tricky deck- Mon 15

Question 1

monogenic mutations which may cause neonatal diabetes

Answer 1

KCNJII and ABCC8 (which form submits of ATP dependent K+ channels)

Question 2

how can mutations in KCNJII and ABCC8 cause diabetes

Answer 2

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

Question 3

monogenic mutations which may cause MODY

Answer 3

HNF1A
HNF1B
HNF4A
Glucokinase

Question 4

which drugs stimulate insulin secretion

Answer 4

GLP-agonist

Sulphonylureas

Question 5

2 rapid insulin analogues

Answer 5

novorapid and aspart

Question 6

2 long lasting analogues

Answer 6

glargine and detemir

Question 7

what is GTN

Answer 7

Glyceryl trinitrate (GTN) is a spray used to relieve angina (chest pain). 
- organic nitrate

Question 8

what does GTN do?

Answer 8

When sprayed under the tongue, it relaxes and widens blood vessels in the heart and in the rest of the body.

Question 9

a disadvantage of GTN

Answer 9

After long-term use for chronic conditions, nitrate tolerance—tolerance to agents such as GTN— may develop in a patient, reducing its effectiveness.

Question 10

define tolerance

Answer 10

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

Question 11

GTN works by

Answer 11

inducing vasorelaxation by generating NO or a related S-nitrosothiol (SNO)

Question 12

GTN stands for

Answer 12

nitroglycerin

Question 13

how do NO and SNO cause vasorelaxation

Answer 13

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

Question 14

mechanism underlying tolerance to GTN is probably

Answer 14

multifactorial

Question 15

suggest two mechanisms underlying GTN tolerance

Answer 15

• increases in production of reactive oxygen species (ROS)

- inhibition of ALDH-2 also underlies classical mechanism-based tolerance in vitro

Question 16

how does inhibition of ALDH-2 underly tolerance

Answer 16

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

Question 17

simple cause of GTN tolerance

Answer 17

tolerance to GTN is caused by down regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) this also generates ROS

Question 18

bioavailability

Answer 18

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.