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Hypothalamic & Pituitary Hormones Flashcards

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0
Q

Receptor for GH and prolactin?

A

JAK/STAT superfamily

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1
Q

Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three main areas:

A
  1. Replacement therapy for hormone deficiency states
  2. Antagonist for diseases that result from excess production of hormones
  3. Diagnostic tools for identifying endocrine abnormalities
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2
Q

GPCRs are receptors for what hormones?

A
  1. TSH
  2. FSH
  3. LH
  4. ACTH
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3
Q

GH, somatotropin

  1. Hypothalamic hormone?
  2. Target organs?
  3. Primary target organ hormone or mediator?
A
  1. GHRH (+), stomatostatin (-)
  2. liver, muscle, bone, kidney, and others
  3. insulin-like growth factor 1 (IGF-1)
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4
Q

TSH

  1. Hypothalamic hormone?
  2. Target organs?
  3. Primary target organ hormone or mediator?
A
  1. TRH (+)
  2. thyroid
  3. thyroxine, triiodothyronine
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5
Q

Adrenocorticotropin (ACTH)

  1. Hypothalamic hormone?
  2. Target organs?
  3. Primary target organ hormone or mediator?
A
  1. CRH (+)
  2. adrenal cortex
  3. glucocorticoids, mineralcorticoids, androgens
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6
Q

Follicle-stimulating (FSH) and Luteinizing hormone (LH)

  1. Hypothalamic hormone?
  2. Target organs?
  3. Primary target organ hormone or mediator?
A
  1. GnRH (+)
  2. gonads
  3. estrogen, progesterone, testosterone
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7
Q

Prolactin (PRL)

  1. Hypothalamic hormone?
  2. Target organs?
  3. Primary target organ hormone or mediator?
A
  1. dopamine (-)
  2. breast
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8
Q

Growth Hormone (somatotropin)

Pharmacodynamics?

A

mediates effects via cell surface receptors that activate JAK/STAT signaling cascades.

binds to two tyrosine receptors -> dimerizes -> self phosphorylate -> signaling cascade -> upregulate genes
(slow effect b/c requires gene expression)

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9
Q

Growth Hormone (somatotropin)

Physiological effects?

A
  1. stimulation of longitudinal growth of bones
  2. increased bone mineral density
  3. increased muscle mass (in GH deficient people)
  4. increased GFR
  5. stimulation of preadipocyte differentiation into adipocytes
  6. anti-insulin actions (decreased glucose utilization and increased lipolysis)
  7. development and increased function of immune system
    7.
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10
Q

Growth Hormone (somatotropin)

Clinical pharmacology?

A
  1. Growth hormone deficiency
    - genetic or damage to pituitary or hypothalamus
    - short stature and adiposity (in children)
    - hypoglycemia (unopposed insulin action)
  2. criteria for diagnosis
    - a growth rate < 4cm per year
    - the absence of a serum GH response to two GH secretagogoues.
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11
Q

Growth Hormone (somatotropin)

recombinant form?

A
  1. somatropin = recombinant GH

2. somatrem = GH analog

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12
Q

Growth Hormone (somatotropin)

clinical condition?

A
  • Growth failure in pediatric pts associated with:
    1. GH deficiency
    2. chronic failure
    3. noonan syndrome
    4. Prader-Willi syndrome
    5. short stature homeobox-containing gene deficiency
    6. Turner syndrome
    7. small for gestational age with failure to catch up by age 2
    8. idiopathic short stature in pediatric pts
  • Growth hormone deficiency in adults
  • wasting in HIV + pts
  • short bowel syndrome in pts who are receiving specialized nutritional support
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13
Q

Growth Hormone (somatotropin)

Primary therapeutic objective?

A
  • growth
  • Improved metabolic state, increased lean body mass, sense of well-being, weight, and physical endurance
  • improved GI function
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14
Q

Growth Hormone (somatotropin)

Adverse effects in children?

A
  • scoliosis (during rapid growth)
  • hypothyroidism
  • intracranial HTN
  • otitis media (increased risk for turner)
  • pancreatitis, gynecomastia, nevus growth
  • diabetic syndrome (chronic use)
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15
Q

Growth Hormone (somatotropin)

Adverse effect in adults?

A
  • peripheral edema, myalgias and arthralgias (hands/wrists)
  • carpal tunnel syndrome
  • proliferative retinopathy (rare)
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16
Q

Growth Hormone (somatotropin)

Contraindications?

A

CYP450 inducer

patients with a known malignancy

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17
Q

IGF-1 Analog - mecasermin

uses?

A
  • IGF-1 deficiency in children

- causes: mutations in gene that encodes for GH receptor and development of neutralizing antibodies to GH.

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18
Q

IGF-1 Analog - mecasermin

Adverse effects?

