Glucocorticoid

Effects

The name glucocorticoid derives from early observations that these glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood. These effects include:

• Stimulation of 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 adipose tissue: A mechanism to conserve glucose.
• Stimulation of glycerol provide another substrate for gluconeogenesis.

Glucocorticoids have potent anti-inflammatory and immunosuppressive properties. This is particularly evident when they are administered at pharmacological doses, but also is important in normal immune responses. As a consequence, glucocorticoids are widely used as drugs to treat inflammatory conditions such as arthritis and dermatitis, and as adjunction therapy for conditions such as autoimmune diseases.

Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extrauterine lung function. Mice with homozygous disruptions in the corticotropin-releasing hormone gene (see below) die at birth due to pulmonary immaturity.

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.

Mode of action

Glucocorticoids bind to the cytosolic promoter region of the target genes. The opposite mechanism is called transrepression. The activated hormone receptor interacts with specific transcription factors and prevents the IL-2 gene.

The ordinary glucocorticoids do not distinguish among transactivation and transrepression and influence both the "wanted" immune and "unwanted" genes regulating the metabolic and cardiovascular functions. At the current time, intensive research is aimed at discovering selectively acting glucocorticoids that will be able to repress only the immune system.

Pharmacologic properties

A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in the glucuronic acid, and are secreted in the urine.

Glucocorticoid potency, duration of effect, and overlapping mineralocorticoid potency varies (Table).

Comparative steroid potencies

Name	Glucocorticoid potency	Mineralocorticoid potency	Duration of action (t1/2 in hours)
Hydrocortisone (Cortisol)	1	1	8
Cortisone acetate	0.8	0.8	oral 8, intramuscular 18+
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
Beclometasone	8 puffs 4 times a day equals 14 mg oral prednisone once a day	-	-
Fludrocortisone acetate	15	200	-
Deoxycorticosterone acetate (DOCA)	0	20	-
Aldosterone	0.3	200-1000	-

Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol. Data refer to oral dosing, except when mentioned. Note that oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not be absorbed from the intestine. Note that fludrocortisone, DOCA, and aldosterone are not considered glucocorticoids, and are included in this table to provide perspective on mineralocorticoid potency.

Hydrocortisone cream or ointment is available nonprescription up to 1% strength. In general, stronger forms require prescription.[1]

Physiologic replacement of glucocorticoid

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 (m² refers to body surface area (BSA), and is a measure of body size; an average man is 1.7 m²).

Medical uses and effects of high-dose glucocorticoids

In much higher doses (termed pharmacologic doses), glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. They are also administered as posttransplantory 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.

Some drugs used are cortisol (hydrocortisone), prednisone and dexamethasone.

Immunosuppressive mechanism

Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-8 and IFN-γ, the most important of which is the IL-2. Smaller cytokine production reduces the T cell proliferation.

Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and of antibody synthesis. The diminished amounts of IL-2 also causes fewer T lymphocyte cells to be activated.

Since glucocorticoid is a Fc receptors on macrophages, so there is a decreased phagocytosis of opsonised cells.

Anti-inflammatory effects

Glucocorticoids influence all types of inflammatory events, no matter what their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes, preventing the phospholipase A2 from coming into contact with its Leukotrienes, are inhibited by the action of Glucocorticoids.

Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemokines, etc.) from neutrophils, macrophages, and mastocytes.

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. These are the side-effects that could be prevented:

• immunosuppression
• diabetes mellitus
• increased skin fragility, easy bruising
• reduced bone density (osteoporosis, higher fracture risk, slower fracture repair)
• weight gain due to increased visceral and truncal fat deposition (central obesity) and appetite stimulation
• 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, pubertal delay
• increased plasma urea formation; negative nitrogen balance
• excitatory effect on central nervous system.

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, metabolic alkalosis.

The combination of clinical problems produced by prolonged, excess glucocorticoids, whether synthetic or endogenous, is termed Cushing's syndrome.

Adrenal suppression and withdrawal

In addition to the effects listed above, use of high-dose steroids for more than a week begins to produce suppression of the patient's adrenal glands because the exogenous glucocorticoids suppress hypothalamic adrenocorticotropic hormone (ACTH). 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 to adrenal insufficiency during times of stress, such as illness. While there is wide individual variation in suppressive dose and time for adrenal recovery, clinical guidelines have been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient. The following is one example, but many variations exist or may be appropriate in individual circumstances.

• If a patient has been receiving daily high doses for 5 days or less, they can be abruptly stopped (or reduced to physiologic replacement if patient is adrenal-deficient). Full adrenal recovery can be assumed to occur by a week afterward.
• If high doses were used for 6-10 days, reduce to replacement dose immediately and taper over 4 more days. Adrenal recovery can be assumed to occur within 2-4 weeks of completion of steroids.
• If high doses were used for 11-30 days, cut immediately to twice replacement, and then by 25% every 4 days. Stop entirely when dose is less than half of replacement. Full adrenal recovery should occur within 1-3 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 a.m. 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. It is difficult to predict the time to full adrenal recovery after prolonged suppressive exogenous steroids; 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

• Immunosuppressive drug
• GITR (glucocorticoid-induced TNF receptor)

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