| Glucocorticoid | |
|---|---|
| Drug class | |
 Chemical structure ofcortisol (hydrocortisone), anendogenous glucocorticoid as well as a medication. | |
| Class identifiers | |
| Synonyms | Corticosteroid; Glucocorticosteroid |
| Use | Adrenal insufficiency;allergic,inflammatory, andautoimmune disorders;asthma;organ transplant |
| ATC code | H02AB |
| Biological target | Glucocorticoid receptor |
| Chemical class | Steroids |
| Legal status | |
| In Wikidata | |
Glucocorticoids (or, less commonly,glucocorticosteroids) are a class ofcorticosteroids, which are a class ofsteroid hormones. Glucocorticoids are corticosteroids that bind to theglucocorticoid receptor[1] that is present in almost everyvertebrate animal cell. The name "glucocorticoid" is aportmanteau of "glucose", "cortex", and "steroid", referring to its role in regulating themetabolism ofglucose, its synthesis in theadrenal cortex, and itssteroidal structure.
Glucocorticoids are part of thefeedback mechanism in theimmune system, which reduces certain aspects of immune function, such asinflammation. They are therefore used in medicine to treat diseases caused by anoveractive immune system, such asallergies,asthma,autoimmune diseases, andsepsis. Glucocorticoids have manyside effects, includingadverse drug reactions.[2] They also interfere with some of the abnormal mechanisms incancer cells, so they are used in high doses to treat cancer. In particular, they inhibitlymphocyte proliferation, which is significant forlymphomas andleukemias. They can also lessen some side effects ofchemotherapy (anticancer drugs).
Glucocorticoids affect cells by binding to theglucocorticoid receptor. The activated glucocorticoid receptor-glucocorticoid complex up-regulates the expression ofanti-inflammatoryproteins in thenucleus (a process known astransactivation) and represses the expression of pro-inflammatory proteins in thecytosol by preventing thetranslocation of othertranscription factors from the cytosol into the nucleus (transrepression).[2]
Glucocorticoids are distinguished frommineralocorticoids andsex steroids by their specificreceptors,target cells, and effects. In technical terms, "corticosteroid" refers to both glucocorticoids andmineralocorticoids (as both are mimics ofhormones produced by theadrenal cortex), but is often used as a synonym for "glucocorticoid". Glucocorticoids are chiefly produced in thezona fasciculata of theadrenal cortex, whereas mineralocorticoids are synthesized in thezona glomerulosa.
Cortisol (or hydrocortisone) is the most important human glucocorticoid and is essential. It regulates and supports importantcardiovascular,metabolic,immunologic, andhomeostatic functions. Increases in glucocorticoid concentrations are an integral part ofstress response and are the most commonly usedbiomarkers to measure stress.[3] Glucocorticoids have numerous non-stress-related functions as well, and glucocorticoid concentrations can increase in response to pleasure or excitement.[4] Varioussynthetic glucocorticoids are available; these are widely utilized ingeneral medical practice and numerousspecialties, either as replacement therapy inglucocorticoid deficiency or to suppress the body's immune system.
Glucocorticoid effects may be broadly classified into two major categories:immunological andmetabolic. In addition, glucocorticoids play important roles in fetaldevelopment andbody fluid homeostasis.[citation needed]
Glucocorticoids function via interaction with the glucocorticoid receptor:[1]
Glucocorticoids are also shown to play a role in the development and homeostasis ofT lymphocytes. This has been shown in transgenic mice with either increased or decreased sensitivity of T cell lineage to glucocorticoids.[6]
The name "glucocorticoid" derives from early observations that thesehormones were involved inglucose metabolism. In the fasted state,cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in the blood.[citation needed]
Metabolic effects:
Excessive glucocorticoid levels resulting from administration as a drug orhyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead toosteoporosis), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids.[6]
Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of thesurfactant necessary for extrauterine lung function. Mice withhomozygous disruptions in thecorticotropin-releasing hormone gene (see below) die at birth due to pulmonary immaturity. In addition, glucocorticoids are necessary for normal brain development, by initiating terminal maturation, remodeling axons and dendrites, and affecting cell survival[10] and may also play a role inhippocampal development. Glucocorticoids stimulate the maturation of the Na+/K+/ATPase, nutrient transporters, and digestion enzymes, promoting the development of a functioning gastro-intestinal system. Glucocorticoids also support the development of the neonate's renal system by increasing glomerular filtration.[citation needed]
Glucocorticoids act on thehippocampus,amygdala, andfrontal lobes. Along withadrenaline, these enhance the formation offlashbulb memories of events associated with strong emotions, both positive and negative.[11] This has been confirmed in studies, whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect was more important in men).[better source needed] The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation.
