Medical Pharmacology Topics
| Preliminary Outline |
Endogenous Corticosteriods Glucocorticoids Cortisol
Mineralocorticoids Aldosterone
Corticosterone
Adrenal Suppressers
GC and MC activity
Mitotane Aminoglutethimide
GC activity only
Metyrapone Ketaconazole
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Steroid hormone systhesis by the adrenal cortex is regulated by the brain. The adrenocorticotrophic hormone (ACTH) is a 39 amino acid peptide synthesized in the pituitary from pro-opiomelanocortin (POMC). The phasic relsease of ACTH peaks around 8:00 a.m. and is istimulated by the hypothalamic corticotropin releasing hormone (CRH).
ACTH stimulates the adrenal cortex to secrete glucocorticoids, mineralocorticoids, and weak androgens such as androsteneione and dehydroepiandosterone.
Mineralocorticoids
Mineralocorticoids control water and electroyte balance. Steroid synthesis is a multi-step process, with many catalytic enzymes involved. The main mineralocorticoid is aldosterone, with normal daily secretions around 0.25 mg (per kg?). Its activity is restricted to the kidney (distal tubule and collecting duct), colon, salivary glands, sweat glands, and the hippocampus.
Aldosterone main function
is in fluid and electrolite balance. In the kidney it enhances reabasorption
of Na
from tubular fluid and increases urinary excretion of H
and K.
An excess of aldosterone activity leads to hypertension, while not enough aldosterone
leads to hypotension and vascular collapse.
Corticosterone is an adrenocortical steroid with little glucocorticoid activity and 15 times the activity of aldosterone. Fludrocortisone is a syntetic mineralocorticoid with no glucocorticoid activity and 125 times the activity of aldosterone.
Glucocorticoids
Glucocorticoids have a role in metabolism, especially adjusting to stress. Cortisol is the main glucocorticoid, with daily secretions around 10-15 mg (per kg?). In general, cortisol can be thought of as a physiologic insulin antagonist, as it affects carbohydrate and lipid metabolism in n opposite manner as insulin. Cortisol diminishes peripheral utilization of glucose, promotes storage of glycogen, maintains fasting glucose levels and allows lipolysis. It also promotes breakdown of protein in muscle and has other actions that ensure well-being in times of stress.
At levels much higher than normal physiological concentrations, corticosteroids suppress th inflamatory/immune response. They inhibit phospholipase activity through lipocortins, decreasing levels of prostaglandings, leukotrines and platelet-activating factor. it also inhibits secretion and effects of pro-inflammatory and trophic cytokines (TNF, IL-1, etc.) through various mechanisms, including upregulation of IkB, and induces poptosis in lymphocytes and immune cells.
Corticosteroids act by altering gene expression through binding a cytosolic receptor. The bound receptor is taken into the nucleus, where it binds to steroid responsive elements. This bining inhibits transcription of POMC, cytokines, collagenase, stromelysin and adhesion molecules, whicle inducing transcription of lipocortin and IkB.
Disorders
of Glucocorticoid Activity
The main disorders of glucocorticoid activity are Addison's disease/syndrome (defficienc) and Cushing's disease/syndrome (excess). They are called diseases when caused by endogenous factors or syndromes when caused by th environment or drug therapy. The cause of either disorder is based on measurement of plasma ACTH or cortisol, or their urinary metabolites, under basal conditions and after pharmacologic intevention.
Addison's disease may be due to primary or secondary adrenal insufficiency. In primary adrenal insuficiency, the adrenal cortex is unresponsive to ACTH, and plasma cortisol levels will remain unchanged after administration of exogenous ACTH. In secondary adrenal insuficiency the pituitary gland is not producing enough ACTH and plasma cortisol levels will increase after administration of exogenous ACTH.
Cushings
disease may be due to adrenal hyperplasia, adrenal tumor or ectopic ACTH production.
The syndrome usually arrises from glucocorticoid administration. Adrenal hyperplasia
is due to excess ACTH from the pituitary, and plasma ACTH levels will increase
after administration of metyrapone, an inhibitor of cortisol synthesis. An adrenal
carcinoma will generate excessive levels of cortisol, and administration of
metyrapone would not change plasma ACTH levels significantly since they may
already be at their lowest. If there is ectopic ACTH production, plasma ACTH
levels will be high even after administration of metyrapone.
Adrenal Cortex Suppresants
Adrenal suppressants are indicated for the diagnosis and management of Cushig's and the treatment of malignancies of the adrenal cortex.
Metyrapone decreases glucocorticoid activity by inhibiting 11-hydroxylase, an enzyme that catalizes a key step to cortisol synthesis but not aldosteone synthesis.
Other inhibitors of the adrenal cortex are ketacozaole and mitotane. Ketacozaole inhibits CYP450 enzymes needed for glucocorticoid synthesis. Mitotane destroys adrenal cortical cells, thus decreasing both glucocoticoid and mineralocorticoid activity.
Glucocorticoid Replacement Therapy
Replacement therapy with glucocorticoids is indicated for adrenal insufficiency and congenital adrenal hyperplasia (?). In primary adrenal insufficiency, both glucocorticoids and mineralocorticoids must be replaced, while only glucocorticoid replacement is needed in secondary insufficiency. Two or three doses are given during the morning and one in the afternoon/evening to mimic the natural rhythm of glucocorticoind release.
The different adrenocortical steroids and synthetic analogs have different levels of glucocorticoid and mineralocorticoid activity. Cortisol has equal glucocorticoid and mineralocorticoid activity. Several synthetic analogs have 4-5 times the activity of cortisol with a lesser mineralocorticoid activity: prednisone, prednisolone, methylprednisolone and triacinolone. Other synthetics have 10-25 times the glucocorticoid activity of cortisol and no mineralocorticoid activity: paramethasone, betamethasone and dexametasone.
Glucocorticoids are highly lipophilic, well absorbed from the GI track and cross most membranes easily. Most are highly protein bound to cortisol binding globulin (CBG) or albumin, 3-30% free in plasma. Metabolism is mostly hepatic.
Glucocortcoid replacement threpy is indicated for many disorders, but also has many side effects. Indications include allergies, hematological disorders, inflammatory disorders (hepatic, rheumatoid, asthma), ocular disorders, renal disease, cerebral edema, collagen disorders (lupus), dermatologic disorders, GI diseases, neuromuscular disorders, septic shock and rheumatic carditis.
Dangers of systemic glucocorticoid therapy include Cushing's syndrome, increased succeptibility to infection, suppression of diagnostic signs of inflammation and problems associated with withdrawal (impaired responsiveness of the hypothalamus-pituitary-adrenal axis leading to adrenal insufficiency). Specific potential adverse reactions include edema, hypokalemia, aggravation of diabetes, negative nitrogen balance, myopathy, osteoporosis, osteonecrois, cutaneous eruption, "steroid psychosis", and growth suppression.
Conditions necessary for a rational therapy using steroids include accurate diagnosis, failure of alternative therapy, the minimum dosage necessary for a therapeutic effect, preferrence to use local administration if possible, the use of steroid-sparing agents (?), use of alternative day therapy if practical, and avoidance of abrupt withdrawal. The risk of adverse effect is determined by dose, duration of treatment and the general health of the patient.
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