deck_2585106 Flashcards
Discuss the pharmacology of growth hormone / somatotropin as a treatment for GH deficiency
In patients with GH deficiency:
- Replacement GH/somatotropin must be parenterally administered
- GH is a peptide hormone that is degraded by stomach peptidases= zero bioavailability
- Requires multi-daily administration
- short half life as a peptide hormone
- Must titrate does to affect as it is a physiologically regulated hormone
- rapid change in concentration would affect regulation pathways
- GH can reduce T4 Levels
- a result of multiple interactions between hypo-pituitary axis pathways
Why could ghrelin be used to treat GH deficiencies?
Ghrelin increases the amount of GHRH release from the hypothalamus -> leads to increased release of GH
GHRH and Ghrelin demonstrate synergy in effect
Why would IGF-1 be useful in treating GH deficiencies?
Insulin-like Growth Factor is the downstream mediator of GH effects - it is released from the liver in response to GH.
It is particularly useful in patients with GH-insensitivity or anti-GH hormones; where the increased administration of either GHRH, GH or Ghrelin would be useless.
Side effects include:
- anabolic muscle building
- hypoglycaemia
What is acromegaly?
Acromegaly is an outcome of too much growth hormone
Patients have disproportionate growth between parts of the body.
Particularly large facial features
What are the treatment options for excessive GH levels?
- Surgery of a GH releasing tumours
- Reduce GH levels
- somatostatin analogues
- dopamine agonist
- Inhibit GH action
- GH antagonist = pegvisomant
How can neuroendocrine tumours be imaged?
Endocrine tumours tend to express somatostatin receptors
Somatostatin receptors internalise upon activation (like most GPCRs), taking the peptide ligand with them
Tumours expressing somatostatin receptors can subsequently be imaged by in vivo radiological scitigraphy
What are the effects of somatostatin?
Somatostatin reduces GH release from the pituitary
It can also reduce TSH levels
Tumour cells expressing somatostatin receptors usually respond to it with reduced GH levels
BUT somatostatin has a very short half life due to enzymatic cleavage and renal elimination to be used as an effective treatment.
Somatostatin analogues have been developed with increased half lives = Octreotide and Lanreotide
- they contain unnatural Depot/D-amino acids that enzymes in our body are poor at degrading
Discuss the binding sites of the GH
How is this useful in the development of GH antagonists
There are two binding sites on the GH receptor:
- Binding site 1 = high affinity for GH binding
- Binding site 2 = for receptor activation
Glycine at amino acid position 119 (in mice) or 120 (in humans) is required for GH activity.
GH antagonists have an altered amino acid at the at a.a 120 position -> thus, able to bind GH receptors but not activate them.
- but these antagonists have a short half-life like GH
- Unable to pegylate them because lysines are involved in binding site 1
Pegvisomant is a mutant GH antagonist that has an altered binding site 1 deficient of lysine amino acids. It can thus be pegylated -> increases the half-life and but reduced binding affinity
What is PEGylation?
PEGylation is the attachment of polyethene glycol groups to compounds in drug design,
PEGylation:
- Increases the size of compound = reduces renal clearance
- Decreases accessibility for proteolytic enzymes
- Improves solubility
Discuss drugs available for the treatment of hyperthyroidism
Iodine (I-)
- Transiently decreases hormone synthesis + release
- Radiactive 131 I- ablates the thyroid gland
THIOAMINES
May lead to goitre or hepatotoxicity. They include:
Carbimazole
- Inhibits thyroid peroxidase
- 1x daily dosing
Propylthiouracil
- inhibits thyroid peroxidase
- inhibits conversion of T4 to T3
- 2–4 doses daily
What drugs can be used to treat hypothyroidism?
Thyroxine (T4)
- First line treatment of hypothyroidism
- Acts mostly after conversion to T3
- 99.96% protein bound in the plasma
(mostly to thyroxine binding globulin)- Volume of distribution about 10 litres
Liothyronine (T3)
- More active than T4 and acts more rapidly
- Less strongly protein-bound than T4
- Half life about 1 day
- Levels are less stable during the day than
those of T4 - Used only in severe hypothyroidism and myxoedema coma
Describe the relationship between T3 and cortisol
Cortisol inhibits the conversion of T4 to T3
AND
T3 inhibits cortisol production
Discuss the interconversion of cortisol and corticosterone
The interconversion of corticol and cortisone is facilitated by two different isoforms of the 11-beta-HSD enzyme
11-beta-HSD-1
- present in the liver to convert cortisone to active cortisol
11-beta-HSD-2
- are co-localised with minerlacorticoid receptors in the kidney to prevent cortisol acting on the MR
- converts cortisol back to cortisone
Describe cortisol deficiency
Cortisol deficiency presents with weakness, fatigue, anorexia, nausea, vomiting, hypotension and hypoglycaemia.
In primary adrenal hypofunction, cortisol deficiency is combined with mineralocorticoid deficiency to cause hyperkalaemia and hyponatraemia, acidosis and dehydration.
Acute adrenocortical insufficiency is a difficult diagnosis to make due to non-specific symptoms
Therefore, treatment upon clinical suspicion is mandatory = it is an emergency condition
How should cortisol deficiency be treated?
Administer cortisol (hydroxycortisone) or cortisone
Oral availability of cortisone is better than cortisol
Patient has to adjust dose to meet needs
- Extra doses for infections and periods of stress
There are no side effects from well-managed
physiological replacement.
But both do taste bitter