In multiple animal studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction of the neurons in the hippocampus area of the brain, which has been connected to lower memory performance.[7][12][8]
Glucocorticoids have also been shown to have a significant impact onvigilance (attention deficit disorder) andcognition (memory). This appears to follow the curve described byYerkes–Dodson law, as studies have shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern. For example,long-term potentiation (LTP; the process of forming long-term memories) is optimal when glucocorticoid levels are mildly elevated, whereas significant decreases of LTP are observed after adrenalectomy (low-glucocorticoid state) or after exogenous glucocorticoid administration (high-glucocorticoid state). Elevated levels of glucocorticoids enhance memory for emotionally arousing events, but lead more often than not to poor memory for material unrelated to the source of stress/emotional arousal.[13] In contrast to the dose-dependent enhancing effects of glucocorticoids on memory consolidation, these stress hormones have been shown to inhibit the retrieval of already stored information.[9] Long-term exposure to glucocorticoid medications, such as asthma and anti-inflammatory medication, has been shown to create deficits in memory and attention both during and, to a lesser extent, after treatment,[14][15] a condition known as "steroid dementia".[16]
Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume by regulating body's action toatrial natriuretic peptide (ANP). Centrally, glucocorticoids could inhibit dehydration-induced water intake;[17] peripherally, glucocorticoids could induce a potent diuresis.[18]
Glucocorticoids bind to the cytosolicglucocorticoid receptor, a type ofnuclear receptor that is activated byligand binding. After a hormone binds to the corresponding receptor, the newly formed complextranslocates itself into thecell nucleus, where it binds toglucocorticoid response elements in thepromoter region of the targetgenes resulting in theregulation of gene expression. This process is commonly referred to as transcriptional activation, ortransactivation.[19][20]
The proteins encoded by these up-regulated genes have a wide range of effects, including, for example:[20]
The opposite mechanism is called transcriptional repression, ortransrepression. The classical understanding of this mechanism is that activated glucocorticoid receptor binds to DNA in the same site where anothertranscription factor would bind, which prevents the transcription of genes that are transcribed via the activity of that factor.[19][20] While this does occur, the results are not consistent for all cell types and conditions; there is no generally accepted, general mechanism for transrepression.[20]
New mechanisms are being discovered where transcription is repressed, but the activated glucocorticoid receptor is not interacting with DNA, but rather with another transcription factor directly, thus interfering with it, or with other proteins that interfere with the function of other transcription factors. This latter mechanism appears to be the most likely way that activated glucocorticoid receptor interferes withNF-κB – namely by recruitinghistone deacetylase, which deacetylate the DNA in the promoter region leading to closing of the chromatin structure where NF-κB needs to bind.[19][20]
Activated glucocorticoid receptor has effects that have been experimentally shown to be independent of any effects on transcription and can only be due to direct binding of activated glucocorticoid receptor with other proteins or with mRNA.[19][20]
For example,Src kinase which binds to inactive glucocorticoid receptor, is released when a glucocorticoid binds to glucocorticoid receptor, and phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in inflammation,epidermal growth factor, reducing its activity, which in turn results in reduced creation ofarachidonic acid – a key proinflammatory molecule. This is one mechanism by which glucocorticoids have an anti-inflammatory effect.[19]
A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in bothpharmacokinetics (absorption factor, half-life, volume of distribution, clearance) andpharmacodynamics (for example the capacity ofmineralocorticoid activity: retention ofsodium (Na+) and water;renal physiology). Because they permeate theintestines easily, they are administered primarilyper os (by mouth), but also by other methods, such astopically onskin. More than 90% of them bind differentplasma proteins, though with a different binding specificity. Endogenous glucocorticoids and some synthetic corticoids have high affinity to the proteintranscortin (also called corticosteroid-binding globulin), whereas all of them bindserum albumin. In the liver, they quickly metabolize by conjugation with asulfate orglucuronic acid, and are secreted in theurine.[citation needed]
