60 - Drug Effects on the Hypothalamic-Pituitary Axis

Question 1

Ghrelin

Answer 1

Under investigation as a therapy for GH deficiency (and other disorders, mostly eating-related).

Influences GH release.

Question 2

How can GH levels be measured in hormone replacement therapy?

Answer 2

Measure levels of tropic hormone

Question 3

Effect of growth hormone-releasing hormone and ghrelin given together

Answer 3

Act synergistically, leading to greater GH release

Question 4

How can GHRH and ghrelin be synergetic for GH release?

Answer 4

GHRH-R elevates cAMP, ghrelin R elevates intracellular Ca2+

Question 5

When is giving IGF-1 useful?

Answer 5

When someone is insensitive to GH (EG Laron dwarfism) or has anti-GH antibodies.
Instead of GH give downstream effect of GH (leads to IGF release from liver)

Question 6

Treatment options for acromegaly
1
2
3

Answer 6

Want to reduce GH levels
✦ Remove tumour (if relevant)
✦ Reduce GH release (somatostatin analogues, dopamine agonist)
✦ Inhibit GH action (GH antagonist, pegvisomant)

Question 7

Effect of dopamine agonists on pituitary disorders

Answer 7

Will sometimes be effective for too much or too little release of hormones from pituitary. Sort of mysterious.

Question 8

How can a GH-releasing tumour be located?

Answer 8

Localise cells that can release GH (will express a somatocretin/somatostatin R)

Somatostatin receptors internalise upon
activation (like many GPCRs), taking the
peptide ligand with them
Tumours expressing somatostatin receptors can
be imaged by in vivo receptor scintigraphy

Question 9

Problem with somatostatin therapy for GH disorders?

Answer 9

Somatostatin has a short half-life (enzymatic cleavage, renal excretion)

Question 10

Way to increase somatostatin half life

Answer 10

Make somatostatin analogues with D-amino acids in them. Fit poorly into degrading enzyme active site.

Question 11

Name for a GH antagonist

Answer 11

Pegvisomant

Question 12

GH antagonism

Answer 12

Replace glycine at position 120 on GH primary structure leads to a high-affinity antagonist.

Question 13

Why does replacing glycine 120 on GH lead to an antagonist?

Answer 13

Binds to GH receptors, doesn’t induce dimerisation, therefore won’t elicit effects

Question 14

Manner in which pharmacokinetics of protein drugs can be improved

Answer 14

Adding poly-ethylene glycol (PEG).
Make molecule larger, reducing renal filtration.
Sterically obstruct proteolytic enzymes.
Improves solubility (PEG is hydrophilic).

Question 15

Why can’t all protein drugs be PEGylated?

Answer 15

PEGylation occurs at lysines.

EG: hGH antagonist has lysines at receptor binding site, so PEGylation would affect binding affinity.

Question 16

Effect of radioactive iodine on thyroid

Answer 16

Radioactive 131I- ablates the thyroid gland.

Stable isotopes protect against radioactive isotopes.

Question 17

Carbimazole

Answer 17

Inhibits thyroid peroxidase (therefore reduces synthesis of T3 and T4).
Taken once a day.

Question 18

Propylthiouracil

Answer 18

Inhibits thyroid peroxidase.
Inhibits conversion of T4 to T3.
Taken 2-4 times per day

Question 19

Thioamine drugs

Answer 19

Carbimazole

Propylthiouracil

Question 20

Side effects of thioamines 
1
2
3
4

Answer 20

May lead to goitre.

Large initial dose, smaller maintenance dose.

May cause agranulocytosis (loss of blood cells), but monitoring blood count is of questionable utility (cell count drops very suddenly, so regular blood tests don’t predict it).

Propylthiouracil more likely to cause hepatotoxicity. Measure baseline liver function.

Question 21

Volume of distribution of T4

Answer 21

10L (quite large)

Question 22

How long does it often take for a drug to reach a steady-state concentration?

Answer 22

About three or four half-lives.

Question 23

Treatment using T3
1
2
3
4
5

Answer 23

✦ More active than T4 and acts more rapidly
- Less strongly protein-bound than T4
✦ Half life about 1 day
✦ Levels are less stable during the day than
those of T4
✦ TSH levels less easily interpreted

Question 24

Treatment for most patients with hypothyroidism

Answer 24

For most patients, use T4 rather than T3.
Use T3 for treating severe hypothyroid and
myxoedema coma.