Glucocorticoids, Mineralocorticoids & Adrenocortical Antagonists Flashcards
Adrenocortical Steroids Drug Types
A. ACTH B. Glucocorticoids C. Mineralocorticoids D. Mineralocorticoid antagonist E. Inhibitors of adrenocortical steroids synthesis or action
ACTH Drugs
- Natural (animal) ACTH
2. Cosyntropin Synthetic ACTH (aa 1-24)
Glucocorticoids Drugs
- cortisol = hydrocortisone
- cortisone acetate
- prednisone
- prednisolone
- methylprednisolone
- dexamethasone
- betamethasone
- triamcinolone
- budesonide inhalalation
Mineralocorticoids Drugs
- Aldosterone
2. Fludrocortisone
Mineralocorticoid antagonist Drug
Spironolactone
Inhibitors of adrenocortical steroids synthesis or action Drugs
- aminoglutethimide
2. ketoconazole
ACTH (AdrenoCorticoTropic Hormone) is?
ACTH (corticotropin) is a peptide of 39 amino acids. It is synthesized as a part of a larger protein, proopiomelanocortin (POMC)
The cause of Cushing’s Syndrome is an?
Overproduction of ACTH by the anterior pituitary.
ACTH Mechanism of Action?
ACTH acts on the adrenal cortex by binding to a specific membrane receptor. The ACTH receptor is a G-protein coupled receptor. ACTH binding activates adenylate cyclase and increases intracellular cAMP.
The major clinical use of ACTH is?
In testing the integrity of the HPA axis to identify patients needing supplemental steroids.
Natural ACTH isolated from?
Animal glands
Synthetic ACTH?
(aa 1-24) called cosyntropin
Hypothalamic-Pituitary-Adrenal Axis (HPA) how to test?
Test of HPA axis: Measure cortisol, inject drug I.M. or I.V. measure cortisol at 30 to 60 min.). Cosyntropin is preferred because the animal product may contain high levels of vasopressin.
The main mineralocorticoid is?
Aldosterone
The main glucocorticoid is?
Hydrocortisone (same as cortisol).
Cortisol is released at?
10 mg/day
Aldosterone is produced at?
0.125 mg/day. (100X difference)
Adrenocortical Steroids Regulation?
Carbohydrate, protein and lipid metabolism.
Maintenance of fluid and electrolyte balance.
Adrenocortical Steroids Preservation of normal function of?
Cardiovascular system, immune system, kidney, skeletal muscle endocrine system and nervous system.
Adrenocortical Steroids Capacity to resist?
Stressful circumstances such as noxious stimuli and environmental changes.
Effects of Adrenocortical Steroids Permissive Effects Define?
Some effects of corticosteroids involve actions with other hormonal regulators that are called permissive effects.
Permissive Effects Only a small amount of glucocorticoid in needed to?
Greatly potentiate their lipolytic effects. Epinephrine and norepinephrine have minor effects on lipolysis in the absence of glucocorticoids.
Corticoids are usually grouped according to three criteria (3 major actions)?
– Effects of carbohydrate metabolism (glycogen deposition and gluconeogenesis)
– Antiinflammatory effects
– Relative potencies in Na+ retention
Most corticosteroid effects occur through?
Binding to nuclear receptors and either increase or decrease DNA transcription leading to changes in concentration of specific proteins.
Most corticosteroid effects are?
Delayed by several hours before corticosteroid therapy becomes manifest.
Some corticosteroid effects are?
Immediate and are mediated by membrane receptors.
Aldosterone and cortisol both bind to?
The mineralocorticoid receptor with equal affinity, but Cortisol is present in the circulation at much higher levels than aldosteone.
The enzyme 11β-hydroxysteroid dehydrogenase
type 2 converts?
Cortisol to cortisone in certain cells of the kidney, colon and salivary glands.
Cortisone does not bind to?
The mineralocorticoid receptor.
Glucocorticoids (cortisol) protect the brain during
starvation?
(even an overnight fast) by keeping blood glucose elevated. The mechanism is by increased gluconeogenesis and glycogenolysis in the liver. Also, in peripheral tissues, glucocorticoids.
Glucocorticoids (cortisol) Effects?
Decrease glucose utilization. Increase proteolysis (aa for gluconeogenesis) Activate lipolysis (glycerol for gluconeogenesis and fatty acids for energy needed for glucose synthesis).
Glucocorticoids oppose?
Insulin: Therefore: Glucocorticoid therapy can create major problems in diabetic patients.
Two major effects of glucocorticoids on lipid
metabolism.
Restribution of body fat (seen in Cushing’s Syndrome and long-term glucocorticoid therapy).
Permissive effects on other agents such as growth hormone and β-adrenergic receptor agonists in increasing lipolysis in adipose tissue.
Aldosterone is the most imporant?
Mineralocorticoid.
Aldosterone acts on?
Distal tubules and collecting ducts of the kidney to increase reabsorption of Na+ and increase excretion of K+ and H+.
Aldosterone has similar actions in the?
Colon, salivary glands and sweat glands.
The overall effect of aldosterone is?
Increased extracellular fluid volume, hypokalemia and alkalosis.
Aldosterone deficiency leads to?
Na+ loss, decreased extracellular fluid volume, hyponatremia, hyperkalemia and acidosis.
Glucocorticoids also contribute to loss of?
