Adrenal Pharmacology Flashcards
Adrenal Medulla
- Consists mainly of chromaffin cells, which are part of the sympathetic nervous
- Location for the conversion of tyrosine to epinephrine (adrenaline) and norepinephrine (noradrenaline) in response to stress
- Responsible for producing and secreting steroid hormones
Zona glomerulosa
- Predominantly regulated by Angiotensin II and extracellular K+
- Has receptor for ACTH, but ACTH is not the main regulator
- Does NOT undergo atrophy in the absence of ongoing stimulation by ACTH (pituitary gland)
- Renin-angiotensin system regulates aldosterone production and secretion from zona glomerulosa
Aldosterone
- Produced in zona glomerulosa accounts
- Maintains the homeostatic balance of electrolytes, including the renal tubular reabsorption of sodium
- Causes the kidneys to increase sodium and water retention
- Increases blood pressure
- Exerts a negative feedback on renin’s release
Cortisol
- Creates Energy Substrates
- Increases gluconeogenesis
- Proteolysis
- Lipolysis
- Maintains BP
- INCREASING sensitivity of blood vessels to catecholamines (epinephrine and norepinephrine) which narrow blood vessel lumen
- Dampens inflammatory and immune response
- Reduces production of prostaglandins and interleukins
- Inhibits T-lymphocytes
What are the two adrenal androgens?
- Dehydroepiandrosterone (DHEA)
- Dehydroepiandrosterone sulfate (DHEAS)
Adrenal Androgens
- Steroid hormones with weak androgenic activity
- Provide a pool of circulating precursors for peripheral conversion to more potent androgens (e.g. testosterone) and estrogens (e.g. estradiol)
- Adrenarche (secretion of adrenal androgens) occurs BEFORE gonadarche (secretion of gonadal sex steroids). Causes appearance of axillary and pubic hair
What is the transport of cortisol?
- > 90% bound to corticosteroid-binding globulin (CBG)
- Bound steroids are physiologically inactive
- Free cortisol increases when binding sites on CBG become saturated (total plasma cortisol > 20 ug/dL)
What factors enhance glucocorticoids metabolism?
- Phenytoin
- Phenobarbital
- Rifampin
- Mitotane
- Hyperthyroidism
What factors reduce glucocorticoid metabolism?
- Chronic liver disease
- Pregnancy
- Hypothyroidism
- Anorexia nervosa
- Protein-calorie malnutrition
- Estrogens
- Surgery and other major physiologic stresses
What are the glucocorticoid effects?
- Immunologic
- Calcium wasting
- Anti-inflammatory
- Demargination
- Neurologic
What are the mineralocorticoid effects?
- Na+ retention
- K+ secretion
Dexamethasone
- Pure glucocorticoid activity
- Useful for severe inflammation and/or nausea
- Ex: Meningitis or anti-emetic regimen
Methylprednisone
- High glucocorticoid activity
- Useful for immunologic flares
- Ex: Multiple sclerosis, rejection
Hydrocortisone
-Equal action
-Useful for adrenal insufficiency
Ex: Sepsis, Addison’s
Fludrocortisone
- Mineralocorticoid Activity
- Useful for Addison’s disease:
- Treat hyperkalemia and hypotension
Cushing syndrome
Supraphysiologic concentrations of glucocorticoids
What is the etiology of Cushing syndrome?
- Endogenous excess production of cortisol
- ACTH-DEPENDENT
- Pituitary corticotrope adenoma = **Cushing disease **(one form of Cushing Syndrome)
- Ectopic secretion of ACTH by NON-pituitary tumor
- ACTH-INDEPENDENT
- Adrenocortical adenoma or carcinoma
- Iatrogenic: Supraphysiologic exogenous glucocorticoids
Low-dose dexamethasone test
- Dexamethasone (1 mg) is taken orally between 11 pm and midnight, and a single blood sample is drawn at 8 am the next morning
- Draw cortisol and dexamethasone level. (Dose is 0.3 mg/m2 in children.)
- Hypercortisolism is diagnosed if dexamethasone is detectable, and cortisol is NOT suppressed (i.e. cortisol level is high).
Late-night salivary cortisol concentration
- Patients collect saliva between 11 pm and midnight (passive drooling into a tube or chewing on a cotton).
- Sample can be kept at room temperature or refrigerated for several weeks before analyzed
High-dose dexamethasone suppression test (DST)
- Obtain baseline cortisol level, then give dexamethasone (2mg every 6 h) for 48 h
- Patients w/ adrenal hypercortisolism or ectopic ACTH syndrome do NOT exhibit decreased cortisol levels
- Decreased cortisol after DST = Cushing disease
CRH test
- 100 ug of ovine CRH (corticorelin) administered IV at time 0
- Cortisol and ACTH levels are measured every 15 min
- Patients with Cushing disease respond to CRH with a rise in cortisol and ACTH
- Patients with adrenal hypercortisolism or ectopic corticotropin syndrome (ECS) do NOT respond to CRH
What is the first line therapy of Cushing Syndrome?
