Flashcards in Adrenocorticosteriods: Deck (31)
Secretion of adrenocorticosteroids and mineralocorticorticoid is controlled by what?
Adrenocorticosteroids: controlled by the pituitary release of corticotrophin (ACTH)
Mineralocorticorticoids (aka aldosterone): under the control of angiotensin
Cortisol (Also called hydrocortisone) exerts a wide range of physiological effects. Its synthesis and secretion are tightly regulated by the CNS, how?
Negative feedback by the circulating cortisol and exogenous glucocorticoids.
--secretion follows a circadian rhythm governed by pulses of ACTH that peak in the early morning hours and after meals, esp after lunch.
Glucocorticoids interact with specific receptor proteins in target tissues. After ligand binding, the glucocorticoid receptor dissociates from its associated proteins and translocates to the nucleus. What happens then?
Interacts with specific DNA sequences within the regulatory regions of affected genes.
--short DNA sequences that are recognized by the activated glucocorticoid receptor (GR) are called glucocorticoid responsive elements (GREs).
--most effects of corticosteroids are not immediate but become apparent after several hours.
Like the GR, the mineralocorticoid receptor (MR) also is a ligand activated transcription factor and binds to a very similar hormone responsive element. How is the MR different from the GR?
The MR has a restricted expression: it is expressed principally in the kidney, colon, salivary glands, sweat glands and hippocampus
Glucocorticoids have a widespread effect because they influence the function of most cells in the body. What are the metabolic effects of glucocorticoids?
Affect carb and protein metabolism
Stimulate and are required for gluconeogenesis and glycogen synthesis in the fasting state.
In periphery, glucocorticoids diminish glucose utilization, increase protein breakdown and the synthesis of glutamine and activate lipolysis, thereby providing amino acids and glycerol for gluconeogenesis.
Increasing serum glucose glucocorticoids stimulate insulin release and inhibit uptake of glucose by muscle cells, while they stimulate hormone sensitive lipase and thus lipolysis, leading to an increase in fat deposition.
The net results of the actions of Glucocorticoids in terms of metabolic are what?
--supply of glucose from gluconeogenesis
--the release of amino acids from muscle catabolism
--inhibition of peripheral glucose uptake
--stimulation of lipolysis all contribute to maintenance of an adequate glucose supply to the brain
Glucocorticoids also have a catabolic effects in lymphoid and connective tissue, muscle, peripheral fat and skin. What are some of these effects?
--decreased muscle mass and weakness and thinning of the skin
--cause of osteoporosis in Cushing's syndrome and impose a major limitation in the long term use.
Antagonize the effect of vitamin D on calcium absorption
Glucocorticoids also have two effects on the lipid metabolism, what are these?
1. Dramatic redistribution of body fat that occurs in settings of endogenous or pharmacologically induced hypercorticism, such as Cushings syndrome
2. Permissive facilitation of the lipolytic effect of other agents, such as GH and beta agonists, resulting in an increase in FFA after glucocorticoid administration
The immunosuppressive effects of glucocorticoids are due to a decrease number of circulating lymphocytes, eosinophils, monocytes and basophils. This is due to redistribution of cells away from the periphery rather than from increased destruction. How do glucocorticoids affect neutrophils?
Increase circulating neutrophils as a result of increased release of marrow, diminished rate of removal from the circulation and increased demargination from vascular walls.
Glucocorticoids are know for what in regards to blood vessels?
1. Vasoconstriction when applied directly to t he skin by suppressing mast cell degranulation
2. Decrease capillary permeability by reducing the amount of histamine released by basophils and mast cells
What are the three mechanisms involved in the suppression of inflammation by glucocorticoids?
1. Inhibit the functions of tissue macrophages and other antigen presenting cells. In addition they influence the inflammatory response by reducing prostaglandin, leukotriene, and platelet activating factor synthesis that results from activation of phospholipase A2
2. Reduce expression of COX2 in inflammatory cells, thus reducing the amount of enzyme available to produce prostaglandins
3. The result in the induction of MAPK phosphatase which leads to the inhibition of MAPK activated proinflammatory signaling pathways
What indirect effects do Glucocorticoids have on the CNS?
Through maintenance of blood pressure, plasma glucose concentrations, and electrolyte concentrations. Also effects on mood, behavior and brain excitability
What effect do Glucocorticoids have that are given chronically?
