60 - Drug Effects on the Hypothalamic-Pituitary Axis Flashcards
Ghrelin
Under investigation as a therapy for GH deficiency (and other disorders, mostly eating-related).
Influences GH release.
How can GH levels be measured in hormone replacement therapy?
Measure levels of tropic hormone
Effect of growth hormone-releasing hormone and ghrelin given together
Act synergistically, leading to greater GH release
How can GHRH and ghrelin be synergetic for GH release?
GHRH-R elevates cAMP, ghrelin R elevates intracellular Ca2+
When is giving IGF-1 useful?
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)
Treatment options for acromegaly
1
2
3
Want to reduce GH levels
✦ Remove tumour (if relevant)
✦ Reduce GH release (somatostatin analogues, dopamine agonist)
✦ Inhibit GH action (GH antagonist, pegvisomant)
Effect of dopamine agonists on pituitary disorders
Will sometimes be effective for too much or too little release of hormones from pituitary. Sort of mysterious.
How can a GH-releasing tumour be located?
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
Problem with somatostatin therapy for GH disorders?
Somatostatin has a short half-life (enzymatic cleavage, renal excretion)
Way to increase somatostatin half life
Make somatostatin analogues with D-amino acids in them. Fit poorly into degrading enzyme active site.
Name for a GH antagonist
Pegvisomant
GH antagonism
Replace glycine at position 120 on GH primary structure leads to a high-affinity antagonist.
Why does replacing glycine 120 on GH lead to an antagonist?
Binds to GH receptors, doesn’t induce dimerisation, therefore won’t elicit effects
Manner in which pharmacokinetics of protein drugs can be improved
Adding poly-ethylene glycol (PEG).
Make molecule larger, reducing renal filtration.
Sterically obstruct proteolytic enzymes.
Improves solubility (PEG is hydrophilic).
Why can’t all protein drugs be PEGylated?
PEGylation occurs at lysines.
EG: hGH antagonist has lysines at receptor binding site, so PEGylation would affect binding affinity.
Effect of radioactive iodine on thyroid
Radioactive 131I- ablates the thyroid gland.
Stable isotopes protect against radioactive isotopes.
Carbimazole
Inhibits thyroid peroxidase (therefore reduces synthesis of T3 and T4).
Taken once a day.
Propylthiouracil
Inhibits thyroid peroxidase.
Inhibits conversion of T4 to T3.
Taken 2-4 times per day
Thioamine drugs
Carbimazole
Propylthiouracil
Side effects of thioamines 1 2 3 4
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.
Volume of distribution of T4
10L (quite large)
How long does it often take for a drug to reach a steady-state concentration?
About three or four half-lives.
Treatment using T3 1 2 3 4 5
✦ 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
Treatment for most patients with hypothyroidism
For most patients, use T4 rather than T3.
Use T3 for treating severe hypothyroid and
myxoedema coma.
