Dexamethasone
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| Systematic (IUPAC) name | |
| (8S,9R,10S,11S,13S,14S,16R,17R)-9- Fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-6,7,8,9,10,11,12,13,14,15,16,17- dodecahydro-3H-cyclopenta[a]phenanthren-3-one | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682792 |
| Pregnancy cat. | C (US) |
| Legal status | ℞ Prescription only |
| Routes | Oral, IV, IM, SC and IO |
| Pharmacokinetic data | |
| Bioavailability | 80-90% |
| Protein binding | 70% |
| Metabolism | hepatic |
| Half-life | 36-54 hours |
| Excretion | renal |
| Identifiers | |
| CAS number | 50-02-2  |
| ATC code | A01AC02 C05AA09, D07AB19, D10AA03, H02AB02, R01AD03, S01BA01, S02BA06, S03BA01 |
| PubChem | CID 5743 |
| DrugBank | DB01234 |
| ChemSpider | 5541 |
| UNII | 7S5I7G3JQL |
| KEGG | D00292 |
| ChEBI | CHEBI:41879 |
| ChEMBL | CHEMBL384467 |
| Chemical data | |
| Formula | C22H29FO5 |
| Mol. mass | 392.461 g/mol |
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Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant. When taken orally, it is 26.6 times more potent than the naturally occurring hormone cortisol and 6.6 times more potent than prednisone.[citation needed]
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[edit] Therapeutic use
[edit] Anti-inflammatory
Dexamethasone is used to treat many inflammatory and autoimmune conditions, such as rheumatoid arthritis and bronchospasm.[1] Idiopathic thrombocytopenic purpura, decreased numbers of platelets due to an immune problem, responds to 40 mg daily for four days; it may be administered in 14-day cycles. It is unclear whether dexamethasone in this condition is significantly better than other glucocorticoids.[2]
It is also given in small amounts[3] (usually five or six tablets) before and/or after some forms of dental surgery, such as the extraction of the wisdom teeth, an operation which often leaves the patient with puffy, swollen cheeks.
It is injected into the heel when treating plantar fasciitis, sometimes in conjunction with triamcinolone acetonide.
It is useful to counteract allergic anaphylactic shock, if given in high doses.
It is present in certain eye drops – particularly after eye surgery– and as a nasal spray (trade name Dexacort), and certain ear drops (Sofradex, when combined with an antibiotic and an antifungal).
Dexamethasone is used in transvenous screw-in cardiac pacing leads to minimize the inflammatory response of the myocardium. The steroid is released into the myocardium as soon as the screw is extended and can play a significant role in minimizing the acute pacing threshold due to the reduction of inflammatory response. The typical quantity present in a lead tip is less than 1.0 mg.
Dexamethasone is often administered before antibiotics in cases of bacterial meningitis. It then acts to reduce the inflammatory response of the body to the bacteria killed by the antibiotics (bacterial death releases proinflammatory mediators that can cause a response which is harmful to the patient), thus improving prognosis and outcome.[4]
[edit] Oncologic uses
Cancer patients undergoing chemotherapy are given dexamethasone to counteract certain side effects of their antitumor treatment. Dexamethasone can augment the antiemetic effect of 5-HT3 receptor antagonists, such as ondansetron.
In brain tumors (primary or metastatic), dexamethasone is used to counteract the development of edema, which could eventually compress other brain structures. It is also given in cord compression, where a tumor is compressing the spinal cord.
Dexamethasone is also used as a direct chemotherapeutic agent in certain hematological malignancies, especially in the treatment of multiple myeloma, in which dexamethasone is given alone or in combination with other chemotherapeutic drugs, including most commonly with thalidomide (thal-dex), lenalidomide, bortezomib (Velcade; Vel-dex),[5] or a combination of Adriamycin (doxorubicin) and vincristine (VAD) or VRD- Velcade, Revlamid and Dexamethasone.
[edit] Endocrine
Dexamethasone is the treatment for the very rare disorder of glucocorticoid resistance.[6][7]
In adrenal insufficiency and Addison's disease, dexamethasone is prescribed when the patient does not respond well to prednisone or methylprednisolone.
