hypothalamic and pituitary hormones Flashcards
what kind of receptors do Growth hormone and prolactin act on?
JAK/STAT superfamily
TSH, FSH, LH, Adrenocorticotropic hormone
act on what receptors?
GPCRs
what type of hormones are:
- Somatropin
- somatrem
Administration
- Recombinant GH (recombinant longer word just like somatropin is longer than analog)
- GH analog
Admin: Subcutaneous admin.
Recominant Growth hormone:- Somatropin AE in children Adults: CI
Children • Generally well tolerated • Scoliosis (during rapid growth) • Hypothyroidism • Intracranial hypertension (rare) • Otitis media (increased risk for Turner Syndrome patients) • Pancreatitis, gynecomastia & nevus growth • Diabetic syndrome (chronic use)
Adults: • Peripheral edema, myalgias & arthralgias (hands & wrists especially) • Carpal tunnel syndrome • Proliferative retinopathy (rare)
CI:
• Cytochrome P450 inducer
• Patients with a known malignancy
IGF-1 Analog:
Name
Structure
Mecasermin
• Complex of recombinant human IGF-1 and recombinant
human IGF-binding protein-3
Mecasernin AE
- Hypoglycemia (eat 20 min before or after admin.)
- Intracranial hypertension (rare)
- Asymptomatic elevation of liver enzymes (rare)
GH secreting adenomas tx.
Small vs Large
• Small GH-secreting adenomas can be treated with GH
antagonists:
• GH receptor antagonists;
• somatostatin analogs; or
• dopamine receptor agonists
• Larger pituitary adenomas require surgery or radiation
Somatostatin Analog
Name
Activity
PK
Octreotide
• Somatostatin inhibits release of GH, TSH glucagon, insulin
& gastrin
Pharmacokinetics
• 45 x more potent in inhibiting GH release than
somatostatin
• 2 x more potent in reducing insulin secretion
• t ½ = ~ 80 min (30 x somatostatin)
• Octreotide acetate long-acting suspension can be given
at 4 week intervals
Somatostatin Analog
Octreotide
CA:
Clinical Applications
• Reduces symptoms caused by hormone-secreting
tumors: acromegaly, carcinoid syndrome, gastrinoma,
glucagonoma, nesidioblastosis, watery diarrhea,
hypokalemia, achlorhydria syndrome & diabetic diarrhea.
• Localizing neuroendocrine tumors
• Acute control of bleeding from esophageal varices
Somatostatin Analog
Octreotide AE:
• Nausea, vomiting, abdominal cramps, flatulence,
steatorrhea (with bulky bowel movements)
• Constipation
• Biliary sludge & gallstones (20-30% patients after 6 month
use)
• Sinus bradycardia (25%) & conduction disturbances(10%)
• Vitamin B12 deficiency (may occur with long-term use)
• Pain at injection site = common (esp. with long-acting)
Dopamine agonists
names?
PK?
Bromocriptine, Cabergoline
Pharmacokinetics
• Oral or as vaginal inserts
• Bromocriptine t1/2 = ~7 h
• Cabergoline t1/2 = ~65 h
Dopamine agonists:
Bromocriptine, Cabergoline AE
Adverse Effects
• Nausea (bromocriptine>cabergoline), headache, lightheadedness,
orthostatic hypotension, fatigue
• Psychiatric manifestations occasionally occur
• High doses = cold-induced peripheral digital vasospasm
• Chronic high-dosage therapy = pulmonary infiltrates
what are Menotropins
Menotropins or human menopausal gonadotropins
(hMG):
Purified extract of FSH and LH
Follitropin and Urofollitropin?
Purified FSH :
Follitropin alpha and follitropin Beta (rFSH): recombinant FSH
Urofollitropin (uFSH): purified human FSH extract
Human Chorionic Gonadotropin?
pK
• Extracted and purified from urine (given IM)
• Choriogonadotropin alpha (rhCG): recombinant form
(given SC)
Pharmacokinetics
• SC or IM injection (usually daily)
Gonadotropin AE
for men and women
Women
• Ovarian hyperstimulation syndrome
• Multiple pregnancies (15-20%)
• Headache, depression, edema, precocious puberty
Men
• Gynecomastia
Gonadotropin releasing hormones and analogs
which ones are more potent and last longer?
PK?
Admin?
Gonadorelin = gonadotropin-releasing hormone
- IV or SC
Goserelin, leuprolide, nafarelin = gondatropin-releasing hormone analogs
- SC, IM, nasal spray (nafarelin) or as sc implant
- more potent and longer lasting
Gonadotropin releasing hormones and analogs
secretions type?
