Dexamethasone

Dexamethasone is a fluorinated glucocorticoid medication and along with antibiotics in tuberculosis.

The long-term use of dexamethasone may result in thrush, bone loss, cataracts, easy bruising, or muscle weakness. In Australia, the oral use is category A, meaning it has been frequently used in pregnancy and not been found to cause problems to the baby. It should not be taken when breastfeeding. It is on the World Health Organization's List of Essential Medicines. In 2023, it was the 246th most commonly prescribed medication in the United States, with more than 1million prescriptions. It is available as a generic medication. In 2023, the combination of dexamethasone with neomycin and polymyxin B was the 260th most commonly prescribed medication in the United States, with more than 1million prescriptions; and the combination of dexamethasone with ciprofloxacin was the 283rd most commonly prescribed medication in the United States, with more than 700,000 prescriptions;

Medical uses

thumb|Dexamethasone phosphate injection ampoules

Anti-inflammatory

thumb|Dexamethasone tablets

Dexamethasone is used to treat many inflammatory and autoimmune disorders, such as rheumatoid arthritis and bronchospasm. Idiopathic thrombocytopenic purpura, a decrease in 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.

It is also given in small amounts before and/or after some forms of dental surgery, such as the extraction of the wisdom teeth, an operation that often causes puffy, swollen cheeks.

Dexamethasone is commonly given as a treatment for croup in children.

Dexamethasone is sometimes injected into the heel when treating plantar fasciitis or heel pain, sometimes in conjunction with triamcinolone acetonide. There is no evidence that this treatment helps in the long term, however, dexamethasone may provide short-term pain relief.

It may be useful to counteract allergic anaphylactic shock, however this is not usually recommended by clinical guidelines.

It is present in certain eye drops – particularly after eye surgery – and as a nasal spray, and certain ear drops (can be combined with an antibiotic and an antifungal). Dexamethasone intravitreal steroid implants have been approved by the US Food and Drug Administration (FDA) to treat ocular conditions such as diabetic macular edema, central retinal vein occlusion, and uveitis. However, the evidence is poor quality relating to the treatment of uveitis, with the potential side effects (cataract progression and raised intraocular pressure) being significant, and the benefits not certainly greater than standard treatment. Dexamethasone has also been used with antibiotics to treat acute endophthalmitis.

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 may be administered before antibiotics in cases of bacterial meningitis. Gram-negative bacteria — to which the causative agent of bacterial meningitis, Neisseria meningitidis, belongs — have highly immunogenic lipopolysaccharides as a component of their cell membrane and trigger a strong inflammatory response. Pre-administration of dexamethasone before the administration of antibiotics acts to reduce that response, thus reducing hearing loss and neurological damage.

thumb|A single ampoule of dexamethasone phosphate for injection

Cancer

People with cancer undergoing chemotherapy are often given dexamethasone to counteract certain side effects of their antitumor treatments. Dexamethasone can increase the antiemetic effect of 5-HT3 receptor antagonists, such as ondansetron. The exact mechanism of this interaction is not well-defined, but it has been theorized that this effect may be due to, among many other causes, inhibition of prostaglandin synthesis, anti-inflammatory effects, immunosuppressive effects, decreased release of endogenous opioids, or a combination of the aforementioned.

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. Evidence on the safety and efficacy of using dexamethasone to treat malignant brain tumors is not clear.

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), or a combination of doxorubicin (Adriamycin) and vincristine or bortezomib/lenalidomide/dexamethasone.

COVID-19

Dexamethasone is recommended by the National Health Service in the UK and the National Institutes of Health (NIH) in the US for people with COVID-19 who need either mechanical ventilation or supplemental oxygen (without ventilation).

The Infectious Diseases Society of America (IDSA) guideline panel suggests the use of glucocorticoids for people with severe COVID-19, defined as people with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The IDSA recommends against the use of glucocorticoids for those with COVID-19 without hypoxemia requiring supplemental oxygen. A meta-analysis of seven clinical trials of critically ill COVID-19 participants, each treated with one of three different corticosteroids found a statistically significant reduction in death.

