1.50 is formed. Finally, microbiological dehydrogenation of this compound at C1¨CC2 and simultaneous deacetylation gives dexamethasone (27.1.51).

  

• Veterinary Drugs and Treatments

  Glucocorticoids have been used in an attempt to treat practically every malady that afflicts man or animal, but there are three broad uses and dosage ranges for use of these agents. 1) Replacement of glucocorticoid activity in patients with adrenal insufficiency, 2) as an antiinflammatory agent, and 3) as an immunosuppressive. Among some of the uses for glucocorticoids include treatment of: endocrine conditions (e.g., adrenal insufficiency), rheumatic diseases (e.g., rheumatoid arthritis), collagen diseases (e.g., systemic lupus), allergic states, respiratory diseases (e.g., asthma), dermatologic diseases (e.g., pemphigus, allergic dermatoses), hematologic disorders (e.g., thrombocytopenias, autoimmune hemolytic anemias), neoplasias, nervous system disorders (increased CSF pressure), GI diseases (e.g., ulcerative colitis exacerbations), and renal diseases (e.g., nephrotic syndrome). Some glucocorticoids are used topically in the eye and skin for various conditions or are injected intra-articularly or intralesionally. The above listing is certainly not complete. For specific dosages and indications refer to the Doses section.
  High dose dexamethasone use for shock or CNS trauma is controversial; recent studies have not demonstrated significant benefit and it actually may cause increased deleterious effects.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Aldesleukin: avoid concomitant use.
  Antibacterials: metabolism accelerated by rifamycins; metabolism possibly inhibited by erythromycin; concentration of isoniazid possibly reduced.
  Anticoagulants: efficacy of coumarins and phenindione may be altered.
  Antiepileptics: metabolism accelerated by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone
  Antifungals: increased risk of hypokalaemia with amphotericin - avoid; metabolism possibly inhibited by itraconazole and ketoconazole; caspofungin concentration possibly reduced (may need to increase dose).
  Antivirals: concentration of indinavir, lopinavir, saquinavir and telaprevir possibly reduced; avoid with rilpivirine; concentration possibly increased by ritonavir.Ciclosporin: rare reports of convulsions in patients on ciclosporin and high-dose corticosteroids.
  Cobicistat: concentration possibly increased by cobicistat.
  Cytotoxics: possibly decreases axitinib concentration, increase dose of axitinib.
  Diuretics: enhanced hypokalaemic effects of acetazolamide, loop diuretics and thiazide diuretics.
  Netupitant: concentration of dexamethasone increased - halve dexamethasone dose.
  Vaccines: high dose corticosteroids can impair immune response to vaccines; avoid concomitant use with live vaccines.

• Stoffwechsel

  Corticosteroids are metabolised mainly in the liver but also in other tissues, and are excreted in the urine. The slower metabolism of the synthetic corticosteroids with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids. Up to 65% of a dose of dexamethasone is excreted in urine within 24 hours.

• Lager

  -20°C (protect from light)

• läuterung methode

  Dexamethasone has been recrystallised from Et2O or small volumes of EtOAc. Its solubility in H2O is 10 mg/100mL at 25o; and is freely soluble in Me2CO, EtOH and CHCl3. [Arth et al. J Am Chem Soc 80 3161 1958; for the -methyl isomer see Taub et al. J Am Chem Soc 82 4025 1960, see Beilstein 8 IV 3501.]

• Einzelnachweise

  [1] Merck’s Index, Nachtrag 1930. Verlag von E. Merck, Darmstadt. 14 Seiten[J]. Archiv der Pharmazie, 1930, 268 6: 444-445. DOI:10.1002/ardp.19302680608

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