A
  • hypoglycemia (eat 20min before or after admin)
  • intracranial HTN
  • asx elevation of liver enzymes
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19
Q

sx’s of GH secreting tumors?

A
  • commonly in adults
  • sx’s:
    1. acromegaly (abnl growth of cartilage, bone tissue, skin, muscle, heart, liver and GI tract)
    2. giantism (if occurs before long bone epiphyses close)
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20
Q

GH hormone secreting tumors - tx?

A

GH antagonists for small adenomas:

  1. GH receptor antagonists
  2. somatostatin analogs
  3. dopamine receptor agonists

Large adenomas require surgery or radiation

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21
Q

Pegvisomant?

A

GH receptor antagonist

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22
Q

Octreotide?

A

somatostatin analog.

inhibits release of GH, TSH, glucagon, insulin, and gastrin

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23
Q

Octreotide

Pharmacokinetics?

A

45x more potent in inhibiting GH release than somatostatin

Octreotide acetate = long-acting suspension can be given at 4 week intervals.

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24
Octreotide Clinical applications?
reduces sx's caused by hormone-secreting tumors localizing neuroendocrine tumors acute control of bleeding from esophageal varices.
25
Octreotide Adverse effects?
nausea, vomiting, abd cramps, flatulence, steatorrhea constipation biliary sludge and gallstones sinus bradycardia and conduction distubances vit B12 deficiency pain at injxn site = common
26
Bromocriptine and Cabergoline?
dopamine agonists
27
Bromocriptine and Cabergoline Clinical applications?
1. adenomas that secrete excess prolactin 2. hyperprolactinemia (standard tx) 3. acromegaly (alone or in addition to surgery, radiation or octreotide)
28
Bromocriptine and Cabergoline Adverse effects?
nausea (bromocriptine > cabergolien), HA, light-headedness, orthostatic hypotension, fatigue psychiatric manifestations occasionally occur high doses = cold-induced peripheral digital vasospasm chronic high-dosage therapy = pulmonary infiltrates
29
what are some gonadotropins?
1. FSH 2. LH 3. hCG
30
what are the effects of FSH and LH in women?
FSH: ovarian follicle devel FSH and LH: ovarian steroidogenesis Luteal stage of mens cycle: estrogen/progesterone production is primary under control of LH. during pregnancy hCG takes over.
31
what are the effects of FSH and LH in men?
FSH: spermatogenesis, conversion of testosterone to estrogen. maintains high local androgen conc in vicinity of devel cells LH: stimulus for production of testosterone
32
gonadotropins Clinical applications?
Infertility: stimulating spermatogenesis in men & induce ovulation in women (IVF)
33
Menotropins?
Aka menopausal gonadotropins Purified extract of FSH and LH
34
Follitropin and urofollitropin?
Purified FSH Follitropn alpha & follitropin beta (rFSH): recombination FSH Urofollitropin (uFSH): purified human FSH extract
35
Human chorionic gonadotropin (hCG)?
``` Extracted and purified from urine (given IM) Choriogonadotropin alpha (rhCG): recombinant form (given SC) ```
36
Gonadotropins Clinical applications?
* ovulating induction: when other tx's don't work * male infertility: Hypogonadal men require both FSH and LH. Tx can consists of 1. hCG alone 2. Alt protocols using urofollitropin, rFSH, and rLH
37
gonadotropins Adverse effects in men and women?
Men: Gynecomastia Women: Ovarian hyperstimulation syndrome Multiple pregnancies HA, depression, edema, precocious puberty
38
1. What is the name of the synthetic gonadotropin-releasing hormone? 2. What are some gonadotropin -releasing hormone analogs?
1. gonadorelin 2. goserelin, leuprolide, nafarelin - more potent and longer lasting than gonadorelin
39
describe GnRH and it's sustained administration...
binds to GPCRs on gonadotroph cell membranes. pulsatile secretion - required to stimulate release of LH and FSH. sustained non-pulsatile admn of GnRH inhibits FSH and LH release (men and women) leading to hypogonadism
40
GnRH and analogs Pharmacokinetics?
gonadorelin = IV or SC. | goserelin, leuprolide, nafarelin = SC, IM, nasal spray (nafarelin) or as SC implant.
41
GnRH and analogs Administration?
continous administration gives biphasic response: 1. first 7 days = agonist response "flare" 2. chronic effects (>1wk) = inhibitory action (d/t receptor down-regulation & changes in signaling pathways)
42
GnRH and analogs Stimulation?
female infertility: use is uncommon (inconvenient & costly) male infertility: in men c hypothalamic hypogonadotropic hypogonadism (pulsatile gonadorelin) diagnostic of LH responsiveness: whether delayed puberty is d/t constitutional delay or hypogandotropic hypogonadism.
43
GnRH and analogs Suppression?
