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Phcol 401 > Quiz #5 Material > Flashcards

Quiz #5 Material Flashcards

1
Q

Neurosecretion of Hormones:

A
  • Hypothalamic neurons secrete hormones
  • Typical neurons secrete neurotransmitters
  • The biochemical mechanism for secretion is the same for both
    • Voltage gated K+ channels…out of cell (repolarize membrane)
    • Voltage gated Na+ channel…into cell (depolarize membrane)
    • Voltage gated Ca++ channel (influx triggers exocytosis release of hormone)
    • Secretory vesicles containing hormone
    • Exocytosis release of hormones
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2
Q

Feedback Control in the HP axis

A
  • Sensory input from environment
  • Central nervous system
  • Hypothalamus→hypothalamic releasing hormones
  • Anterior pituitary→anterior pituitary hormones released into blood
  • Target gland→ultimate hormones released
    • Can feedback regulate at anterior pituitary, hypothalamus, or central nervous system
  • Ultimate hormonal response
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3
Q

Anterior Pituitary Hormones

A
  • Growth Hormone (GH, Somatotropin)
  • Thyroid Stimulating Hormone (TSH)
  • Adrenocorticotropic Hormone (ACTH)
  • Follicle Stimulating Hormones (FSH)
  • Luteinizing Hormone (LH)
  • Prolactin
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4
Q

Growth Hormone

A
  • Stimulates secretion of IGF-1 and IGF-2
  • Regulates body growth and metabolism
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5
Q

Thyroid Stimualting Hormone

A

Stimulation secretion of thyroid hormones and growth of thyroid gland

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6
Q

ACTH

A

Stimulates cortisol secretion by the adrenal cortex and promotes growth of adrenal cortex

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7
Q

FSH

A
  • Stimulates growth and development of ovarian follicles
  • Promotes secretion of estrogen by ovaries
  • Required for sperm production
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8
Q

LH

A
  • Responsible for ovulation, corpus luteum formation, and ovarian secretion of female sex hormones
  • Stimulates cells in the testes to secrete testosterone
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9
Q

Prolactin

A
  • Stimulates breast development and milk production
  • Involved in testicular formation
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10
Q

GH Has Direct Effects on Muscle, Adipose, and Liver

A
  • Muscle
    • Increase amino acid uptake
    • Increase protein synthesis
    • Decrease glucose uptake
    • Increased Muscle Mass
  • Liver
    • Increase protein synthesis
    • Increase RNA synthesis
    • Increase gluconeogenesis
    • Increase somatomedin production
  • Adipose
    • Increase lipolysis
    • Decrease glucose uptake
    • Decreased adiposity
  • Somatomedins (IGF-1 and IGF-2)
    • Bone Chondrocytes
      • Increase collagen synthesis
      • Increase protein synthesis
      • Increase cell proliferation
      • Increased linear growth
    • Many Organs and Tissues
      • Increase protein synthesis
      • Increase RNA synthesis
      • Increase DNA synthesis
      • Increase cell number and size
      • Increase tissue growth and organ size
  • Overall effect of GH is to promote skeletal growth and the accumulation of lean body mass
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11
Q

Feedback Control in the HPL axis

A
  • IGF-1 and IGF-2 negative feedback control on GH
    • Increase Somatostatin (GHIH)
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12
Q

Cytokine Signaling Mechanism

A
  • Cytokines interact with the membrane receptors of the cytokine receptor super family
  • JAK tyrosine kinases and lead to phosphorylation of STAT transcription factors
  • Phosphorylated STAT dimerize and translocate to nucleus
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13
Q

Disorders of GH Release and Action

A
  • Hypothalamus
    • Dysplasia, trauma, surgery, hypothalamic tumors, genetic defects in GHIH or GHRH gene
  • Pituitary Gland
    • Dysplasia, trauma, surgery, pituitary tumors, genetic defects in GH gene
  • Sites if IGF production
    • GH receptor defect
    • Full: Laron’s dwarfism=high [GH], but low [IGF]
    • Partial: Pygmies=normal [GH], but low [IGF-1]
  • Cartilage
    • Resistance to IGF-1
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14
Q

