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Endo II Exam 2 - Pharm and CLMD > Lecture 4: Receptors, Signaling, Hypothalamic, and Pituitary Hormones > Flashcards

Lecture 4: Receptors, Signaling, Hypothalamic, and Pituitary Hormones Flashcards

1
Q

Which 2 hormones bind to cytokine receptor-linked kinases and what are the effectors and pathway used for signaling?

A
  • GH and prolactin
  • JAK and tyrosine kinases
  • Pathways = STAT, MAPK, PI 3-kinase, IRS-1, IRS-2
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2
Q

What type of receptor does TGF-β bind to and what is the signaling pathway?

A

Serine kinase —> Smads

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3
Q

List the 9 hormones that binds Gαs and result in stimulation of cAMP signaling pathway.

A
  • FSH, LH, ACTH, TSH
  • CRH, GHRH and glucagon
  • PTH and PTHrP
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4
Q

Which hormone acts through the Gαi receptor and results in inhibition of cAMP production and activation of K+/Ca2+ channels?

A

Somatostatin

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5
Q

Which 2 hormones act through the Gαq receptor and stimulate the PLC, DAG, IP3, PKC, voltage-gated Ca2+ channel pathway of signaling?

A

TRH and GnRH

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6
Q

Which receptor does insulin bind, what are the effectors of the pathway and results in activation of waht signaling pathway?

A
  • Receptor tyrosine kinase
  • Effectors = tyrosine kinases, IRS-1 to IRS-4
  • Signaling via RAS/MAPK and PI 3-kinase
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7
Q

Which kinase-linked receptor lacks intrinsic enzyme activity and when occupied associates w/ and activates cytosolic kinases?

A

Cytokine receptors i.e., receptors for GH and PRL

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8
Q

How do serine/threonine kinase receptors differ from RTKs?

A

Similar in structure to RTKs but phosphorylate serine and/or threonine residues (instead of tyrosine)

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9
Q

Briefly describe the steps of the kinase signaling cascade upon ligand binding.

A
  • Ligand binds kinase-linked receptor —> receptor dimerization
  • Close assoc. of 2 intracellular kinase domains allows autophosphorylation of intracellular tyrosine residues
  • End result of cascase is to activate or inhibit, via phosphorylation, a variety of TF’s that induce/suppress genes
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10
Q

What is the role of the β and γ subunits of GPCRs?

A
  • Form a dimer and remain together as βγ complex
  • βγ confers both membrane locazlization of the G-protein and directs signaling such as activation of ion channels and binding sites for G-protein receptor kinases
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11
Q

What is the role of adenylyl cyclase?

A

Enzyme responsible for converting ATP —> cAMP

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12
Q

What is the role of Phospholipase C?

A

Enzymes responsible for PIP2 —-> DAG and IP3 formation

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13
Q

What is the role of the Rho A/Rho kinase system as a target of GPCRs?

A

Controls activity of many signaling pathways influencing cell growth and proliferation, smooth m. contraction, etc.

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14
Q

List 5 steroids which bind classic steroid nuclear recptors.

A
  • Glucocorticoids (GR)
  • Mineralocorticoids (MR)
  • Estrogen (ER)
  • Progesterone (PR)
  • Androgens (AR)
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15
Q

List 7 ligands for the nuclear receptors which are not classified as classic steroid nuclear receptors.

A
  • Retinoids
  • Thyroid hormone
  • Vitamin D
  • Xenobiotics
  • Androstane
  • Lipids and Fatty Acids
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16
Q

What is the function of the DNA binding domain (DBD) of a nuclear receptor?

A
  • Highly conserved and functions to recognize and bind specific sequences of DNA called HREs upstream of target gene
  • Also plays a role in receptor dimerization
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17
Q

What is the function of the C-terminal ligand-binding domain (LBD) of a nuclear receptor?