[edit] Obstetrics
Dexamethasone may be given to women at risk of delivering prematurely to promote maturation of the fetus' lungs. This has been associated with low birth weight, although not with increased rates of neonatal death.[8]
[edit] High altitude illnesses
Dexamethasone is used in the treatment of high altitude cerebral edema, as well as pulmonary edema. It is commonly carried on mountain climbing expeditions to help climbers deal with altitude sickness.[9][10]
[edit] Off-label use
[edit] Congenital adrenal hyperplasia
Dexamethasone has been used as an off-label prenatal treatment for the symptoms of congenital adrenal hyperplasia (CAH) in female fetuses. CAH causes a variety of physical abnormalities, notably ambiguous genitalia in girls. Early prenatal CAH treatment has been shown to reduce some CAH symptoms, but it does not treat the underlying congenital disorder.
A small clinical trial found long-term effects on verbal working memory among the small group of children treated prenatally, but the small number of test subjects means the study cannot be considered definitive.[11][12] Administration of prenatal dexamethasone has been the subject of controversy over issues of informed consent and because treatment must predate a clinical diagnosis of CAH in the female fetus.
A study utilizing Freedom of Information Act findings to "detail an extremely troubling off-label medical intervention employed in the U.S. on pregnant women to intentionally engineer the development of their fetuses for sex normalization purposes." [13] Glucocorticoids may alter “fetal programming,” potentially resulting in serious metabolic problems that will not become apparent until adulthood.[11][14][13] Prenatal treatment of female fetuses could prevent those fetuses from becoming lesbians after birth, may make them more likely to engage in "traditionally" female-identified behaviour and careers, and more interested in bearing and raising children.[15] The essay suggests prenatal "dex" treatments constitute the first known attempt to use an in utero method to attempt to reduce the incidence of homosexuality in humans.[16] A medical consensus in 2010 by the Endocrine Society and affiliated organizations indicated prenatal dexamethasone for CAH should be regarded as experimental and should only be used in Institutional Review Board-approved controlled clinical trials at centers large enough to collect meaningful data.[17]
[edit] Abuses
Dexamethasone has also been used in the hope of enhancing sports performance.[18]
Long term use of dexamethasone under the brand name Oradexon is widespread among prostitutes in Bangladesh in spite of the dangers, because it helps them develop fat easily.[19][20]
Since dexamethasone is a CYP2D6 enzyme inducer, it can increase the effects of many prodrugs and protoxins which are metabolized via CYP2D6 (ex. tramadol, codeine) by directly increasing the amount of the active metabolite produced.
[edit] Diagnostic use
Dexamethasone is also used in a diagnostic context, namely in its property to suppress the natural pituitary-adrenal axis.
Patients presenting with clinical signs of glucocorticoid excess (Cushing's syndrome) are generally diagnosed by a 24-hour urine collection for cortisol or by a dexamethasone suppression test. During the latter, the response of the body to a high dose of glucocorticoids is monitored. Various forms are performed. In the most common form, a patient takes a nighttime dose of either 1 or 4 mg of dexamethasone, and the serum cortisol levels are measured in the morning. If the levels are relatively high (over 5 µg/dL or 150 nmol/L), then the test is positive and the patient has an autonomous source of either cortisol or ACTH, indicating Cushing's syndrome where the tumor does not have a feedback mechanism. If ACTH levels are lowered by at least 50%, this would indicate Cushing's disease, since the pituitary adenoma has a feedback mechanism that has been reset to a higher level of cortisol. Longer versions rely on urine collections on oral dexamethasone over various days.
[edit] Veterinary use
Combined with marbofloxacin and clotrimazole, dexamethasone is available under the name Aurizon, CAS number 115550-35-1, and used to treat difficult ear infections, especially in dogs. It can also be combined with trichlormethiazide to treat horses with swelling of distal limbs and general bruising.[21]
[edit] Contraindications
Some of these contraindications are relative:
- Existing gastrointestinal ulceration
- Cushing's syndrome
- Severe forms of heart insufficiency
- Severe hypertension
- Uncontrolled diabetes mellitus
- Systemic tuberculosis
- Severe systemic viral, bacterial, and fungal infections
- Pre-existing wide angle glaucoma
- Osteoporosis
[edit] Side effects
If dexamethasone is given orally or by injection (parenteral) over a period of more than a few days, side effects common to systemic glucocorticoids may occur. These may include:
- Stomach upset, increased sensitivity to stomach acid to the point of ulceration of esophagus, stomach, and duodenum
- Increased appetite leading to significant weight gain
- A latent diabetes mellitus often becomes manifest, glucose intolerance is worsened in patients with pre-existing diabetes
- Immunosuppressant action, particularly if given with other immunosuppressants, such as cyclosporine, may allow bacterial, viral, and fungal disease to progress more easily and can become life-threatening; fever as a warning symptom is often suppressed.
