Chemistry:Hydrocortisone

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Hydrocortisone is the name for the hormone cortisol when supplied as a medication.[1] It is a corticosteroid and works as an anti-inflammatory and by immune suppression.[2] Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD.[2] It is the treatment of choice for adrenocortical insufficiency.[3] It can be given by mouth, topically, rectally or by injection.[2] Stopping treatment after long-term use should be done slowly.[2]

Common side effects may include mood changes, increased appetite, hyperglycemia, hypertension, and edema (swelling).[4] With long-term use, common side effects include osteoporosis, adrenal insufficiency, upset stomach, physical weakness, easy bruising, and candidiasis (yeast infections).[2][4] It is unclear if it is safe for use during pregnancy.[5]

Hydrocortisone was patented in 1936 and approved for medical use in 1941.[6][7] It is on the World Health Organization's List of Essential Medicines.[8] It is available as a generic medication.[2] In 2023, it was the 182nd most commonly prescribed medication in the United States, with more than 2 million prescriptions.[9][10]

Medical uses

Hydrocortisone is the pharmaceutical term for cortisol used in oral administration, intravenous injection, or topical application. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients needing steroid treatment but unable to take oral medication, and perioperatively in patients on long-term steroid treatment to prevent an adrenal crisis. It may also be injected into inflamed joints resulting from diseases such as gout.[citation needed]


It may also be used rectally in suppositories to relieve the swelling, itch, and irritation in hemorrhoids.[11]

It may be used as an acetate form (hydrocortisone acetate), which has slightly different pharmacokinetics and pharmacodynamics.[11][12]

  • Cortisol for injection
    Cortisol for injection
  • A tube of hydrocortisone cream, purchased over-the-counter
    A tube of hydrocortisone cream, purchased over-the-counter
  • Hydrocortisone 10 mg oral tablets (depicted a package for Russian market)
    Hydrocortisone 10 mg oral tablets (depicted a package for Russian market)

Pharmacology

Pharmacodynamics

Hydrocortisone is a corticosteroid, acting specifically as both a glucocorticoid and as a mineralocorticoid. That is, it is an agonist of the glucocorticoid and mineralocorticoid receptors.[citation needed]

Hydrocortisone has low potency relative to synthetic corticosteroids.[13] Compared to hydrocortisone, prednisolone is about 4 times as potent and dexamethasone about 40 times as potent in terms of anti-inflammatory effect.[14] Prednisolone can also be used as cortisol replacement, and at replacement dose levels (rather than anti-inflammatory levels), prednisolone is about 8 times more potent than cortisol.[15] The equivalent doses and relative potencies of hydrocortisone compared to various other synthetic corticosteroids have also been reviewed and summarized.[13]

The endogenous production rate of cortisol is approximately 5.7 to 9.9 mg/m2 per day, which corresponds to an oral hydrocortisone dose of approximately 15 to 20 mg/day (for a 70-kg person).[16][17] One review described daily cortisol production of 10 mg in healthy volunteers and reported that daily cortisol production could increase up to 400 mg in conditions of severe stress (e.g., surgery).[18]

The total and/or free concentrations of cortisol/hydrocortisone required for various glucocorticoid effects have been determined.[18]

Pharmacokinetics

Absorption

The bioavailability of oral hydrocortisone is about 96% ± 20% (SD).[18][19] The pharmacokinetics of hydrocortisone are non-linear.[18] The peak level of oral hydrocortisone is 15.3 ± 2.9 (SD) μg/L per 1 mg dose.[18] The time to peak concentrations of oral hydrocortisone is 1.2 ± 0.4 (SD) hours.[18]

The topical percutaneous absorption of hydrocortisone varies widely depending on experimental circumstances and has been reported to range from 0.5 to 14.9% in different studies.[20] Some skin application sites, like the scrotum and vulva, absorb hydrocortisone much more efficiently than other application sites, like the forearm.[20][21][22] In one study, the amount of hydrocortisone absorbed ranged from 0.2% to 36.2% depending on the application site, with the ball of the foot having the lowest absorption and the scrotum having the highest absorption.[22] The absorption of hydrocortisone by the vulva has ranged from 4.4 to 8.1%, relative to 1.3 to 2.8% for the arm, in different studies and subjects.[22][23][24]

Distribution

Most cortisol in the blood (all but about 4%) is bound to proteins, including corticosteroid binding globulin (CBG) and serum albumin. A pharmacokinetic review stated that 92% ± 2% (SD) (92–93%) of hydrocortisone is plasma protein-bound.[18] Free cortisol passes easily through cellular membranes.[25] Inside cells it interacts with corticosteroid receptors.[26]

