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Gabe's Endocrinology > Drug Effects on the Hypothalamic Pituitary Axis > Flashcards

Drug Effects on the Hypothalamic Pituitary Axis Flashcards

1
Q

Where is growth hormone released from?

A

Anterior pituitary

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2
Q

What is growth hormone released in response to?

A

GHRH and Ghrelin signals from the hypothalamus

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3
Q

What does Ghrelin play a role in peripherally?

A

Appetite

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4
Q

What does growth hormone stimulate?

A

Liver to synthesise and release IGF-1

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5
Q

What do IGF-1 and somatostatin do in the blood?

A

Act as a negative feedback loop to the pituitary, inhibiting GH release

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6
Q

Where are the 3 different places growth hormone release can go wrong?

A
  1. Growth hormone insensitivity: GH doesn’t work – won’t stimulate release of IGF-1
  2. Secondary deficiency: pituitary doesn’t produce GH
  3. Tertiary deficiency: no release of GH because hypothalamus doesn’t release Ghrelin or GHRH
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7
Q

What happens to GH levels in growth hormone insensitivity?

A

Levels are elevated because IGF-1 isn’t released, inhibiting GH release.

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8
Q

What is growth hormone also known as?

A

Somatotropin

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9
Q

Why can’t growth hormone supplement be administered orally?

A

Because there is zero bioavailability after oral adminstration - it is broken down and digested.

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10
Q

How is growth hormone administed?

A

By injections, multiple times a day because of its short half-life.

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11
Q

What is common among HRT therapies?

A

Titrating the dose until effect is seen.

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12
Q

What can GH cause a reduced level of?

A

Thyroxine (T4)

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13
Q

What role does Ghrelin play in GH release?

A

Ghrelin receptor elevates Ca2+ and the GHRH receptor elevates cAMP, acting synergistically.

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14
Q

When is IGF-1 administered?

A

In patients with GH insensitivity (e.g. Laron dwarfism) and patients with anti-GH antibodies.

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15
Q

What happens if there’s not enough growth hormone?

A

Stunted growth

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16
Q

What happens if there’s too much growth hormone?

A

Depending on what time in development, e.g. acromegaly (often caused by GH-releasing tumour)

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17
Q

What are the treatment options for too much growth hormone?

A
  • Remove tumor (if relevant)
  • Reduce GH release
  • Inhibit GH action
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18
Q

Which therapeutics can reduce GH release?

A

Somatostatin analogues and dopamine agonists (can stimulate a reduction in GH release from pituitary)

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19
Q

How can GH action be inhibited?

A

Pegvisomant - GH antagonist

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20
Q

How can neuroendocrine tumours be imaged?

A
  • Somatostatin receptors internalise upon activation (like many GPCRs), taking the tagged peptide ligand with them
  • Tumors expressing somatostatin receptors can be imaged by in vivo receptor scintigraphy
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21
Q

Do tumour cells expressing receptors for somatostatin respond to somatotatin?

A

Yes - they reduce secretion of GH

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22
Q

Why does somatostatin only work for a short period of time?

A

Because it has a short half-life, undergoes enzymatic cleavage and renal elimination

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23
Q

How can somatostatin be modified to extend its half-life?

A

Modify it by adding D amino acids - humans can’t cleave D amino acids, giving octreotide and lanreotide.

24
Q

How do you get Pegmisovant?

A

Turn GH into an antagonist and improve its pharmacokinetics and dynamics.

25
Q

What type of a receptor does GH bind to?

A

Tyrosine kinase receptor

26
Q

What happens when GH binds to its receptor?

A

The tyrosine kinase receptor dimerises, with the binding sites on both GH receptor monomers binding to GH.

27
Q

What is G120K-GH?

A

A GH receptor antagonist that binds one GH receptor monomer but blocks dimerisation by filling the second monomers cleft with lysine.

28
Q

Why does G120K need to be PEGylated?

A

Because it still has a short half-life, like GH.

29
Q

What is PEGylation?

A

Conjugation of the bioactive (e.g. G120K-GH) molecule with PEG polymer chains.

30
Q

What does PEGylation achieve?

A
  • Increase in molecule size, reducing renal filtration.
  • PEG is hydrophilic, improving solubility.
  • Decreased proteolytic enzmyme accessibility
31
Q

What is one disadvantage to PEGylation?

