Adrenocorticosteroids Drugs

Adrenocorticosteroid hormones are steroid molecules produced by the adrenal cortex. Both natural and synthetic corticosteroid are used for diagnosis and treatment of disoders of adrenal fuction. Secretion of adrenocortical steroid is controlled by the pituitary release of corticotropin (ACTH). Secretion of the salt retaining hormon aldosteron is primarily under the influence of angiotensin.

The adrenal cortex release a large number of steroids in the circulation. Some have minimal biologic activity and function primarily as precursors, and there are some for which no fuction has been established. The hormonal steroids may be classified as those having important effects on intermediary metabolismand immune fuction / Glucocorticoids, those having principally salt retaining activity/ mineralocorticoids, and those having androgenic or estrogenic activity
The naturally occurring Glucocorticoids , Cortisol ( Hydrocortison )
Pharmacocinetics cortisol exerts a wide range of physiologic effects, including regulation of intermediary metabolism, cardiovascular, function, growth, and immunity. Its syntesis and secretion are tightly regulated by the central nervous system, which is very sensitive feedback by the circulating cortisol and exogenous ( synthetic) glucocorticoids. cortisol is synthesis from cholesterol 
Pharmacodynamics

• Mechanism of action.glucocorticoid effect are mediated widely distributed glucocorticoid reseptors. These proteins  are members of the superfamily of nuclear reseptors that include steroid, sterol, thyroid, vitamin A, and many other receptors with unknown or nonexisttent ligands/ organ reseptors.

• Metabolic effect. Glucocorticoids have important dose related effect on carbohydrate, protein, and fatmetabolism.Glucocorticoid stimulated and required for gluceogenesis and glycogen synthesis in the fasting state. they stimulate phosphoenolpyruvatecarboxykinase, glucose 6-phosphate and glycogen synthase and the release of amino acids in the course of muscle catabolism. Glucocorticoids increase serum glucose levels and stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone sensitive lipase and lypolysis. the increased insulin secresion stimulates lipogenesis and to a lesser degree inhibit lipolysis, leading, to a net increase in fat deposition combined with increased release of fatty acids and glycerols into the circulation 

• Physiologic effects. The glucocorticoids have widespread effect because they influence the function of most cells in the body. The major metabolic consequences of glucocorticoid secretion or administation are due to direct action of these hormones in the cell. however some important effect are the result of hemostatic responses by insulin and glucagon.

• Antianabolic effect. Although glucocorticoids stimulate RNA and protein synthesisin the liver, they have catabolic and antianabolic effects in lymphoid and connective tissue, muscle, peripheral fat, and skin. Supraphysiologic amounts of glucocorticoids lead to decrease musclle mass and weakness and thinning of the skin. catabolic and antianabolic effects on bone are the cause of osteoporosis in cushing's syndrome and impose a major limitation in the long term therapeutic use of glucocorticoids. in children glucocorticoids reduce growth. this effect be partially prevented by administration of growth hormone in high doses.

• Anti inflammatory and immunosuppresive effects. Glucocorticoids dramatically reduce the manifestation of inflammations. anti inflammatory and immunosuppresive effects of glucocorticoids are largely due to the actions describe above. in human complement activation is unaltered, but its effects are inhibited. Antibody production can be reduced by large doses of steroids, though it is unaffected by moderate dosage. The anti inflammatory and immunosuppresive effects of these agents are widely useful therapeutically but are also responsible for some of their most serious adverse effects

• Other effects. Glucocorticoids have important effects on the nervous system. Adrenal insufficiency causes marked slowing of the alpha rhythm of the electroencephalogram and is associated with depression. Increase amounts of glucocorticoid often produce behavioral distrubances in humans, initially insomnia and euphoria and subsequently depression. Large doses of glucocorticoid may increase intracarnial pressure. Glucocorticoids given chronionically suppress the pituitarry release of ACTH, growth hormone,  thyroid stimulating hormone and luteinizing hormone. Large doses of glucocorticoids have been assosiated with the development of peptic ulcer, possibly by suppresing the local immune respone against Helicobacter pylory. They also promote fat redistribution in the body, with increase of visceral, facial, nuchal, and supraclavicularfat, and they appear to antagonize the effects of vitamin D on calcium absorbtion. Glucocorticoid also have omportant effects on the hematopoietic system. In addition to their effects on leukocytes, they increase the number of platelets and red blood cells