- Psychiatric disturbances, including personality changes, irritability, euphoria, or mania and mood swings.
- Osteoporosis under long term treatment, pathologic fractures (e.g., hip)
- Muscle atrophy, negative protein balance (catabolism)
- Elevated liver enzymes, fatty liver degeneration (usually reversible)
- Cushingoid (syndrome resembling hyperactive adrenal cortex with increase in adiposity, hypertension, bone demineralization, etc.)
- Depression of the adrenal gland is usually seen, if more than 1.5 mg daily are given for more than three weeks to a month.
- Hypertension, fluid and sodium retention, edema, worsening of heart insufficiency (due to mineralocorticoid activity)
- Dependence with withdrawal syndrome is frequently seen.
- Increased intraocular pressure, certain types of glaucoma, cataract (serious clouding of eye lenses)
- Dermatologic: Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, erythema, impaired wound-healing, increased sweating, rash, striae, suppression of reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.
- Pronounced night sweats.
- Allergic reactions (though infrequently): Anaphylactoid reaction, anaphylaxis, angioedema.
Other side effects have been noted, and should cause concern if they are more than mild.
The short-time treatment for allergic reaction, shock, and diagnostic purposes usually does not cause serious side effects.
Novelist Michael Cox believed his first book, The Meaning of Night was a side effect of prescription dexamethasone, giving him both "formidable energy" while quelling his creative doubts.[22]
[edit] Interactions
- NSAIDs and alcohol: increased risk of gastrointestinal ulceration
- Mineralocorticoids: increased risk of hypertension, edema and heart problems
- Oral antidiabetic drugs and insulin: antidiabetic therapy may have to be adjusted
- Tramadol: increased conversion to O-desmethyltramadol
- Codeine: increased conversion to morphine
Other interactions (with certain antibiotics, estrogens, ephedrine, digoxin) are known.
[edit] Synthesis
To synthesise dexamethasone, 16β-methylprednisolone acetate is dehydrated to the 9,11 dehydro derivative. This is then reacted with a source of hypobromite, such as basic N-bromosuccinimide, to form the 9α-bromo-11β-hydrin derivative, which is then ring-closed to an epoxide. A ring-opening reaction with hydrogen fluoride in tetrahydrofuran gives dexamethasone.[23][24]
[edit] References
- ^ Till, John. "Paramedic Clinical Training Aid". Retrieved 30 August 2011.
- ^ Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines DB, Gernsheimer TB, Godeau B, Grainger J, Greer I, Hunt BJ, Imbach PA, Lyons G, McMillan R, Rodeghiero F, Sanz MA, Tarantino M, Watson S, Young J, Kuter DJ (January 2010). "International consensus report on the investigation and management of primary immune thrombocytopenia". Blood 115 (2): 168–86. doi:10.1182/blood-2009-06-225565. PMID 19846889.
- ^ Schmelzeisen R, Frölich JC (1993). "Prevention of postoperative swelling and pain by dexamethasone after operative removal of impacted third molar teeth". Eur. J. Clin. Pharmacol. 44 (3): 275–7. doi:10.1007/BF00271371. PMID 8491244.
- ^ van de Beek D, de Gans J, McIntyre P, Prasad K (2007). "Corticosteroids for acute bacterial meningitis". Cochrane Database Syst Rev (1): CD004405. doi:10.1002/14651858.CD004405.pub2. PMID 17253505.
- ^ Harousseau JL, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM, Hulin C, Benboubker L, Fuzibet JG, Renaud M, Moreau P, Avet-Loiseau H (November 2006). "Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study". Haematologica 91 (11): 1498–505. PMID 17043025.
