List 4 results of mass effect from pituitary adenomas
1. pituitary hypo function (hypo-pit stalk is compressed)
2. visual field defects
3. diplopia, ptosis or altered facial sensation (CN palsy)
4. headache
What is an example of a pituitary hormone that will INCREASE in secretion due to mass effect impingement on the hypothalamic-pituitary stalk? Explain.
prolactin; DA from the hypothalamus is blocked from inhibiting it
With the exception of prolactinomas, what is the primary mode of therapy of AP tumors?
transsphenoidal surgery
Only AP tumor for which medical therapy is equally efficacious as surgery
lactotroph (prolactinoma)
List 3 effects of persistent hyperprolactinemia
1. hypogonadism
2. gynecomastia
3. galactorrhea
Why does persistent hyperprolactinemia cause hypogonadism, amenorrhea and infertility?
prolactin inhibits GnRH release (which means it also reduces LH and FSH release)
Endogenous inhibitor of prolactin release
Dopamine
Prolactinoma cells contain what receptors?
D2 receptors
How do Dopamine agonist inhibit PRL synthesis and secretion?
mechanism q
hint:think cellular
dec synthesis and secretion
induce apoptosis of lactotrophs
2 drugs used to treat prolactinomas
1. bromocriptine
2. cabergoline
sketchy:Carbergoline burglar and bromocriptine broom
MOA and indication for bromocriptine
D2 agonist; prolactinoma
MOA and indication for cabergoline
D2 agonist; prolactinoma
Which drug approved for prolactinomas is preferable?why?
cabergoline
-- longer half-life, duration of action, normalizes PRL levels and restores fertility better than bromocriptine
Which drug for prolactinoma has less CYP interactions?
cabergoline
note:bromocriptine has high affinity for CYP3A
T or F: Bromocriptine is highly protein bound to albumin
T
T or F:Bromocriptine and cabergoline do not have a linear ration between dose
F: relationship is linear
Why is it recommended that bromocriptine be taken with food?
causes vomiting when fasting
Side effects of cabergoline and bromocriptine can be limited by:
starting with a low dose and increasing slowly
Bromocriptine and cabergoline have the same side effects. What are two that stand out?
orthostatic hypertension (slight)
depression
note:ADRs with cabergoline are less severe and shorter in duration compared to bromocriptine
Drug class that increases the plasma level of dopamine agonists?
macrolide antibiotics
What drug class has its effects enhanced by dopamine agonists?
adrenergic agonists
Which anti-viral treatment enhances the adverse effects of dopamine agonists?
efavirenz
Give 2 drug interactions that are limited to bromocriptine and not shared with cabergoline
1. ethanol potentiates side effects
2. inhibitor of CYP 3A4
Under normal conditions, what increases GH release from the AP?
growth hormone-releasing hormone (GHRH)
Under normal conditions, what are 2 things that decrease GH release from the AP?
1. somatostatin (from hypothal)
2. IGF-1 (from liver)
Therapy for somatotroph adenomas are typically given when the disease cannot be controlled after surgery. What are the two therapy options?
This is just a general question (he had the text in blue box)
-Centrally inhibitors of GH secretion
-GH receptor blocking agent
What are the 2 first generations somatostatin analogues?
octreotide
lanreotide
MOA and indication for octreotide
somatostatin analog (binds SSTR2 and SSTR5) to decrease GH synthesis and secretion which decreases GH stimulated IGF-1 secretion; somatotrophs (GH-secreting tumor)
sketchy:stop sign
MOA and indication for lanreotide
somatostatin analog (binds SSTR2 and SSTR5) to decrease GH synthesis and secretion which decreases GH stimulated IGF-1 secretion; somatotrophs (GH-secreting tumor)
Outside of its affect on somatotrophs, what are 2 effects of a somatostatin analog?
Asking what other hormones are affected
1. TSH suppression from thyrotrophs
2. suppression of glucagon and insulin from pancreas
How are octreotide and lanreotide both cleared from the body?
by both liver and kidneys
-- may require reduce dosing if either is impaired
Most commonly reported side effect somatostatin analogs (octerotide and lanrotide)?
gallbladder abnormalities (sludge, stones) due to decreased contraction
Which class of patients with GH secreting tumors are more likely to have cardiac side effects due to somatostatin analogs?
Pt with acromegaly
Bioavailability of what drug is reduce during concomitant administration with all somatostatin analogs (octerotide and lanrotide)?
cyclosporine
Octreotide/lanreotide/pasireotide may have an additive effect with what drug class?
bradycardia-inducing drugs (e.g. B-blockers)
What does SSAs do to insulin and oral. hypoglycemic agents?
inhibit insulin secretion, thus doses may need adjusted
What is the effect on CYP3A4 by octreotide/lanreotide? Pasireotide?
O/L: decreased activity
Pasireotide: increased activity
What is the second gen. SSA?
pasireotide
MOA and indication for pasireotide?
