Pharamcology of pituitary drugs Flashcards
What is acromegaly?
A disorder caused by excess growth of hormones, increasing the growth of body tissues and causing metabolic dysfunction (occurs in adults)
What are the characteristics of Acromegaly?
- Swelling of soft tissues in hands and feet
- Enlarged bones in the skull, hands, and feet
- Joint pains
- Headaches
- Barrel chest
- Cardiomegaly
- Carpal tunnel syndrome
- Diabetes
- HTN
What is the target of pharmacotherapy (acromegaly)?
Decrease the production of GH, activity of GH and release of IGF-1
What is hyperprolactinemia?
PRL is elevated: galactorrhea in non-breastfeeding women or in men, pituitray microadenoma or adenoma
What is the target of pharmacotherapy in hyperprolactinemia?
Decrease PRL formation, dopamine like molecules
What are the different types of pituitary drugs?
Somatostatin analogues
GH receptor antagonists
Dopamine agonists
What is the function of somatostatin analogues?
Enhance somatostatin -mediated inhibition of GH release
What are examples of somatostatin analogues?
Octreotide
Lanreotide
Pasireotide
What is the function of GHR antagonists?
Antagonists, competitive inhibitors, at GH receptors
What are examples of GHR antagonists?
Pegvisomant
What is the function of dopamine agonists?
Enhance D2 dopamine receptor activity
What are examples of dopamine agonists?
Bromocriptine
Cabergoline
Quinagolide
What is somatostatin?
A small polypeptide is also found in neurons throughout the body, intestine, stomach, and pancreas (SST14 and SST28)
What is the function of somatostatin?
Inhibits the release of not only GH but also insulin , glucagon and gastrin
How many isoforms of somatostatin are there?
5, all coupled to G proteinsn
Which isoforms of somatostatin are expressed in the anterior pituitary?
SST1, 2, 3, 5 (all expressed from 4), but they are all expressed to different extents
What are the SST analogues?
They are synthetic analogues of SST
What is the half-life of SSt analogs like in comparison to SST?
Longer half-life than SST
SST –> 1 to 3 minutes
Which receptors do SST analogues bind to preferentialy?
SST2 and SST5 receptors
What is the MOA of SST analogues?
- Hormone Secretion Inhibition: Inhibition of adenylyl cyclase (AC)
- Anti-Proliferative and Growth-Inhibitory Effects: Pathways involved in cell proliferation inhibition:
–> Protein Tyrosine Phosphatase (PTP)
–> Akt pathway inhibition - Induction of apoptosis
- Anti-angiogenesis
What is the hormone secretion inhibition action of SST analogues?
- Activation of SSTs reduces intracellular cyclic AMP (cAMP) levels, which leads to decreased calcium influx ([Ca²⁺]) into the cell.
- The reduction in calcium levels inhibits exocytosis of secretory vesicles, resulting in decreased hormone secretion.
What are the anti-proliferative and growth-inhibitory effects of the SST analogs (PTP)?
- PTP activation dephosphorylates signaling molecules that promote cell division.
- This reduces mitogen-activated protein kinase (MAPK) activity, leading to a decrease in proliferation markers like Ki-67 and inducing cell cycle arrest.
What are the anti-proliferative and growth-inhibitory effects of the SST analogs (Atk pathway inhibition)?
- Upregulation of p21 and p27 (cell cycle inhibitors), resulting in cell cycle arrest.
- Downregulation of Zac1, a transcription factor that promotes growth, further inhibiting cell proliferation.
What is the induction of apoptosis action of SST analogs?
Increase caspase-8 activity, promoting programmed cell death (apoptosis)
What is the anti-angiogenesis action of SST analogs?
Reduced VEGF production decreases blood vessel formation, suppressing the tumor’s abilty to grow and spread
What is the PK of Octeoride?
Subcutaneous x2 daily, half-life of about 90 minutes, duration of action is about 12 hours
If Octeoride is given IM, how often should it be given?
Long-acting, slow-release form, given once every 4 weeks
What receptors does Octeoride bind to?
SST2 > SST5 > SST3 but not SST1
What are the therapeutic uses of Octeroride?
- Decreases GH synthesis in acromegaly
- Main therapy: neuroendocrine tumors or carcinoids
- Decreases tumor size but it is reversed when treatment stops
What is Lenreotide?
Long-acting octapeptide SST analog
Available in prefilled syringes
What receptors does Lanreotide bind to?
SST2 > SST5
What are the PK of Lanreotide?
Deep SubQ injection (every 4 weeks) - prolonged suppression of GH secretion
Efficacy comparable to Octeoride
What is Pasireotide?
Long-acting cyclo-hexapeptide SST analog
What receptors does Pasireotide bind to?
Binds to multiple SST receptors (1, 2, 3, and 5) and the highest affinity for SST5 receptor
What are the therapeutic uses of Pasireotide?
Approved treatment of Cushing disease and acromegaly
What are other therapeutic uses of SST analogs?
- Block growth factors and cytokines are used for the treatment of symptoms associated with metastatic carcinoid tumors (flushing and diarrhea) and adenomas secreting VIP
- Octeoride and Lanreotide –> thyrotrope adenomas that over-secrete TSH (failed surgery)
- Octeoride –> treatment of acute variceal bleeding and for perioperative prophylaxis in pancreatic surgery
What are the adverse effects of SST analogs?
