Hypothalamic and Pituitary Hormones Flashcards

1
Q

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

A

(1) as replacement therapy for hormone
deficiency states
(2) as antagonists for diseases that result from
excess production of hormones
(3) as diagnostic tools for identifying endocrine
abnormalitie

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2
Q

Growth Hormone overview? Pharmacodynamics?

A
  • Predominantly required during childhood & adolescence
  • Effects mediated mainly by IGF-1

Pharmacodynamics
• Mediates effects via cell surface receptors that activate JAK/STAT signaling cascades

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3
Q

Physiological effects of GH(somatotropin)?

A

• Stimulation of longitudinal growth of bones
• Increased bone mineral density
• Increased muscle mass (in GH deficient people)
• Increased GFR
• Stimulation of preadipocyte differentiation into adipocytes
• Anti-insulin actions (decreased glucose utilization &
increased lipolysis)
• Development & increased function of immune system

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4
Q

Growth Hormone(somatotropin ) clinical pharmacology?

A

Clinical Pharmacology
Growth Hormone Deficiency
• Genetic or damage to pituitary or hypothalamus
• Short stature and adiposity (in children)
• Hypoglycemia (unopposed insulin action)
Criteria for Diagnosis
(1) A growth rate < 4cm per year, and
(2) the absence of a serum GH response to two GH
secretagogues

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5
Q

recombinant GH PK and analogs?

A
Somatropin = recombinant GH
Somatrem = GH analog

Pharmacokinetics
• Active blood levels = persist for ~ 36 h
• Given subcutaneously 3-7 times a week

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6
Q

Growth failure in pediatric patient with primary therapeutic goal of growth, list etiologies

A
Growth hormone deficiency
Chronic renal failure
Noonan syndrome
Prader-Willi syndrome
Short stature homeoboxcontaining
gene deficiency
Turner syndrome
Small for gestational age with
failure to catch up by age 2
Idiopathic short stature in
pediatric patients
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7
Q

Clinical use of recombinant GH in

Growth hormone deficiency in adults:

Wasting in HIV +ve patients:

Short bowel syndrome in
patients who are receiving
specialized nutritional support:

A

Growth hormone deficiency in adults: Improved metabolic state,
increased lean body mass,
sense of well-being

Wasting in HIV +ve patients: Increased lean body mass, weight, and physical endurance

Short bowel syndrome in
patients who are receiving
specialized nutritional support: Improved GI function

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8
Q

Recombinant GH AE in children?

A
  • 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)
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9
Q

Recombinant GH AE for adults and contraindications?

A
Adults
• Peripheral edema, myalgias &amp; arthralgias (hands &amp; wrists
especially)
• Carpal tunnel syndrome
• Proliferative retinopathy (rare)
Contraindications
• Cytochrome P450 inducer
• Patients with a known malignancy
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10
Q

IF1-Analog and use?

A

• Small number of children with growth failure have IGF-1
deficiency
• Causes: mutations in gene that encodes for GH receptor
& development of neutralizing antibodies to GH

Mecasermin
• Complex of recombinant human IGF-1 and recombinant
human IGF-binding protein-3

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11
Q

Mescasermin AE?

A
  • Hypoglycemia (eat 20 min before or after admin.)
  • Intracranial hypertension (rare)
  • Asymptomatic elevation of liver enzymes (rare)
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12
Q

GH secreting tumor symptoms?

A

• GH-producing cells (somatotrophs) can form secreting
tumors (more commonly in adults)
Symptoms
• Acromegaly (abnormal growth of cartilage, bone tissue,
skin, muscle, heart, liver & GI tract)
• Giantism (if occurs before long bone epiphyses close)

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13
Q

GH secreting tumor treatments?

A

• 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

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14
Q

Analog example of somatostatin and what does it inhibit?

A

Octreotide
• Somatostatin inhibits release of GH, TSH glucagon, insulin
& gastrin

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15
Q

Somatostatin analog octreotide PK?

