Hydrocortisone Explained

Hydrocortisone is the name for the hormone cortisol when supplied as a medication.[1] 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, or by injection.[2] Stopping treatment after long-term use should be done slowly.[2]

Side effects may include mood changes, increased risk of infection, and edema (swelling).[2] With long-term use common side effects include osteoporosis, upset stomach, physical weakness, easy bruising, and candidiasis (yeast infections).[2] It is unclear if it is safe for use during pregnancy.[4] Hydrocortisone is a glucocorticoid and works as an anti-inflammatory and by immune suppression.[2]

Hydrocortisone was patented in 1936 and approved for medical use in 1941.[5] It is on the World Health Organization's List of Essential Medicines.[6] It is available as a generic medication.[2] In 2021, it was the 192nd most commonly prescribed medication in the United States, with more than 2million prescriptions.[7] [8]

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.

It may be used topically for allergic rashes, eczema, psoriasis, itching and other inflammatory skin conditions. Topical hydrocortisone creams and ointments are available in most countries without prescription in strengths ranging from 0.05% to 2.5% (depending on local regulations) with stronger forms available by prescription only.

It may also be used rectally in suppositories to relieve the swelling, itch, and irritation in haemorrhoids.

It may be used as an acetate form (hydrocortisone acetate), which has slightly different pharmacokinetics and pharmacodynamics.[9]

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.

Hydrocortisone has low potency relative to synthetic corticosteroids.[10] Compared to hydrocortisone, prednisolone is about 4times as potent and dexamethasone about 40times as potent in terms of anti-inflammatory effect.[11] Prednisolone can also be used as cortisol replacement, and at replacement dose levels (rather than anti-inflammatory levels), prednisolone is about 8times more potent than cortisol.[12] The equivalent doses and relative potencies of hydrocortisone compared to various other synthetic corticosteroids have also been reviewed and summarized.

The endogenous production rate of cortisol is approximately 5.7 to 9.9mg/m2 per day, which corresponds to an oral hydrocortisone dose of approximately 15 to 20mg/day (for a 70-kg person).[13] [14] One review described daily cortisol production of 10mg in healthy volunteers and reported that daily cortisol production could increase up to 400mg in conditions of severe stress (e.g., surgery).

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

Pharmacokinetics

Absorption

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

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.[15] Some skin application sites, like the scrotum and vulva, absorb hydrocortisone much more efficiently than other application sites, like the forearm.[16] [17] 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. 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.[18] [19]

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. Free cortisol passes easily through cellular membranes.[20] Inside cells it interacts with corticosteroid receptors.[21]

Metabolism

Hydrocortisone is metabolized by 11β-hydroxysteroid dehydrogenases (11β-HSDs) into cortisone, an inactive metabolite. It is additionally 5α-, 5β-, and 3α-reduced into dihydrocortisols, dihydrocortisones, tetrahydrocortisols, and tetrahydrocortisones.[22]

Elimination

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

Chemistry

See also: List of corticosteroids.

Hydrocortisone, also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is a naturally occurring pregnane steroid.[23] [24] A variety of hydrocortisone esters exist and have been marketed for medical use.

Society and culture

Legal status

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. The applicant for this medicinal product is Diurnal Europe BV.[25] 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.[26]

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.

Research

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.[27]

