Burkin: Adrenal Pharmacology Flashcards
Describe the feedback regulation of the anterior pituitary hormones
Hormone regulation can be ultra-short-loop, short-loop, or long-loop.
Ultra-short loop regulation occurs when hypothalamic hormones regulate the release of hormones from the hypothalamus itself.
Short-loop regulation occurs when pituitary hormones regulate the release of hormones from the hypothalamus. Long-term regulation occurs when hormones released from the target tissue feed back on the hypothalamus.
6 hormones released from the hypothalamus, and their effects on the pituitary
corticotropin-releasing hormone –> increases ACTH
thyroptropin-releasing hormone –> increases TSH & prolactin
gonadotropin-releasing hormone –> increases LH/FSH
growth hormone-releasing hormone –> increases GH
somatostatin –> decreases GH
dopamine –> decreases prolactin
Describe the pattern of release of growth hormone from the anterior pituitary
low pulsatile pattern throughout the day, large increase in GH at night
What does growth hormone do to the following?
insulin sensitivity lipolysis IGF-1 protein synthesis epiphyseal (bone) growth
decreases insulin sensitivity increases lipolysis increased IGF-1 increased protein synthesis increased epiphyseal bone growth
What things stimulate growth hormone synthesis?
GHRH hypoglycemia exercise certain amino acids sleep
What things inhibit growth hormone synthesis?
somatostatin
IGF-1 via negative feedback
hyperglycemia
What happens when you have excess growth hormone?
gigantism (if early in life)
acromegaly (excess soft tissue hyperplasia after body growth has stopped)
How do you treat excess growth hormone?
remove tumor
give somatostain analog like octreotide
Things that can lead to primary GH deficiency?
hypothalamic (GHRH) or pituitary lesions
**can cause dwarfism (if occurs early in life) or adult hypopituitarism (weakness, pale skin, no sex drive, genital atrophy, menstrual cycle cessation)
What are some reasons for retarded growth when GH levels are normal?
GH receptor defect
IGF-1 deficiency (African pygmies)
(blank) is a recombinant form of human GH and is used to treat patients with GH deficiency.
somatrophin
What conditions is growth hormone used to treat?
Turners syndrome –> increases final adult height
Children with FTT due to chronic renal failure or HIV infection
Adults with AIDS-associated wasting
**recombinant bovine GH can be used to increase milk production in dairy cows
Discuss the feedback of growth hormone secretion
GHRH causes release of GH from the pituitary - increases body growth, lipolysis, and decreases glucose uptake, also acts on liver to produce IGF-1
Somatostatin decreases GH secretion from pituitary
What cells produce prolactin?
lactotropes & somatomammotropes of the anterior pituitary
What are the actions of prolactin?
milk production
increased maternal behavior
antagonizes gonadotropin action in the gonads –> decreased steroidogenesis
How are prolactin levels controlled?
inhibited by hypothalamic dopamine
stimulated by oxytocin, TRH, VIP & estrogen
What are some causes of excess prolactin? How can you treat this?
microadenoma of lactotropes
dopamine receptor blockers (antipsychotics)
stress
vigorous exercise
treat with dopamine agonist (Bromocryptine)
What does increased prolactin cause in males? In females?
in males: inferility
in women: amenorrhea, galactorrhea, infertility
Stimulates release of milk during lactation and contributes to the initiation of uterine contraction during labor; used intravenously to induce or reinforce labor and as a nasal spray to induce postpartum lactation
oxytocin
Secreted in response to rising plasma tonicity or falling blood pressure. Deficiency causes diabetes insipidus.
vasopressin (ADH)
(blank) is used to treat diabetes insipidus. Bedtime administration is also used to treat nocturnal enuresis.
desmopressin acetate (ADH analog)
Partial or complete loss of adrenocortical function
Addison’s disease
Suppression in the ability of the adrenal cortex to produce corticosteroids
Adrenal suppression
A metabolic disorder caused by excess secretion of adrenocorticoid steroids
Cushing’s disease
POMC is cleaved to form which endocrine peptides?
ACTH
melanocyte stimulating hormone (MSH)
beta-endorphin
Three layers of the adrenal cortex & what do they produce?
Zona glomerulosa –> aldosterone
Zona fasciculata –> cortisol
Zona reticularis –> androgens
The adrenal medulla is made up of chromaffin cells & produces (blank)
catecholamines
Which zone of the adrenal cortex is ACTH independent and is sensitive to Ang II? Which zones are ACTH dependent?
glomerulosa is ACTH independent
reticularis/fasciculata are ACTH dependent
How does ACTH increase the production of steroid hormones in the zona fasciculata? What is the rate limiting step in this process?