A

Some activity is lost because the PEG polymer chains get in the way.

32
Q

Where on the bioactive molecule does PEGylation occur? Why is this a problem from G120K-GH? How is it overcome?

A
  • At lysines - there are 2 lysines involved in site 1 binding, making G120K-GH completely inactive!
  • Overcome by further mutations (B2036), resulting in an antagonist with good affinity by short half-life.
33
Q

What is trade off for in vivo efficacy if pegvisomant?

A

Pharmacodynamics (decreased affinity) for pharmacokinetics (increased exposure).

34
Q

How is thyroid hormone stimulated to be released from the thyroid gland?

A

Thyrotropin-releasing hormone (TRH) from hypothalamus stimulates anterior pituitary to release thyroid stimulating hormone (TSH) which then stimulates thyroid gland to release thyroid hormone to target tissues.

35
Q

What inhibits releases of thyrotropin-releasing hormone (TRH) and thyroid stimulating hormone (TSH)?

A

Thyroid hormone released from thyroid gland.

36
Q

What is Grave’s disease?

A

Hyperthyroidism: Stimulatory autoantibodies against the thyroid gland stimulate synthesis and increase release of thyroid hormone, resulting in higher levels of thyroid hormone but also decreased levels of TRH and TSH.

37
Q

What is Hashimoto’s disease?

A

Hypothyroidism: Destructive antibodies against the thyroid gland leads to decreased release of thyroid hormone and resultant increase in levels of TRH and TSH (due to lack of thyroid hormone)

38
Q

How is thyroid hormone stimulated?

A
  1. Follicular cell synthesises enzymes and thyroglobulin for colloid.
  2. A Na+-I- symporter brings I- into the cell. The pendrin transporter moves I- into the colloid.
  3. Enzymes add iodine to tyrosine on thyroglobulin to make T3 and T4
  4. Thyroglobulin is taken back into the cell in vesicles.
  5. Intracellular enzymes separate T3 and T4 from the protein.
  6. Free T3 and T4 enter the circulation.
39
Q

What is the transient effect of iodide in hyperthyroid conditions?

A

Reduces hormone synthesis and release.

40
Q

What can be used to ablate the thyroid gland in hyperthyroidism?

A

Radioactive 131I-.

41
Q

What protects the thyroid gland against radioactive isotopes?

A

Stable isotopes.

42
Q

Which 2 drugs are used to treat hyperthyroidism (Grave’s disease)?

A

Carbimazole and propylthiouracil.

43
Q

What is the action of carbimazole?

A

Inhibits thyroid peroxidase.

44
Q

What is the action of propylthiouracil?

A

Inhibits thyroid peroxidase and conversion T4 and T3

45
Q

What are the potential side effects of thioamines?

A

Goitre

Agranulocytosis

Hepatotoxicity

46
Q

Why should baseline liver function be tested if a patient is on propylthiouracil?

A

Because it causes hepatotoxicity.

47
Q

What does the amount of drug in the circulation depend on?

A

Affinity and the relative circulation of drug and protein.

48
Q

What is the general binding protein of the circulation?

A

Albumin

49
Q

What is the binding protein for thyroxine?

A

Thyroxine binding globulin

50
Q

What are the treatments for Hashimoto’s disease?

A

Thyroxine (T4) and Liothyronine (T3)

51
Q

When is thyroxine treatment of Hashimoto’s disease most active?

A

When thyroxine (T4) is converted into T3.

52
Q

What is the half-life of thyroxine?

A

7 days

53
Q

What is more active in the treatment of Hashimoto’s disease than T4?

A

T3 - Liothyronine

54
Q

What are the disadvantages of liothyronine (T3) in the treatment of Hashimoto’s disease?

A
  • Less strongly protein-bound than T4
  • Half-life of about 1 day
  • Levels are less stable during the day than those of T4 - TSH levels less easily interpreted.
55
Q

What should be used to treat most patients with Hashimoto’s disease?

A

T4

56
Q

When should T3 be used to treat Hashimoto’s disease?

A

When there’s severe hypothyroid and myxoedoema coma.

57
Q

What is the interplay between cortisol and T3?

A

Cortisol inhibits conversion of T4 to T3.

T3 inhibits cortisol production.

Gabe's Endocrinology (17 decks)

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