Notes and References

  1. Book: Becker KL . Principles and Practice of Endocrinology and Metabolism. 2001. Lippincott Williams & Wilkins . 978-0-7817-1750-2 . 762 . en. live. https://web.archive.org/web/20160914013845/https://books.google.ca/books?id=FVfzRvaucq8C&pg=PA762. 14 September 2016.
  2. Web site: Hydrocortisone. Drugs.com. American Society of Health-System Pharmacists. 30 August 2016. 9 February 2015. live. https://web.archive.org/web/20160920063137/https://www.drugs.com/monograph/hydrocortisone.html. 20 September 2016.
  3. Book: Hamilton R . Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. 2015. Jones & Bartlett Learning. 978-1-284-05756-0. 202.
  4. Web site: Hydrocortisone Pregnancy and Breastfeeding Warnings. Drugs.com. 1 September 2016. live. https://web.archive.org/web/20160920090158/https://www.drugs.com/pregnancy/hydrocortisone.html. 20 September 2016.
  5. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 978-3-527-60749-5 . 484 . en . 7 September 2020 . 10 January 2023 . https://web.archive.org/web/20230110032528/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA484 . live .
  6. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  7. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  8. Web site: Hydrocortisone - Drug Usage Statistics . ClinCalc . 14 January 2024 . 12 April 2020 . https://web.archive.org/web/20200412043726/https://clincalc.com/DrugStats/Drugs/Hydrocortisone . live .
  9. Leite FM, Longui CA, Kochi C, Faria CD, Borghi M, Calliari LE, Monte O . [Comparative study of prednisolone versus hydrocortisone acetate for treatment of patients with the classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency] . Portuguese . Arq Bras Endocrinol Metabol . 52 . 1 . 101–8 . February 2008 . 18345402 . 10.1590/s0004-27302008000100014. free .
  10. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, Brown JP, Cohen A, Kim H . A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy . Allergy Asthma Clin Immunol . 9 . 1 . 30 . August 2013 . 23947590 . 3765115 . 10.1186/1710-1492-9-30 . free .
  11. Web site: Dexamethasone. drugs.com. 14 June 2013. live. https://web.archive.org/web/20130621041355/http://www.drugs.com/pro/dexamethasone.html. 21 June 2013.
  12. Caldato MC, Fernandes VT, Kater CE . 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 . 15761542 . 10.1590/S0004-27302004000500017 . free . 13986916 .
  13. Book: Arvat E, Falorni A . Cortisol Excess and Insufficiency . S. Karger AG . Frontiers of Hormone Research . 2016 . 978-3-318-05840-6 . 10 April 2023 . 1-PA61 . 27 April 2023 . https://web.archive.org/web/20230427010953/https://books.google.com/books?id=jew6DAAAQBAJ&pg=RA1-PA61 . live .
  14. Book: Ghizzoni L, Cappa M, Chrousos GP, Loche S, Maghnie M . 2011 . Pediatric Adrenal Diseases: Workshop, May 16-18, 2010, Turin (Italy) . Karger Medical and Scientific Publishers . 174– . 978-3-8055-9643-5 . 1020003143 . 10 April 2023 . 10 April 2023 . https://web.archive.org/web/20230410220229/https://books.google.com/books?id=gde44-zDr_oC&pg=PA174 . live .
  15. Wester RC, Maibach HI . Percutaneous absorption of topical corticosteroids . Current Problems in Dermatology . 21 . 45–60 . 1993 . 8299376 . 10.1159/000422362 . 978-3-8055-5712-2 .
  16. Bormann JL, Maibach HI . Effects of anatomical location on in vivo percutaneous penetration in man . Cutaneous and Ocular Toxicology . 39 . 3 . 213–222 . September 2020 . 32643443 . 10.1080/15569527.2020.1787434 . 220439810 .
  17. Book: Percutaneous Absorption . Wester RC, Maibach HI . Regional Variation in Percutaneous Absorption . 8 June 2021 . 165–174 . CRC Press . 10.1201/9780429202971-11 . 978-0-429-20297-1 . 132864025 .
  18. Britz MB, Maibach HI, Anjo DM . Human percutaneous penetration of hydrocortisone: the vulva . Archives of Dermatological Research . 267 . 3 . 313–316 . 1980 . 7406539 . 10.1007/BF00403852 . 33367289 .
  19. Oriba HA, Bucks DA, Maibach HI . 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 . 8746334 . 10.1111/j.1365-2133.1996.tb07606.x . 30076779 .
  20. Charmandari E, Johnston A, Brook CG, Hindmarsh PC . 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 . 11250647 . 10.1677/joe.0.1690065 . free .
  21. Book: Boron WF, Boulpaep EL . Medical Physiology . 2nd . Saunders . Philadelphia . 2011 . 978-1-4377-1753-2 .
  22. Nikolaou N, Hodson L, Tomlinson JW . 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 . 105808 . March 2021 . 33418075 . 10.1016/j.jsbmb.2021.105808 . 230716310 .
  23. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies . 14 November 2014 . Springer . 978-1-4757-2085-3 . 316 . live . https://web.archive.org/web/20170908213347/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA316. 8 September 2017.
  24. Book: Index Nominum 2000: International Drug Directory. 2000. Taylor & Francis. 978-3-88763-075-1. 524–. 19 June 2020. 10 January 2023. https://web.archive.org/web/20230110093813/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA524. live.
  25. Web site: Efmody: Pending EC decision . European Medicines Agency (EMA) . 25 March 2021 . 27 March 2021 . 4 May 2021 . https://web.archive.org/web/20210504065409/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/efmody . dead . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  26. Web site: Efmody EPAR . European Medicines Agency (EMA) . 24 March 2021 . 14 June 2021 . 14 June 2021 . https://web.archive.org/web/20210614223631/https://www.ema.europa.eu/en/medicines/human/EPAR/efmody . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  27. Sterne JA, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, Annane D, Azevedo LC, Berwanger O, Cavalcanti AB, Dequin PF, Du B, Emberson J, Fisher D, Giraudeau B, Gordon AC, Granholm A, Green C, Haynes R, Heming N, Higgins JP, Horby P, Jüni P, Landray MJ, Le Gouge A, Leclerc M, Lim WS, Machado FR, McArthur C, Meziani F, Møller MH, Perner A, Petersen MW, Savovic J, Tomazini B, Veiga VC, Webb S, Marshall JC . 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 . 32876694 . 7489434 . 10.1001/jama.2020.17023 . free .

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