tricky deck- Mon 15 Flashcards
monogenic mutations which may cause neonatal diabetes
KCNJII and ABCC8 (which form submits of ATP dependent K+ channels)
how can mutations in KCNJII and ABCC8 cause diabetes
Production of ATP due to increased intake of glucose by B cells does not cause K+ channels to close, meaning depolarisation of the membrane does not occur- calcium channels don’t open - not translocation of insulin secretory vesicles
monogenic mutations which may cause MODY
HNF1A
HNF1B
HNF4A
Glucokinase
which drugs stimulate insulin secretion
GLP-agonist
Sulphonylureas
2 rapid insulin analogues
novorapid and aspart
2 long lasting analogues
glargine and detemir
what is GTN
Glyceryl trinitrate (GTN) is a spray used to relieve angina (chest pain). - organic nitrate
what does GTN do?
When sprayed under the tongue, it relaxes and widens blood vessels in the heart and in the rest of the body.
a disadvantage of GTN
After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as GTN— may develop in a patient, reducing its effectiveness.
define tolerance
Tolerance is defined as the loss of symptomatic and hemodynamic effects of GTN and/or the need for higher doses of the drug to achieve the same effects
GTN works by
inducing vasorelaxation by generating NO or a related S-nitrosothiol (SNO)
GTN stands for
nitroglycerin
how do NO and SNO cause vasorelaxation
NO and SNOs activate the target enzyme soluble guanylyl cyclase (sGC), increasing tissue levels of the second messenger cGMP. A cGMP-dependent protein kinase I (cGK-I) mediates vasorelaxation by phosphorylating proteins that regulate intracellular Ca2+ levels
mechanism underlying tolerance to GTN is probably
multifactorial
suggest two mechanisms underlying GTN tolerance
- increases in production of reactive oxygen species (ROS)
- inhibition of ALDH-2 also underlies classical mechanism-based tolerance in vitro
how does inhibition of ALDH-2 underly tolerance
Buildup of GTN and/or NO byproducts in mitochondria may lead to mitochondrial damage and uncoupling of respiration .
Increased production of superoxide and other ROS would in turn oxidize critical thiols, including active-site thiols in ALDH-2 , further attenuating GTN-biotransformation.
Mitochondrial production of ROS would promote both mechanism-based tolerance and cross tolerance.
The extent to which ALDH-2 contributes to GTN tolerance (impaired relaxation to GTN) and cross tolerance (e.g., impaired endothelium-dependent relaxation) in vivo remains to be elucidated
simple cause of GTN tolerance
tolerance to GTN is caused by down regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) this also generates ROS
bioavailability
the proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect.