In September 2020, the European Medicines Agency (EMA) endorsed the use of dexamethasone in adults and adolescents, from twelve years of age and weighing at least , who require supplemental oxygen therapy. Dexamethasone can be taken by mouth or given as an injection or infusion (drip) into a vein. Although dexamethasone, and other glucocorticoids, reduce mortality in COVID-19 they have also been associated with an increased risk of secondary infections, secondary infections being a significant issue in critically ill COVID-19 patients.

The mechanism of action of dexamethasone involves suppression of late-stage interferon type I programs in severe COVID-19 patients.

Surgery

Dexamethasone is used fairly regularly, often as a single intravenous dose, during surgery to prevent postoperative nausea and vomiting, manage pain, potentially reduce the amount of pain medication required, and help reduce post-surgery hospitalisation time.

Endocrine

Dexamethasone is the treatment for the very rare disorder of glucocorticoid resistance.

In adrenal insufficiency and Addison's disease, dexamethasone is prescribed when the patient does not respond well to prednisone or methylprednisolone.

It can be used in congenital adrenal hyperplasia in older adolescents and adults to suppress adrenocorticotropic hormone (ACTH) production. It is typically given at night.

Pregnancy

Dexamethasone may be given to women at risk of delivering prematurely to promote maturation of the fetus's lungs. This administration, given from one day to one week before delivery, has been associated with low birth weight, although not with increased rates of neonatal death.

Dexamethasone has also been used during pregnancy as an off-label prenatal treatment for the symptoms of congenital adrenal hyperplasia (CAH) in female babies. CAH causes a variety of physical abnormalities, notably ambiguous genitalia. Early prenatal CAH treatment has been shown to reduce some CAH symptoms, but it does not treat the underlying congenital disorder. This use is controversial: it is inadequately studied, only around one in ten of the fetuses of women treated are at risk of the condition, and serious adverse events have been documented. Experimental use of dexamethasone in pregnancy for fetal CAH treatment was discontinued in Sweden when one in five cases had adverse events.

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.

High-altitude illnesses

Dexamethasone is used in the treatment of high-altitude cerebral edema (HACE), as well as high-altitude pulmonary edema (HAPE). It is commonly carried on mountain-climbing expeditions to help climbers deal with complications of altitude sickness.

Nausea and vomiting

Intravenous dexamethasone is effective for the prevention of nausea and vomiting in people who had surgery and whose post-operative pain was treated with long-acting spinal or epidural spinal opioids.

The combination of dexamethasone and a 5-HT3 receptor antagonist such as ondansetron is more effective than a 5-HT3 receptor antagonist alone in preventing postoperative nausea and vomiting.

Sore throat

A single dose of dexamethasone or another steroid speeds the improvement of a sore throat.

Contraindications

Contraindications of dexamethasone include,

Common

Acne
Amnesia
Birth defect
Cataract (in long-term treatment, occurs in about 10% of patients)
Confusion
Depression
Dyspepsia
Euphoria
Headaches
Hiccups (in long-term treatment, occurs in about 11% of patients)
Hyperglycemia
Hypertension
Impaired skin healing and wound repair
Increased appetite
Increased risk of viral, bacterial, fungal, and parasitic infections
Insomnia
Irritability
Malaise
steroid induced Muscle atrophy and myopathy
Nausea
Ocular hypertension
Osteoporosis
Vertigo
Vomiting
Weight gain

Unknown frequency

Abdominal distension
Adrenal suppression
Allergic reactions (including anaphylaxis)
Arterial thrombosis
Aspergillosis
Bruising
Candidiasis
Cardiomyopathy
Cleft palate
Corneal or scleral thinning
Cushing's syndrome
Edema
Esophageal ulcer
Facial plethora
Glaucoma
Growth stunting (in children)
Herpes zoster
Hypernatremia
Hypertriglyceridemia
Hypocalcemia
Hypokalemia
Intracranial hypertension (with long-term treatment)
Leukocytosis
Mania
Mucormycosis
Pancreatitis (inflammation of the pancreas)
Papilledema
Peptic ulcer
Perineal or vulvar pruritus (upon IV administration)
Protein catabolism (causing nitrogen depletion)
Psychological dependence
Psychosis
Seizures
Skin atrophy
Striae
Telangiectasia
Thromboembolism
Venous thrombosis
Vertebral collapse

