Drug effects on the hypothalamic pituitary axis Flashcards Preview

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Flashcards in Drug effects on the hypothalamic pituitary axis Deck (38)
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Describe the pathway for GH release and its effects?

GH released in response to GHRH and ghrelin from brain

Release inhibited by somatostain

Gh released from pituitary and travels to liver

Liver is stimulated to produce IGF-1 > effects of GH

IGF-1 provides negative feedback to pituitary


Which parts of the GH pathway can go wrong?

Hormone insensitivity: can make a hormone that doesn't work
End up with high levels of GH 

Secondary deficiency: pituitary doesn't produce growth hormone

Tertiary deficiency: no release of GH, because brain isn't telling it to be released  



How can GH be administered? Why?

How often must it be administered? Why?

Parenteral administration only, as it has zero bioavailability after oral administration 

Administered daily or multi-daily, as it has a short half-life in the plasma


What does of GH is administered to patients?

Titrate dose to effect

Varies across patients 


Describe the effect of Gh on T4?

GH can cause reduced T4 levels


What is somatotropin?



Describe the effect of modifying ghrelin on GH?

Get more GH release for any given level of GHRH in the presence of more ghrelin 


In which cases is treatment with IGF-1 useful?

GH insensitivity

Patients with anti-GH Ab


Describe the side effects of treatment with IGF-1?

Like insulin > acute hypoglycaemia 


Describe the effects of having too much growth hormone?

Depending on when you have too much, can become very large (gigantism) or parts of your body can become very large (acromegaly)


Describe the approach to treatment of excess GH?

Remove tumour

Reduce GH release 

Inhibit GH action 


How can tumours that are causing excess GH release be localised?

Use receptor kinetics to localise 

Somatostatin receptors internalise upon activation, taking peptide ligand with them

Tumours expressing somatostatin receptors can be imaged by in vivo receptor scintigraphy


Describe the approaches to reducing GH release?

Somatostatin administration

Somatostatin reduces GH release from pituitary 


Describe the effect of somatostatin administration?

Reduced GH release from pituitary 


How is somatostatin administered?

Parenteral administration only

Short-half life > regular injections 


In which form is somatostatin administered? 


Octreotide and lanreotide

Somatostain analogues that have been modified to prevent enzymatic cleavage and extend half-life (somatostain has a very short half-life)


How is resistance to enzymatic cleavage commonly achieved?

Insert 'unnatural' D amino acids


How can the effectiveness of treatment with somatostatin analogues be increased?

In some patients, addition of dopamine agonists


How can GH action be inhibited?

Administration of GH antagonists


How can GH receptor binding be disrupted?

Alter glycine at position 120 (addition of side chain in receptor prevents site 2 binding)


Describe the pharmacokinetic properties of G120K-GH?

High affinity antagonist

Short half-life


How is the half-life of G120K-GH increased?


Addition of PEG:
increases size, which reduces renal filtration
improves solubility
decreases access for proteolytic enzymes 



What is the problem with PEGylated G120K-GH?

How was this overcome?

PEGylation occurs at lysines, but there are two lysines involved in site 1 binding

So, end up with completely inactive molecule

Further mutated molecule to produce pegmisovant


Describe the pathway for thyroid hormone release?

TRH > pituitary > TSH > thyroid gland > thyroid hormone

Thyroid hormone provides negative feedback to both pituitary and brain  


How is the thyroid hormone pathway affected in Grave's disease?

Stimulatory Ab against thyroid gland > excessive release of thyroid hormone 

Increased negative feedback to pituitary (decreased TSH) and brain (decreased TRH)


How is the thyroid hormone pathway affected in Hashimoto's disease?

Destructive Ab > loss of thyroid tissue > decreased thyroid hormone production

Loss of negative feedback to pituitary (increased TSH) and brain (increased TRH)


How can hyperthyroidism due to Grave's disease be treated?

Iodide > transiently reduce hormone synthesis and release 

Radioactive 131I- > ablate thyroid gland 

Carbimazole > inhibits thyroid peroxidase 

Propylthiouracil > inhibits thyroid peroxidase and conversion of T4 to T3


What is carbimazole used to treat?

Describe its action.


Used to treat hyperthyroidism

Inhbits thyroid peroxidase 


What is propylthiouracil used to treat?

Describe its action.


Used to treat hyperthryroidism

Inhibits thyroid peroxidase and conversion of T4 to T3


What are thioamines?

Carbimazole and propylthiouracil