ACTH binds to Gs –> increases cAMP –> activates a protein kinase –> cholesterol is then delivered to the mitochrondrial matrix via the StAR protein –> increased synthesis of steroid hormones (takes hours)
**rate limiting step is the delivery of cholesterol to the mito via StAR
Describe the mineralocorticoid pathway from cholesterol to aldosterone
cholesterol –> pregnenolone (via ACTH)–> progesterone –> 11-deoxycorticosterone –> corticosterone –> 18-hydroxycorticosterone (via AngII) –> aldosterone
(blank) has a large affect on the production of aldosterone
Ang II
What enzyme catalyzes the transformation of cortciosterone to 18-hydroxycorticosterone (which is converted to aldosterone)?
Ang II
How much cortisol is released daily?
10mg
When is cortisol secreted?
first thing in the morning (high levels)
**corresponds to light-dark cycles
Cortisol circulates bound to (blank) and (blank)
transcortin (cortisol binding globulin); albumin
Parenterally administered form of ACTH, with a T1/2 of 15 minutes
Cosyntropin
Acthar
Used as a diagnostic agent in adrenal insufficiency
normal rise in cortisol rules out adrenal failure
Cosyntropin (ACTH synthetic peptide)
Cortisol is a permissive hormone. What does this mean?
low levels of catecholamine have little effect on lipolysis, but in the presence of cortisol, there is marked activation of lipolysis
(blank) is the major form of glucocorticoid; it is bound to (blank) in the circulation
cortisol; transcortin
Cortisol is essential to life. What does cortisol do in regards to metabolism of carbohydrates, proteins & lipids?
stimulates protein breakdown to amino acids (especially muscles)
facilitates lipid breakdown in adipose tissue to fatty acids & glycerol
promotes hepatic gluconeogenesis from amino acids, glycerol, & fatty acids
makes glucose available to the brain by inhibition utilization by other tissues
This is a major form of adrenal androgens
A weak androgen that is not important in males, but is an important source of androgen in females
DHEA
What does DHEA do in females?
enhances pubertal growth spurt
maintains secondary sex characteristics - pubic & axillary hair
libido
**there is some conversion of DHEA to estrogen in peripheral tissues
A glucocorticoid with a low degree of protein binding, is given to pregnant women in premature labor to hasten fetal lung maturation (increase surfactant)
Betamethasone
Has significant glucocorticoid activity, but because of its long duration of action compared to aldosterone it is favored in conditions requiring mineralocorticoid therapy (e.g. adrenalectomy)
Fludrocortisone
Mineralocorticoids and glucocorticoids work in essentially the same manner. Specificity relies on the (blank) and the association of response elements in specific genes.
target cell
mineralocorticoids act on renal tubule vs glucocorticoids in the tissues
What is it called when you have aldosterone excess?
Conn’s syndrome (primary)
or
secondary hyperaldosteronism
What causes aldosterone excess?
hypersecreting tumor of Z. glomerulosa (primary)
high renin-angiotensin (secondary)
Symptoms of excess aldosterone?
hypernatremia –> HTN
hypokalemia
What is it called when you have excess cortisol?
Cushing’s syndrome
What can cause excess cortisol?
excess CRH/ACTH (hypothal disorder vs pituitary tumor)
adrenal tumor
ectopic ACTH (lung cancer)
What are the symptoms of excess cortisol?
hyperglycemia
excess protein breakdown –> muscle weakness
abnormal fat distribution
insulin resistance
decreased immune response & inflammatory response
What is it called when you have androgen excess?
congenital adrenal hyperplasia
What can cause androgen excess?
genetic deficiencies in cortisol synthesizing enzymes
21- and 11-OH
What are the symptoms of excess androgens?
inappropriate masculinization –>
pseudohermaphroditism in females
precocious puberty in males
What is it called when you have cortisol & aldosterone deficiency?
primary adrenal insufficiency (Addison’s disease)
What can cause primary adrenal insufficiency?
destruction or atrophy of the adrenal cortex
What are the symptoms of primary adrenal insufficiency (Addison’s disease)?
related to cortisol deficiency –>
poor response to stress
hypoglycemia
low metabolic activities
What is it called when you just have a cortisol deficiency? What causes this?
secondary adrenal insufficiency;
insufficient ACTH due to hypothalamus/pituitary failure
What are these signs & symptoms of?