Total body Ca2+ by multiple poorly understood mechanisms (gut and kidney)
The most striking effects on the cardiovascular system are?
From mineralocorticoid actions to increase Na+ retention resulting in hypertension. These effects can lead to cerebral hemorrhage, stroke and hypertensive cardiomyopathy.
Another major effect on the cardiovascualr system is
To enhance vascular reactivity to other substances (usually through increased synthesis of adrenergic receptors).
Normal corticosteroid levels are required for?
Normal muscle function.
Adrenocortical insufficiency (Addison’s disease) causes?
Diminished work capacity and fatigue. {Caused by decreased capacity of the circulatory system.}
An excess of either glucorticoids or mineralocorticoids will?
Impair muscle function.
Primary aldosteronism causes muscle weakness due to?
Hypokalemia.
Glucocorticoid therapy can also lead to muscle weakness due to?
Muscle wasting (steroid myopathy) (increased proteolysis).
Effects of Corticosteroids on the CNS are direct effects on?
Mood, behavior and brain excitability euphoria leading to a felling of well-‐being, high motor activity, insomnia, restlessness.
Addison’s disease effects on CNS?
Apathy, depression and irritability.
Some are frankly psychotic.
Cushing’s syndrome effects on CNS?
High incidence of neuroses and psychoses.
Effects of Corticosteroids on Blood Cells?
Increased hemoglobin and erythrocytes. Glucocorticoids also decrease eosinophils, monocytes and basophils (in a few hours after administration).
Glucocorticoids increase PMNs.
Addison’s disease has a (blank) effect on lymphocytes?
Increases lymphocytes. Glucocorticoid therapy decrease lymphocytes.
Glucorticoids suppress?
Inflammation caused by stress (mechanical, chemical, infectious and immunological).
Glucorticoids enormous clinical utility in suppressing
inflammation makes them some?
Of the most often prescribed drugs.
Glucocorticoids inhibit release of?
Arachidonic acid and its metabolites (prostaglandins and leukotrienes) through decreased expression of phospholipase-A2.
Glucocorticoids inhibit production and release of?
Cytokines (especially IL-1, IL-6, and TNF-α). They inhibit histamine release.
Glucorticoids Absorption?
Effective when given by mouth. Absorbed readily from intramuscular sites, conjunctival sac, skin, respiratory tract, and other local sites.
Glucorticoids Transport
Circulating cortisol is 90% bound to proteins. Only
unbound corticosteroids can enter cells.
Two proteins account for binding - corticosteroid
binding protein (CBP, an α-globulin secreted by the
liver) and albumin. CBP has high affinity for binding,
but low capacity. Albumin has low affinity, but high capacity. CBP increases several-fold in pregnancy and during estrogen treatment.
Cortisol or hydrocortisone
(Cortef, Hydrocortone)
Route
T½, relative
Oral, IM, IV
Short
Cortisone acetate
(Cortone acetate)
Route
T½, relative
Oral, IM, IV
Short
Prednisone (Deltasone)
Route
T½, relative
Oral
Intermediate
Prednisolone (Delta-Cortef)
Route
T½, relative
IM, IV
Intermediate
Methylprednisolone (Medrol)
Route
T½, relative
Oral, IM, IV
Intermediate
Dexamethasone (Decadron)
Route
T½, relative
Oral, Topical, IM, IV
Long
Betamethasone (Celestone)
Route
T½, relative
Oral, Topical
Long
Triamcinolone (Aristocort)
Route
T½, relative
Oral, Topical
Long
Side Effects of Glucocorticoid Therapy
Suppression of ACTH and TSH production from the
pituitary.
Osteoporosis
Chronic administration renders some individuals prone to diabetes.
Increased incidence of peptic ulcers. Perforated ulcers
go undetected.
CNS side effects - arousal and euphoria. Followed by depression, sleep disturbances.
Side Effects of Glucocorticoid Therapy IN MEN
Glucocorticoids can suppress gonadotroph secretion which can cause hypogonadism due to decreased testosterone production.
Side Effects of Glucocorticoid Therapy IN WOMEN
Glucocorticoids can stop ovulation, or cause dysmenorrhea or dysfunctional uterine bleeding.
Side Effects of Glucocorticoid Therapy IN CHILDREN
Glucocorticoids may impair linear growth rate (decreased GH and inhibition of IGF-1 effects)
Cessation after long term Glucocorticoid therapy has?
Very serious consequences, possibly fatal!
Secretion of aldosterone by the adrenal gland is controlled by two mechanisms:
Renin-angiotensin system (angiotensin II stimulates aldosterone secretion)
Plasma potassium levels (High K+ increases secretion.)
ACTH mediated release is secondary to these two stimuli.
Aldosterone Physiological Actions
Acts on the distal convoluted tubules in the kidney:
Promotes sodium reabsorption & Increases excretion of potassium & H+
Side Effects of Aldosterone Therapy
Excessive salt and water retention.
Increased blood volume.
Congestive heart failure.
Inhibitors of Synthesis and Action of Adrenocortical
Steroids
Aminoglutethimide
Ketoconazole
Aminoglutethimide Mechanism?
Inhibits P450scc in synthetic pathway.
Inhibits overproduction of cortisol in Cushing’s syndrome.
Ketoconazole Mechanism?
Antifungal agent.
Inhibits P45017α and P450scc to block cortisol in Cushing’s syndrome