Withdrawal

Sudden withdrawal after long-term treatment with corticosteroids can lead to It is highly selective for the GR over the mineralocorticoid receptor (MR), and in relation to this, has minimal mineralocorticoid activity. This is in contrast to endogenous corticosteroids like cortisol, which bind to and activate both the GR and the MR. However, higher doses of dexamethasone override the export capacity of P-glycoprotein and enter the brain to produce central activation of GRs. The molecular and crystal structure of dexamethasone has been determined by X-ray crystallography. It is a stereoisomer of betamethasone, the two compounds differing only in the spatial configuration of the methyl group at position 16 (see steroid nomenclature).

Synthesis

To synthesize 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.

class=skin-invert-image|700px|center|thumb|Dexamethasone synthesis

Spectroscopy

In chemistry, spectroscopy is used to analyze products of reactions. To understand if dexamethasone is synthesized from a reaction, spectroscopy must be taken and compared to the literature spectrum. There are multiple spectroscopy analyses that can be taken including 1H NMR, 13C NMR, IR, Mass spectrometry, and UV/vis spectroscopy.<div class="skin-invert-image"><gallery mode="nolines" widths="400" heights="350" caption="NMR spectrum for dexamethasone">

File:1H NMR for Dexamethasone.png|1H NMR spectrum for dexamethasone

File:13C NMR for Dexamethasone.png|13C NMR spectrum for dexamethasone

File:UV-vis spectroscopy of Dexamethasone.png|UV-vis spectrum of dexamethasone

</gallery></div>

Using IR spectroscopy, the peaks show the functional groups found in the molecule. Peaks at 3472, 1662, and 1618 represent alcohol, aldehyde, and alkene functional groups. UV-vis spectroscopy is another way to analyze a product to figure out what it is.

Finally, mass spectroscopy showed peaks at: 393.1, 355.2 147.1 m/z. The peak at 393.1 m/z is the peak for dexamethasone as its molecular weight is 392.46 m/z.

Analogues

A notable related compound is the membrane-limited dexamethasone-BSA.

History

Dexamethasone was first synthesized by Philip Showalter Hench in 1957.

On 16 June 2020, the RECOVERY Trial announced preliminary results stating that dexamethasone improves survival rates of hospitalized patients with COVID-19 receiving oxygen or on a ventilator. Benefits were only observed in patients requiring respiratory support; those who did not require breathing support saw a worse survival rate than the control group, although the difference may have been due to chance.

A preprint containing the full dataset was published on 22 June 2020, and demand for dexamethasone surged after the publication of the preprint. The preliminary report was published in The New England Journal of Medicine on 18 July 2020. The final report was published in February 2021.

The World Health Organization (WHO) states that dexamethasone should be reserved for seriously ill and critical patients receiving COVID-19 treatment in a hospital setting, and the WHO Director-General stated that "WHO emphasizes that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision. There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm." In July 2020, the WHO stated they were in the process of updating treatment guidelines to include dexamethasone or other steroids. In September 2020, the WHO released updated guidance on using corticosteroids for COVID-19.

In July 2020, the European Medicines Agency (EMA) started reviewing results from the RECOVERY study arm that involved the use of dexamethasone in the treatment of patients with COVID-19 admitted to the hospital to provide an opinion on the results and in particular the potential use of dexamethasone for the treatment of adults with COVID-19. In September 2020, the EMA received an application for marketing authorization of dexamethasone for COVID-19.

Society and culture

Price

Dexamethasone is inexpensive. In the United States a month of medication is typically priced less than .

Dexamethasone and most glucocorticoids are banned by sporting bodies including the World Anti-Doping Agency.

Veterinary use

Combined with marbofloxacin CAS number 115550-35-1and clotrimazole, dexamethasone is available under the name Aurizon, CAS number 50-02-2, 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. Dexamethasone is also used for emergency patients with hypoadrenocorticism as the drug does not interfere with adrenocorticotropic hormone stimulation testing.