Glucocorticoid
Glucocorticoid | ||
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Chemical class Steroids | | |
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In Wikidata |
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of
Glucocorticoids are part of the
Glucocorticoids affect cells by binding to the glucocorticoid receptor. The activated glucocorticoid receptor-glucocorticoid complex up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of pro-inflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).[2]
Glucocorticoids are distinguished from
Effects
Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic. In addition, glucocorticoids play important roles in fetal development and body fluid homeostasis.
Immune
Glucocorticoids function via interaction with the glucocorticoid receptor (see details below):
- Upregulate the expression of anti-inflammatory proteins.
- Downregulate the expression of proinflammatory proteins.
Glucocorticoids are also shown to play a role in the development and homeostasis of
Metabolic
The name "glucocorticoid" derives from early observations that these
Metabolic effects:
- Stimulation of gluconeogenesis, in particular, in the liver: This pathway results in the synthesis of glucose from non-hexose substrates, such as amino acids and glycerol from triglyceride breakdown, and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids.
- Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis.
- Inhibition of glucose uptake in muscle and adiposetissue: A mechanism to conserve glucose
- Stimulation of provide another substrate for gluconeogenesis.
- Increase in sodium retention and potassium excretion leads to hypernatremia and hypokalemia[5]
- Increase in hemoglobin concentration, likely due to hindrance of the ingestion of red blood cell by macrophage or other phagocyte.[1]
- Increased urinary uric acid[6]
- Increased urinary calcium and hypocalcemia[7]
- Alkalosis[8]
- Leukocytosis[9]
Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to osteoporosis), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for glucocorticoids.[4]
Developmental
Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the
Arousal and cognition
Glucocorticoids act on the
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.[5][10][6]
Glucocorticoids have also been shown to have a significant impact on
Body fluid homeostasis
Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume by regulating body's action to atrial natriuretic peptide (ANP). Centrally, glucocorticoids could inhibit dehydration-induced water intake;[15] peripherally, glucocorticoids could induce a potent diuresis.[16]
Mechanism of action
Transactivation
Glucocorticoids bind to the cytosolic
The proteins encoded by these up-regulated genes have a wide range of effects, including, for example:[18]
- Anti-inflammatory – lipocortin I, p11/calpactin binding protein, secretory leukocyte protease inhibitor 1 (SLPI), and Mitogen-activated protein kinase phosphatase (MAPK phosphatase)
- Increased gluconeogenesis – glucose 6-phosphatase and tyrosine aminotransferase
Transrepression
The opposite mechanism is called transcriptional repression, or
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 with NF-κB - namely by recruiting histone deacetylase, which deacetylate the DNA in the promoter region leading to closing of the chromatin structure where NF-κB needs to bind.[17][18]
Nongenomic effects
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.[17][18]
For example,
Pharmacology
A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in both
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.
The data below refer to oral administration. Oral potency may be less than
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 | [23][24] |
Cortisone | 25 | 0.8 | 0.8 | 8–12 | [23][24] |
Prednisone | 5 | 4 | 0.3 | 12–36 | [23][24] |
Prednisolone | 5 | 4–5 | 0.3 | 12–36 | [23][24] |
Methylprednisolone | 4 | 5 | 0.25–0.5 | 12–36 | [23][24] |
Meprednisone | 4 | 5 | 0 | [23] | |
Intermediate-acting glucocorticoids | |||||
Triamcinolone | 4 | 5 | 0 | 12–36 | [23][24] |
Paramethasone | 2 | 10 | 0 | N/A | [23][24] |
Fluprednisolone | 1.5 | 15 | 0 | [23] | |
Long-acting glucocorticoids | |||||
Betamethasone | 0.6 | 25–40 | 0 | 36–72 | [23][24][25] |
Dexamethasone | 0.75 | 30 | 0 | 36–72 | [23][24] |
Mineralocorticoids | |||||
Fludrocortisone | 2 | 10 | 250 | 18–36 | [23][24] |
Desoxycorticosterone acetate | 0 | 20 | |||
1 Activity is relative to hydrocortisone |
Therapeutic use
Glucocorticoids may be used in low doses in adrenal insufficiency. In much higher doses, oral or inhaled glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. Inhaled glucocorticoids are the second-line treatment for asthma. They are also administered as post-transplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes. Newly emerging evidence showed that glucocorticoids could be used in the treatment of heart failure to increase the renal responsiveness to diuretics and natriuretic peptides. Glucocorticoids are historically used for pain relief in inflammatory conditions.[26][27][28] However, corticosteroids show limited efficacy in pain relief and potential adverse events for their use in tendinopathies.[29]
Replacement
Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing. This is approximately 6–12 mg/m2/day of hydrocortisone (m2 refers to body surface area (BSA), and is a measure of body size; an average man's BSA is 1.9 m2).
