Drugs Affecting the Hypothalamo-Pituitary Axis

Question 1

Growth hormone is released by

Answer 1

pituitary gland

Question 2

GH release is stimulated by

Answer 2

GHRH, ghrelin

Question 3

GH release is inhibited by

Answer 3

somatostatin

Question 4

GH acts on the

Answer 4

liver to produce IGF-1

Question 5

What negative feedback loop regulates GH release?

Answer 5

IGF-1

Question 6

What causes GH insensitivity?

Answer 6

IGF-1 is not released in response to circulating GH, tf [GH] increases

Question 7

What causes secondary GH deficiency?

Answer 7

Pituitary does not produce GH, tf no circulating GH or IGF-1

Question 8

What causes tertiary GH deficiency?

Answer 8

Brain does not stimulate GH release from pituitary (no GHRH or ghrelin) tf no circulating GH or IGF-1

Question 9

What is the treatment for GH deficiency?

Answer 9

daily or multi-daily IV GH administration (not orally available); ghrelin under investigation

Question 10

What is the action of ghrelin with GHRH?

Answer 10

Synergistic; get more GH release in combination then either on their own

Question 11

GHRH receptor elevates

Answer 11

cAMP

Question 12

Ghrelin receptor elevates

Answer 12

Ca2+

Question 13

What is the treatment for GH insensitivity or anti-GH antibodies?

Answer 13

IGF-1

Question 14

What are the treatments for overproduction of GH?

Answer 14

remove GH secreting tumour; reduce GH release; or inhibit GH action

Question 15

How is GH release reduced?

Answer 15

Somatostatin analogues and dopamine agonists

Question 16

How is GH action inhibited?

Answer 16

GH antagonist pegvisomant

Question 17

How are GH-secreting tumours localized?

Answer 17

Inject radioactive somatostatin which will bind to somatostatin receptors on tumours expressing them; the receptors internalize the radioactive ligand and can be imaged

Question 18

What are the limitations in using somatostatin to reduce GH release?

Answer 18

IV administration; short half-life peptide tf enzymatically cleaved and renally eliminated; reduces TSH too

Question 19

How can somatostatin (and other peptides) be modified to extend its half-life?

Answer 19

Incorporation of D-aa’s to prevent enzymatic cleavage;

Question 20

Somatostatin analogues

Answer 20

octerotide, lanreotide

Question 21

What are the limitations in inhibiting GH action?

Answer 21

GH has a short half-life tf an antagonist has to compete with GH for receptors and last a long time (pharmacokinetcs) to prevent the action of GH in a prolonged manner

Question 22

What is the effect of PEGylation?

Answer 22

adding polyethylene glycol chains to molecules increases solubility and size (decreasing renal clearance and availability to proteolytic enzymes) without impacting much on efficacy of the drug

Question 23

What is pegmisovant?

Answer 23

GH antagonist

Question 24

How does pegmisovant work?

Answer 24

PEGylated to extend half-life; binds and blocks tyrosine kinase GH receptors

Question 25

Why doesn't altering the 120 glycine on GH produce an effective GH antagonist?

Answer 25

It has a short half-life and is cleared without much effect; tf need to increase half-life (PEGylation)

Question 26

How are pharmacokinetics and pharmacodynamics traded off (eg pegmisovant)

Answer 26

pharmacodynamics/affinity must be decreased to improve pharmacokinetics/increase the exposure by increasing half-life

Question 27

What is Grave's disease?

Answer 27

Excessive release of thyroid hormone by the thyroid gland due to antibody stimulation of TSH receptors

Question 28

What is Hashimoto's thyroiditis?

Answer 28

Autoantibodies attack the thyroid gland inhibiting production of thyroid hormone

Question 29

What is the treatment for hyperthyroidism (Grave's disease)?

Answer 29

Iodide, radioactive iodide thyroid ablation, thioamines to prevent synthesis and release of TH

Question 30

What is the treatment for hypothyroidism (Hashimoto's)?

Answer 30

Thyroxine

Question 31

What is TBG?

Answer 31

Thyroid binding globulin - plasma protein that binds thyroxine and gives it a long half-life (~1wk), acts as reservoir of T4

Question 32

What is the difficulty in prescribing thyroxine for hypothyroidism?

Answer 32

Low volume distribution (10L) bc 99.96% bound to TBG in the blood and a long half-life mean a slow onset of action that can lead to poor compliance

Question 33

What are the cardiac risks of thyroxine?

Answer 33

Have to start at low doses and titrate up because a rapid increase in thyroxine in a short period of time can cause tachycardia and arrythmia

Question 34

Why is thyroxine preferred over T3 for hypothyroidism?

Answer 34

T4 correlates with TSH levels which are the biomarker of the efficacy of TH replacement therapy - easy to monitor; shorter-half life (less forgiving once-daily dosing)