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 conc during mens cycle, tx limited to 6mos. uterine leiomyomata (fibroids) (leuprolide, goserelin, nafarelin): can reduce fibroid size and combined c suppl iron can improve anemia. prostate cancer (leuprolide, goserelin): combined therapy c continuous GnRH agonist and an androgen receptor antagonist is effective as castration in reducing serum testosterone. central precocious puberty (leuprolide, nafarelin): must confirm dx before tx begins advanced breast and ovarian cancer tx of amenorrhea & infertility in women c polycystic ovarian disease thinning of endometrial lining: preparation for endometrial ablation procedure in women c dysfunctional uterine bleeding.
44
Gonadorelin Adverse effects?
- HA, light-headedness, nausea, flushing - swelling of SC injxn site - Generalized hypersensitivity dermatitis (long-term admin) - Rare acute hypersensitivity rxns. - Sudden pituitary apoplexy & blindness (pts c gonadotropin-secreting pituitary tumor)
45
Goserelin, leuprolide, nafarelin adverse effects in women and men?
women: - menopausal sx's (hot flushes, sweats, HA) - depression, diminished libido, generalized pain, vaginal dryness & breast atrophy - ovarian cysts - reduced bone density men: hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, injxn site rxns.
46
Goserelin, leuprolide, nafarelin contraindications?
pregnant and breast-feeding women
47
Name the GnRH receptor antagonists?
cetrorelix | ganirelix
48
cetrorelix, ganirelix clinical applications?
suppression of gonadotropin production: prevent LH surge during controlled ovarian hyperstimulation.
49
Name the ACTH hormone analogs?
corticotropin | cosyntropin
50
why is ACTH analogs less use?
limited utility as a therapeutic agents (less predictable and convenient than corticosteroid therapy)
51
corticotropin, cosyntropin pharmacodynamics and features?
- act via MC2R (GPCR -> increased cAMP) to stimulate adrenal cortex to secrete glucocorticoids, mineralcorticoids and androgen precursor. - ACTH normally released from pituitary in pulses c highest conc at 6am and lowest in evening. secretion also stimulation by stress. - cortisol suppresses its release (-ve feedback)
52
corticotropin, cosyntropin clinical applications?
diagnostic tool for differentiating b/w primary adrenal insufficiency (addison's disease) and secondary adrenal insufficiency (inadequate ACTH secretion) Infantile spasm (West syndrome) tx
53
name the posterior pituitary hormones?
antidiuretic hormone | oxytocin
54
oxytocin pharmacodynamics?
acts on GPCRs -> stimulates release of prostaglandins and leukotrienes that augment uterine contraction small doses - increase force and frequency of contractions higher doses - evoke sustained contractions. weak antidiuretic and pressor activity (vasopressin R activation) contraction of myoepithelial cells surrounding mammary alveoli -> milk ejection.
55
Oxytocin Pharmacokinetics?
IV used for initiation and augmentation of labor IM used for control of postpartum bleeding
56
oxytocin clinical applications?
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
57
oxytocin Adverse effects?
excessive stimulation of uterine contractions: fetal distress, placental abruption, uterine rupture inadvertent activation of vasopression receptors: excessive fluid retention, water intoxication -> hyponatremia, heart failure, seizures, death bolus injxns can lead to hypotension: adm IV as dilute sln at a controlled rate.
58
oxytocin contraindications?
``` fetal distress prematurity abnl fetal presentation cephalopelvic disproportion uterine rupture predisposition ```
59
oxytocin antagonist and it's tx?
Atosiban (not in US) | tx of preterm labor
60
vasopressin (ADH) agonists?
vasopressin | desmopressin
61
features of vasopressin?
released in response to rising plasma tonicity or falling BP both antidiuretic & vasopressor activities.
62
vasopressin, desmopressin pharmacogynamics?
2 GPCRs activated ``` V1R = vascular smooth muscle -> vasoconstriction V2R = renal tubule cells -> increased water permeability and water reabsorption ```
63
vasopressin, desmopressin Pharmacokinetics?
vasopressin: IV, IM desmopressin: IV, SC, intranasally or orally
64
vasopressin, desmopressin clinical applications?
DOC for diabetes insipidus vasopressin: esophageal variceal bleeding and colonic diverticular bleeding desmopressin: coagulopathy tx in hemophilia A and von Willebrand's disease
65
vasopressin, desmopressin Adverse Effects?
HA, nausea, abd cramps, allergic rxns overdosage = hyponatremia/seizures.
66
vasopressin antagonists?
conivaptan
67
conivaptan clinical use?
pts c hyponatremia (d/t elevated vasopressin) | has high affinity for V1 and V2 receptors.

Pharmacology (13 decks)

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