Pharm of Hypothalamic, Anterior, and Posterior Pituitary Hormones

Question 1

Hypothalamic vs Pituitary Agents

Answer 1

• Hypothalamic:
  
  • Growth Hormone releasing hormone (GHRH)
  • Thyrotropic releasing hormone (TRH)
  • Corticotropin releasing hormone (CRH)
  • Gonadotropin releasing hormone (GnRH)
  • Dopamine (DA)
  • Somatostatin (SST)
• Anterior Pituitary–> Endocrine glands/Liver/Bone/other–>target
  
  • Growth Hormone (GH)
  • Thyroid Stimulating Hormone (TSH)
  • Adrenocorticotropin (ACTH)
  • Luteinizing hormone (LH)
  • Follicle Stimulating hormone (FSH)
  • Prolactin (PRL)
• Posterior Pituitary–>Target Tissues
  
  • Antidiuretic hormone (ADH)
  • Oxytocin

Question 2

Drugs that mimic or block the effects of hypothalamic & Pituitary Hormones

Answer 2

• Anterior Pituitary
  
  • Growth Hormone:
    
    • Agonist Action
      
      • Somatropin
      • Mecasermin
    • Antagnoist Action
      
      • Octreotide
      • Pegvisomant
  • Gonadotropins:
    
    • Agonist Action
      
      • Mixed LH & FSH
        
        • Menotropins
      • LH
        
        • Lutropin
        • hCG
      • FSH
        
        • Follitropin
  • Prolactin
    
    • Antagonist Action
      
      • D2 dopamine agonists
        
        • bromocriptine
• Hypothalamus
  
  • GnRH
    
    • Agonist Action
      
      • Gonadorelin
    • Antagonist Action
      
      • GnRH receptor agonist-leuprolide
      • GnRH receptor antagonist-ganirelix
• Posterior Pituitary:
  
  • Oxytocin
    
    • Agonist action
      
      • Oxytocin
    • Antagonist Action
      
      • Atosiban (not FDA approved)
  • Vasopressin:
    
    • Agonist Action
      
      • Desmopressin
    • Antagonist Action
      
      • Conivaptan

Question 3

Growth Hormone Axis:

Stimulatory vs inhibitory inputs and hormones

Answer 3

• Stimulatory inputs:
  
  • genetics
  • exercise
  • Increased:
    
    • grhelin
    • amino acids
  • Decreased
    
    • blood sugar
    • fatty acids
• Stimulatory hormones:
  
  • Hypothalamus-GH releasing Hormone (GHRH)
  • Anterior Pituitary- Growth Hormone (GH)
  • Liver-Insulin-like growth factor 1 (IGF-1)
• Inhibitory inputs: Negative feedback
  
  • Genetics
  • lethargy, stress, disease
  • Decreased
    
    • ghrelin
    • amino acids
  • Increased
    
    • blood sugar
    • fatty acids
• Inhibitory hormones:
  
  • hypothalamus-Somatostatin (SST)
    
    • direct downregulation

Question 4

clinical presentation of low GH

Answer 4

• affects growth and development of jaws and teeth
• Children
  
  • short stature:
    
    • Delayed dental age
    • Delayed replacement of deciduous teeth by permanent teeth
    • Newly erupted permanent teeth often require ortho tx
  • low age-adjusted growth velocity
  • hypoglycemia due to unopposed action of insulin
    
    • IGF-1 expression and postnala growth are GH-dependent during 1st year
  • Subnormal serum GH after stimulation
• Adults:
  
  • Decreased:
    
    • muscle mass
    • exercise capacity
    • bone density
  • Generalized obesity
  • weak/lack of energy
  • Dyslipidemia
  • Reduced cardiac output

Question 5

Pharmacological management of low GH

Answer 5

• Tesamorelin
• Somatotropin
• Mecarsermin
  
  • patients that do not respond to GH or somatotropin
    
    • mutations in receptor
    • antibodies against hormone
    • IGF-1 deficiency

Question 6

Tesamorelin

Answer 6

• Synthetic GHRH
• Mechanism=GHRH agonist
• used clinically to diagnose GH and GHRH sufficiency
• not used in disorders of GHRH or GH/IGF-1 secretion
  
  • used to reduce excess abdomina fat in adult patients with HIV
• No side effects
• no contraindications

Question 7

Somatotropin

Answer 7

• Recombinant form of GH
• Mechanism: GH agonist
• Used in both adults and children
  
  • additional symptoms
• Given to:
  
  • children
    
    • during active growth (before epiphyseal fusion)
  • older children
    
    • higher dosesae
    • may be extended past puberty and into adulthood
• Side effects:
  
  • Children: Well tolerated
    
    • can have rare but serious side effects:
      
      • pseudotumor cerebri
      • slipped capital femoral epiphysis
      • scoliosis progression
      • edema
      • hyperglycemia
  • Adults: Less tolerated

Question 8

Mecasermin

Answer 8

• recombinant IGF-1
• mechanism: IGF-1 agonist
• Used in children with growth failure and unresponsive to GH therapy
• Side effect:
  
  • Hypoglycemia
    
    • high carb meal or snack 20 minutes before administration limits

Question 9

clinical presentation of High GH

Answer 9

• Presentation: highly dependent on age
• Excess growth hormone can affect jaws and teeth:
  
  • Gigantism- GH excess before fusion of growth plates
    
    • prognathic mandible
    • malocclusion
    • hypercementosis
  • Acromegaly- GH excess in adults
    
    • change in occlusion
    • prognathism
    • jaw thickening
• Test=GH supression test (Not Tesamorelin)
  