Suppress the pituitary release of ACTH, growth hormone, Thyroid stimulating hormone, and LH
Large Doses of Glucocorticoids have been associated with the development of what?
Peptic ulcers, possibly by suppressing the local immune response against H. pylori
What effect does Glucocorticoids have on the fetal lungs?
Production of pulmonary surfactant are stimulated by glucocorticoids
The development of many synthetic steroids with anti-inflammatory and immunosuppressive activity have been developed what are these?
---rapidly and completely absorbed orally, have longer half lives, reduced mineralocorticoid activity and selected compounds can be given IM, IV or topically
Moving on to Mineralocorticoids, the most important is aldosterone. Fludrocortisone, a synthetic corticosteriod, is the most commonly prescribed salt retaining hormone. What is the action of this drug?
Promotes reabsorption of sodium from the distal part of the convoluted tubule and cortical collecting tubules, also increases urinary excretion of K and H
--excessive levels of aldosterone produced lead to hypokalemia, metabolic alkalosis, increased plasma volume and HTN
Mineralocorticoids act by binding to the mineralocorticoid receptor in the cytoplasm of target cells. The major effect of activation of the receptor is increased expression of?
Epithelial Sodium Channel (ENaC)
Lets review the anti-inflammatory to salt retaining ratio of the various steroids. First we will start with the Short to medium acting glucocorticoids.
Hydrocortisone: 1 to 1
Prednisone: 4 to 0.3
Methylprednisolone: 5 to 0.25
Next are the intermediate acting glucocorticoids
Triamcinolone: 5 to 0
Next are the long acting glucocorticoids
Dexamethasone: 30 to O
(often used for cancer pain)
Finally the mineralocorticoids
Fludrocortisone: 10 to 250
Aldosterone: 0.3 to 3000
Moving on to Clinical Pharmacology. First lets discuss Chronic Addison's Disease (Primary Adrenocortical Insufficiency). What is this?
Weakness, fatigue, weight loss, hypotension, hyperpigmentation, and inability to maintain the blood glucose level during fasting.
--hydrocortisone must be given daily with increased amounts during periods of stress, also, fludrocortisone must be given for the salt retaining effects
What therapy is given when acute adrenocortical insufficiency is suspected?
Tx started immediately:
--large amounts of parenteral hydrocortisone in addition to correction of fluid and electrolyte abnormalities and tx of precipitating factors
Give high dose IV hydrocortisone until patient is stable
--dose will be reduced and placed on maintenance
Salt retaining hormone replacement will be resumed when the total hydrocortisone dosage has been adequately reduced.
Next in clinical pharmacology is adrenocortical Hypo and Hyperfunction. First up is Congenital Adrenal Hyperplasia. What is this caused by?
Defects in cortisol synthesis either in CRH production in the hypothalamus or in corticotropin production by the pituitary
What is the most common congenital adrenal hyperplasia?
Decrease or lack of 21 beta hydroxylase activity.
--leads to the reduction in cortisol synthesis and a compensatory increase in ACTH release.
--gland becomes hyperplastic and produces large amounts of precursors such as 17-hydroxyprogesterone that can be diverted to the androgen pathway, leading to virilization
--patient will present initially with acute adrenal crisis and should be treated the same as someone with addison's crisis.
--once the patient is stable then oral hydrocortisone, or prednisone is begun as well as Fludrocortisone
Next adrenocortical Hypo and Hyperfunction is Cushing's Syndrome. Symptoms are associated with the chronic presence of excessive glucocorticoids. What some features?
Rounded, plethoric face and trunk obesity
Protein loss: muscle wasting, thinning, purple striae and easy bruising of the skin, poor wound healing and osteoporosis
Mental disorders, HTN and diabetes
--tx with removal of the tumor or resection of one or both adrenals. patients need large doses of cortisol before and after surgery. dose then needs to be reduced slowly to normal levels
The third adrenocortical hypo and hyperfunction is Aldosteronism. What is this?
Results from excessive production by an adrenal adenoma.
--renal loss of K (hypokalemia, alkalosis and elevation of serum Na)
--tx with aldosterone antagonist: spironolactone
It is sometimes necessary to suppress the production of ACTH to identify the source of a particular hormone or to establish whether its production is influenced by the secretion of ACTH. What is the dexamethasone suppression test?
Used for dx of Cushing's syndrome
--has used for dx of depressive psychiatric states