Endocrine Pharmacology

Question 1

How is GnRH administered?

Answer 1

• Endogenous agonist is Gonadorelin (10 aa decapeptide)

- Because it is a peptide, it can be administered both IV and Subcutaneously.

Question 2

Administration of a small dose of GnRH can be helpful in detecting what?

Answer 2

• Delayed puberty/ menarche.
• If the failure is at the level of the anterior pituitary or the ovary, GnRH will not be helpful. If it is due to low, or lack of GnRH release from the hypothalamus, menarche will commence.

Question 3

How do treat Hypogonadotropic Hypogonadalism?

Answer 3

-Intermittent, small doses of GnRH promotes the release of FSH/ LH to treat infertility, particularly in patients with low GnRH output.

Question 4

True or False: GnRH analogues act to desensitize the pituitary and gonadotrophs.

Answer 4

True.

–>Administration of exogenous GnRH, or it’s synthetic analogue Leuprolide Acetate, instead of stimulating FSH/ LH release, desensitizes and down- regulates GnRH receptors on the anterior pituitary, ultimately resulting in decreased FSH and LH after an initial flare.

Question 5

Leuprolide Acetate:

Answer 5

–>Continuous administration leads to eventual decrease in FSH and LH levels after an initial flare (due to down regulation)

Question 6

Ganirelix:

Answer 6

–>Competitive GnRH antagonists (Ganirelix) can be used- however, Ganirelix can cause Ovarian Hyper-Sensitivity Syndrome (OHSS)

-Decreases Gonadotropin output.

Question 7

Uses of Leuprolide Acetate (GnRH analogue) and Ganirelix (GnRH antagonist):

Answer 7

• Suppression of Gonadal Hormones (Continuous administration of GnRH leads to a decrease in FSH and LH and a subsequent decrease in estrogen and progesterone.
• -Administered subcutaneously.
• -In Males: Used to decrease risk of Prostate Cancer (Decrease Androgen/ Testosterone Levels)
• -In Females: Decrease Risk of Endometriosis and Uterine Fibroids
• When FSH/ LH levels are decreased, the prostate tissue proliferation in males and endometriosis in females undergo regression.
• Drawback: Rare incidence of OHSS

Question 8

Porcine Corticotropin (ACTH):

Answer 8

-Not longer used

Question 9

Cosyntropin

Answer 9

• Synthetic form of truncated human corticotropin.
• Tests for primary or secondary cortisol deficiency issues
• Fewer allergic reactions compared to animal preparation.

Question 10

Corticorelin ovine triflutate (CRH- Acthrel):

Answer 10

• A recombinant ovine- CRH –> ACTH –>Cortisol.
• -It is indicated for differentiating/ distinguishing between pituitary and ectopic production of ACTH in patients with ACTH- dependent Cushing Syndrome (increases levels of corticosteroids)

Question 11

Somatrem:

Answer 11

GnRH Analogue
-Administered via parental routes for the treatment of GH deficiency (dwarfism) in children, as well as for the management of AIDS body wasting syndrome.

Question 12

Somatotropin:

Answer 12

• Recombinant hGH

- 191 amino acids in length

Question 13

Octreotide:

Answer 13

(8 amino acid synthetic peptide)
-Short chain peptide analog of somatostatin that suppress GH and insulin- like growth factor (IGF) levels.

-Used for treatment of gigantism, acromegaly and GI hormone secreting tumours.

Question 14

Somatostatin:

Answer 14

Growth Hormone Releasing Inhibiting Hormone

Question 15

Pegvigomant:

Answer 15

GH receptor antagonist

• 191 AA peptide which blocks the GH receptor and reduces the production of Somatomedins (IGF)
• Administered subcutaneously or intradermal
• Used for the treatment of gigantism and acromegaly

Question 16

Prolactin:

Answer 16

• Released from the anterior pituitary to increase milk secretion (lactogenesis and galactopoiesis)
• -Increases lactose, casein and lactalbumin in the mammary alveoli.
• Inhibited by Dopamine via D2 receptors.
• An increase in PRL leads to a decrease in GnRH (hyper stimulation can cause amenorrhea and galactorrhea in females, and infertility in males.

-Feedback inhibitor of GnRH following high plasma prolactin levels is the reason why during lactation, some females experience secondary amenorrhea in females.

Question 17

Hyperprolactemia:

Answer 17

Results in infertility in males and secondary amenorrhea in females.

Question 18

How does the DA- PRL complex allow for lactation in females?

Answer 18

-During lactation, there is less PIF release (DA) resulting in increased Prolactin needed to maintain lactation. Increased lactation can also lead to secondary amenorrhea.

Question 19

What are the 3 sites of PRL acts on?

Answer 19

1. The Breast- promotes milk secretion
2. On the Hypothalamus- Blocks GnRH release
3. On the Testes and Ovaries (lessens the production of LH and FSH- leading to secondary amenorrhea)

Question 20

Phenothiazine, Haloperidol

Answer 20

Non- Selective DA antagonists

-Act low PRL release

Question 21

Metoclopromide, Domperidone

Answer 21

• D2 selective antagonist

- Enhance PRL secretion

Question 22

Bromocriptine

Answer 22

D2 Selective Agonist

• Decrease PRL release
• Binds lactotrophs to block PRL release.

Adverse Effects:

• Orthostatic hypotension
• Digital Vasospasm
• Nausea

Question 23

Cabergoline

Answer 23

• A newer and effective D2 agonist
• -Prevents PRL release.
• -Is the drug of choice for treating Prolactinomas

*More potent and more expensive- is only used in patients who do not respond well to Bromocriptine

Question 24

What is the effect of breast feeding on OT levels?

Answer 24

With increased breast feeding, oxytocin release is maintained and it contributes to milk let down or milk ejection. OT and REL secretion are examples of positive feedback modulation.

Question 25

The physiological role of ADH in the kidney:

Answer 25

• The physiological role of ADH is to reabsorb water from the renal collecting ducts in the kidney to maintain plasma volume via stimulation of renal V2 receptors on the collecting ducts, which is linked to AC and an increase in cAMP level.
• In pharmacological doses, AVP/ ADH is a vasoconstrictor/ vasopressor via activation of vascular V1 receptors.

-Binding V1 receptor= vasoconstriction

• Binding V2 receptor= water reabsortion
• Vasopressin binds V2 receptors on the nephron, which activates AC and increase cAMP levels, leading to increased water absorption. (Promotes aquaporin water channels)

-If ADH is not present, it will lead to increased water loss known as Diabetes Insipidus.

Question 26

Demsopressin Acetate:

Answer 26

DDAVP

• A synthetic peptide is given intranasal, orally or subcutaneously.
• 4000x more potent than AVP.
• Selective V2 agonist (avoids undesirable V1 effects of vasoconstriction.
• AVP activates both
• Used to treat Neurogenic Diabetes Insipidus (CentralDI or Pituitary DI)
• Can’t be used to treat Nephrongenic Diabetes.
• Used to treat Nocturnal enuresis in children and elderly patients.
• Also used to treat Hemophilia A and Von Willebrand’s Disease (Factor VIII deficiency)

Question 27

What is the drug of choice to treat Nephrogenic DI?

Answer 27

Hydrochlorothiazide

Question 28

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Answer 28

Leads to chronic hypervolemia hyponatriemia.

Question 29

ADH Antagonists:

Answer 29

Tolvaptan (non-peptide V2 antagonist)

AE: Hypernatremia

-Osmotic demyelination occurs if hyponatriema is corrected too quickly.