Idiopathic GH problems

A
  • Precious Puberty
    • Due to hypothalamic tumor
    • Really tall
  • GH deficiency
    • Plasma GH values didn’t rise after provocative testing (give insulin or arginine)
    • Really short
  • Typical symptoms of GH deficiency are:
    • Short statures
    • Cherubic appearance
    • Obesity
    • Delayed skeletal age
  • Provocative testing
    • Intravenous administration of insulin or arginine
    • Used to see if patient produces expected levels of GH
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15
Q

Laron Syndrome: Rare Genetic Mutation in GH Receptor

A
  • Patients have short statures
  • Suffer from
    • Hypoglycemia
    • Poor muscle development
    • Obesity
    • Osteoporosis
  • Long lived and resistant to diabetes or cancer
  • Can be treated with IGF-1 to correct growth and certain metabolic changes
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16
Q

Treatment for GH deficiency

A
  • Main goal is to monitor serum IGF-1 levels
  • Use until epiphyses are fused (puberty) or into adulthood
  • Metabolic effects: acceleration of puberty, pancreatitis, intercranial hypertension, may increase risk of leukemia, stroke
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17
Q

Other Indications for RnGH use

A
  • Small for gestational age (SGA)
    • Smaller than most other babies after the same number of weeks of pregnancy
    • GH used if don’t catch up to growth by age 2
  • Prader-Willi Syndrome (PWS)
    • Short stature, polyphagia, obesity, hypogonadism, and mild mental retardation
    • GH supports growth, increased muscle mass, lessens polyphagia and obesity
  • Turner Syndrome (TS)
    • Lots of symptoms, but short stature is the main GH defect
    • GH supports growth
  • Idiopathic Short Stature (ISS)
    • 2 SD below normal growth, growing at a rate in which won’t reach normal adult height, growth plates haven’t yet fused
    • GH supports growth
    • Requires higher GH doses than GH deficient patients; genetic factors influence dose
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18
Q

Other Treatment Options for low GH

A
  • Recombinant human IGF-1
    • Optimal dosing necessary
    • For patients with GH receptor mutants (Laron dwarfs)
  • Sermorelin (synthetic GHRH)
    • Less effective than GH
    • Won’t work if defect is in pituitary
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19
Q

Hypersecretion of Growth Hormone

A
  • Usually due to pituitary hormone
  • Pre-puberty: gigantism
  • Post-puberty: acromegaly
    • Growth of some tissues
    • Metabolic effects: Type 2 diabetes and cardiovascular risks
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20
Q

Treatment of GH Excess

A
  • Surgery
  • Bromocriptine (dopamine agonist)
    • Paradoxical since dopamine normally stimulates GH release
  • Octreotide (somatostatin analog)
    • Best, more specific at inhibiting GH than somatostatin
  • Pegvisomant (GH receptor antagonist)
    • A peptide that binds and prevent GH action
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21
Q

Vasopressin Receptors in Body

A
  • V1 Receptors
    • G Coupled IP3 Receptor System
    • Increase vascular smooth muscle contraction (BP)
    • Increase liver glycogenolysis
    • Increase ACTH release
    • Increase prostaglandin synthesis
  • V2 Receptors
    • G Couple cAMP Receptor System
    • Increase water resorption in the kidney by increasing the water permeability of aquaporin-2 water channels in renal luminal membranes
  • V3 in pituitary with V1 like mechanism
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22
Q

Vasopressin Function in Kidneys

A
  • Binds receptors in distal or collecting tubules
  • Resorption of water
  • Tubules are impermeable to water without vasopressin
  • Insertion of water channels
    • Decrease plasma osmolarity
    • Increase urine osmolarity
23
Q

Kidney Aquaporins

A
  • Aquaporin-2
    • Regulated by V2R stimulated by cAMP
    • Is a target for cAMP mediated PKA phosphorylation
    • Vesicles containing AQP2 fuse to the apical membrane when cell is stimulated by vasopressin
  • Aquaporin-3
    • Resides constitutively on the basolateral membrane
    • Allow water to flow out of cell after entering through AQP2 channel
24
Q