A

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

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16
Q

Somatostatin analog octreotide clinical applications?

A

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

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17
Q

Somatostatin analog octreotide AE?

A

Adverse Effects
• 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)

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18
Q

Two examples of dopamine agonists?

A

Bromocriptine and Cabergoline

Pharmacokinetics
• Oral or as vaginal inserts
• Bromocriptine t1/2 = ~7 h
• Cabergoline t1/2 = ~65 h

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19
Q

Clinical applications of dopamine agonists?

A

Clinical Applications
• Hyperprolactinemia
Standard treatment. Dopamine agonists shrink pituitary
prolactin-secreting tumors, lower circulating prolactin
levels, and restore ovulation in ~70% women with
microadenomas & ~30% with macroadenomas
• Acromegaly
Alone or in addition to surgery, radiation or octreotide
admin

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20
Q

Dopamine agonists AE?

A

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

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21
Q

Gonadotropin hormones and action in women?

A
  • Follicle-Stimulating Hormone (FSH)
  • Luteinizing Hormone (LH)
  • Human Chorionic Gonadotropin (hCG)

Women
FSH: ovarian follicle development
FSH & LH: ovarian steroidogenesis
Luteal stage of menstrual cycle: estrogen &
progesterone production is primarily under control of LH.
During pregnancy hCG takes over.

22
Q

Gonadotropin action in Men?

Clinical applications?

A

Men
FSH: Spermatogenesis, conversion of testosterone to
estrogen. Maintains high local androgen concentrations in
vicinity of developing cells
LH: Stimulus for production of testosterone

Clinical Applications
Infertility: Stimulate spermatogenesis in men & induce ovulation in women (IVF)

23
Q

Purified FSH examples?

LH preparations?

A

Follitropin a and follitropin b (rFSH): recombinant FSH
Urofollitropin (uFSH): purified human FSH extract

Recombinant LH: Lutropin alfa

24
Q

What are menotropins?

Human Chorionic Gonadotropin recombinant?

A

Menotropins or human menopausal gonadotropins
(hMG): Purified extract of FSH and LH

HCG
• Extracted and purified from urine (given IM)
• Choriogonadotropin a (rhCG): recombinant form
(given SC)

25
Q

Pharmacodynamics Gonadotropins?

A

Pharmacodynamics
• Act through GPCR’s
• Coordinated pattern of FSH and LH secretion during the
menstrual cycle is required for normal follicle
development, ovulation and pregnancy

26
Q

Gonadotropins Clinical Applications?

A

Clinical Applications
• Ovulation Induction
Expensive and complicated so reserved for when
other treatments don’t work
• Male Infertility
Treatment of hypogonadal men requires both FSH
and LH. Treatment can consist of:
• hCG alone or,
• alternative protocols using urofollitropin, rFSH and
rLH

27
Q

Gonadotropin AE?

A
Women
• Ovarian hyperstimulation syndrome
• Multiple pregnancies (15-20%)
• Headache, depression, edema, precocious puberty
Men
• Gynecomastia
28
Q

Gonadotropin-Releasing Hormone and Analogs examples?

A

Gonadorelin = gonadotropin-releasing hormone
Goserelin, leuprolide, nafarelin = gonadotropinreleasing
hormone analogs

29
Q

GnRH action?

A

• 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

30
Q

Chemical structure of Gonadorelin and analogs?

A

Chemical Structure
• Gonadorelin = synthetic human GnRH
• Analogs = more potent & longer-lasting than
gonadorelin

31
Q

GnRH and analogs pk?

A
Pharmacokinetics
Gonadorelin = IV or SC
Analogs = SC, IM, nasal spray (nafarelin) or as SC implant
Gonadorelin t1/2 = 4 min
Analog t1/2’s = ~3 h
32
Q

Admin of GnRH and analogs?

A
Pharmacokinetics
Gonadorelin = IV or SC
Analogs = SC, IM, nasal spray (nafarelin) or as SC implant
Gonadorelin t1/2 = 4 min
Analog t1/2’s = ~3 h
33
Q

GnRH and analogs clinical applications of stimulation?

A

• Female infertility: Use is uncommon (inconvenient &
costly)
• Male infertility: In men with hypothalamic
hypogonadotropic hypogonadism (pulsatile gonadorelin)
• Diagnosis of LH responsiveness: Whether delayed
puberty is due to constitutional delay or hypogonadotropic
hypogonadism

34
Q

GnRH and analogs clinical applications of suppression?

A

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 and 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 & 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

35
Q

Gonadorelin AE?

A

• 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)

36
Q

AE and contraindications of GnRH analogs in women? Men?

A

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)
Contraindications
• Pregnant and breast-feeding women

Men
• Hot flushes, sweats, edema, gynecomastia, decreased
libido, decreased hematocrit, reduced bone density,
asthenia, & injection site reactions

37
Q

GnRH receptor antagonists examples and clinical applications?

A

Cetrorelix, ganirelix = Competitive antagonists of
GnRH receptors

Clinical Applications
• Suppression of Gonadotropin Production: Prevent LH surge during controlled ovarian hyperstimulation

38
Q

Adrenocorticotropic hormone analogs examples and limitations?

A

Corticotropin, cosyntropin = ACTH analogs
Limited utility as a therapeutic agents (less predictable
and convenient than corticosteroid therapy

39
Q

Adrenocorticotropic hormone analogs moa, clinical applications and AE

A

MOA
• Act via MC2R (GPCR → cAMP) to stimulate adrenal
cortex to secrete glucocorticoids, mineralocorticoids &
androgen precursor

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

Adverse Effects
• Similar to glucocorticoids

40
Q

Oxytocin Pharmacodynamics?

A

• 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

41
Q

Posterior Pituitary Hormones?

A
  • Posterior pituitary does not synthesize hormones
  • Consists of axon terminals of hypothalamic neurons
  • Neurons release two neurotransmitters into capillaries:
  • antidiuretic hormone
  • oxytocin
42
Q

Oxytocin PK?

A

Pharmacokinetics
• IV used for initiation & augmentation of labor
• IM used for control of postpartum bleeding
• t1/2 = 5 min

43
Q

Oxytocin clinical applications?

A

• 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

44
Q

Oxytocin AE?

A

• 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

45
Q

Oxytocin Contraindications?

name an oxytocin antagonist?

A
  • Fetal distress
  • Prematurity
  • Abnormal fetal presentation
  • Cephalopelvic disproportion
  • Uterine rupture predisposition

Oxytocin antagonist
Atosiban
• Used for treatment of preterm labor (NOT in US)

46
Q

Vasopressin example and action?

A

Desmopressin
• Vasopressin is released in response to rising plasma
tonicity or falling BP
• Has both antidiuretic & vasopressor activities

47
Q

Desmopressin overview?

A
  • Long-acting synthetic analog of vasopressin
  • Minimal V1 activity
  • Antidiuretic-to-vasopressor ratio 4000 x vasopressin
48
Q

Vasopressin agonist Pharmacodynamics and PK?

A

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 = 1.5-2.5
h)

49
Q

Vasopressin agonist clinical applications?

A

• Drugs of choice for Diabetes Insipidus
• Vasopressin: Esophageal variceal bleeding & colonic
diverticular bleeding
• Desmopressin: Coagulopathy treatment in Hemophilia A
and von Willebrand’s disease

50
Q

Vasopressin AE?

Vasopressin antagonist example and action?

A
  • Headache, nausea, abdominal cramps, allergic reactions
  • Overdosage = hyponatremia & seizures

Conivaptan
• Approved for use in patients with hyponatremia (due to
elevated vasopressin)
• Conivaptan has high affinity for V1 & V2 R’s