A
  • Selectively binds to agonists or antagonists and confers ligand-dependent activation
  • Ligand binds –> LBD undergoes conformational change = recruitment of coactivators or corepressors for activation or repression of gene transcription
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18
Q

What is responsible for the inhibition of FSH, LH, and GnRH is both women and men?

A
  • Women = estrogen and progesterone
  • Men = androgens
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19
Q

What hormone provides negative feedback for both ACTH and CRH?

A

Cortisol

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20
Q

Which hormones provide negative feedback to inhibit GH production and release?

A
  • Somatotrpin release-inhibiting factor (SRIF) = Somatostatin inhibits production
  • GH and IGF-1 provide neg. feedback
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21
Q

Which kind of dopamine receptor is responsible for the inhibition of prolactin and what specific type of GPCR is it?

A
  • D2 dopamine receptor
  • Dopamine receptor coupled to Gi
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22
Q

What is the effect of disruption of the pituitary stalk and the hypothalamohypophysial portal vessesl on anterior pituitary hormones?

A
  • FSH, LH, ACTH, TSH, and GH will ↓↓↓
  • Prolactin will ↑↑↑
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23
Q

How do the effects of endogenous release of GnRH differ from that of a continous infusion?

A
  • Endogenous = pulsatile manner —> stimulates LH and FSH
  • Continous GnRH and its analogs –> inhibit LH and FSH
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24
Q

What is the recombinant human form of GH (rhGH) used clinically and is identical to the predominant native form of human GH?

A

Somatropin

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25
Q

How does the half-life of endogenous GH differ from that of active blood levels of rhGH (somatropin)?

A
  • Endogenous GH = 20-25 minute half-life
  • Somatropin (rhGH) = active blood levels for 36 hours
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26
Q

What is the effect of GH (somatotropins) on CYPs?

A

Induction of P450s

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27
Q

What is the effect of GH on muscle and in lipid cells (anabolic/catabolic)?

A
  • Anabolic effect on muscle cells
  • Catabolic effect on lipid cells
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28
Q

What is the effect of GH vs. IGF-1 on insulin sensitivity?

A
  • GH ↓ insulin sensitivity (causes mild hyperinsulinemia) and hyperglycemia
  • IGF-1 acts thru IGF-1 and insulin receptors to lower serum glucose and reduce insulin

*GH and IGF-1 have opposite effects on insulin sensitivity*

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29
Q

Other than using GH as an agent for tx of deficiency in adults or short stature in children, what are a couple other clinical uses?

A
  • Wasting in pt’s with AIDS
  • Pt’s w/ short bowel syndrome who are dependent on total parenteral nutrition
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30
Q

How well tolerated is GH treatment in children and what are 6 of the associated AE’s?

A
  • Well tolerated in children; rare AE’s include:
  • Intracranial HTN (vision changes, HA, N/V)
  • Scoliosis
  • Otitis media in pt’s with Turner Syndrome
  • Hypothyroidism
  • Pancreatitis
  • Gynecosmastia
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31
Q

What are 4 AE’s which may be seen in adults treated with GH (somatropin)?

A
  • Peripheral edema
  • Myalgias
  • Arthralgias
  • Carpal tunnel syndrome
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32
Q

Treatment with GH is contraindicated in which patients?

A

Pt’s w/ known malignancy

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33
Q

What is the IGF-1 agonist (rhIGF-1) called?

A

Mecasermin = (rh)IGF-1

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34
Q

What is the IGF-1 agonist (rhIGF-1), Mecasermin, used for clinically?

A
  • Tx of growth failure and short stature in children w/ severe primary IGF-1 deficiency, which is not responsive to exogenous GH
  • Children with GH gene deletions who have developed neutralizing antibodies to recombinant GH therapy
  • Laron syndrome (GH insensitivity)
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35
Q

What is special about mecasermin rinfabate?

