Glucocorticoids

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Glucocorticoids

Replacement Therapy

The glucocorticoid cortisol (hydrocortisone) and the mineralocorticoid aldosterone are produced in the adrenal cortex. Both steroidal hormones are vital for adapting to stressful situations (illness or surgery). Pituitary ACTH stimulates the production of cortisol, while angiotensin II stimulates the production of aldosterone. In case of adrenal insufficiency (primary or Addison’s disease), replacement therapy with cortisol and aldosterone is necessary. In case of reduced ACTH production (secondary insufficiency), only cortisol replacement is needed. Cortisol is administered orally (30 mg/day: 2/3 of the dose in the morning, 1/3 after lunch). The dose is increased 5-10 times during stressful situations. Oral administration of aldosterone has a weak effect, so the mineralocorticoid fludrocortisone (0.1 mg/day) is prescribed instead.

Pharmacodynamic Therapy with Glucocorticoids

At high non-physiological concentrations, cortisol and other glucocorticoids prevent the development of all phases of inflammation (exudation, proliferation, scarring), i.e. the body’s reactions to the introduction of foreign and toxic substances. The mechanism of action is influenced by many factors, based on changes in gene transcription. The synthesis of lipocortin, which blocks the inflammatory reaction, is stimulated. Lipocortin inhibits the enzyme phospholipase A2, resulting in reduced synthesis of arachidonic acid and inflammatory mediators such as prostaglandins and leukotrienes. Glucocorticoids also weaken the enzymatic synthesis of many other proteins that play an important role in the inflammatory reaction, such as the synthesis of interleukins and other cytokines under the influence of phospholipase A2 and cyclooxygenase-2. Very high doses injected can cause non-gene-related effects affecting membrane receptors.

Therapeutic effect. Glucocorticoids are used to treat „undesirable“ inflammatory reactions, such as allergy, rheumatoid arthritis, etc., to achieve anti-allergic, immunosuppressive and anti-inflammatory effects.

Side effects. With short-term use of glucocorticoids, even at high doses, there are practically no side effects. With long-term use, changes similar to Cushing’s syndrome (endogenous hypercortisolism) develop. After the inflammatory reactions are suppressed with glucocorticoids, the patient shows an increased susceptibility to infections and impaired wound healing. Consequences of increased glucocorticoid activity include enhanced gluconeogenesis and glucose release, transition of glucose to triglycerides (fat deposition: „moon face“, trunk obesity), steroid diabetes if insulin production is insufficient, increased catabolism of protein leading to atrophy of skeletal muscles (thin limbs), osteoporosis, growth disorders in children, and skin atrophy. Increased mineralocorticoid activity leads to retention of NaCl and water with increased blood pressure, tendency to edema, and loss of KCl with the risk of hypokalemia.

Chronic use of glucocorticoids can also cause mental disorders, primarily euphoric and manic mood changes.

To mitigate or eliminate the iatrogenic Cushing’s syndrome, synthetic cortisol derivatives with reduced (e.g. prednisolone) or no mineralocorticoid activity (e.g. triamcinolone, dexamethasone) are used. The glucocorticoid activity of these drugs is enhanced, and the anti-inflammatory activity and inhibitory effect on the pituitary correlate with each other. There are no derivatives that have only anti-inflammatory effects. The „glucocorticoid“ Cushing’s syndrome cannot be avoided. The table compares the glucocorticoid and mineralocorticoid activity of the various preparations.

Local application allows achieving a therapeutic concentration at the site of administration and avoiding systemic effects. It is advisable to prescribe drugs that undergo rapid biotransformation and inactivation after diffusion from the application site. For inhalation, glucocorticoids with rapid presystemic elimination are used: beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate. However, local side effects are also possible, such as candidiasis of the oral mucosa and hoarseness of the voice with inhalations, or skin atrophy, striae, telangiectasias, steroid acne with topical application, as well as cataract and increased intraocular pressure with eye drops.

The lowest possible doses should be prescribed for long-term use. It should be remembered that endogenous glucocorticoid production will decrease through the feedback mechanism. Therefore, too low a dose may be insufficient, and the anti-inflammatory effect will not manifest.

To prevent adrenal atrophy, glucocorticoids should be administered in a circadian rhythm, with the daily dose given in the morning, or every other day with a double dose in the morning. Both methods have the disadvantage that symptoms of the disease may reappear between doses.