myopathy, central obesity, Moon face, Acne, hirsutism, bruising and capillary fragility, hypertension, glucose intolerance, hypokalemia, arteriosclerosis, infections, oestoporosis, hypogonadism
Cushings syndrome
Most cases of Cushings syndrome are (blank) dependent
ACTH
**~80% are ACTH dependent (either pituitary tumors or lung cancers), while 20% are ACTH independent (benign adrenal adenomas or malignant adrenal carcinomas)
To confirm Cushings disease (blank) can be ordered. Treatment with (blank) causes a reduction in cortisol in normal patients. In Cushings patients cortisol will remain the same or even elevated.
dexamethasone suppression test; dexamethasone
How do corticosteroids affect carbohydrate & protein metabolism?
stimulate formation of glucose
diminish peripheral utilization of glucose & promote the storage of glucose as glycogen
How do corticosteroids affects lipid metabolism?
redistribute body fat in the hypercorticoid state
**buffalo hump, moon face, thin extremities
What affects do corticosteroids have on the CNS?
Addison’s patients are apathetic, depressed and irritable some displaying frank psychosis
Administration of corticosteroids to normal patients induces a feeling of well being
What affects do corticosteroids have on the blood?
increase red cell hemoglobin & red cell content of blood –> people with Cushings get polycythemia & people with Addison’s get normochromic normocytic anemia
increase neutrophils
decrease lymphocytes, eosinophils, basophils, & monocytes
What are the anti-inflammatory effects of glucocorticoids?
decrease circulating lymphocytes & suppress cytokines
suppress inflammation to all stimuli
block early & late events in the inflammatory process
Glucocorticoids are extremely useful as (blank) agents in numerous clinical settings, such as transplantation
anti-inflammatory
Glucocorticoids cause decreased synthesis of pro-inflammatory (blank) by decreasing the effectiveness of transcription factors like AP-1. In this way, they reduce (blank).
cytokines; inflammation
Corticosteroid can be administered in the following ways
inhaled oral topical injectible enema
What happens when you withdraw from corticosteroids after being on a high dose?
adrenal insufficiency
fever, myalgia (muscle pain), joint pain & malaise
How should you withdraw from a high dose steroid treatment after weeks to months?
delayed return of adrenal function
**must slowly reduce the dose over 1-2 weeks
What are the side effects of high dose corticosteroid use?
hypokalemia alkalosis & edema increased susceptibility to infection peptic ulceration (with H pylori infection) myopathy behavioral disturbance cataracts osteoporosis growth arrest in children
(blank) act on the distal tubules of the kidney to enhance reabsorption of Na+
mineralocorticoids
In hypercorticoid state, what happens to Na+, water, and K+?
too much Na+, higher extracellular fluid volume, hypokalemia
What are the four inhibitors of adrenal steroid biosynthesis?
aminoglutethamide
ketoconazole
trilostane
metyrapone
Inhibits the first step in steroid biosynthesis (P450scc) from cholesterol interrupting production of both cortisol and aldosterone
Useful in decreasing hypersecretion of cortisol from autonomously functioning adrenal tumors and hyper-secretion due to overproduction of ACTH
Is employed in the treatment of Cushing’s disease, cortisol and mineralocorticoid supplements can be added to manage the induced insufficiency
Aminoglutethimide
How does aminoglutethimide work? When is it used?
inhibits the first step in steroid biosynthesis from cholesterol –> interrupts the production of both cortisol & aldosterone
used in Cushing’s disease
Anti-fungal drug
Inhibits P450 17a enzymes required for cortisol synthesis
Inhibits P450scc enzyme at high concentrations
Is used to in a number of conditions to inhibit steroid synthesis: adrenal carcinoma, hirsutism, breast and prostate cancer
Ketoconazole
Inhibits 3-beta-hydroxy steroid dehydrogenase
blocks formation of cortisol and aldosterone and causes increased excretion of 17-keto steroids
Can be used in the treatment of Cushing’s disease
Benefit over aminoglutethamide is not clear and drug has not received extensive use
Trilostane
Blocks 11-beta-hydroxylation terminating synthesis at 11-desoxycortisol and resulting in renal excretion of 17-OH-steroids
11-desoxycortisol is a weak inhibitor of ACTH production
Result is an increase in ACTH production permitting assessment of the pituitary release of ACTH and adrenal response in the form of 17-OH-steroid in the urine
Metyrapone
Which enzymes does ketoconazole block?
P450 17 alpha (for cortisol synthesis) & P450 at high concentration
What enzyme does trilostane inhibit? What does it block?
3-beta-hydroxy steroid dehydrogenase;
blocks formation of cortisol & aldosterone –> increases 17-keto steroids
What enzyme does metyrapone block?
11-beta-hydroxylase
What can metyrapone be used for?
for the assessment of Cushing’s disease –> when administered, it results in an increase in ACTH production & increased steroid precursors. If no increase in 11-deoxycortisol –> indicates adrenal insufficiency
