pituitary pharma (3+4)

Question 1

A synthetic analogue (agonist) for ACTH that is used in the ACTH stimulation test to diagnose adrenal insufficiency (if there is no increase)
* Less allergic than ACTH and longer duration of action.
* The plasma cortisol level is measured at 0 and 60 minutes after administration.
If adrenal insufficiency is primary = glucocorticoids level will not change much. If adrenal insufficiency is secondary or tertiary = marked increase in glucocorticoids level after administering Cosyntropin.

Answer 1

Cosyntropin

Question 2

It’s administered subcutaneously. Can’t be given orally because it’s a protein.
* Increases cAMP
* Acute effect = promotes cholesterol
* Chronic effect = transcription of genes and enzyme synthesis
* Dose=0.25mg
* Taken by the liver & the kidney.

Answer 2

Cosyntropin

Question 3

A human post-menopausal hormone (Women’s urine)
* Treats infertility because it has LH & FSH like effects.
* We give it to patients, then we measure ovarian follicles, and if the diameter reaches
14 mm, ovulation is induced by hCG.
hCG is administered every 3 days for 12 days.
* In males (infertility): it has LH, FSH like effect, we administer it to promote spermatogenesis and hCG is administered to increase the synthesis and secretion of testosterone.
* Used in pituitary disorders when GnRH is not effective.
* Is given IV (not orally)

Answer 3

Menotropin

Question 4

Synthetic analogs/agonist of GnRH.
* Much longer duration of action than GnRH action. (longer half-life)
* Short term or pulsatile administration increases the synthesis & release of both LH
& FSH.

Answer 4

Leuprolide, Goseralin, Nafarelin

Question 5

However, chronic administration inhibits the release of both LH & FSH by causing a reduction in the number of GnRH receptors.
* Adverse effects: decrease bone density, vaginal atrophy, dryness, hot flashes, erectile dysfunction

Answer 5

Leuprolide, Goseralin, Nafarelin

Question 6

(All of them) used in conditions that are mediated by steroids such as:
- Endometriosis, uterine fibroids, precocious puberty, prostate cancer; most of these are mediated by excess steroid hormones and because of the longer half- life, these drugs will inhibit LH and FSH release and therefore they suppress the synthesis and release of steroids, such as estrogen and progesterone.
-Side effects:
-initially (during the first 3-4 days) they may aggravate
these conditions = Flare effect!
-second phase: complete suppression of the synthesis & release of LH and FSH, so their effect is not immediate.
-MOA: exposing receptors for long period of time, they will desensitize.

Answer 6

Leuprolide, Goseralin, Nafarelin

Question 7

Pure GnRH antagonist.
* immediate effect (no flare effect) & competes with GnRH for the same receptor.

Answer 7

• Ganirelix, Abarelix:

Question 8

Treats ovarian over stimulation and premature LH surge.

Answer 8

Ganirelix

Question 9

Treats prostate cancer.

Answer 9

Abarelix

Question 10

Dopamine agonist
* treats hyperprolactinemia (blocks prolactin)
* 7 hours duration (half life)
* Treats infertility that’s caused by hyperprolactinemia.

Answer 10

Dopamine agonist
* treats hyperprolactinemia (blocks prolactin)
* 7 hours duration (half life)
* Treats infertility that’s caused by hyperprolactinemia.

Question 11

Dopamine agonist.
* 70 hours duration of action. (D2 agonist) with less side effects - Side effects of all dopamine agonists:

Answer 11

Cabergoline

Question 12

Orthostatic hypotension (major SE)
* Vomiting and nausea: because of the activation of chemoreceptor trigger zone
which is located outside the blood brain barrier.(not due to irritation of GI).

Answer 12

Cabergoline

Question 13

synthetic analogue of ADH (similar structure) the only difference is the arginine.
* Arginine in L-form in ADH.
* Arginine in D-form in Desmopressin.
* We cannot use ADH in the treatment of nephrogenic diabetes insipidus
because of end- organ resistance (the receptor doesn’t work in case of ADH) so they use desmopressin instead.

