7.06 Drugs affecting the Hypothalamic-Pituitary Axis

Question 1

Describe the normal growth hormone axis

Answer 1

• GHRH is synthesised and secreted from the hypothalamus
• This stimulates GH release from the anterior pituitary
• This acts in the liver to cause IGF release to act on target tissues
• Somatostatin from the hypothalamus inhibits the release of GHRH
• Ghrelin also promotes

Question 2

What would the axis look like if there were growth hormone insensitivity?

Answer 2

Insensitivity means that the liver is not responsive to GH levels and the lack of negative feedback increases the levels of GH release with no impact on rising IGF

Question 3

What would secondary and tertiary deficiencies in growth factor look like?

Answer 3

• Secondary means that there is a lack in the GH itself
• Tertiary means there is a lack of GHRH

Question 4

Why does growth hormone (somatostatin) have zero bioavailability after oral administration?

Answer 4

Because it is a protein (nutrient) so oral administration leaves it prone to enzymatic degradation in the mouth and gut. So therapeutically it requires parenteral (through an injection)

Question 5

What is another consequence of the protein nature of Somatostatin?

Answer 5

• Short half-life
• Daily or multi-daily

Requires: titration of dose to effect: replacing a physiologically regulated hormone.

Question 6

There is lots of interaction between endocrine system… How does Growth hormone impact thyroxine levels?

Answer 6

GH can cause reduced T4 levels

Question 7

Why is it important to titrate the doses of growth hormone?

Answer 7

• Too much = develop acromegaly
• Too little = short of stature or will have different deficiencies in adults

Growth hormone also has trophic effects and has a long acting effect - thus need to monitor the releasing hormone

Question 8

How do the Ghrelin and GHRH receptors respond to cause production and release of GH

Answer 8

GHRH receptor: elevates cAMP

Ghrelin receptor: elevates Ca2+

Question 9

What evidence shows that a combination of Ghrelin and GHRH elicits a larger release of GH synergistically

Answer 9

Because of the two different mechanisms achieving the same goal, there is scope for large amplification when combined

Ghrelin is under investigation as a therapy for GH deficiency (and other disorders, mostly eating-related)

Question 10

How can IGF-1 (insulin-like growth factor 1) be used pharmaceutically?

Answer 10

Useful for GH-insensitivity (called Laron dwarfism) and patients with anti-GH antibodies

Question 11

What are the side effects of IGF-1?

Answer 11

Sometimes hypoglycaemia due the insulin like effects of IGF-1

Question 12

What does too much growth hormone manifest as?

Answer 12

Acromegaly

Elongation and growth of structures with lots of cartilage continue growing especially the jaw, nose, hands and feet. Can lead to arthritis and other consequences

Question 13

What are some therapeutic options for increased growth hormone?

Answer 13

• Remove tumor (if relevant)
• Reduce GH release: somatostatin analogues and dopamine agonist
• Inhibit GH action: GH antagonist, pegvisomant

Question 14

How can we localize the GH secreting tumours?

Answer 14

Find the tumour by exploiting receptor kinetics to localise GH receptor expressing tumours

This is because the GH receptor in these gets internalised when bound to a ligand GH

Question 15

Somatostatin can be used to reduce GH release (the more somatostatin, the more inhibition on the anterior pituitary to produce GH)

Describe somatostatin in terms of pharmacokinetics

Answer 15

It has poor pharmacokinetics

• Somatostatin reduces GH release from the pituitary (but can also reduce TSH)
• Tumor cells expressing receptors for somatostatin usually respond to somatostatin with reduced secretion of GH
• Somatostatin has a very short half-life due to enzymatic cleavage and renal elimination (it is also a protein)

Question 16

What is a major strategy to confer resistance to enzymatic cleavage for somatostatin (and other proteins) for use therapeutically?

Answer 16

The native form of the proteins is made up of L-amino acids (the natural kind). Changing the structure of proteins by replacing some of the L-amino acids to D-amino acids make the peptides fit less well in proteolytic enzymes

These analogues give longer half lives (but they still have renal degradation)

Question 17

What two additional methods can be used to better the pharmacokinetics of peptides?

Answer 17

• Depot formulations also exist
• Addition of dopamine agonists (bromocriptine or cabergoline) my increase effectiveness

Question 18

Describe growth hormone antagonists

Answer 18

It has been found that a Glycine at amino acid position 119 is essential for GH to have its action as a growth hormone. Mutant GH without this amino acid (replaced) causes a loss in agonist activity.

Question 19

Describe the normal binding of growth hormone to the growth hormone receptor.

Answer 19

The growth hormone receptor is part of the tyrosine kinase family receptor: Binding of growth hormone causes receptors to dimerises and then have the intracellular signalling effects.