Regulation of Vasopressin Secretion

A
  • Hypothalamic osmoreceptors
    • Dehydration: secretion increased
  • Secretion increased when BP and volume drops
    • Stretch receptors in heart and large arteries
    • Not as sensitive as osmolarity changes
  • Stimulus of vasopressin is nausea and vomiting
25
Q

Diabetes Insipidus

A
  • Vasopressin dysregulation
  • Neurogenic diabetes insipidus
    • Deficiency in secretion from posterior pituitary
    • Caused from head trauma, infection, tumors involving hypothalamus, or genetic mutation in vasopressin gene
  • Nephrogenic diabetes insipidus
    • Kidney unable to respond to vasopressin
    • Common cause is renal disease
    • Less common are mutation in the vasopressin receptor gene or the AQP2 gene
26
Q

Diabetes Insipidus

A
  • Excessive urination
  • Must differentiate from polydipsia
  • Rarely life threatening if lots of water is available
27
Q

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

A
  • Excessive release of vasopressin
  • Hyponatremia, hypo-osmolality
  • Causes:
    • CNS injuries/malignancies
    • Psychotropic drugs
28
Q

Therapeutic Uses of Vasopressin

A
  • Neurogenic diabetes insipidus (not use chronically)
  • Acute bleeding from esophageal varices or colonic diverticula
  • CPR, often a alternative to epi
  • Vasodilatory shock
29
Q

Therapeutic Use of Desmopressin

A
  • Neurogenic diabetes insipidus
  • Bedwetting
  • Mild to moderate hemophilia
    • Hemophilia A (boosts factor VIII)
    • Von Willebrand Syndrome (I and IIa only)
      • VWF bind to VIII and prevent degradation
      • Recruit factor VIII to site of clot
30
Q

Cautions and Contraindication for vasopressin/desmopressin use

A
  • Caution with conditions aggravated by water retention
  • Avoid in cardiac insufficiency or with diuretics
  • Caution in CF
  • Vascular disease due to vasoconstriction
  • Renal impairment, less effective and excreted slower
  • Oxytoxic effect in 3rd trimester of pregnancy
31
Q

Antagonists or enhancers of vasopressin action

A
  • APAP or indomethacin: block prostaglandin synthesis in kidney and increase response to vasopressin
  • Lithium: polyuria and antagonize vasopressin effects
  • Demeclocycline: antagonize vasopressin action on kidney downstream of V2R
32
Q

Vasopressin Receptor Antagonists

A
  • Useful for hyponatermia associated with:
    • SIADH
    • CHF edema
    • Cirrhosis edema
  • V1a/V2R antagonist
    • Conivaptan
  • V2R specific antagonist
    • Tolvaptan
    • Lixivaptan
33
Q

Oxytocin: Contraction of mammary alveoli

A
  • Oxytocin stimulates contraction of myoepithelial cells, causing milk to be ejected into the ducts and cisterns
34
Q

Oxytocin: Maternal bonding

A
  • Increased in cerebrospinal fluid during birth
  • Continued suckling of an infant stimulates release of oxytocin during feeding
  • Oxytocin released from pituitary can’t re-enter brain because of BBB
    • Effects of oxytocin are due to release from centrally projecting hypothalamic neurons
35
Q

Oxytocin Receptors in the Body

A
  • Oxytocin acts through oxytocin receptors
  • IP3 mechanism
  • Mobilization of calcium
  • Increase uterine and mammary smooth muscle contraction
36
Q

Other factors that regulate oxytocin

A
  • Sensitive to acute stress (inhibited)
  • Production of oxytocin and response to oxytocin are modulated by circulating levels of sex steroids
    • Increase uterine oxytocin receptors late in gestation results from increased circulating estrogen
    • Burst of oxytocin at birth is triggered by cervical and vaginal stimulation by fetus and abruptly declining progesterone
  • A number of enzymes in a variety of tissues degrade oxytocin
    • Oxytocinase appears in maternal plasma during pregnancy
    • Produced in placenta
    • Through to protect the fetal brain from being squished by reducing excitability
37
Q

