Some pearls from the pharm DSA Flashcards
GH toxicity and contraindications
i) Treatment is well tolerated in children; rare adverse effects include intracranial hypertension (manifested as vision changes, headache, nausea, or vomiting), scoliosis, otitis media in patients with Turner syndrome, hypothyroidism, pancreatitis, gynecomastia
ii) Adults have more adverse effects than children, including peripheral edema, myalgias, arthralgias, carpal tunnel syndrome
iii) Contraindicated in patients with a known active malignancy
MECASERMIN
a) A small number of children with growth failure have severe IGF-1 deficiency that is not responsive to exogenous GH (due to mutations in the GH receptor and the GH receptor signaling pathway, development of neutralizing antibodies to GH, or IGF-1 gene defects)
b) Mecasermin is recombinant human IGF-1; used to treat growth failure as indicated above
c) Subcutaneous administration
d) Most common adverse effect is hypoglycemia (eating 20 minutes before administration prevents hypoglycemia)
uses of GH antagonists
a) Utilized for the treatment of anterior pituitary adenomas that secrete GH
i) GH-secreting tumors can cause acromegaly in adults and, if they occur before the long bone epiphyses close, can cause gigantism
ii) Small GH-secreting adenomas can be treated with GH antagonists, either by suppressing GH secretion (somatostatin analogs, dopamine receptor agonists) or by direct inhibition of the GH receptor (pegvisomant)
iii) Larger pituitary adenomas are treated with surgery or radiation
Somatostatin (SST) analogs
i) SST is a 14-amino-acid peptide found in the hypothalamus, other parts of the CNS, the pancreas, and GI tract that inhibits the release of GH, TSH, glucagon, insulin, and gastrin
ii) Exogenous SST has limited therapeutic value due to its short duration of action (half-life 1-3 minutes) and effects on multiple secretory systems
iii) Longer-acting SST analogs have been developed (octreotide, lanreotide)
Octreotide
(1) Most widely used SST analog
(2) 45 times more potent than SST in inhibiting GH release, twice as potent as SST in reducing insulin secretion (hyperglycemia is rare)
(3) Subcutaneous administration; half-life approximately 80 minutes; depot forms available
(4) Reduces symptoms associated with hormone-secreting tumors, including acromegaly
(5) Adverse effects include nausea, vomiting, abdominal cramps, flatulence, steatorrhea with bulky bowel movements, gallstones, cardiac effects (sinus bradycardia, conduction disturbances), vitamin B12 deficiency
Lanreotide
(1) Approved for the treatment of acromegaly
(2) Effects comparable to octreotide on reducing GH levels and normalizing IGF-1 concentrations
Pegvisomant
i) MOA: GH receptor antagonist
ii) A recombinant analogue of human GH covalently bound to polyethylene glycol (PEG) polymers (PEG reduces clearance)
iii) GH receptors bound to pegvisomant do not stimulate downstream JAK/STAT signaling
iv) Used to treat acromegaly (more effective than somatostatin analogs)
PROLACTIN
a) PRL is a 198-amino-acid hormone produced in the anterior pituitary that resembles GH in structure
b) Principle hormone responsible for lactation
c) No preparations are available for use in PRL-deficient patients
d) For patients with symptomatic hyperprolactinemia (women present with amenorrhea and galactorrhea while men present with a loss of libido and infertility), inhibition of PRL secretion can be achieved with dopamine agonists, which inhibit prolactin release from the pituitary
e) Hypogonadism and infertility associated with hyperprolactinemia result from inhibition of GnRH release
DOPAMINE AGONISTS, MOA
a) Bromocriptine and cabergoline are ergot derivatives used to treat hyperprolactinemia
b) At higher doses, bromocriptine is also used to treat acromegaly (because GH release is also reduced) and Parkinson disease
c) MOA: dopamine D2 receptor agonists
d) Available as an oral preparation or vaginal suppository
e) Cabergoline has a longer half-life than bromocriptine (65 hours vs. 5-7 hours), higher affinity and greater selectivity for the D2 receptor
pharmacology of dopamine agonists
i) Dopamine agonists are the standard medical treatment for hyperprolactinemia
ii) Cabergoline generally is used because of its lower incidence of side effects; when pregnancy is desired, bromocriptine is preferred
iii) Shrink pituitary PRL-secreting tumors, lower circulating PRL levels, and restore ovulation in 70% of women with microadenomas and 30% of women with macroadenomas
iv) Used alone or in combination with pituitary surgery, radiation therapy, or octreotide administration to treat acromegaly
toxicity and CIs of dopamine agonists
i) Nausea, headache, light-headedness, orthostatic hypotension, and fatigue are most common
ii) Psychiatric manifestations occur occasionally and can take months to resolve
iii) Pulmonary infiltrates may occur with chronic high-dose therapy
iv) Patients with macroadenomas who are pregnant continue therapy
v) Patients with microadenomas who are pregnant discontinue therapy because microadenoma growth during pregnancy is rare
vi) Dopamine agonists are not recommended to suppress postpartum lactation due to increased incidence of stroke or coronary thrombosis
OXYTOCIN
a) Stimulates uterine contraction; elicits milk ejection in lactating women
b) 9-amino-acid peptide that differs in sequence from that of vasopressin at positions 3 and 8
c) Administered intravenously for initiation and augmentation of labor and intramuscularly for control of postpartum bleeding
VASOPRESSIN (ANTIDIURETIC HORMONE, ADH)
a) Peptide hormone released in response to rising plasma osmolality or falling blood pressure
b) Possesses antidiuretic and vasopressor properties
c) Vasopressin and desmopressin are utilized clinically
d) Desmopressin is a long-acting synthetic analog of vasopressin with minimal V1 receptor activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin
e) Pharmacokinetics
i) Vasopressin is administered via IV or IM; desmopressin is administered IV, subcutaneously, intranasally, or PO
ii) Desmopressin half-life is longer than vasopressin (1.5-2.5 hours vs. 15 minutes)
f) Pharmacodynamics
i) MOA: activates the V1 and V2 receptors (GPCRs)
ii) V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction
iii) V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules
iv) Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor
g) Clinical pharmacology
i) Vasopressin and desmopressin are the treatments of choice for pituitary diabetes insipidus
ii) Vasopressin can be used to treat vasodilatory shock when fluids and catecholamines fail to raise blood pressure
iii) Desmopressin is used for the treatment of coagulopathy in hemophilia A and von Willebrand disease
ADH toxicity and contraindications
i) Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely
ii) Overdose can result in hyponatremia and seizures
iii) Vasopressin should be used with caution in patients with coronary artery disease due to vasoconstriction
VASOPRESSIN ANTAGONISTS
i) Majority are still under investigation
ii) Conivaptan and tolvaptan are approved for use
iii) MOA: antagonists of vasopressin V1a and V2 receptors (tolvaptan is more selective for V2 receptors)
iv) In clinical trials, vasopressin antagonists relieve symptoms and reduce signs of hyponatremia and heart failure
