Pharmacology Flashcards
What is the effect of early growth hormone deficiency?
dwarfism, but growth is in proportion
Where is growth hormone released from?
anterior pituitary
Which hormones influence the secretion of GH?
GHRH, Ghrelin, and somatostatin
What is the action of growth hormone?
stimulate the liver to release IGF-1, the effector growth hormone
What are the three ways in which the growth hormone axis can go wrong?
GH insensitivity - liver cannot respond
Secondary deficiency - Pituitary doesn’t produce GH
Tertiary deficiency - hypothalamus not stimulated, no GHRH
What’s the replacement drug for growth hormone? What’s the method of administration?
Somatotropin
IV injection, because it’s a peptide with zero oral bioavailability
How often does a patient need to inject somatotropin if the person needs replacement therapy?
daily or multiple times a day, because of the short half life
Peptides are not bound to carrier protein
T/F GH can cause reduction in T4 level
True, there is interaction between the GH and TSH release
Why do GHRH and ghrelin have synergetic response?
they work on the same pathway. GHRH elevates cAMP while Ghrelin elevates Ca2+ level
In what situations do we use IGF-1 replacement therapy
When the patient is GH-insensitive or when patient has anti-GH antibody
What’s the side effect of using IGF-1 therapy
hypoglycaemia, because of the insulin like behaviour
What causes acromegaly
excessive level of GH, so the face becomes chunky and hands/feet grow out of proportion
What are the options for treating acromegaly?
remove tumour (if it’s the cause)
reduce GH release
inhibit GH action
how do we reduce GH release?
use somatostatin analogue (inhibit action of pituitary)
dopamine agonist
what’s the name of the drug inhibiting GH action?
pegvisomant - a GH antagonist
How can we use somatostatin analogue to identify tumours
tumours are very rich in somatostatin2 receptors
use tagged somatostatin analogue, and tumours will accumulate radioactive SST and internalise receptors. We then use imaging to find the tumour
What is the disadvantage of use somatostatin as a acromegaly therapy?
it has a very short half life, rapidly broken down by enzymatic cleavage and renal elimination
What’s the strategy in modifying the SST analogue?
add D-amino acids to prevent enzymatic breakdown
make the molecule smaller also prevents some enzymatic action
What are the two modified SST drugs?
Octreotide
Lanreotide
Why is glycine at codon 120 on the human GH gene necessary?
GH needs to bind to two receptors. Any substitution at 120 will allow binding on site 1, but any side chain will prevent binding of site 2, hence stopping dimerisation and activation
What is the use of PEGylation
increase size to reduce renal filtration
improve solubility
decrease accessibility for proteolytic enzymes
What’s the disadvantage of PEGylation?
it tends to reduce some activity as PEG gets in the way. In GH, PEG occurs at lysine, which interferes with binding site 1
How many mutation on GH does pegvisomant have?
9
What are the drug treatment for Graves’
radioactive iodine to ablate the thyroid or use carbimazole
What’s the action of carbimazole
inhibit thyroid peroxidase
What’s the additional effect of using propylthiouracil instead of carbimazole
It blocks conversion of T4 to T3 as well, but you have to take 2-4 doses a day
Propylthiouracil and carbimazole are both thioamines. What are the side effects of thioamines?
possible goitre
agranulocytosis
hepatotoxicity (propylthiouracil only)
What are the drugs to treat Hashimoto?
Liothyronine (T3)
Thyroxine (T4)
How does T3 interact with cortisol?
cortisol inhibits conversation of T4 to T3
T3 inhibits cortisol production
When is liothyronine preferred over thyroxin?
when treating severe hypothyroid and myxoedma coma
why is there usually poor compliance for patients taking thyroxine?
there is a slow accumulation and onset of action
where are the three peaks of cortisol release?
wake up time
mid day
early evening
How is cortisol excreted?
it gets converted to cortisone in the kidney and then excreted
Which enzyme coverts cortisol to cortisone?
11-b-hydroxysteroid-dehydrogenase 2 (HSD2)
Where does cortisone get activated?
in the liver by HSD1
Why doesn’t cortisol have effect on aldosterone receptors when it has higher affinity?
HSD2 is a physiological ligand to aldosterone receptor. Cortisol is converted to cortisone when it is in contact with the receptor
Why is it hard to diagnose acute adrenocortical insufficiency?
the presenting signs are often nonspecific
Why do patients need extra cortisol doses during infection?
normal cortisol level goes up during illnesses
What’s the incentive to be compliant when being placed on cortisol therapy?
overdose can lead to weight gain
what’s the most common iatrogenic complication of cortisol therapy
Cushing syndrome
What are the two internal pathways associated with steroid action?
trans-activation (dimerisation and response to GREs)
Trans-repression (inhibit AP-1 and NF-kB)
How do we minimise adrenal suppression?
avoid long-lasting drugs
alternate day dosing
morning dosing to mimic physiological rhythm
This will allow for ACTH secretion and recover atrophic cells
How is ciclesonide better than the previous generation of glucocorticoids?
it is given as a pro drug. it is also lipophilic with low oral bioavailability. Hence there is low system effect