  • blood levels measured before and after sugar consumed
  • glucose decreases levels of GH

Question 10

Pharmacological management of High GH

Answer 10

• Pegvisomant
• Octreotide or Lanreotide
• Bromocriptine or cabergoline

Question 11

Pegvisomant

Answer 11

• mutant GH derivative
• Mechanism=GH Antagonist
  
  • cross-link GH receptors
  • does not induce conformation change so no activation of receptor
    
    • prevents GH from activating GH signaling pathways
• Does not reduce GH secretion
• May elevate liver enzymes and induce lipodystrophy

Question 12

Octreotide

Answer 12

• or Lanreotide
• Synthetic SST analogs
• Mechanism: SST agonist
  
  • longer half lives than SST (SST=1-3 min)
• Tx: Acromegaly and gigantism
  
  • reduce GH and IGF-1
• Octreotide is the Most widely used SST analog
• Side effects:
  
  • GI disturbances
  • Gallstones
  • abnormal cardiac conduciton

Question 13

Bromocriptine

Answer 13

• or cabergoline
• Dopaine Agonist with high affinity for DA D₂ receptors (prolactin)
  
  • but can reduce GH release at high doses in patients with acromegaly
• mechanism: unclear
• only 70% of patients respond
  
  • can increase GH in patients without acromegaly
• Only affects GH and prolactin

Question 14

Dopamine pathway

Answer 14

• Positive feedback control=Prolactin
• Dopamine inhibits prolactin release from anterior pituitary

Question 15

Clinial Presentation: Low Prolactin

Answer 15

• Not a medical problem
• Problem for women who want to breastfeed and cannot due to low prolactin
• no approved treatments in US

Question 16

Pharmacological management of low prolactin

Answer 16

• Domperidone

Question 17

Domperidone

Answer 17

• Stimulate prolactin production
• Not FDA approved due to cardiac concerns
• Single patient expanded access for tx of severe GI motility disocers but not endocrine

Question 18

Clinical Presentation of High prolactin

Answer 18

• most common pituitary hormone hypersecretion in both sexes
• Thyrotropin releasing hormone (TRH) can stimulate prolactin secretion
  
  • When High TRH due to primary hypothyroidism
  • Thyroid hormone levels may help diagnose underlying disorder
• Male and Females patients may present with hypogonadism
  
  • Females
    
    • infertility
    • oligo or amenorrhea
      
      • galactorrhea
  • Males
    
    • loss of libido
    • ED
    • infertility
• these Symptoms indicate the CROSS talk b/w receptors can lead to change in multiple systems
  
  • patient management=complex

Question 19

Pharmacological management of High Prolactin

Answer 19

• Bromocriptine and cabergoline
  
  • Mechanism: dopamine agonists
    
    • high affinity for dopamine D2 receptors
  • Standard first line treatment to suppress prolactin release in patients with hyperprolactinemia
• Side effects:
  
  • Common:
    
    • Nausea
    • Headache
    • Light-head
    • orthostatic hypertension
    • fatigue
  • Sometimes:
    
    • psychiatric manifestations
    • eryhromelalgia
    • pulmonary infiltrates
    • cold-induced peripheral digital basospasms
• Remember: GH suppressive @ high doses

Question 20

Clinical Presentation of Oxytocin pathway

Answer 20

• Oxytocin–>Mammary gland, uterine muscles
• induces labor for conditions requiring expedited vaginal delivery
  
  • uncontrolled maternal diabetes
  • intrauterine infection
  • worsening preeclampsia
• Augment protracted labor
• stop vaginal bleeding due to uterine atony

Question 21

Oxytocin side effects

Answer 21

• excess stimulation of uterine contractions which leads to
  
  • fetal distress
  • placental abruption
  • uterine rupture
• inadvrtent activation of vasopressing receptors leads to:
  
  • excessive fluid retention or water retention
    
    • leads to:
      
      • hyponatremia
      • heart failure
      • seizures
      • death
• SHOULD NOT BE USED in fetal distress or malpresentation, placental abruption, and other predispositions for uterine rupture

Question 22

Pharmacological management of oxytocin pathway

Answer 22

• Atosiban
  
  • Oxytocin antagonist
  • not FDA approved in US
    
    • approved for preterm labor outside US

Question 23

Vasopressin/ADH pathway: Clinical presentation

Answer 23

• Diabetes insipidus (polyuria and polydipsia)
• esophageal variceal and/or colonic diverticular bleeding

Question 24

Pharmacological management: Low Vasopressin

Answer 24

• Vasopressin or desmopressin
• Desmopressin
  
  • synthetic analgue
  • mechanism: Vasopressing agonists
  • can also treat:
    
    • diabetes insipidus from vasopressin deficiency
    • nocturnal ensuresis and coagulopathy in hemophilia A & Von willebrand
• Desmopressin vs vasopressin
  
  • Fewer V₁ side effects
  • longer acting
• Vasopressin:
  
  • excessive vasoconstriction
• Both associated with:
  
  • headache
  • nausea
  • agitation
  • allergic rxns
  • abdominal cramps

Question 25

Clinical presentation of low vasopressin

Answer 25

* Fluid retention from excess vasopressin * associated with hyponatremia or acute heart failure

Question 26

Pharmacological management of High vasopressin

Answer 26

* Conivaptan * vasopressin antagonist * V_1a and V₂ * Tolvaptan * vasopressing antagonist * Higher affinity for V₂\>V₁ * Side effects: * only give for 30 days=risk of hepatotoxicity and life-threatening liver failure