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Dr. Cook - Exam 7
Terms in this set (43)
Steroid Hormones of the Adrenal Gland
Addison discovered importance of adrenal glands in his patients in 1849.
Addison's Disease is chronic adrenocortical insufficiency.
Later, it was discovered that bilateral adrenalectomy in animals was fatal.
Still later, the adrenal cortex was found to be responsible for control of both carbohydrate metabolism and electrolyte balance.
The important steroid hormones of the adrenal cortex are glucocorticoids and mineralcorticoids.
Cushing discovered hypercorticism in his patients in 1912.
Cushing Syndrome is increased adrenocortical secretion.
AdrenoCorticoTropic Hormone (ACTH)
The cause of Cushing's Syndrome is an overproduction of ACTH by the anterior pituitary.
ACTH (corticotropin) is a peptide of 39 amino acids.
It is synthesized as a part of a larger protein, proopiomelancortin (POMC).
Corticotropin-Like Intermediate-lobe Peptide (CLIP)
CLIP is a peptide derived from ACTH.
The intermediate lobe of the pituitary is a thin area between the anterior and posterior pituitary.
CLIP is involved in regulation of sleep patterns and circadian rhythm.
No pharmacologic uses for it yet.
ACTH Mechanism of Action
Acts on the adrenal cortex by binding to its specific membrane receptor.
The receptor is a G-protein coupled receptor.
Binding activated adenylate cyclase and increases intracellular cAMP.
ACTH Therapeutics and Diagnostics
The major clinical use of ACTH is in testing the integrity of the HPA axis to identify patients needing supplemental steroids.
Test of HPA axis: Measure cortisol, inject drug IM or IV and measure cortisol at 30 to 60 minutes.
Natural ACTH Isolated from Animal Glands
H.P Acthar Gel
Synthetic ACTH (AA 1-24) called Cosyntopin (Cortrosyn)
Cosyntropin is preferred because the animal product may contain high levels of vasopressin.
Secretion of Adrenal Steroids
The main mineralocorticoid is aldosterone and the main glucocorticoid is hydrocortisone (cortisol).
Cortisol is released more rapidly each day then aldosterone is produced each day.
Adrenals also release androgens.
Normal life expectancy is restored in adrenal insufficiency by replacing glucocorticoids and mineralcorticoids (without androgens).
It is suggested that androgen (DHEA) are needed in later life for improved well-being in women.
DHEA is low in chronic diseases so it may alleviate adverse consequences of aging in men and women.
Effects of Adrenocortical Steroids
Regulation of carbohydrate, protein, and lipid metabolism is done by glucocorticoids.
Maintenance of fluid and electrolytes balance is done by mineralcorticoids.
Preservation of normal function of cardiovascular, immune, kidney, skeletal muscle, endocrine, and nervous systems.
Capacity to resist stressful circumstances such as noxious stimuli and environmental changes.
Permissive Effects of Adrenocortical Steroids
Effects of corticosteroids that involve action with other hormonal regulators.
Ex: If you increase levels of Epinephrine, the glucocorticoids levels increase to lipase the increased Epinephrine.
Adrenocortical Steroids Mechanism of Action
Most corticosteroid effects occur through binding to a nuclear receptor and either increase or decrease DNA transcription leading to changes in concentration of specific proteins.
Most effects are delayed by several hours before corticosteroid therapy becomes manifest.
Some effects are immediate and are mediated by membrane receptors.
Aldosterone and Cortisol both bind to the mineralcorticoid receptor with equal affinity.
Cortisol is present in the circulation at much higher levels than aldosterone.
The enzyme 11Beta-hydroxysteroid dehydrogenase type 2 converts cortisol to cortisone in certain cells of the kidney, colon, and salivary glands.
Cortisone does NOT bind the mineralcorticoid receptor.
Carbohydrate and Protein Metabolism
Glucocorticoids (cortisol) protect the brain during starvation (even an overnight fasting) by keeping blood glucose elevated.
It does this by increased gluconeogenesis and glycogenolysis in the liver.
In peripheral tissues, it decreases glucose utilization, increases proteolysis, and activates lipolysis.
All these effects oppose insulin so this type of therapy could cause major problems for diabetic patients.
Major effects of glucocorticoids:
Retribution of body fat which is seen in Cushing Syndrome and long-term glucocorticoid therapy(increased fat at back or neck and in the face so you get rounded face).
Permissive effects on other agents such as growth hormone and beta-adrenergic receptor agonists in increasing lipolysis in adipose tissue.
Electrolyte and Water Balance
Aldosterone acts on kidney distal tubules and collecting ducts to increase reabsorption of sodium (and water) and increase excretion of potassium.
Aldosterone has similar effects in the colon, salivary glands, and sweat glands.
Overall effect is increased extracellular fluid volume, hypokalemia, and alkalosis.
Aldosterone deficiency leads to sodium loss, decreased extracellular fluid volume, hyponatremia, hyperkalemia, and acidosis.
Mineralcorticoids increases sodium retention which results in hypertension.
These effects can lead to cerebral hemorrhage, stroke, and hypertensive cardiomyopathy.
