Hydrocortisone

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 hemorrhoids. File:Cortisol for injection.jpg|Cortisol for injection File:Tube of hydrocortisone cream.jpg|A tube of hydrocortisone cream, purchased over-the-counter File:Hydrocortisone Cortef 10 mg Кортеф Гидрокортизон.jpg|Hydrocortisone 10 mg oral tablets (depicted a package for Russian market) ==Side effects==

Side effects of hydrocortisone include hypertension, salt and water retention, hypokalemia, adrenal suppression, immunosuppression, increased risk of infections and infectious reactivation, Cushingoid symptoms, and neuropsychiatric symptoms such as depression, among many others. The side effects of hydrocortisone are dose-dependent, with many of them occurring only at higher doses. In addition, it has been found to increase nighttime awakenings and time spent awake. It is thought that the glucocorticoid activity of hydrocortisone is responsible for REM sleep suppression, while its mineralocorticoid activity mediates its SWS enhancement. ==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. Compared to hydrocortisone, prednisolone is about 4times as potent and dexamethasone about 40times as potent in terms of anti-inflammatory effect. 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. The equivalent doses and relative potencies of hydrocortisone compared to various other synthetic corticosteroids have also been reviewed and summarized. 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). Some skin application sites, like the scrotum and vulva, absorb hydrocortisone much more efficiently than other application sites, like the forearm. 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. 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. Inside cells it interacts with corticosteroid receptors. Metabolism Hydrocortisone is metabolized by 11β-hydroxysteroid dehydrogenases (11β-HSDs) into cortisone, an inactive metabolite. Only a very small proportion of hydrocortisone is excreted unchanged (<1%). The elimination half-life of hydrocortisone ranges from about 1.2 to 2.0hours, 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==

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

Hydrocortisone was discovered in the 1930s. It was introduced as a prescription medication in the United States in 1952. In 1979, topical hydrocortisone became available as a non-prescription over-the-counter drug in the United States. == 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. 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. 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==

Depression Cortisol is released in response to stress and both cortisol and stress have been extensively implicated in depression. People with depression show hypothalamic–pituitary–adrenal axis (HPA axis) hyperactivity, elevated cortisol levels, flattened diurnal cortisol rhythms, and reduced glucocorticoid sensitivity. Findings on the cortisol awakening response (CAR) in people with depression have been mixed, with some studies finding a greater CAR and others finding a blunted CAR, possibly related to different types of depression. Most research has focused on lowering cortisol levels or reducing cortisol signaling to treat depression, as the predominant paradigm has been that excess glucocorticoid signaling may contribute to depression. Cortisol has an inverted U-shaped association with mood and other functions, with both hypercortisolemia (e.g., Cushing's syndrome) and hypocortisolemia (e.g., Addison's disease) associated with depression compared to more moderate levels. Relatedly, depression is thought to be a heterogeneous condition, and different subtypes of depression may have different levels of HPA axis and cortisol signaling. However, in contrast to the case of chronic stress and cortisol elevation, numerous studies have shown that cortisol is instead related to mood-protective and anxiolytic effects during acute stress and actually functions as an adaptive and resilience-promoting hormone in this context. There are even rare case reports of corticosteroid misuse, addiction, and dependence. Similarly, restitution of daily cortisol rhythms with administration of low-dose hydrocortisone early in the day theoretically might also be helpful for some types of depression. It is proposed to work by reducing retrieval of aversive memories and facilitating extinction of aversive memories. It has been found to be the most effective intervention for prevention of PTSD, whereas a variety of other modalities were ineffective. Hypocortisolism may be involved in this condition and in related conditions like fibromyalgia. Hydrocortisone has been clinically studied in the treatment of ME/CFS. A 2016 systematic review found that it had been assessed for this purpose in six clinical studies. A 2010 narrative review reported that hydrocortisone provided short-term reductions in fatigue and symptoms, but had limitations like temporary benefits, rapid loss of effectiveness upon discontinuation, only a minority of individuals benefiting, and there being no known treatment response predictors, concluding that hydrocortisone could not be recommended for treatment of ME/CFS. == References ==