Metabolism

Hydrocortisone is metabolized by 11β-hydroxysteroid dehydrogenases (11β-HSDs) into cortisone, an inactive metabolite.[19][18] It is additionally 5α-, 5β-, and 3α-reduced into dihydrocortisols, dihydrocortisones, tetrahydrocortisols, and tetrahydrocortisones.[27][18][19]

Elimination

The elimination half-life of hydrocortisone ranges from about 1.2 to 2.0 (SD) hours, with an average of around 1.5 hours, regardless of oral versus parenteral administration.[18][19] The duration of action of systemic hydrocortisone has been listed as 8 to 12 hours.[13]

Chemistry

See also: Chemistry:List of corticosteroids and List of corticosteroid esters § Hydrocortisone esters

Hydrocortisone, also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is a naturally occurring pregnane steroid.[28][29] A variety of hydrocortisone esters exist and have been marketed for medical use.[28][29]

Society and culture

In March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Efmody, intended for the treatment of congenital adrenal hyperplasia (CAH) in people aged twelve years and older.[30] The applicant for this medicinal product is Diurnal Europe BV.[30] Hydrocortisone (Efmody) was approved for medical use in the European Union, in May 2021, for the treatment of congenital adrenal hyperplasia (CAH) in people aged twelve years and older.[31]

Anti-competitive practices

In the UK, the Competition and Markets Authority (CMA) concluded an investigation into the supply of hydrocortisone tablets, finding that from October 2008 onwards, drug suppliers Auden McKenzie and Actavis plc had charged "excessive and unfair prices" for 10mg and 20mg tablets and entered into agreements with potential competitors, paying companies who agreed not to enter the hydrocortisone market and enabling Auden McKenzie and Actavis to supply the drugs as "generic" rather than branded products and thereby escape price controls until eventually other companies entered the market. Auden and Actavis overcharged the UK's National Health Service for over ten years. Fines totalling over £255m were levied against the companies involved in this breach of competition law.[32]

Research

Chronic fatigue syndrome

Cortisol levels have been found to be altered in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).[33][34][35] Hydrocortisone has been clinically studied in the treatment of ME/CFS.[36][37][38] A 2016 systematic review found that it had been assessed for this purpose in six clinical studies.[36] Its clinical effectiveness was conflicting in the studies, ranging from not effective, to slightly or mildly effective, to moderately effective.[36] Four of the studies came from one research group.[36] The systematic review called for higher-quality trials.[36] A 2015 systematic review found that the clinical data on hydrocortisone for ME/CFS was inconclusive.[39]

COVID-19

Hydrocortisone was found to be effective in reducing mortality rate of critically ill COVID-19 patients when compared to other usual care or a placebo.[40]

References

  1. ↑ (in en) Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 2001. p. 762. ISBN 978-0-7817-1750-2. https://books.google.com/books?id=FVfzRvaucq8C&pg=PA762. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Hydrocortisone". American Society of Health-System Pharmacists. 9 February 2015. https://www.drugs.com/monograph/hydrocortisone.html. 
  3. ↑ Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. p. 202. ISBN 978-1-284-05756-0. 
  4. ↑ 4.0 4.1 "Hydrocortisone: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD" (in en). https://www.webmd.com/drugs/2/drug-6731-581/hydrocortisone-oral/hydrocortisone-oral/details. 
  5. ↑ "Hydrocortisone Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/hydrocortisone.html. 
  6. ↑ U.S. Patent 2,183,589
  7. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 484. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA484. Retrieved 7 September 2020. 
  8. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  9. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Hydrocortisone Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Hydrocortisone. 
  11. ↑ 11.0 11.1 Cite error: Invalid <ref> tag; no text was provided for refs named anusol-acetate
  12. ↑ "[Comparative study of prednisolone versus hydrocortisone acetate for treatment of patients with the classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency]" (in Portuguese). Arq Bras Endocrinol Metabol 52 (1): 101–8. February 2008. doi:10.1590/s0004-27302008000100014. PMID 18345402. 
  13. ↑ 13.0 13.1 13.2 "A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy". Allergy Asthma Clin Immunol 9 (1). August 2013. doi:10.1186/1710-1492-9-30. PMID 23947590. 
  14. ↑ "Dexamethasone". drugs.com. https://www.drugs.com/pro/dexamethasone.html. 
  15. ↑ "One-year clinical evaluation of single morning dose prednisolone therapy for 21-hydroxylase deficiency". Arquivos Brasileiros de Endocrinologia e Metabologia 48 (5): 705–712. October 2004. doi:10.1590/S0004-27302004000500017. PMID 15761542. 
  16. ↑ Cortisol Excess and Insufficiency. Frontiers of Hormone Research. S. Karger AG. 2016. p. 1-PA61. ISBN 978-3-318-05840-6. https://books.google.com/books?id=jew6DAAAQBAJ&pg=RA1-PA61. Retrieved 10 April 2023. 
  17. ↑ Pediatric Adrenal Diseases: Workshop, May 16-18, 2010, Turin (Italy). Karger Medical and Scientific Publishers. 2011. pp. 174–. ISBN 978-3-8055-9643-5. OCLC 1020003143. https://books.google.com/books?id=gde44-zDr_oC&pg=PA174. Retrieved 10 April 2023. 
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 Cite error: Invalid <ref> tag; no text was provided for refs named pmid15634032
  19. ↑ 19.0 19.1 19.2 19.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid18611115
  20. ↑ 20.0 20.1 "Percutaneous absorption of topical corticosteroids". Current Problems in Dermatology 21: 45–60. 1993. doi:10.1159/000422362. ISBN 978-3-8055-5712-2. PMID 8299376. 
  21. ↑ "Effects of anatomical location on in vivo percutaneous penetration in man". Cutaneous and Ocular Toxicology 39 (3): 213–222. September 2020. doi:10.1080/15569527.2020.1787434. PMID 32643443. 
  22. ↑ 22.0 22.1 22.2 "Regional Variation in Percutaneous Absorption". Percutaneous Absorption. CRC Press. 8 June 2021. pp. 165–174. doi:10.1201/9780429202971-11. ISBN 978-0-429-20297-1. 
  23. ↑ "Human percutaneous penetration of hydrocortisone: the vulva". Archives of Dermatological Research 267 (3): 313–316. 1980. doi:10.1007/BF00403852. PMID 7406539. 
  24. ↑ "Percutaneous absorption of hydrocortisone and testosterone on the vulva and forearm: effect of the menopause and site". The British Journal of Dermatology 134 (2): 229–233. February 1996. doi:10.1111/j.1365-2133.1996.tb07606.x. PMID 8746334. 
  25. ↑ "Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". The Journal of Endocrinology 169 (1): 65–70. April 2001. doi:10.1677/joe.0.1690065. PMID 11250647. 
  26. ↑ Medical Physiology (2nd ed.). Philadelphia: Saunders. 2011. ISBN 978-1-4377-1753-2. 
  27. ↑ "The role of 5-reduction in physiology and metabolic disease: evidence from cellular, pre-clinical and human studies". The Journal of Steroid Biochemistry and Molecular Biology 207. March 2021. doi:10.1016/j.jsbmb.2021.105808. PMID 33418075. 
  28. ↑ 28.0 28.1 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 316. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA316. 
  29. ↑ 29.0 29.1 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 524–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA524. Retrieved 19 June 2020. 
  30. ↑ 30.0 30.1 "Efmody: Pending EC decision". 25 March 2021. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/efmody.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  31. ↑ "Efmody EPAR". 24 March 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/efmody.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  32. ↑ This article contains OGL licensed text This article incorporates text published under the British Open Government Licence: Competition and Markets Authority, Decision: Hydrocortisone tablets. Excessive and unfair pricing and Anti-competitive agreements, published 31 March 2022, accessed 1 June 2023
  33. ↑ "A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)". J Transl Med 21 (1). July 2023. doi:10.1186/s12967-023-04295-0. PMID 37408028. 
  34. ↑ "Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders". Biol Psychol 87 (2): 183–194. May 2011. doi:10.1016/j.biopsycho.2011.02.002. PMID 21315796. 
  35. ↑ "Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis". Psychoneuroendocrinology 38 (11): 2405–2422. November 2013. doi:10.1016/j.psyneuen.2013.07.004. PMID 23916911. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 "A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis". Clin Ther 38 (6): 1263–1271.e9. June 2016. doi:10.1016/j.clinthera.2016.04.038. PMID 27229907. 
  37. ↑ "Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial". Lancet 353 (9151): 455–458. February 1999. doi:10.1016/S0140-6736(98)04074-4. PMID 9989716. 
  38. ↑ "Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial". JAMA 280 (12): 1061–1066. 1998. doi:10.1001/jama.280.12.1061. PMID 9757853. 
  39. ↑ "Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop". Ann Intern Med 162 (12): 841–850. June 2015. doi:10.7326/M15-0114. PMID 26075755. 
  40. ↑ "Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis". JAMA 324 (13): 1330–1341. October 2020. doi:10.1001/jama.2020.17023. PMID 32876694. 

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