Another effects is to enhance vascular reactivity to other substances (usually through increased synthesis of adrenergic receptors).
Corticosteroids and Skeletal Muscle
Normal corticosteroid levels are required for normal skeletal muscle function.
Adrenocortical insufficiency (Addison's disease) causes diminished work capacity and fatigue.
Excess of corticosteroids will impair muscle function.
Primary aldosteronism causes muscle weakness due to hypokalemia.
Glucocorticoid therapy can lead to muscle weakness due to muscle wasting.
Effects of Corticosteroids on the CNS
There are direct effects on mood, behavior, and brain excitability.
Glucocorticoid treatment results in euphoria and felling of well-being, high motor activity, insomnia, and restlessness.
Addison's disease: apathy, depression, and irritability. Sometimes psychotic.
Cushing's Syndrome: High incidence of neuroses and psychoses.
Effects on Blood Cells
Increased hemoglobin and erythrocytes.
Addison's disease: increases lymphocytes and glucocorticoid therapy decreases lymphocytes.
Glucocorticoids also decrease eosinophils, monocytes, and basophils.
Glucocorticoids increase polymorphonuclear leukocytes.
Anti-Inflammatory Immunosuppressive Actions
These effects are profound.
Glucocorticoids suppress inflammation caused by stress.
Highly prescribed for suppressing inflammation.
Glucocorticoids inhibit release of arachidonic acid and its metabolites (prostaglandins and leukotrienes) through decreased expression of phospholipase A2.
These inhibit production and release of cytokines.
Also inhibit histamine release.
Effective when given by mouth.
Absorbed readily from intramuscular sites, conjunctival sac (under eyelid), skin, respiratory tract, and other local sites.
Circulating Cortisol is 90% bound to proteins.
Corticosteroid binding protein (alpha globulin secreted by liver) and albumin are the proteins that bind these.
CBP has high affinity for binding, but low capacity.
Albumin has low affinity for binding, but high capacity.
CBP increases several-fold in pregnancy and during estrogen treatment.
Side Effects of Glucocorticoid Therapy
Suppression of ACTH and TSH production from the pituitary.
Time of recovery from this suppression is dependent on dose and length of therapy.
Don't stop therapy abruptly!!
Osteoporosis (especially in children and postmenopausal women)
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 and sleep disturbances.
In Men, Side Effects
Glucocorticoids can suppress gonadotropin secretion which can cause hypogonadism due to decreased testosterone production.
In Women, Side Effects
Glucocorticoids can stop ovulation, or cause dysmenorrhea or dysfunctional uterine bleeding.
In Children, Side Effects
Glucocorticoids may impair linear growth rate (decreased growth hormone and inhibition of IGF-1 effects).
Therapeutic Uses of Corticosteroids
Risks/Benefits of therapy must be assessed in each patient.
Appropriate dose determined by trial and error.
Single dose usually not harmful.
Treatment for 1 week unlikely results in suppression of HPA axis.
Longer term therapy increases risk.
Cessation after long-term therapy has very serious consequences, possibly fatal.
Must use smallest dose that achieves desired effect.
Acute Adrenal Insufficiency Disorders of Adrenal Gland or Abrupt Withdrawal of Glucocorticoids
IV isotonic NaCl + 5% glucose + corticosteroids
IV Hydrocortisone (cortisol)
Chronic Adrenal Insufficiency (less severe symptoms)
Daily Hydrocortisone, Cortisone, Dexamethasone, or Prednisone.
Most require mineralcorticoids (Fludrocortisone)
Congenital Adrenal Hyperplasia
Genetic disorder lacking enzymes to produce Cortisol or Aldosterone or both resulting in increased ACTH secretion for lack of feedback.
Hydrocortisone with or without Fludrocortisone.
Oral Prednisone or injections into the knee
Allergic Disease for Long-Term Treatment
Antihistamines for moderate symptoms.
IV Methylprednisolone for severe symptoms.
Intranasal steroids for allergic rhinitis.
Many and varied depending on patients and symptoms.
Paradoxical but can be used in certain AIDS or meningitis cases.
Usually only used for anti-inflammatory effect for these cases.
GI Diseases like Chronic Ulcerative Colitis, Crohn's Disease
Hydrocortisone, Prednisone, Budesonide (very high first pass effect) delayed release capsules for local effect in small intestine and ascending colon.
Acute Lymphocytic Leukemia and Lymphoma
Antilymphocytic effect- several glucocorticoids
Budesonide (Pulmicort) inhalation suspension for oral inhalation.
Renin-Angiotensin system (angiotensin II stimulates aldosterone secretion)
Plasma potassium levels (high K+ increases secretion)
ACTH mediated release is secondary to these 2 stimuli.
Side Effects of Aldosterone Therapy
Excessive salt and water retention.
Increased blood volume.
Congestive heart failure.
Inhibits P450scc in synthetic pathway.
Inhibits overproduction of Cortisol in Cushing's Syndrome.
Inhibits P45017a and P450scc to block Cortisol in Cushing's Syndrome.
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