• GnRH binds to GPCRs on gonadotroph cell membranes
• Pulsatile GnRH secretion is required to stimulate release
of LH and FSH
• Sustained nonpulsatile admin. of GnRH inhibits FSH
and LH release (men & women) leading to hypogonadism
uses of GnRH analogs:
Suppression
Agents are more commonly used for suppression of
gonadotropin release
• Controlled ovarian hyperstimulation (leuprolide,
nafarelin): Critical to suppress endogenous LH surge that
could prematurely trigger ovulation
• Endometriosis (leuprolide, goserelin, nafarelin): Pain
often decreased by abolishing exposure to cyclical changes in estrogen & progesterone concentrations
during menstrual cycle. Treatment limited to 6 months
• Uterine Leiomyomata (fibroids) (leuprolide, goserelin,
nafarelin): Can reduce fibroid size and combined with
supplemental iron can improve anemia
• Prostate Cancer (leuprolide, goserelin): Combined
therapy with continuous GnRH agonist and an androgen
receptor antagonist is effective as castration in reducing
serum testosterone
• Central Precocious Puberty (leuprolide, nafarelin):
Must confirm diagnosis before treatment begins
• Advanced Breast and Ovarian Cancer
• Treatment of Amenorrhea & Infertility in women with
Polycystic Ovary Disease
• Thinning of Endometrial lining: Preparation for endometrial ablation procedure in women with dysfunctional uterine bleeding
Women
• Menopausal symptoms (hot flushes, sweats, headaches)
• Depression, diminished libido, generalized pain, vaginal
dryness & breast atrophy can occur
• Ovarian cysts (generally resolve)
• Reduced bone density & osteoporosis (long treatment)
Gonadorelin - AE
• Headache, light-headedness, nausea, flushing
• Swelling at SC injection site
• Generalized hypersensitivity dermatitis (long-term admin.)
• Rare acute hypersensitivity reactions
• Sudden pituitary apoplexy & blindness (reported in
patients with a gonadotropin-secreting pituitary tumor)
Men
• Hot flushes, sweats, edema, gynecomastia, decreased
libido, decreased hematocrit, reduced bone density,
asthenia, & injection site reactions
CI: Pregnant and breast feeding women
GnRH receptor anatagonist
CA?
Cetrorelix, ganirelix = Competitive antagonists of GnRH receptors
Clinical Applications
• Suppression of Gonadotropin Production: Prevent LH
surge during controlled ovarian hyperstimulation
Adrenocorticotropic hormone analogs
MOA?
Corticotropin, cosyntropin = ACTH analogs
Limited utility as a therapeutic agents (less predictable
and convenient than corticosteroid therapy)
MOA:
• Act via MC2R (GPCR –> increase cAMP) to stimulate adrenal cortex to secrete glucocorticoids, mineralocorticoids and androgen precursor
• ACTH normally released from pituitary in pulses with
highest concentration at ~ 6am and lowest in evening.
Secretion also stimulated by stress
• Cortisol suppresses its release (-ve feedback)
Adrenocorticotropic hormone analogs CA?
AE?
Clinical Applications
• Diagnostic tool for differentiating between primary adrenal insufficiency (Addison’s disease) and secondary adrenal insufficiency (inadequate ACTH secretion)
• Infantile spasm (West Syndrome) treatment
AE: similar to glucocorticoids
Oxytocin - pharmacodynamics?
pK?
• Acts on GPCRs –> stimulates release of prostaglandins &
leukotrienes that augment uterine contraction
• Small doses increase force & frequency of contractions
• Higher doses evoke sustained contractions. Weak
antidiuretic & pressor activity (vasopressin R activation)
• Contraction of myoepithelial cells surrounding mammary
alveoli –> milk ejection
Pharmacokinetics
• IV used for initiation & augmentation of labor
• IM used for control of postpartum bleeding
• t1/2 = 5 min
Oxytocin CA
• Labor Induction: When early vaginal delivery is required
(Rh problems, maternal diabetes, preeclampsia, ruptured
membranes)
• Augment Normal Labor: When labor is protracted or
displays arrest disorder
• Control of uterine hemorrhage
oxytocin AE
• Severe toxicity is rare
• Excessive stimulation of uterine contractions: Fetal
distress, placental abruption, uterine rupture
• Inadvertent activation of vasopressin receptors:
Excessive fluid retention, water intoxication
hyponatremia, heart failure, seizures, death
• Bolus injections can lead to hypotension: Administer
IV as dilute solution at a controlled rate
oxytocin CI
- Fetal distress
- Prematurity
- Abnormal fetal presentation
- Cephalopelvic disproportion
- Uterine rupture predisposition
OXYCTOCIN ANTAGONIST?
ATOSIBAN
- used for treatment of preterm labor (NOT IN US)
Desmopressin
- Long-acting synthetic analog of vasopressin
- Minimal V1 activity
- Antidiuretic-to-vasopressor ratio 4000 x vasopressin
Vasopressin agonistis
PD
PK
Vasopressin and desmopressin:
Pharmacodynamics
• 2 GPCRs activated
• V1R = vascular smooth muscle –> vasoconstriction
• V2R = renal tubule cells –> increased water permeability &
water reabsorption
Pharmacokinetics
• Vasopressin: IV, IM (t1/2 = ~15 min)
• Desmopressin: IV, SC, intranasally or orally (t1/2 = 1.5-2.5h)
DOCs for Diabetes insipidus
- Vasopressin agonist
• Vasopressin: Esophageal variceal bleeding & colonic
diverticular bleeding
• Desmopressin: Coagulopathy treatment in Hemophilia A
and von Willebrand’s disease
Vasopressin agonist AE
- Headache, nausea, abdominal cramps, allergic reactions
* Overdosage = hyponatremia & seizures
Vasopressin antagonist
Conivaptan
• Approved for use in patients with hyponatremia (due to
elevated vasopressin)
• Conivaptan has high affinity for V1 & V2 R’s