Surgery (resection of the tumor), chemotherapy, or radiation
What are the pharmacotherapy for Cushing Syndrome that INHIBIT adrenal hormone synthesis?
- Ketoconazole
- Metyrapone
- Etomidate
Ketoconazole
- Drug Class: Antifungal agent, but Steroidogenesis inhibitor at higher dose
- MOA:
- Blocks production of cortisol and aldosterone
- Antiadrenergic activity within adrenal cortex
- Useful in adrenocortical carcinomas, breast/prostate cancer, and to reduce hirsutism and acne (in PCOS—adrenergic side effects)
- CYP3A4 inhibitor
What are the side effects of ketoconazole?
- **Elevation of hepatic transaminases/hepatotoxicity **
- N/V
- Can cause gynecomastia and hypogonadism in men
- Teratogenic
Metyrapone
- Drug class: Steroidogenesis inhibitor
- MOA: Block production of cortisol (BUT NOT ANDOGENS)
- Often given with ketoconazole (to prevent androgen side effects)
- Can be used in pregnancy, but NOT breastfeeding!
- Stimulation Test
- Used to evaluate the HPA axis
- Metyrapone blocks conversion of **11-deoxycortisol to cortisol **
What are side effects of Metyrapone?
- Androgenic side effects, including hirsutism and acne
- N/V, edema
- Blood pressure and electrolyte disruption
Etomidate
- Drug class: Steroidogenesis inhibitor
- Used as an Anesthetic
- Given IV for severe Cushing Syndrome
What are the side effects of Etomidate?
- Pain and myoclonus on injection site
- Adrenal suppression when given long-term
What are the pharmacotherapy for Cushing Syndrome that DESTROYS cells within the adrenal gland?
- Mitotane
Mitotane
- Drug Class: Adrenolytic Agent
- MOA:
- Cytotoxicity–> destroys cells within the adrenal gland
- Also INCREASES extra-adrenal metabolism of exogenously administered corticosteroids
- CYP3A4 inducer
- High doses of steroid replacement therapy often needed after therapy
What are the side effects of Mitotane?
- Significant neurologic and GI side effects
- High doses of steroid replacement therapy often needed after therapy (prednisone or dexamethasone)
- AVOID in pregnancy and breastfeeding
What is the pharmacotherapy for Cushing Syndrome?
Mifepristone
Glucocorticoid Receptor Antagonist
Mifepristone
- Drug Class: Glucocorticoid-Receptor Blocking Agent
- Progesterone receptor antagonist used to terminate pregnancy
- Also a nonselective antagonist of glucocorticoid receptors
- Causes INCREASE in ACTH and cortisol levels
- We’re not going to see a reduction of cortisol—so can’t use cortisol as a marker to see drug efficacy
- **FDA approved for the treatment of hyperglycemia in patients with Cushing syndrome associated with diabetes or glucose intolerance who are either not candidates for surgery or did not respond to surgery **
What are the side effects of Mifepristone?
- Increases endogenous and ACTH levels
- Fatigue
- N/V
- Arthralgias
- Headache
- Hypertension
- Hypokalemia
- Edema
- Endometrial thickening
What is the pharmacotherapy for Cushing Disease that inhibit ACTH?
Pasireotide
Pasireotide
**Novel SST analog that is medical treatment option for CDDirectly targets ACTH secretion and pituitary adenoma **
* Drug Class: Neuromodulatory Agent (somatostatin analog); high binding affinity for SST receptor 5, the predominant receptor in human corticotroph adenomas that is not downregulated by high cortisol levels
* MOA:
- Target neurotransmitter (somatostatin) capable of pituitary ACTH production
What are the side effects of Pasireotide?
- Hyperglycemia & increased A1c, likely due to impaired insulin secretion
- B/c somastatin analogs also affect the pancreas and also the GI tract and affect a lot of different things
- GI discomfort—diarrhea, N/V, abdominal pain
- Hypotension
Primary hyperaldosteronism
- Source = adrenal gland
- Usually caused by bilateral adrenal hyperplasia or aldosterone-producing adenoma (Conn syndrome)
Secondary hyperaldosteronism (outside of adreneal gland)
- Excessive stimulation of the zona glomerulosa by an extra-adrenal factor
- Excessive potassium intake, oral contraceptive use, pregnancy, congestive heart failure, cirrhosis, renal artery stenosis
What are some symptoms of hyperaldosteronism?