- ^ Chrousos GP, Detera-Wadleigh SD, Karl M (December 1993). "Syndromes of glucocorticoid resistance". Ann. Intern. Med. 119 (11): 1113–24. doi:10.1059/0003-4819-119-11-199312010-00009. PMID 8239231.
- ^ Charmandari E, Kino T, Ichijo T, Chrousos GP (May 2008). "Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder". J. Clin. Endocrinol. Metab. 93 (5): 1563–72. doi:10.1210/jc.2008-0040. PMC 2386273. PMID 18319312.
- ^ Bloom SL, Sheffield JS, McIntire DD, Leveno KJ (April 2001). "Antenatal dexamethasone and decreased birth weight". Obstet Gynecol 97 (4): 485–90. doi:10.1016/S0029-7844(00)01206-0. PMID 11275014.
- ^ Cymerman a, Rock PB (1994). Medical Problems in High Mountain Environments. A Handbook for Medical Officers. USARIEM-TN94-2. US Army Research Inst. of Environmental Medicine Thermal and Mountain Medicine Division Technical Report. Retrieved 2010-09-06.
- ^ Eledrisi MS (April 2007). "First-line therapy for hypertension". Ann. Intern. Med. 146 (8): 615. PMID 17438328.
- ^ a b Hirvikoski T, Nordenström A, Lindholm T, Lindblad F, Ritzén EM, Wedell A, Lajic S (February 2007). "Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone". J. Clin. Endocrinol. Metab. 92 (2): 542–8. doi:10.1210/jc.2006-1340. PMID 17148562.
- ^ Lajic S, Nordenström A, Hirvikoski T (2011). "Long-term outcome of prenatal dexamethasone treatment of 21-hydroxylase deficiency". Endocr Dev 20: 96–105. doi:10.1159/000321228. PMID 21164263.
- ^ a b Dreger A, Feder EK, Tamar-Mattis A (2012). "Prenatal Dexamethasone for Congenital Adrenal Hyperplasia". Journal of Bioethical Inquiry: 1–18. doi:10.1007/s11673-012-9384-9.
- ^ Marciniak B, Patro-Małysza J, Poniedziałek-Czajkowska E, Kimber-Trojnar Z, Leszczyńska-Gorzelak B, Oleszczuk J (May 2011). "Glucocorticoids in pregnancy". Curr Pharm Biotechnol 12 (5): 750–7. PMID 21342122.
- ^ Dreger A, Feder EJ, Tamar-Mattis A (2010-06-29). "Preventing Homosexuality (and Uppity Women) in the Womb?". Bioethics Forum blog. The Hastings Center. Retrieved 2011-10-11.
- ^ Elton C (2010-06-18). "A Prenatal Treatment Raises Questions of Medical Ethics". TIME. Retrieved 2010-07-05.
- ^ Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC (September 2010). "Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline". J. Clin. Endocrinol. Metab. 95 (9): 4133–60. doi:10.1210/jc.2009-2631. PMC 2936060. PMID 20823466.
- ^ "FIS Doping Control statement on Kowalcyzk". International Ski Federation. 2005-06-13. Retrieved 2006-07-30.
- ^ Moorhead J (2010-04-05). "A new danger for sex workers in Bangladesh". The Guardian.
- ^ Dummett M (2010-04-30). "Bangladesh's dark brothel steroid secret". BBC News.
- ^ "Trichlormethiazide and Dexamethasone for veterinary use". Wedgewood Pharmacy. Retrieved 2008-01-23.
- ^ The Times 4 April 2009 Michael Cox: Publisher's editor who scored a...
- ^ Arth GE, Fried J, Johnston DBR, Hoff, DR, Sarett HL, Silber RH, Stoerk HC, Winter CA (1958). "16-Methylated steroids. II. 16α-Methyl analogs of cortisone, a new group of anti-inflammatory steroids. 9α-Halo derivatives". Journal of the American Chemical Society 80 (12): 3161. doi:10.1021/ja01545a063.
- ^ Taub D, Hoffsommer (1958). "16β-Methyl cortical steroids". Journal of the American Chemical Society 80 (16): 4435. doi:10.1021/ja01549a095. Text " RD, Slates HL" ignored (help); Text " lWendler NL " ignored (help)
[edit] External links
- "Understanding Dexamethasone and Other Steroids".
- "Dexamethasone". U.S. National Library of Medicine: Drug Information Portal.
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