Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (pertaining to glucose + cortex ) derives from its role in the regulation of the metabolism of glucose, its synthesis in the adrenal cortex, and its steroidal structure.
Glucocorticoids Pharmacology – Mechanism of action:
Glucocorticoids bind to the cytosolic glucocorticoid receptor (GR), a type nuclear receptor that is activated by ligand binding. After a hormone binds to the corresponding receptor, the newly formed complex translocates itself into the cell nucleus, where it binds to glucocorticoid response elements (GRE) in the promoter region of the target genes resulting in the regulation of gene expression. This process is commonly referred to as transcriptional activation, or transactivation.
The proteins encoded by these up-regulated genes have a wide range of effects, including, for example:
anti-inflammatory – lipocortin I, p11/calpactin binding protein, secretory leukoprotease inhibitor 1 (SLPI), and Mitogen-activated protein kinase phosphatase (MAPK phosphatase)
increased gluconeogenesis – glucose-6-phosphatase and tyrosine aminotransferase
The opposite mechanism is called transcriptional repression, or transrepression. The classical understanding of this mechanism is that activated GR binds to DNA in the same site where another transcription factor would bind, which prevents the transcription of genes that are transcribed via the activity of that factor. While this does occur, the results are not consistent for all cell types and conditions; there is no generally accepted, general mechanism for transrepression.
New mechanisms are being discovered where transcription is repressed, but the activated GR 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 GR 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.
Activated GR 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 GR with other proteins or with mRNA.
For example Src kinase which binds to inactive GR, is released when a glucocorticoid binds to GR, and phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in inflammation, epidermal growth factor (EGF), reducing its activity, which in turn results in reduced creation of arachidonic acid – a key proinflammatory molecule. This is one mechanism by which glucocorticoids have an anti-inflammatory effect.
Uses of Glucocorticoids:
Glucocorticoids are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as:
- Autoimmune diseases (e.g. Multiple sclerosis, Crohn’s disease, Ulcerative colitis) and
Glucocorticoids have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over the counter. They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. This includes mainly inhibitory effects on lymphocyte proliferation (treatment of lymphomas and leukemias) and mitigation of side effects of anticancer drugs.
Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.
Therapeutic use of Glucocorticoids:
- 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.
- Anti-inflammatory: Glucocorticoids are potent anti-inflammatories, regardless of the inflammation’s cause; their primary anti-inflammatory mechanism is lipocortin-1 (annexin-1) synthesis. Lipocortin-1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2), the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect. In addition, Glucocorticoids also suppress cyclooxygenase expression.
- Hyperaldosteronism: Glucocorticoids can be used in the management of familial hyperaldosteronism type 1. They are not effective, however, for use in the type 2 condition.
Side effects of Glucocorticoids:
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:
- Hyperglycemia due to increased gluconeogenesis, insulin resistance, and impaired glucose tolerance (“steroid diabetes”); caution in those with diabetes mellitus
- Increased skin fragility, easy bruising
- Negative calcium balance due to reduced intestinal calcium absorption
- Steroid-induced osteoporosis: reduced bone density (osteoporosis, osteonecrosis, higher fracture risk, slower fracture repair)
- Weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation
- Hypercortisolemia with prolonged and/or excessive use (also known as, exogenous Cushing’s syndrome)
- Impaired memory and attention deficits
- Adrenal insufficiency (if used for long time and stopped suddenly without a taper)
- Muscle breakdown (proteolysis), weakness, reduced muscle mass and repair
- Expansion of malar fat pads and dilation of small blood vessels in skin
- Anovulation, irregularity of menstrual periods
- Growth failure, delayed puberty
- Increased plasma amino acids, increased urea formation, negative nitrogen balance
- Excitatory effect on central nervous system (euphoria, psychosis)
- Glaucoma due to increased cranial pressure
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 11β-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, and metabolic alkalosis.[expand title=”References for Glucocorticoids Pharmacology:”]