Binds SSTR5 on somatotropin adenoma cells to dec GH synthesis which also dec GH stimulated IGF-1 secretion
indication=somatotriph adenoma
T or F: Second gen. SSAs have an affinity for SSTR5 5x higher than 1st gens.
T
How is pasireotide excreted?
hepatic route and found in feces
What should be monitor when patients are taking pasirotide?
glycemic status
What are ADRs of pasirotide?
adrenal insufficiency symptoms
high freq. of hyperglycemia
abd liver function test
What 2 drugs should be considered for a GH-secreting tumor treatment if SS analogs and pegvisomant aren't effective? Why?
DA agonists (bromocriptine and cabergoline)
note-reduced GH and IGF (these are less effective)
Competitive GH receptor antagonist?
pegvisomant
MOA of pegvisomant?
Competitive GH receptor antagonist
What is the main effect of pegvisomant?
reduced IGF-1 levels (no effect on tumor size)
note:typically combined w/ SSA which causes significant reduction in tumor size
What is a hormonal consequence of effective pegvisomant therapy?
elevation of GH secretion
-- due to lack of IGF-1 feedback inhibition
List 2 drug interactions for pegvisomant
1. insulin/oral hypoglycemics need reduced dosing
2. opioids (need higher dose of pegvisomant)
What is the role of medical therapy in Tx Cushing's Disease?
short-term adjunctive therapy until surgery is done
What are the 3 medical therapies for corticotroph adenoma (cushings)? What do they do?
1.adrenolytic agents (inhibit cortisol synthesis and secretion.)
2.pituitary directed agents (inhibit ACTH synthesis)
3.Glucocorticoid receptor antagonist (diminish effect of cortisol)
3 adrenolytic agents?
ketoconazole
metyrapone
mitotane
pituitary directed agents?
pasireotide
note:same drug that is a secondary SSA
Glucocorticoid receptor antagonist?
mifepristone
MOA (2) and indication for ketoconazole in treating pituitary adenomas
1. inhibits 11B-hydroxylase (aldosterone path)
2. inhibits 17,20 lyase (sex steroid path)
dec cortisol synthesis
indication: Cushing's disease
Organ that can experience severe injury with ketoconazole therapy
liver (severe hepatic injury)
Explain why ketoconazole can cause gynecomastia, oligospermia and decreased libido in men.
sex steroid synthesis is inhibited by 17,20-lyase blockage
Main drug interaction with ketoconazole
This is a CYP thing
CYP3A4 inhibition
What metabolite increases in concentration when ketoconazole or metyrapone are used?
DOC (deoxycorticosterone)
MOA of metyrapone?
inhibits cortisol synthesis and secretion bc it inhibits 11 B-hydroxylase in cortisol and aldosterone synthesis pathway
Stand out ADRs of metyrapone? (3)
hirsutism
HTN
hypocortisolism
Main drug interaction of metyrapone?
inhibits glucuronidation of acetaminophen (increasing toxicity)
MOA of mitotane (3)
1. inhibits side-chain cleavage NZ
2. inhibits 3B-hydroxysteroid dehydrogenase
3. inhibits 11B-hydroxylase
dec cortisol and sex steroid syn
Adrenolytic agent with a preference for the zona fasciulata
mitotane
-- less of effect on DOC
Adrenolytic agent capable of causing mitochondrial degeneration and necrosis of the adrenal cortex
mitotane
note:CNS depression also stand out ADR
List 2 drug classes that have enhanced effects in a patient on mitotane
1. MAO inhibitors (orthostatic hypotension)
2. Vitamin K antagonists (increased bleeds)
Somatostatin analog approved to treat Cushing's Disease
Pasireotide
Compared to octreotide and lanreotide, what receptor has a higher affinity for pasireotide? Why is this important?
SSTR5
-- SSRT5 is strongly expressed on corticotroph adenomas (pasireotide used for Cushing's disease)
What is the effect of pasireotide?
inhibition of synthesis and secretion of ACTH
-- less adrenal cortisol synthesis
MOA of mifepristone (2)
1. competitive inhibitor of glucocorticoid receptor
2. competitive inhibitor of progesterone receptor
blocks the action of GC and PR
CI for mifepristone
pregnancy (can induce abortion b/c of anti-progesterone effect)
Indication for mifepristone
control of hyperglycemia secondary to hypercortisolism
What lab finding is unique about the adrenal insufficiency that can be caused by mifepristone?
insufficiency despite elevated cortisol and ACTH levels
Electrolyte imbalance caused by mifepristone therapy
hypokalemia
-- excess cortisol binds to mineralocorticoid receptor
-serum Na and K must be monitored
Cushing syndrome agent that can cause endometrial thickening and vaginal bleeding
mifepristone
-- due to progesterone receptor blockade
NZ that metabolizes mifepristone
CYP3A4 (lots of drug interactions)