Oxytoxic Drugs

A
  • Synthetic Oxytocin Analogs
    • Carboteocin, demoxytocin
    • Destroyed in GI tract
    • IM or IV administration does not enter brain, excluded by BBB
    • Used to induce labor and support labor in case of non-progression of birth
  • Ergometrine: preparation of ergot
    • Chemically similar to LSD
    • Used to facilitate delivery of the placenta and to prevent bleeding after childbirth
    • Causes smooth muscle in blood vessels to narrow, reducing blood flow
    • Usually combined with oxytocin as syntometrine
  • Misoprostol: prostaglandin E1 analog
    • Commonly used to induce labor
    • Causes uterine contractions and the ripening of the cervix
    • More effective in starting labor than other drugs used for labor induction
      • Oxytocin analogs don’t work well when the cervix is not yet ripe
      • Can be used with oxytocin
    • Often used for nonsurgical abortions
      • In many countries, commonly used with mifepristone (RU486)
38
Q

Oxytocin: Advantages and Disadvantages

A
  • Advantages
    • Causes uterus to contracts
    • Acts within 2.5 minutes when given IM
    • Generally does not cause side effects
  • Disadvantages
    • More expensive than ergometrine
    • IM or IV preparations only
    • Not heat stable
39
Q

Ergometrine: Advantages and Disadvantages

A
  • Advantages
    • Low price
    • Effects lasts 2-4 hours
  • Disadvantages
    • Takes 6-7 minutes to become effective when given IM
    • Oral form insufficiently effective
    • Causes tonic uterine contraction
    • Increased risk of hypertension, vomiting, headache
    • Contraindicated in women with hypertension or heart disease
    • Not heat stable
40
Q

Synometrine: Advantages and Disadvantages

A
  • Advantages
    • Combined effect of rapid action of oxytocin and sustained action of ergometrine
  • Disadvantage
    • Increased risk of hypertension, nausea and vomiting
    • Not heat stable
41
Q

Misoprostol: Advantages and Disadvantages

A
  • Advantages
    • Shorter time from induction to birth
    • Low cost
    • Oral, vaginal, rectal administration
    • Heat stable
  • Disadvantages
    • Possible torn uterus when used for labor and delivery
      • More common in women who have had previous uterine surgery, a previous C-section, or several previous births
    • Rare amniotic fluid embolism
42
Q

Steroid Biosynthesis: Cortisol as an example

A
  • ACTH binds to ACTH receptor
  • G-alpha activates adenylyl cyclase and increases cAMP
  • cAMP activates protein kinases
  • Protein kinases activate cholesterol esterases to release free cholesterol
  • Protein-mediates transport of cholesterol into mitochondrion
  • The cholesterol is converted to pregnenolone
  • Pregnenolone→progesterone→17-hydroxyprogesterone→11-deoxycortisol→cortisol
43
Q

Transfer of cholesterol into mitochondrion

A
  • Cholesterol is transported from the cytoplasm by transporter proteins that dock to the outer mitochondrial membrane
  • Cholesterol in then inserted into the outer membrane
  • The rate limiting step lies with the steroidogenic acute regulatory protein (StAR), which facilitates cholesterol crossing the aqueous inner membrane space
  • The mechanism of StAR is not known
  • Once transferred to the inner membrane, conversion of cholesterol to pregnenolone occurs by the membrane-bound cytochrome P450scc
44
Q

Enzymology of steroid synthesis:

