Endo (pt 5/7) Adrenal Flashcards
Describe the cascade of events from Hypothalamus to the release of hormones from the Adrenal Cortex.
1) Stress causes the release of Corticotropin Releasing Factor (CTRF) from the Hypothalamus
2) CTRF communicates with the Anterior Pituitary to release Corticotropin (ACTH)
3) ACTH stimulates the Adrenal Cortex to release gluco or mineralocorticoids.
Have important effects on:
-Intermediary metabolism (the intracellular process by which nutritive material is converted into cellular components)
-CV function
-Growth
-Immune Function
Glucocorticoids (Cortisol)
Controlled primarily by circulating Angiotensin and Potassium.
-Important salt-retaining effects
Mineralocorticoids (Aldosterone)
A normal adult, in the absence of stress, secretes 10-20 mg/day.
-Secretion follows circadian rhythm (highest in AM and after meals, declining throughout the day)
-Governed by pulses of ACTH
Cortisol
What time of day is best to administer exogenous cortisol?
Evening, because patients are most sensitive to PM dosing of exogenous steroids due to the decline of endogenous steroids in the evening.
90% of endogenous Cortisol is bound to ____ in the plasma, and 5% is bound to ____, leaving 5% free.
CBG; Albumin
Endogenous cortisol doesn’t rly bind to Albumin, but synthetics do, like _____.
Dexamethasone (synthetics bind to albumin, not CBG)
What is the half-life of Cortisol, and what makes it increase/decrease?
1/2 = 60-90 min
Increase: exogenous administration, stress (Surgery)
Decrease: hypothyroidism, liver dz
How is Cortisol metabolized and excreted?
Hepatic metabolism, urinary excretion.
1% excreted unchanged
20% converted to Cortisone
30% excreted as dihydroxy ketone metabolites
Explain the pharmacodynamics of Cortisol
1) Cortisol is present in the blood bound to Corticosteroid Binding Globulin (CBG).
2) Cortisol is added to the receptor, making it unstable.
3) Cortisol can now cross into the nucleus of the cell, where it binds with Nuclear Receptors (GRE), regulating transcription of the target gene.
___ - ____% of all genes are regulated by glucocorticoids.
10-20%.
Significant amount of actions r/t growth factors that are produced from the combination of steroid + receptor that moved into transcription. After gene transcription occurs, we see the anti-inflammatory, anti-growth, and immunosuppressive effects of glucocorticoids.
What are some of the physiologic effects of Cortisol?
-Cortisol can stimulate Mineralocorticoid receptors as well.
-Provides negative feedback to the Anterior Pituitary to suppress ACTH release
-Influence the function of most cells of the body
-Necessary for the vascular and bronchial smooth muscle responses to catechols
-Necessary for the for the lypolytic response of fat cells to catechols, ACTH and GH
What are the effects of mineralocorticoid receptor stimulation by cortisol?
-Sodium and fluid retention with a loss of Potassium (Hypokalemia, hypochloremic alkalosis, HTN)
-IF pt has low protein, renal disease or liver disease they will show signs of fluid overload and edema
-IF pt has heart disease, Sodium retention will promote heart failure
-Pts may need: Potassium supplements, Sodium/Salt restrictions, No additional mineralocorticoid therapy
What are the effects of Cortisol mainly due to?
Proteins synthesized from mRNA transcribed from their target organs
Where are the catabolic/anti-anabolic effects of Cortisol seen?
Seen mostly in Lymphoid, connective tissue, muscle, peripheral fat and skin
What are the catabolic & anti-anabolic effects of Supraphysiologic amounts (high doses) of glucocorticoids?
↓Muscle mass
Thinning of skin
Anti-anabolic effect on bone (Ex. osteoporosis of Cushing’s Syndrome)
What are the anti-inflammatory effects of glucocorticoids?
-Profound effects on the concentration, distribution, & function of peripheral leukocytes
-Suppressive effects on the inflammatory cytokines, chemokines & other inflammatory mediators
What are the Immunosuppressive effects of a Single dose of short-acting glucocorticoid?
-Inc Neutrophil concentration
-↓ Lymphocytes, monocytes, eosinophils & basophils
-Peak effect = 6hrs and then decrease starting at 24hrs
What are the Immunosuppressive effects of a Large dose (20mg/d prednisone) of glucocorticoid?
Decreased Antibody production, leading to:
-↓ ability to phagocytose and kill micro-organisms
-↓ TNF alpha, interleukin, metalloproteins, plasminogen factor (dec signaling of immune system)
General Immunosuppressive effects of Glucocorticoids?
-Inhibit phospholipase A2
-↓COX2 and therefore ↓ prostaglandins
-Transdermal: Vasoconstriction (suppression of mast cell degranulation, decreased histamine release from mast cells and basophils)
What are some misc. results of increased glucocorticoids?
-Insomnia, euphoria, depression and ↑ ICP (pseudotumor cerebri)
-Suppression of ACTH, GH, TSH, & LH
-Peptic Ulcer Disease
-Fat redistribution to viscera, face, nape of neck and supraclavicular
-Antagonize the effects of Vit D on Calcium absorption
-↑ RBC’s and platelets
Glucocorticoids have a dose related effect on ______, _______, and _____ metabolism.
carbohydrates, proteins, and fat
What is the metabolic goal of glucocorticoids?
Goal: maintain adequate glucose supply to the brain. Brain will steal glucose from everything else (pull up from proteins and fats).
How will glucocorticoids sacrifice muscle to make glucose available for the brain?
1) Stimulate phosphoenol carboykinase, G6phosphatase, glycogen synthesis, and the release of AAs in the course of muscle catabolism
2) Inhibit the uptake of glucose by muscle cells.
Increased insulin release stimulates what related to fats?
Increased insulin release (from increased serum glucose) stimulates lipogenesis and inhibits lipolysis = net increase in fat deposition + increased release of fatty acids and glycerol
What do glucocorticoids do in a fasting state to contribute to the glucose supply in the brain?
-Glucose from gluconeogenesis
-Release of amino acids from muscle catabolism
-Inhibition of peripheral glucose uptake
-Stimulation of lipolysis
Cortisol Deficiency can have what systemic effects?
-Impair renal function
-Increased vasopressin secretion
-Decreased ability to excrete H20
-Fetal Lung immaturity
Explain why infants need glucocortoids if mom is cortisol deficient?
-Glucocorticoids stimulate surfactant development in the fetus.
-Betamethasone 12mg IM x 1 dose with an additional dose 18 – 24h later
-Reduces the incidence of respiratory distress syndrome in premature infants (earlier than 34 weeks).
What is the drug of choice for reducing respiratory distress syndrome in premature infants and why is it chosen?
Betamethasone; Maternal protein binding and placental metabolism is less than that of cortisol, which allows increased transfer across the placenta.
How are synthetic corticosteroids synthesized?
-Cholic acid of cattle
-Steroid Sapogenins of plants
Explain the pharmacokinetics behind synthetic corticosteroids.
-Rapidly and completely absorbed orally
-Transported and metabolized similar to endogenous
-Metabolized in Liver and excreted in Urine
-Can change affinity for gluco or mineralocorticoid receptors
-Adding a side chain creates stability and promotes duration of action.
T/F: Prednisone is a Prodrug that is rapidly converted to Prednisolone (active product) in the the body.
True
Which synthetic corticosteroid is the most similar to Cortisol in terms of anti-inflammatory and salt-retaining activity?
Hydrocortisone
Which synthetic Mineralocorticoid has some anti-inflammatory effects, but considerably more salt retaining effects?
Fludrocortisone
Which synthetic glucocorticoid is 4x more anti-inflammatory than Cortisol, much less (0.3) salt retaining ability?
Prednisone
Which synthetic, long-acting glucocorticoid is 30x more anti-inflammatory than Cortisol, but has no salt-retaining effects?
Dexamethasone
Symptoms of Cushing’s due to large dose steroid use for longer than 2 weeks.
Iatrogenic Cushing’s Syndrome
Synthetic corticosteroid therapy for < ___wks does not typically cause Cushing’s like symptoms
2; Patients can occasionally display insomnia, behavioral changes (hypomania) and peptic ulcers after only a few days (but typically don’t get Cushing’s like symptoms)
What are toxicity symptoms of Synthetic Corticosteroids?
-Inc insulin needs = weight gain
-Impaired Wound healing
-Infections masked due to anti-inflammatory effects
-Diabetes
-Peptic Ulcers
-Severe Myopathy
-Increased IOP/Glaucoma
-Benign Intracranial HTN
-Adrenal Suppression (Labile BP)
Long-term therapy can cause depression, post subcapsular cataracts, and increased IOP/glaucoma.
Explain Stress-Dose Steroids
-More than 2 weeks of glucocorticoid therapy can cause adrenal suppression
-Supplement at times of minor stress
-Supplement for severe stress (accidental trauma, major surgery)
-Therapy must be tapered not abruptly discontinued
Why must corticosteroid therapy be tapered and not abruptly discontinued?
-2-12 months for the HPA function to return to normal
-Additional 6-9 months for normal Cortisol levels
What is the stress dose of steroids for minor stress?
2x’s the normal dose for 23-48 hours
What is the stress dose of steroids for major stress?
Up to 10x’s the normal dose for 48-72 hours
What conditions would you caution the use of synthetic corticosteroids in?
-Peptic Ulcers
-Heart Disease or HTN with HF (steroids can produce HD/HF by acting on mineralocorticoid receptors and causing water retention)
-Infectious illnesses (Varicella & TB)
-Psychoses (Can cause hypomania, behavioral changes)
-Diabetes (can cause insulin resistance)
-Glaucoma
What do you monitor for in the patient taking synthetic corticosteroids?
Hyperglycemia
Glycosuria
Sodium Retention/Edema
Hypokalemia
Peptic Ulcers
Osteoporosis
Hidden infection
What are the S/Sx of Chronic Adrenocortical Insufficiency (Addison’s Dz)?
Weakness
Fatigue
Weight loss
Hypotension
Hyperpigmentation
Inability to maintain blood glucose during fasting
What is the treatment for Chronic Adrenocortical Insufficiency (Addison’s Dz)?
Combination therapy of:
-Glucocorticoids (Hydrocortisone)
-Mineralocorticoids (Fludrocortisone)
What is the treatment for Acute Adrenocortical Insufficiency?
-High dose IV glucocorticoid therapy
-Tx fluid/electrolyte imbalances
-Tx precipitating factors
-Taper glucocorticoid therapy and initiate Mineralocorticoid therapy when stable
T/F: Acute Adrenocortical Insufficiency needs to be treated immediately.
True (emergency)
In utero defect in the synthesis of cortisol from cholesterol.
-No negative feedback to the Anterior Pituitary, so have high amounts of ACTH.
-Results in hyperplastic adrenal gland and over production of androgen precursors, leading to altered genitalia.
-Fetus can be born in an acute crisis of low levels of glucocorticoids.
-Tx: give Mom Dexamethasone while pregnant, and when fetus is born, give stress dose glucocorticoids. When glucocorticoids stabilize, give doses of both gluco and mineralocorticoids.
Congenital Adrenal Hyperplasia.
What is the usual cause and treatment of Cushing’s Disease (Adrenocortical Hyperfunction)?
-Cause: Bilateral adrenal hyperplasia, usually due to a ACTH secreting anterior pituitary adenoma
-Tx: surgical removal of tumor, irradiation of one or both adrenal glands, and large doses of cortisol (up to 300 mg Hydrocortisone) during/after surgery that must be tapered.
Why does the patient need high dose corticosteroids after ACTH secreting tumor is removed?
Body is used to high doses of glucocorticoids. Need high doses of exogenous to avoid an immediate drop in the glucocorticoid level. Steroid levels then need to be tapered to avoid crisis.
What are the S/Sx of Cushing’s Syndrome (excessive glucocorticoids)?
-CNS irritability, personality changes, mental disorders (due to hyperglycemia in the brain)
-High susceptibility to infection
-Na/Fluid retention (Cortisol acts on mineralocorticoid receptors as well)
-Poor wound healing
-HTN
-DM
-Truncal obesity, thin extremities, moon face, buffalo hump
-Significant protein loss/muscle wasting
-Thin skin, purple striae, easily bruised.
-GI distress due to increased acid
-Loss of menses and male hair growth in women and gynecomastia in men
Primary generalized glucocorticoid resistance. (Adrenocortical Hyperfunction)
Chrousos Syndrome
T/F: Chrousos Syndrome is due to mutations of the Glucocorticoid and Mineralocorticoid receptors.
False; just glucocorticoid receptor mutation
How does the Hypothalamus and HPA system compensate for Chrousos syndrome?
Increased secretion of ACTH, leading to:
-Increased Cortisol
-Increased Androgens
-Increased Mineralocorticoid activity
What are the S/Sx of Chrousos Syndrome (Primary generalized glucocorticoid resistance)?
-HTN
-Potassium Imbalances
-Hyperandrogenism
What are the manifestations of Hyperandrogenism?
-Virilization - the development of male physical characteristics (such as muscle bulk, body hair, and deep voice) in a female or precociously in a boy
-Precocious puberty
-Acne
-Hirsutism
-Male pattern baldness
-Menstrual irregularity
What is the treatment for Chrousos Syndrome?
Treat with high doses of synthetic glucocorticoids with NO inherent mineralocorticoid activity (Dexamethasone)
What are the causes of Aldosteronism?
1) Excessive production of aldosterone by an adrenal adenoma
2) From abnormal secretion by hyperplastic glands
3) From a malignant tumor
What are the S/Sx of Aldosteronism?
Related to the increase in Na/Water retention:
-Hypertension
-Weakness
-Tetany
-Renal loss of K+ leads to hypokalemia, alkalosis, increased serum Na+
-Low (suppressed) levels of plasma renin activity & angiotensin II
What is the treatment for Aldosteronism?
Spironolactone (Aldosterone receptor blocking agent)
What are some non-adrenal disorders where glucocorticoids are used?
Allergic Rxns
GI Diseases
Inflammatory Conditions of Bones/Joints
Neurologic disorders
Organ transplants
Pulmonary Dzs
Where are mineralocorticoids synthesized?
Zona glomerulosa of the adrenal cortex
An endogenous precursor of Aldosterone.
-Secretion is primarily under the control of ACTH (not a low salt diet)
-Secretion increases with adrenocortical carcinoma & congenital adrenal hyperplasia with decreased P450c11 or P450c17 activity
Deoxycorticosterone (DOC)
Exogenous, has both glucocorticoid and mineralocorticoid activity.
-Potent salt retaining activity
-Used in the tx of adrenocortical insufficiency
-Has glucocorticoid effects, but at regular doses it doesn’t really produce anti-inflammatory or anti-GH effects.
Fludrocortisone
What are the examples of the steroid synthesis inhibitors?
-Aminoglutethimide (Cushing’s)
-Ketoconazole (Cushing’s)
-Arbiraterone (Refractory Prostate C)
A potent, non-selective inhibitor of adrenal and gonadal steroid synthesis.
Ketoconazole
-Has a high affinity for the glucocorticoid receptor
-Creates generalized glucocorticoid resistance
-Half life of 20 hrs (longer than most natural and synthetic glucocorticoids)
-Extensive binding to albumin (not CBG)
-Recommended for patients with ectopic ACTH secretion or adrenal cancer that have failed tx with other agents
Mifepristone (RU-486)
Used in the tx of Primary Aldosteronism.
-Slow onset
-Actions last for 2-3 days after discontinued
-Restores potassium levels
-Also an androgen antagonist
-Diuretic – plays a role in the treatment of heart failure
-Can be used for tx of hirsutism and acne in women
Spironolactone
A Mineralocorticoid antagonist that is more selective than spironolactone.
-No androgen receptor effects
-Used in the tx of HTN and HF
Epleronone
What are the 6 adverse effects associated with Estrogen therapy?
1) Thromboembolism
2) MI
3) HTN
4) HA
5) Peripheral edema
6) Nausea