Answer 13

Desmopressin

Question 14

Treats syndrome of inappropriate ADH (SIDH) by decreasing the sensitivity of V2 receptors to ADH. (V2 receptors selective)

Answer 14

Demeclocycline

Question 15

Treats syndrome of inappropriate ADH (SIDH) by decreasing the sensitivity of V2 receptors to ADH. (V2 receptors selective)

Answer 15

Lithium

Question 16

V1 and V2 antagonist.
* Treats syndrome of inappropriate ADH (SIDH), IV.

Answer 16

• Conivaptan (aquaretics)

Question 17

Selective V2 antagonist.
* Treats syndrome of inappropriate ADH (SIDH), given orally so it has greater
advantage.

Answer 17

• Tolvaptan

Question 18

Diagnostic uses o Delayed puberty
* Administer dose at 100 μg, IV.
* LH measure (0, 15, 30, 40, 60, 90 min)
* If a peak LH response (15.6 mU/ml)
- Impending puberty (if >15.6 mU/ml)
- Hypogonadotropic hypogonadism (if impaired response)

Answer 18

GnRH (Gonadorelin)

Question 19

therapeutic uses
- Given in low pulsatile dose to treat infertility.
- IV (t1/2 4 min), SC, Intranasal (t1/2 3 hrs.).

Answer 19

GnRH (Gonadorelin)

Question 20

• Pulsatile administration (every 90 mins)à↑ FSH, LH secretion
• Continuous administrationà↓ FSH, LH secretion - Adverse effects: male® gynocomastia
  female® ovarian hyperstimulation

Answer 20

GnRH (Gonadorelin)

Question 21

Growth hormone inhibitory hormone § MOA: ↑ K+ channels

Answer 21

Somatostatin

Question 22

pulsatile: 10-20 pulses daily, peaks 60-90 mins after sleep , short half-life : 20 mins Released from somatotrophs of anterior pituitary metabolized by liver and kidney
Peaks during periods of rapid growth (neonates, childhood, puberty) then declines in late childhood. Neonates>children>women>men
Transported by GH binding protein (loose binding)

Answer 22

GH

Question 23

ghrelin synthesized by stomach and arcuate nucleus of hypothalamus. Binds to receptor on cell membrane and activates PLC (secondary messenger) leading to GH release ● others:
-GHRH: most important, synthesized by hypothalamus then transported to anterior pituitary by portal system, act on GHRHR which is a receptor of high specificity and sensitivity and activate 2nd messenger ( cAMP) leading to GH release
- Low glucose: hypoglycemia —> GH secretion
- Neurotransmitters: DA (acts on β2 receptors), 5-HT(Serotonin), Adrenergic agonists (eg. Clonidine acts on D2 receptors)
- Onset of sleep( peaks 60-90 mins after sleep)

Answer 23

promote secretion of GH

Question 24

Somatostatin: synthesized by hypothalamus, binds to receptors on anterior pituitary, decrease cAMP and increase K+ channels leading to repolarization = no GH release ● IGF-1: by negative feed-back on pit. and hypoth.
Diet : if high in carbs inhibits GH release , but if high in protein Promote GH release inhibit secretion of GH

Answer 24

inhibit secretion of GH :

Question 25

• Linear growth in children (mediated by IGF-1)
• Increases activity of osteo/chondroblast
• It can promote calcium absorption in GI tract and inhibit calcium secretion by the kidneys - Increases collagen synthesis (main component of bone) - Positive nitrogen balance
• Increase protein synthesis, decrease protein degradation
• Cortisol has opposite effects (negative nitrogen balance)
• Lipolysis
• Growth hormone promotes lipolysis, FA oxidation and thus increase the circulation of free fatty acids. GH
  can also switch the self to produce energy from lipids rather than from glucose, the end product will be acetoacetic acid ketoacidosis (ketone bodies are synthesized by liver)

Answer 25

Growth Hormone Actions

Question 26

• Plasma glucose levels (mainly increase hence diabetogenic effect)
  1) increasing gluconeogenesis
  2) decease glucose uptake by insulin sensitive tissues like muscles
  3) antagonizing the action of insulin. 4) increase glycogenolysis
  -Acute effect: increases glucose uptake by target tissues (ex: fat, muscle) -Chronic effect: decreases glucose uptake by target tissues (inhibits uptake)