Glucocorticoid potency, duration of effect, and the overlapping mineralocorticoid potency vary.Cortisol is the standard of comparison for glucocorticoid potency. "Hydrocortisone" is the name used for pharmaceutical preparations of cortisol.[citation needed]
The data below refer to oral administration. Oral potency may be less thanparenteral potency because significant amounts (up to 50% in some cases) may not reach the circulation.Fludrocortisone acetate anddeoxycorticosterone acetate are, by definition, mineralocorticoids rather than glucocorticoids, but they do have minor glucocorticoid potency and are included in this table to provide perspective on mineralocorticoid potency.[citation needed]
| Name | Glucocorticoid potency | Mineralocorticoid potency | Terminal half-life (hours) |
|---|---|---|---|
| Cortisol (hydrocortisone) | 1 | 1 | 8 |
| Cortisone | 0.8 | 0.8 | 8 |
| Prednisone | 3.5–5 | 0.8 | 16–36 |
| Prednisolone | 4 | 0.8 | 16–36 |
| Methylprednisolone | 5–7.5 | 0.5 | 18–40 |
| Dexamethasone | 25–80 | 0 | 36–54 |
| Betamethasone | 25–30 | 0 | 36–54 |
| Triamcinolone | 5 | 0 | 12–36 |
| Deflazacort | 6.5 | – | 1.3 |
| Fludrocortisone acetate | 15 | 200 | 24 |
| Deoxycorticosterone acetate | 0 | 20 | – |
| Aldosterone | 0.3 | 200–1000 | – |
| Beclometasone | 8 sprays 4 times every day equivalent to orally 14 mg prednisone once a day | – | – |
| Synthetic Glucocorticoid | Equivalent Dose (mg) | Anti-inflammatory Activity1 | Mineralocorticoid Activity1 | Biological Half Life (hrs) | References |
|---|---|---|---|---|---|
| Short-to medium-acting glucocorticoids | |||||
| Hydrocortisone | 20 | 1 | 1 | 8–12 | [25][26] |
| Cortisone | 25 | 0.8 | 0.8 | 8–12 | [25][26] |
| Prednisone | 5 | 4 | 0.3 | 12–36 | [25][26] |
| Prednisolone | 5 | 4–5 | 0.3 | 12–36 | [25][26] |
| Methylprednisolone | 4 | 5 | 0.25–0.5 | 12–36 | [25][26] |
| Meprednisone | 4 | 5 | 0 | [25] | |
| Intermediate-acting glucocorticoids | |||||
| Triamcinolone | 4 | 5 | 0 | 12–36 | [25][26] |
| Paramethasone | 2 | 10 | 0 | N/A | [25][26] |
| Fluprednisolone | 1.5 | 15 | 0 | [25] | |
| Long-acting glucocorticoids | |||||
| Betamethasone | 0.6 | 25–40 | 0 | 36–72 | [25][26][27] |
| Dexamethasone | 0.75 | 30 | 0 | 36–72 | [25][26] |
| Mineralocorticoids | |||||
| Fludrocortisone | 2 | 10 | 250 | 18–36 | [25][26] |
| Desoxycorticosterone acetate | 0 | 20 | |||
| 1 Activity is relative to hydrocortisone | |||||
Glucocorticoids may be used in low doses inadrenal insufficiency. In much higher doses, oral or inhaled glucocorticoids are used to suppress variousallergic,inflammatory, and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment forasthma. They are also administered as post-transplantory immunosuppressants to prevent theacute transplant rejection and thegraft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit laterreparative processes. Newly emerging evidence showed that glucocorticoids could be used in the treatment ofheart failure to increase the renal responsiveness to diuretics and natriuretic peptides. Glucocorticoids are historically used for pain relief in inflammatory conditions.[28][29][30] However, corticosteroids show limited efficacy in pain relief and potential adverse events for their use intendinopathies.[31]
Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normalcortisol production; this is referred to as physiologic, replacement, or maintenance dosing. This is approximately 6–12 mg/m2/day of hydrocortisone (m2 refers tobody surface area (BSA), and is a measure of body size; an average man's BSA is 1.9 m2).[citation needed]
Glucocorticoids causeimmunosuppression, and the therapeutic component of this effect is mainly the decreases in the function and numbers oflymphocytes, including bothB cells andT cells.
The major mechanism for this immunosuppression is through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB is a critical transcription factor involved in the synthesis of many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote the immune response. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to mount a response.[2]
Glucocorticoids suppresscell-mediated immunity by inhibiting genes that code for the cytokinesIL-1,IL-2,IL-3,IL-4,IL-5,IL-6,IL-8 and IFN-γ, the most important of which is IL-2. Smallercytokine production reduces theT cell proliferation.[32]
Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect – glucocorticoid-induced apoptosis. The effect is more prominent in immature T cells still inside in the thymus, but peripheral T cells are also affected. The exact mechanism regulating this glucocorticoid sensitivity lies in theBcl-2 gene.[33]
Glucocorticoids also suppress thehumoral (antibody-mediated) immunity, thereby causing ahumoral immune deficiency. Glucocorticoids causeB cells to express smaller amounts ofIL-2 and ofIL-2 receptors. This diminishes both B cell clone expansion andantibody synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated.
The effect of glucocorticoids onFc receptor expression in immune cells is complicated. Dexamethasone decreasesIFN-γ stimulatedFc gamma RI expression inneutrophils while conversely causing an increase inmonocytes.[34] Glucocorticoids may also decrease the expression ofFc receptors in macrophages,[35] but the evidence supporting this regulation in earlier studies has been questioned.[36] The effect ofFc receptor expression inmacrophages is important since it is necessary for thephagocytosis ofopsonised cells. This is because Fc receptors bindantibodies attached to cells targeted for destruction by macrophages.
Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause; their primary anti-inflammatory mechanism islipocortin-1 (annexin-1) synthesis. Lipocortin-1 both suppressesphospholipase A2, thereby blockingeicosanoid production, and inhibits variousleukocyte inflammatory events (epithelialadhesion,chemotaxis,phagocytosis,respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation,prostaglandins andleukotrienes. They inhibit prostaglandin synthesis at the level ofphospholipase A2 as well as at the level ofcyclooxygenase/PGE isomerase (COX-1 and COX-2),[37] the latter effect being much like that ofNSAIDs, thus potentiating the anti-inflammatory effect.
In addition, glucocorticoids also suppresscyclooxygenase expression.[38]
Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays forrhinitis orinhalers forasthma. These preparations have the advantage of only affecting the targeted area, thereby reducing side effects or potential interactions. In this case, the main compounds used arebeclometasone,budesonide,fluticasone,mometasone andciclesonide. In rhinitis, sprays are used. For asthma, glucocorticoids are administered asinhalants with ametered-dose ordry powder inhaler.[39] In rare cases, symptoms ofRadiation-induced thyroiditis has been treated with oral glucocorticoids.[40]
Glucocorticoids can be used in the management offamilial hyperaldosteronism type 1. They are not effective, however, for use in the type 2 condition.[citation needed]
Glucocorticoids could be used in the treatment of decompensated heart failure to potentiate renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large doses of loop diuretics.[41][42][43][44][45][46][47]
Resistance to the therapeutic uses of glucocorticoids can present difficulty; for instance, 25% of cases of severeasthma may be unresponsive to steroids. This may be the result of genetic predisposition, ongoing exposure to the cause of the inflammation (such asallergens), immunological phenomena that bypass glucocorticoids, pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism) and viral and/or bacterial respiratory infections.[32][48]
Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes.[49] To prevent this, much research has been focused recently on the elaboration of selectively acting glucocorticoid drugs. Side effects include:
In high doses, hydrocortisone (cortisol) and those glucocorticoids with appreciable mineralocorticoid potency can exert a mineralocorticoid effect as well, although in physiologic doses this is prevented by rapid degradation of cortisol by11β-hydroxysteroid dehydrogenase isoenzyme 2 (11β-HSD2) in mineralocorticoid target tissues. Mineralocorticoid effects can include salt and water retention,extracellular fluid volume expansion,hypertension,potassium depletion, andmetabolic alkalosis.
Glucocorticoids causeimmunosuppression, decreasing the function and/or numbers ofneutrophils, lymphocytes (including bothB cells andT cells),monocytes,macrophages, and theanatomical barrier function of the skin.[54] This suppression, if large enough, can cause manifestations ofimmunodeficiency, includingT cell deficiency,humoral immune deficiency andneutropenia.[citation needed]
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In addition to the effects listed above, use of high-dose glucocorticoids for only a few days begins to produce suppression of the patient'sadrenal glands suppressing hypothalamiccorticotropin-releasing hormone (CRH) leading to suppressed production ofadrenocorticotropic hormone (ACTH) by the anterior pituitary.[21] With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid.
During this recovery time, the patient is vulnerable toadrenal insufficiency during times of stress, such as illness. While suppressive dose and time for adrenal recovery vary widely, clinical guidelines have been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient. The following is one example:
Glucocorticoids may also decrease the number of Fc receptors on macrophages, but this immunosuppressive function is controversial because of the lack of sensitivity in Fc receptor techniques and the high concentration of glucocorticoids used in previous experiments.