- GIT: diarrhea, nausea, abdominal pain, flatulence, steatorrhea
- Asymptomatic cholesterol gallstones (during long-term treatment)
- Bradycardia and QT prolongation - in patients with underlying cardiac disease
- Hypothyroidism
- Hypocorticolism
How is hypocorticolism an adverse effect of SST analogs?
Pasireotide suppresses ACTH secretion –> decreases cortisol secretion –> hypocortisolism
How are asymptomatic gallstones an adverse effect of SST analogs?
Inhibition of gallbladder emptying, hepatic bile secretion, and sphincter motility, as well as modification of bile composition –> gallstonestasis
What is Pegvisomant?
A modified version of GH (mutated-inactive/recombinant protein) bound to PEG polymers
A highly sensitive antagonist of growth hormone receptor
What is the MOA of Pegvisomant?
- Binds to the GHR with high affinity at binding site one and blocks the binding of endogenous GH to GHR
- Does not activate downstream JAK/STATsignaling or stimulate IGF-1 secretion
What are the PK of Pegvisomant?
Administered SubQ
The dose is titrated at 4 to 6-week intervals based on serum IGF-1
When can Pegvisomant be gievn weekly?
When IGF-1levels are not fully controlled
What are the contraindications of Pegvisomant?
- Should not be used in patients with an unexplained elevation of hepatic transaminases
–> Liver function should be monitored in all patients
What are the concerns that are associated with Pegvisomant?
Loss of negative feedback by GH and IGF-1 may increase the growth of GH-secreting adenomas –> careful follow-up by pituitary MRI is recommended
What are the common adverse effects of Pegvisomant?
Pain
Arthralgia
Fever
Chills
Body aches
Flu symptoms
Nausea
Diarrhea
GI discomfort
Dizziness
Skin reaction
Abnormal liver function tests
Pain or irritation where the medicine was injected
GH increases gluconeogenesis
What are clinically significant adverse effects of GHR agonists?
Systemic hypersensitivity
Lipohypertrophy at injection sites
Hypoglycemia in diabetes
What is the MOA of dopamine agonists?
- Activation of D2 dopamine receptors
- Suppression of PRL production and relief of the inhibitory effect of hyperprolactinemia on ovulation (useful in prolactinoma treatment)
What kind of treatment options are dopamine agonists?
Initial treatment of choice
–> Surgery and radiation are reserved for patients who either do not respond or are intolerant of DA receptor agonists
What are examples of Dopamine agonists?
Bromocriptine
Cabergoline
Quinagolide
What is Bromocriptine?
A semisynthetic ergot alkaloid
What is the MOA of Bromocriptine?
Interacts with D2 receptors –> inhibits release of PRL
Also activates D1 dopamine receptors to a lesser extent
What are the effects of Bromocriptine?
Normalizes serum PRL levels in 70 to 80%, decreases tumor size in more than 50% of patients with prolactinoma
Hyperprolactinemia and tumor growth recur on cessation of therapy in most patients
What are the clinical uses of Bromocriptine?
To prevent lactation, treat galactorrhea due to excessive prolactin secretion
Treat prolactin-secreting pituitary tumors
Treatment in Parkinsonism and acromegaly
What are the PK of Bromocriptine?
Well absorbed orally, extensive first-pass metabolism
May be administered vaginally, with fewer GI side effects
What are the adverse effects of Bromocriptine?
More commonly nausea and vomiting, headache, and postural hypotension on initial use
Less frequently: nasal congestion, digital vasospasm, CNS effects
What are examples of CNS effects due to Bromocriptine?
Psychosis, nightmares, and insomnia
What is Cargoline (Dostinex)?
Ergot derivative
What are the PK of Cabergoline compared to Bromocriptine?
Has a longer half-life, higher affinity, and a greater selectivity for the D2 receptor
Undergoes significant first-pass metabolism in the liver
In higher doses what is Cabergoline useful for as a treatment?
Useful in acromegaly at higher doses, alone or in combination with SST analogs
Why is Cabergoline the preferred drug for the treatment of hyperprolactinemia?
Greater efficacy but fewer side effects
Induces remission in a significant number of patients with prolactinomas
What are the adverse effects of Cabergoline?
Nausea
Hypotension
Dizziness
Linked to valvular heart disease, possibly due to its agonist activity at 5HT2B receptors
What is Quinagolide?
Non-ergot D2 receptor agonist
What is the half-life of Quinagolide?
22 hours
What are the contraindications of Quinagolide?
Not to be used when pregnancy is intended
How often is Quinagolide administered?
Once daily
What are tocolytic drugs?
Drugs to suppress uterine contractions
What is the aim of tocolytic drugs?
Prolong and delay gestation in patients, inhibition of acute preterm labor
What are examples of tocolytic drugs?
NSAIDs
Ca2+ channel blockers
Beta-androgenic agonists
Oxitocyn inhibitors
What is an example of Oxytocin inhiboitors?
Atosiban, widely used in Europe but is not FDA-approved in the US