Answer 26

Growth Hormone Actions

Question 27

GH analogue.
- Recombinant human growth hormone-rhGH- (somatropin).
- It’s amino acid sequence is identical with that of endogenous human GH. - Used for children with GH
deficiency Rout of Administration:
- Subcutaneously, daily administration more effective
- SC for adult GH deficiency * Bioavailability – SC, 75%, IM, 60%. so SC is better

Answer 27

GH deficiency
treatment
* Somatropin:

Question 28

an analog of GH. It is very similar to the naturally occurring GH with the exception that it has the
additional methionine amino acid in the end of the single chain.
- First GH analog to be used therapeutically
- Used for children with GH deficiency
- Route of Administration + Drug interactions + Adverse effects:
Similar to Somatropin (usually given SC but sometimes IM)
-(nutropin depot injection): new somatrem , IM once or twice / month (not daily)

Answer 28

GH deficiency
treatment * Somatrem:

Question 29

IGF-1 analogue
- Treats growth retardation from GH resistance (Laron Dwarfism or receptor defect)
- Mecasermin is also used to treat patients who have growth hormone antibodies within their circulation.

Answer 29

GH deficiency
treatment Mecasermin

Question 30

A 6 amino acid peptid, Ghrelin synthetic analog
-MOA: Distinct receptor from GHRH receptor, activates PLC > Phosphatidylinositol triphosphate(IP3) and Diacylglycerol(DAG)
-Route of administration: Intranasaly, long-acting -t 1⁄2; 70 mins (long t1/2)

Answer 30

GH deficiency
treatment hexarelin

Question 31

-Decrease insulin sensitivity (secondary DM) -Increase incidence of malignancy
-Increase the activity of cytochrome P-450 (increase clearance of other drugs) - drug inter actions:
-Interfering with growth promoting action of some agents
- Androgens, estrogens, anabolic steroids interfere with linear growth of children
- Glucocorticoids increase protein degradation, decrease Ca absorption from GI, increase Ca excretion

Answer 31

GH DEFECIENCY TREATMENT – SIDE EFFECTS & INTERACTIONS

Question 32

GH excess can be resolved by inhibiting GH release or by blocking its receptor.
Transphenoidal surgery
Octreotide (sandostatin):
Synthetic analogue of somatostatin.
- Actions:
- Inhibits release of GH, inuslin, glucagon. - 40x more potent than somatostatin
Inhibits basal and TRH-stimulated TSH secretion
- inhibits secretion of GI peptides/pancreatic hormones: insulin, glucagon, VIP, gastrin, and others.
Microspheres – 4-week interval, IM
Hepatic metabolism, 32% renal elimination Unchanged Starting dose (50 μg), Increment (50 μg) 1 to 2
*
weeks
- Peak concentration 15-30 min
- t1/2 (90 min) vs somatostatin (3 min)
- Duration of action (4-8 hrs) it is more selective towards somatostatin type 2receptors than somatostatin.
*
* *
Bromocriptine- cabergoline
- Dopamine B2 agonist - Inhibits GH secretion.
Normalizes IGF-I in 35% of patients
Adverse effect: nausea, vomiting (due to the activation of the chemoreceptor trigger zone), dizziness, postural hypotension.
The chemoreceptors trigger zone is located in the area postrema which is outside the blood brain barrier. Start at reduced doses to minimize adverse effects
* Pegvisomant (somavert)
- Blocks GH receptor (GH receptor antagonist) / Competitve inhibitor
Initially, it will increase GH secretion, because of the negative feedback inhibition, you’re blocking the receptor so later on it will be good

Answer 32

GH EXCESS TREATMENT

Question 33

• Carcinoid tumors
  -Pancreatic cell tumors (VIPomas); secretion of vasoactive intestinal peptide - Adverse effects:
• Bradycardia (major SE)
  -Gallbladder contractility ->biliary sludge and/or gallstones (decreased bile formation) - GI disturbances- pain, nausea, diarrhea, Gastritis, Helicobacter Pylori infection

Answer 33

Clinical Uses: - GH excess: