Drug Effects on the Hypothalamo-Pituitary Axis Flashcards
What is the effect of ghrelin on GH release?
Stimulates
What is the abnormality in GH insensitivity? What are the biochemical findings?
GH fails to stimulate IGF-1 release
Increased GH, decreased IGF-1
What is the abnormality in secondary GH deficiency? What are the biochemical findings?
The pituitary does not produce GH
Decreased GH, decreased IGF-1
What is the abnormality in tertiary GH deficiency? What are the biochemical findings?
Most commonly there is no production of GHRH (but can also be absence of ghrelin), due to variety of causes
Decreased GH, decreased IGF-1, decreased GHRH or ghrelin
Why can’t GH be given orally?
It has zero bioavailability after oral administration as it is a peptide hormone and is broken down by the liver (first-pass metabolism)
How is GH administered?
Daily or multi-daily parenterally via injection
What is the effect of GH on T4?
Can reduce T4 levels
Does GH have a short or long half-life?
Short; it is a peptide hormone
What is the relationship between GHRH and ghrelin?
Synergistic (stimulation of the GHRH receptor elevates cAMP, and stimulation of the ghrelin receptor elevates Ca2+)
What is the possible therapeutic application of ghrelin?
Therapy for GH deficiency and eating-related disorders
What is the 2 therapeutic applications of IGF-1? What is 1 possible side effect?
For GH-insensitivity (Laron dwarfism) and patients with anti-GH antibodies
May cause hypoglycaemia
What are the 3 possible treatment options for GH excess?
Tumour removal (if relevant)
Reduction of GH release via somatostain analogues or DA antagonist
Inhibition of GH action via GH antagonist or GH receptor antagonist
What is pegvisomant?
A GH receptor antagonist
How can GH-secreting tumours be located?
Treating the patient with a circulating tagged somatostatin analogue, which binds SST2 receptors
SST2 receptors internalise upon activation (like many GPCRs), taking the radioligand with it
The tumour can then be visualised by in vivo receptor scintigraphy
What effect does somatostatin have on the pituitary?
Reduces GH release
Can also reduce TSH release
What is the problem with using somatostatin as a potential therapy for GH excess? How can these be overcome?
Requires parenteral administration and has a short half-life
Can be overcome by using analogues with “unnatural” AAs (e.g. D-AAs), as these confer resistance to enzymatic cleavage
Give 2 examples of somatostatin analogues
Octreotide
Lanreotide
How can the effectiveness of somatostatin analogues be increased?
By including a DA agonist (e.g. bromocriptine or cabergoline)
How do GH antagonists work?
By replacing the glycine at position 120 in hGH (119 in mice), necessary as it produces a cleft in the hormone which allows for site 2 binding and receptor activation, with a lysine residue (the side chain prevents site 2 binding)
What type of receptor is the GH receptor? Describe its structure
Tyrosine kinase-type
Has 2 binding sites; binding site 1 is high affinity, site 2 is lower affinity but leads to receptor activation
How can the half-life of GH antagonists be increased? How is this achieved?
Via PEGylation
Increases the size of the molecule to reduce renal filtration
PEG hydrophilicity improves solubility
Decreases accessibility for proteolytic enzymes
What is the drawback of PEGylation of GH antagonists?
PEGylation occurs at lysines, which are required for site 1 binding, and so the binding affinity is reduced
What is B2036? What advantages and disadvantages does it have compared with PEGylated GH antagonists?
A GH antagonist with 9 mutations
Retains lysine residues so has good affinity
No PEGylation so has a short half-life
What is the difference in terms of the actions and daily dosing of carbimazole and propylthiouracil?
Carbimazole inhibits TPO; given once daily
Propylthiouracil inhibits TPO and deiodinase; given 2-4 times daily