A
  • Combo of rhIGF-1 and insulin-like GF binding protein-3 (IGFBP-3)
  • IGFBP-3 serves to prolong the action of IGF-1 in the body
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36
Q

How is the IGF-1 agonist (rhIGF-1), Mecasermin, administered and what is the most common AE and how can this be avoided?

A
  • Subcutaneous administration
  • Hypoglycemia is most common, so eating 20 mins before administration is recommended
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37
Q

What are 2 somatostatin (SST) analogs?

A
  • Octreotide
  • Lanreotide
38
Q

How likely are somatostatin analogs used in tx of acromegaly to assure biochemical control of disease (improving clinical sx’s and tumor shrinkage)?

A

Only in a subset of patients

39
Q

How much more potent is octreotide than SST in inhibiting GH release and reducing insulin secretion?

A
  • 45x more potent in inhibiting GH release
  • 2x as potent as SST in reducing insulin secretion (hyperglycemia is rare)
40
Q

How is octreotide administered; what is the half-life?

A
  • Subcutaneous administration
  • Half-life = 80 minutes
41
Q

Which sx’s associated with hormone secreting tumors do the SST analogs, octreotide and lanreotide, reduce?

A
  • Acromegaly****
  • Carcinoid syndrome
  • Gastrinoma + glucagonoma + VIPoma (WDHA syndrome)
  • Nesidioblastosis (aka hyperinsulinemic hypoglycemia )
  • Diabetic diarrhea
42
Q

What are some of the GI and cardiac AE’s associated with SST analogs, Octreotide and Lanreotide?

A
  • Diarrhea, nausea, and abdominal pain (50% of pt’s)
  • GB sludge and gallstones**, due to ↓ GB contraction and bile secretion
  • Cardiac = bradycardia + conduction disturbances
43
Q

Pt’s taking the SST analogs, Octreotide and Lanreotide, are at risk for what vitamin deficiency?

A

Vitamin B12

44
Q

What is the GH receptor antagonist and its MOA?

A
  • Pegvisomant
  • A PEG derivative of mutant GH that binds to GH recetor and allows receptor to dimerize, but does NOT activate JAK-STAT pathway or stimulate IGF-1
45
Q

How do octreotdie and lanreotide differ from pegvisomant?

A
  • Octreotide and lanreotide are somatostatin analogs which inhibit GH release; also inhibit release of GHRH and TRH
  • Pegvisomant works by blocking the GH receptor
46
Q

What are the 3 drugs used in tx of acromegaly?

A
  • SST analogs: octreotide + lanreotide
  • GH receptor antagonist: pegvisomant
47
Q

What is the purified human FSH extracted from urine of postmenopausal women called?

A

Urofollitropin (uFSH)

48
Q

What are the 2 recombinant forms of FSH?

A

Follitropin alfa and beta (rFSH)

49
Q

How does the half-life and estrogen stimulation ability of rFSH compare to uFSH?

A

rFSH preparations have a shorter half-life, but stimulate estrogen secretion equal to or greater than uFSH (rFSH = very expensive)

50
Q

Which type of FSH preparation is used for ovulation induction in patients who previously received pituitary suppression?

A

Urofollitropin (uFSH)

51
Q

Which type of FSH preparation is used for ovulation induction in patients in whom the cause of infertility is functional ad not caused by primary ovarian failure?

A

Follitropin alfa and beta (rFSH alfa and beta)

52
Q

Which FSH preparation is use for spermatogenesis induction?

A

rFSH alfa = follitropin alfa

53
Q

uFSH + rFSH alfa and beta can be used with assisted reproductive technologies (ART) for what?

A

Development of multiple follicles

54
Q

What is the recombinant form of human LH called and what is it used for clinically?

A
  • Lutropin alfa
  • Only in combo w/ follitropin alfa for stimulation of follicular development in infertile women w/ profound LH deficiency
55
Q

What is the recombinant form of hCG called?

A

Choriogonadotropin alfa (rhCG)

56
Q

What are the 3 clinical uses for hCG?

A
  • Induce ovulation and pregnancy in anovulatory, infertile females
  • Tx of hypogonadotropic hypogonadism
  • Spermatogenesis induction with follitropin alfa
57
Q

What are the 2 clinical uses for rhCG?

A
  • Induces ovulation in infertile females who have been pretreated w/ follicle stimulating hormones
  • Induces ovulation and pregnancy in infertile females when the cause of infertility is functional
58
Q

How are gonadotropin preparations (FSH, LH, and hCG) administered?

A

SQ or IM injection

59
Q

What are the AE’s associated with gonadotropin treatments?

A
  • Overstimulation of the ovaries during ovulation induction leading to uncomplicated enlargement that usually resolves
  • Ovarian hyperstimulation syndrome: ovarian enlargement + ascites + hydrothorax + hypovolemia; sometimes shock
  • Risk of multiple pregnancies: ↑ risk for gestational diabetes, preeclampsia and preterm labor
60
Q

What is the prototypical GnRH analog called and how is it administered?

A
  • Leuprolide
  • Pulsatile IV administration every 1-4 hours stimulates FSH and LH secretion
61
Q

Explain the biphasic response which occurs with continous administration of the GnRH analogs?

A
  • First 7-10 days = agonist effect results in ↑ concentrations of gonadal hormones (referred to as flare)
  • >10 days = inhibitory action causing drop in concentration of gonadotropins and gonadal steroids (due to receptor down-regulation and changes in the signaling pathways)
62
Q

Other than the prototypical GnRH analog, Leuprolide, what is the suffix of the other drugs in this class?

A
  • -relin
  • Goserelin + histrelin + nafarelin + triptorelin and gonadorelin
63
Q

What are 3 clinical situations in which GnRH analogs (i.e., Leuprolide) are useful for stimulation of gonadotropin production?

A
  • Female infertility
  • Male inferitility
  • Diagnosis of LH responsiveness
64
Q

What are 5 clinical situations in which GnRH analogs (i.e., Leuprolide) are useful for suppression of gonadotropin production?

A
  • Controlled ovarian hyperstimulation (i.e., to prevent premature ovulation by endogenous LH in IVF patients)
  • Endometriosis
  • Uterine leiomyomata (uterine fibroids)
  • Prostate cancer
  • Central precocious puberty
65
Q

Continous treatment of women with a GnRH analog causes what common sx’s?

A

Typical menopause sx’s, including hot flushes, sweats, and HA

66
Q

In addition to sx’s of menopause, what are 6 other AE’s associated with GnRH analogs in women; which is specific to long-term use?

A
  • Depression
  • Diminshed libido
  • Generalized pain
  • Vaginal dryness
  • Breast atrophy
  • ↓ bone density and osteoporosis w/ long-term use
67
Q

What are 2 contraindications for the use of GnRH analogs?

A
  • Pregnancy
  • Breast feeding
68
Q

What are 7 AE’s associated with continous GnRH analog secretion in males?

A
  • Hot flushes + sweats
  • Edema
  • Gynecomastia
  • ↓ libido
  • ↓ hematocrit
  • ↓ bone density
69
Q

What are the 2 GnRH receptor antagonists indicated for controlled ovarian hyperstimualtion procedures (i.e., to prevent premature ovulation)?

A
  • Ganirelix
  • Cetrorelix
70
Q

Which 2 GnRH receptor antagonists are used to treat advanced prostate cancer?

A
  • Abarelix
  • Degarelix
71
Q

Why are GnRH antagoists (abarelix and degarelix) preferred over GnRH agonists (leuprolide) in the treatment of advanced prostate cancer?

A
  • GnRH antagonists reduce gonadotropin and androgen concentrations significantly more rapidly (immediately)
  • Avoids the testosterone surge
72
Q

What are the dopamine D2 receptor agonists used to treat hyperprolactinemia?

A

Bromocriptine and cabergoline

73
Q

Other than hyperprolactinemia, what else is the D2 receptor agonist, bromocriptine, used for for?

A

Tx Acromegaly and Parkinsons disease

74
Q

How are the D2 receptor agonists, bromocriptine and cabergoline, formulated for administration?

A

Oral or vaginal suppository

75
Q

Which D2 receptor agonist, bromocriptine or cabergoline, has the longest half-life?

A

Cabergoline has 65 hour half-life vs. 15 hours for bromocriptine

76
Q

Why are dopamine agonists not recommended to suppress postpartum lactation?

A

Due to increased incidence of stroke or coronary thrombosis

77
Q

What are the most common, rare, and long-term tx AE’s associated with D2 receptor agonists, bromocriptine and cabergoline?

A
  • Most common = Nausea, HA, light-headedness, fatigue, and orthostatic hypotension
  • Psychiatric manifestations occur occasionally and can take months to resolve
  • Pulmonary infiltrates may occur w/ chronic high-dose therapy
78
Q

What is the recommendation for pregnant pt’s w/ macroadenomas vs. microadenomas in regards to continuing therapy with D2 receptor agonists, bromocriptine and cabergoline?

A
  • Pregnant w/ MACROadenomacancontinue therapy
  • Pregnant w/ micoadenoma should discontinue therapy because microadenoma growth during pregnancy is rare
79
Q

Why is a women given IV oxytocin before labor and IM injection after?

A
  • IV for initiation and augmentation of labor
  • IM for control of postpartum bleeding
80
Q

How does desmopressin differ from vasopressin in terms of receptor activity and half-life?

A
  • Desmopressin is longer-acting (half life = 1.5-2 hours) and is more selective for V2 receptor (minimal V1 receptor activity)
  • Vasopressin has a half-life of 15 minutes and activates both V1 receptors (vasoconstriction) and V2 receptors of renal tubule cells
81
Q

Extrarenal vasopressin (V2) receptors regulate the release of which coagulation factors; why is this significant?

A
  • Factor VIII and von Willebrand factor
  • Desmopressin is used for tx of coagulopathy in hemophilia A and von Willebrand disease
82
Q

What are the tx’s of choice for central DI; which is the preferred agent?

A
  • Desmopressin and vasopressin
  • Desmopressin is preferred due to selectivity of V2 receptor
83
Q

What are the AE’s associated with desmopressin and vasopressin?

A
  • HA
  • Nausea
  • Abdominal cramps
  • Agitation
  • Allergic rxn are rare
84
Q

What occurs in OD with desmopressin and vasopressin?

A

HYPOnatremia and seizure

85
Q

Vasopressin should be used with caution in which patients?

A

Pt’s with coronary artery disease due to vasoconstriction

86
Q

What are the 2 vasopressin (ADH) antagonists and how do they differ in their MOA?

A
  • Tolvaptan is selective for V2 receptors
  • Conivaptan is nonselective and blocks V1 and V2 receptors
87
Q

Vasopressin antagonists, Conivaptan and Tolvaptan, are utilized in the tx of what?

A

Euvolemic and hypervolemic HYPOnatremia (i.e., CHF and SIADH)

88
Q

Conivaptan and tolvaptan (ADH-receptor antagonists) are metabolized by which CYP?

A

CYP3A4

89
Q

Which ADH-receptor antagonist was found to reduce EF, ↓ body weight and improve dyspnea in pt’s with CHF?

A

Tolvaptan

90
Q

Bromocriptine works by inhibiting what?

A

Prolactin and GH

91
Q

List 5 dopamine D2 receptor antagonists which can be used to increase prolactin levels?

A
  • Domperidone
  • Metoclopramide
  • Haloperidol
  • Risperidone
  • Sulpiride

Endo II Exam 2 - Pharm and CLMD (7 decks)

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