Therapeutic immunosuppression
Glucocorticoids cause immunosuppression, and the therapeutic component of this effect is mainly the decreases in the function and numbers of lymphocytes, including both B cells and T 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 suppress
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 the Bcl-2 gene.[31]
Glucocorticoids also suppress the humoral immunity, thereby causing a humoral immune deficiency. Glucocorticoids cause B cells to express smaller amounts of IL-2 and of IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated.
The effect of glucocorticoids on
Anti-inflammatory
Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause; their primary anti-inflammatory mechanism is
In addition, glucocorticoids also suppress cyclooxygenase expression.[36]
Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays for
Hyperaldosteronism
Glucocorticoids can be used in the management of
Heart failure
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.[39][40][41][42][43][44][45]
Resistance
Resistance to the therapeutic uses of glucocorticoids can present difficulty; for instance, 25% of cases of severe asthma may be unresponsive to steroids. This may be the result of genetic predisposition, ongoing exposure to the cause of the inflammation (such as allergens), immunological phenomena that bypass glucocorticoids, pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism) and viral and/or bacterial respiratory infections.[30][46]
Side effects
Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on the elaboration of selectively acting glucocorticoid drugs. Side effects include:
- Immunodeficiency (see section below)
- diabetes mellitus
- Increased skin fragility, easy bruising
- Negative calcium balance due to reduced intestinal calcium absorption[47]
- Steroid-induced osteoporosis: reduced bone density (osteoporosis, osteonecrosis, higher fracture risk, slower fracture repair)
- Weight gain due to increased visceral and truncal central obesity) and appetite stimulation; see corticosteroid-induced lipodystrophy
- Hypercortisolemia with prolonged or excessive use (also known as, exogenous Cushing's syndrome)
- Impaired memory and attention deficits[48] See steroid dementia syndrome.
- Adrenal insufficiency (if used for long time and stopped suddenly without a taper)
- Muscle and tendon breakdown (proteolysis), weakness, reduced muscle mass and repair[49][29]
- Expansion of malar fat pads and dilation of small blood vessels in skin
- Lipomatosis within the epidural space[50]
- Excitatory effect on central nervous system (euphoria, psychosis)
- Anovulation, irregularity of menstrual periods
- Growth failure, delayed puberty
- Increased plasma amino acids, increased urea formation, negative nitrogen balance
- Glaucoma due to increased ocular pressure
- Cataracts
- Topical steroid withdrawal
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 by
Immunodeficiency
Glucocorticoids cause
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Fungi
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Viruses
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Withdrawal
This article needs more primary sources. (May 2018) |
In addition to the effects listed above, use of high-dose glucocorticoids for only a few days begins to produce suppression of the patient's
During this recovery time, the patient is vulnerable to adrenal 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:
- If patients have been receiving daily high doses for five days or less, they can be abruptly stopped (or reduced to physiologic replacement if patients are adrenal-deficient). Full adrenal recovery can be assumed to occur by a week afterward.
- If high doses were used for six to 10 days, reduce to replacement dose immediately and taper over four more days. Adrenal recovery can be assumed to occur within two to four weeks of completion of steroids.
- If high doses were used for 11–30 days, cut immediately to twice replacement, and then by 25% every four days. Stop entirely when dose is less than half of replacement. Full adrenal recovery should occur within one to three months of completion of withdrawal.
- If high doses were used more than 30 days, cut dose immediately to twice replacement, and reduce by 25% each week until replacement is reached. Then change to oral hydrocortisone or cortisone as a single morning dose, and gradually decrease by 2.5 mg each week. When the morning dose is less than replacement, the return of normal basal adrenal function may be documented by checking 0800 cortisol levels prior to the morning dose; stop drugs when 0800 cortisol is 10 μg/dl. Predicting the time to full adrenal recovery after prolonged suppressive exogenous steroids is difficult; some people may take nearly a year.
- Flare-up of the underlying condition for which steroids are given may require a more gradual taper than outlined above.
See also
- List of corticosteroids
- List of corticosteroid cyclic ketals
- List of corticosteroid esters
- Aminoglutethimide blocks glucocorticoid secretion
- GITR(glucocorticoid-induced TNF receptor)
- Glucocorticoid receptor
- Immunosuppressive drug
- Membrane glucocorticoid receptor
- Metyrapone blocks glucocorticoid secretion
- Selective glucocorticoid receptor agonist
- Topical glucocorticoids
- Topical steroid
- Steroid atrophy
- Topical steroid withdrawal
- Non-steroidal anti-inflammatory drug(NSAID)
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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.
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Further reading
- Wolkowitz OM, Burke H, Epel ES, Reus VI (Oct 2009). "Glucocorticoids. Mood, memory, and mechanisms". Annals of the New York Academy of Sciences. 1179: 19–40. S2CID 222085554.
External links
- Glucocorticoids at the U.S. National Library of Medicine Medical Subject Headings (MeSH)