Thus growth hormones have 2 binding sites motifs.

• Binding site 1 has high affinity
• Binding site 2 leads to receptor activation

Question 20

How do the growth hormone antagonists interfere the normal binding and activation of GH receptors?

Answer 20

Mutant GH usually has a removal of the glycine and replacement with something else. This removes binding site 2 meaning binding is enabled (competition) but activation is not enabled (antagonist).

It is still a peptide so still has a short half-life

Question 21

What is PEGylation?

How is it useful in pharmacokinetics?

Answer 21

Hanging a polyethylene glycol (PEG) –Carbon chains with O2 scattered through them

• Makes molecules larger (prevents renal filtration)
• It makes it hard for proteolytic enzymes from reaching the protein core – increases steric hindrance
• Makes them more soluble (longer half-life)

Question 22

Where in the GH peptide would PEGylation occur?

What is the problem encountered by this?

Answer 22

PEGylation occurs at the lysines.

This is a problem because there are two lysines involved in site 1 binding, this reduces the affinity of the binding of the mutant GH

Question 23

What technique is used to counteract the reduced affinity of binding coming from the PEGylation of lysines?

Answer 23

Modification other amino acids in the peptide to compensate for the lysine.

There is still a short half life

Question 24

Describe the drug Pegvisomant

Answer 24

A growth hormone antagonist with the glycine replaced (antagonist activity), PEGylated with the lysine replaced.

It is a trade off between a reduced affinity somewhat (tolerable), not enough to completely reduce use

Question 25

Describe the normal thyroid hormone axis

Answer 25

* The hypothalamus secretes thyroid releasing hormone to the anterior pituitary * The anterior pituitary responds by secretion of thyroid stimulating hormone (TSH) * TSH travels to the thyroid to stimulate production of thyroid hormone

Question 26

Describe what happens in Hashimoto’s Disease

Answer 26

**= Autoimmune hypothyroidism** There is a destructive antibody that attacks the thyroid gland to prevent production of the thyroid hormones. This leads to a reduced negative inhibition on the hypothalamus and pituitary leading to high levels of TRH and TSH

Question 27

What is a short-term treatment for hyperthyroidism?

Answer 27

Provision of Iodide (I-) This **transiently** reduces hormone synthesis and release (likely due to some feedback pathway)

Question 28

What is a major treatment for hyperthyroidism? What is a major drawback of this treatment and how is it counteracted?

Answer 28

Radioactive 131 Iodine (I-) ablates the thyroid gland. There is a high risk of radioactive exposure causing thyroid cancer (especially in children) This is somewhat counteracted by also introducing _stable isotopes_ that compete for the same binding sites) to protect against radioactive isotopes.

Question 29

What is Carbimazole
?

Answer 29

A thioamine Inhibits thyroid peroxidase and thus prevents the iodinated thyroxine from being formed Administered Once daily

Question 30

What is Propylthiouracil
?

Answer 30

Another thioamine drug that Inhibits thyroid peroxidase **and** inhibits the conversion of T4 to T3 2–4 doses daily

Question 31

What are some side effects of thioamine drugs?

Answer 31

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

Question 32

Administering Thyroxine (T4) to treat hypothyroidism experiences binding proteins. What are the consequences of this?

Answer 32

* T4 binds to thyroxine binding globulin in the bloodstream. * T4 becomes very protein bound (leading to a long half life of about a week) and thus protected from renal filtration acting like a reservoir

Question 33

What does the amount of drug bound depend on?

Answer 33

Amount of drug bound depends on **affinity** and the **relative concentrations** of drug and protein

Question 34

What is an important consideration for drug binding to proteins?

Answer 34

Drugs may compete for particular binding sites

Question 35

Describe albumin as a binding protein

Answer 35

Albumin is a general binding protein, but specific proteins exist for several hormones (e.g. thyroxin binding globulin)

Question 36

What is Liothyronine? Why is it used pharmaceutically?

Answer 36

A T3 analogue * It is more reactive than T4 and is more rapidly acting * It is less strongly bound that T4 (thus has a shorter half life) * However, Levels are less stable during the day (fluctuations)

Question 37

What is the therapeutic use of Liothyronine?

Answer 37

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

Question 38

99.96% of Thyroxine protein bound in the plasma (mostly to Thyroxine binding globulin). What does this mean for the volume of distribution?

Answer 38

It has a very low volume of distribution

Question 39

What is a major drawback of the long half life of thyroxine?

Answer 39

Long half-life means it takes a long time for therapeutic levels achieve (takes 4-5 half-lives to reach steady state concentrations) loading dose leads to cardiac complications - tachycardia and arythmias.

Question 40

Describe the interplay between T3 and cortisol

Answer 40

* Cortisol inhibits T4 to T3 * T3 inhibits cortisol production