- Muscle weakness, fatigue, paresthesia, and headache
- Hypertension
- Tetany/paralysis
- Polydipsia/nocturnal polyuria
What is the pharmacotherapy of hyperaldosteronism?S
Spironolactone
Spironolactone
- A nonselective aldosterone-receptor antagonist
- MOA: Competes with aldosterone for binding at the aldosterone receptor; at doses above recommended doses, also inhibits aldosterone synthesis within the adrenal gland
- Dosed between 25 and 400 mg/day
What are the side effects of spironolactone?
- GI discomfort
- Impotence
- Gynecomastia
- Menstrual irregularities
- Hypotension
- Hyperkalemia
What are some common symptoms of adrenal insufficiency?
- Lack of energy
- Weakness
- Weight loss
- GI symptoms
- Hyponatremia
- Craving for salt
- Headaches
- Memory impairment
- Depression
- Postural dizziness
What
What are some early symptoms of adrenal insufficiency?
Non-specific
- Malaise
- Myalgias
- Anorexia
What are some acute symptoms of adrenal insufficiency?
- Vomiting
- Fever
- Hypotension
- Shock
Abnormal cosyntropin stimulation test
- Serum cortisol measured at baseline and 30 to 60 minutes after the injection of 250 ug IM or IV of cosyntropin
- If plasma cortisol remains low and fails to rise greater than 10 ug/dL above baseline, this is indicative of adrenal insufficiency
Cosyntropin
Synthetic peptide that corresponds to residues 1-24 of corticotropin (human ACTH)
Addison’s Disease
- Primary adrenal insufficiency
- Levels of CRH and ACTH increased
- Hyperpigmentation in areas of increased friction
What is the etiology of Addison’s Disease?
- Autoimmune dysfunction
- Tuberculosis
- Adrenalectomy
- Medications that inhibit cortisol synthesis (ketoconazole) or accelerate cortisol metabolism (phenytoin, rifampin, phenobarbital)
What is the diagnosis of Addison’s disease?
- Abnormal cosyntropin stimulation test
- Elevated ACTH
- Low aldosterone
What is the treatment of Addison’s Disease?
Glucocorticoid plus Mineralocorticoid replacement
Secondary and Tertiary adrenal insufficiency
- Reduced glucocorticoid and adrenal androgen production secondary to low ACTH
- Normal concentrations of mineralocorticoids (normal aldosterone)
What is the etiology of secondary and tertiary adrenal insufficiency?
- Exogenous steroids
- Mirtazapine and progestins, such as medroxyprogesterone acetate and megestrol acetate
What is the diagnosis of secondary adrenal insufficiency?
- Abnormal cosyntropin stimulation test
- Low or normal ACTH
- Normal aldosterone
What is the treatment of secondary or tertiary adrenal insufficiency?
Glucocorticoid replacement
Glucocorticoid Replacement
- Hydrocortisone or cortisone (starting dose 10 mg and 5 mg 8 hours later)
- Initial dosing schedule: AM and then 8 hours later
- Can be used two or three times daily
What do you monitor for in Glucocorticoid replacement therapy?
- Body weight, postural blood pressures, subjective energy levels, and signs glucocorticoid excess every 6 to 8 weeks to assess proper glucocorticoid replacement
- Disappearance of hyperpigmentation and the resolution of electrolyte abnormalities are indicators of adequate replacement
How do you prevent an adrenal crisis?
- Additional 5 to 10 mg hydrocortisone shortly before strenuous activities (exercise)
- Patients should be told to double their daily dose during times of severe physical stress such as febrile illnesses or injury
- For major trauma, surgery, or in critically ill patients, larger doses, up to 10 times the usual daily dose may be required. **Standard regimen is hydrocortisone 100 ng parenterally every 8h. Following surgery, the dose is halved each day until it is reduced to routine maintenance levels
**
Mineralocorticoid Replacement
- ONLY needed for PRIMARY adrenal deficiency (Addison’s)
- Fludrocortisone acetate 0.05 to 0.2 mg once a day (start LOW)
What are the adverse effects of fludrocortisone?
- Gastric upset
- Edema
- Hypertension
- Hypokalemia
- Insomnia, excitability
- Diabetes mellitus
- In addition, patient weight, blood pressure, and electrocardiogram should be monitored regularly
Adrenal crisis
Wha t* Triggers are anything that increases adrenal requirements dramatically
- Stress situations, surgery, infections, and trauma
- HPA-axis suppression brought on by abrupt withdrawal of chronic glucocorticoid use
What are the symptoms of adrenal crisis?
- GI symptoms (nausea, vomiting, and abdominal pain)
- Dehydration
- Hyponatremia
- Hyperkalemia
- Weakness, lethargy, and hypotension