Synthetic Corticosteroids  
Pharmacokinetics Pharmaceutical steroids are usually synthesized from cholic acid obtained from cattle or steroid sapogenins found in plants.Futher modifications of these steroids have led to the marketing of a large group of synthetics steroids with special characteristics that are pharmacologically and therapeutically important.
Pharmacodynamics
the actions of the synthetic steroids are similiar to those of cortisol . they bind to the specifif intracelluler receptor proteins and produce the same effects but have different ratio of glucocorticoid to mineralocorticoid potency.
Toxicity
the benefits obtained from use of the glucocorticoid vary consideraby. use of these drugs must be carefully weighed in each patient against their widespread effects on every part of the organism. the major undesirable effects of the glucocorticoids are the result of their hormonal action, which lead to the clinical picture of iatrogenic cushing's sundrome
When the glucocorticoids are used for short periods <2 weeks, it is unusual to see serious adverse effect even with moderately large dose. however, insomnis, behavioral, change ( primarily hypomania), and acute peptic ulcer are occasionally observed even after only a few days of treatment. acute pancreatitis is rate but serious acute adverse effect of hight dose glucocorticoids.

• Metabolic effects most patients who are given dayli doses of 100 mg of hydrocortisone or more for longer than 2 weeks undergo a series of changes that have been termed iatrogenic Cushing's syndrome 
• Other complication. other serious side effects include peptic ulcers and their consequences. The clinical findings associated with certain disoders, particularly bacterial and mycotic infections, may be masked by the corticosteroids, and patient must be carefully watched to avoid serious mishap when large dose are used.The frequency of severe myopathy is greater in patients treated with long acting glucocorticoids. The administration of such compounds has been associated with nausea, dizziness, and weight loss in some patients. It is treated by changing drugs, reducing dosage, and increaseing potassium and protein intake.
• Adrenal Suppresion When corticosteroids are administered for more than 2 weeks, adrenal suppresion may occur. if treatment extends over weeks to months, the patint should be given appropriate supplementary theraphy at times of minor stress ( twofold dose increasefor 24-48 hours) or severe stress ( up to tenfold dose increase for 48-72 hours ) such as accidental trauma or major surgery. If corticosteroids dasage is to be reduce, it should be tapered slowly. If theraphy is to be stopped, the reduction process should be quite slow when the dose reaches replacement levels.

Contraindications and cautions
Patient receiving these drugs must be monitored carefully for the development of hyperglycemia, glycosuria, sodium retention with edema hypertention, hypokalemia, peptic ulcer, osteoporosis,
the dosage should be kept as low as possible, and intermittent administration should be employed when satisfactory therapeutic results can be obtained on this scedule. Even patients maintained on relatively low doses of corticosteroids may required supplementary therapy at time of stress, such as when surgical procedures are perfomed or intercurrent illness or accidents occur
these agents must be used with great caution in patients with peptic ulcer, heart disease, or hypertension with heart failure, certain infectious illnesses such as varicella and tuberculosis, psychoses, diabetes, osteoporosis or glaucoma
Mineralocorticoids ( aldosterone, deoxycorticosterone, Fludrocortisone )
The most important mineralocorticoid in humans is aldosterone. however, small amounts of deoxycorticosterone (DOC) are also formed and released. Although the amount is normally insignificant, DOC was of some omportance therapeutically in the past. its action, effects, and metabolism are qualitetively similiarto those describe below for aldosterone
Fludrocortisone, a synthetic corticosteroid is the most commonly prescribed salt retaining hormone

Preparations Glucocorticoids for oral and parenteral use

•  Bethamethasone
• cortisone
• dexamethasone 
• hydrocortisone 
• methylprednisolone 
• prednisolone 
• prednisone
• triamcinolone 

Mineralocorticoids

• Fludocortisone acetate