A
  • Cholesterol→prenenolone
  • Enzymes:
    • A=17 alpha hydroxylase
    • B=3 beta dehydrogenase
    • C=21 alpha hydroxylase
    • D=11 beta hydroxylase
  • Pregnenolone→17-hydroxy-pregnenolone (A)
  • Pregnenolone→progesterone (B)
  • Progesterone→17-hydroxy-progesterone (A)
  • 17-hydroxy-pregnenolone→17-hydroxy-progesterone (B)
  • Progesterone→deoxycorticosterone (C)
  • 17-hydroxy-progesterone→11-deoxycortisol (C)
  • deoxycorticosterone→coricosterone (D)
  • 11-deoxycortisol→cortisol (D)
  • 17-hydroxy-pregnenolone→dehydroepiandrosterone
  • dehydroepiandrosterone→androstenedione (B)
  • androstenedione→testosterone
  • testosterone→estradiol (aromatase)
45
Q

Key aspects of steroid metabolism

A
  • Inactivated by glucuronide conjugation in the liver
  • Converted to less active steroid
    • Estradiol→estrone→estriol
  • Altered to have increased affinity or altered specificity
    • Testosterone→dihydrotestosterone
      • Increases affinity for androgen receptor
      • Catalyzed by 5-alpha-reductase
  • Testosterone→Estradiol
    • Altered receptor specificity
    • Catalyzed by aromatase
46
Q

Mechanism of Steroid Action

A
  • Steroid hormones interact with intracellular receptors of the nuclear receptor super family
  • Different than membrane receptors in that they are transcription factors
  • Directly activate gene transcription without kinase cascade
  • Dimerize and translocate to the nucleus after binding their ligands
47
Q

Nuclear receptor agonism/antagonism

A
  • Agonists
    • Endogenous ligands normally upregulate gene expression
    • Agonists induce a receptor conformation that favors coactivator binding
  • Antagonists
    • No effect on transcription in the absence of endogenous ligand
    • Block endogenous ligand effects by competitive binding
    • Antagonists induce a conformation of the receptor that prevents coactivator binding and promotes corepressor binding
48
Q

Inverse agonists and selective modulators

A
  • Inverse agonists
    • Some receptors promote a low level of transcription without agonists
    • Some synthetic ligands reduce the basal level of activity
  • Selective receptor modulators (SRMs)
    • Some synthetic ligands have an agonist response in some tissues and an antagonistic response in other tissues
    • It is though that these work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism
    • Where coactivators are more abundant, the SRM behaves as an agonist
    • Where corepressors are more abundant, the SRM is an antagonist
49
Q

Therapeutic Uses of Agonists/Antagonists

A
  • Replacement therapy
    • Adrenal steroids for Addison’s disease
    • Estrogen and progesterone for menopause
  • Pharmacologic (non-physiological) uses
    • Glucocorticoids as anti-inflammatory agents
    • Estrogen/progesterone for contraception
    • Androgens for increased muscle mass
    • Mifepristone (RU486) for pregnancy termination
  • Cancer chemotherapy
    • Tamoxifen for breast cancer
    • Flutamide/bicalutamide for prostate cancer
50
Q

‘Tripartite’ Pharmacology of Nuclear Receptor Action

A
  • Ligands
    • Natural, synthetic, environmental
  • Receptor
    • Subtypes, isoforms, splice variants
  • Effectors
    • DNA response elements, Co-regulators (activators, repressors), other TFs or Res
  • Actions
    • Transcription, other actions
51
Q

Mechanisms of Nuclear Receptor Functions

A
  • Classical
  • NRE-independent
  • Ligand independent
  • Nongenomic
52
Q

Genomic vs. Nongenomic

A
  • Genomic
    • Changes in gene expression
    • Delayed (hrs-days)
    • Required nuclear receptor
    • Prevented by transcription and translation inhibitors
  • Nongenomic
    • Changes in existing enzyme activity and/or protein structure
    • Rapid (sec-min)
    • Unknown cytosolic mechanisms
    • Not affected by transcription and translation inhibitors
53
Q

The complexity of nuclear receptor activation

A
  • The mechanism(s) by which nuclear recptors activate transcription will depend on:
    • The receptor subtype
    • The dimeric form
    • The ligand (endogenous, environmental, synthetic)
    • The cell or tissue type

Phcol 401 (10 decks)

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