Vasodilators Flashcards
What are drugs that regulate cGMP
Organic nitrates
PDE inhibitors
Natriuretic peptide
What effect does elevated cGMP have on vascular smooth muscle
relaxes it
Why are K channel openers vasidilatory
-K sets the membrane potential. The longer the K -channel is open the closer the membrane potential is to the K equilibrium
-The closer the membrane potential is to the K equilibrium potential, the harder it is to depolarize the membrane enough top open voltage gated Ca channels.
-Ca channels not open, no constriction
Name the K channel agonists/openers
Minoxidil
Diazoxide
Adenosine
Minoxidil MOA, side effects, cAMO or cGMP?,
Minoxidil is a prodrug that binds and opens k channels and inhibits ca influx through voltage gated ca channel.
side effects- hypertrichosis
cAMP
Diazoxide indication?
used iv for htn binds to K channel, also used for hyperinsulinemia to inhibit release of insulin from pancrease
Adenosine MOA
Does not directly bind to k channel like minoxidil and diazoxide, it binds to a GPCR called A1, which is coupled to a K channel. Causes relaxaton.
G(beta gamma) binds and activates
GIRK- conducts K+
efflux & membrane
hyperpolarization
know structure of minoxidil, diazoxide and adenosine
where and how is nitric oxide generated
Nitric oxide is produced in vascular endothelium.
arginine converted to citruline and NO
What is the name of the enzyme used to create nitric oxide in vascular endothelium
eNOS
how is enos activated
by calcium calmodulin
is NO cAMP or cGMP
cGMP
whole process of how NO is made and causes vasodilation
-arginie is converted to citruline and NO in endothelium by eNOS
-NO diffuses into vascular SM
-NO activates and binds guanylyl cyclase (contains heme center) and converts GTP to cGMP
-cGMP inhibits activation of contraction by activating cGKI (protein kinase G)
What is cGKI
protein kinase G
what does cGKI do?
relaxes smooth muscle
How does cGKI cause relaxation of smooth muscle
-Inhibits Cav1.2 and inhibits Ca influx
-activates myosin phosphatase I
-Enhanced Ca uptake into ER by phosphalamban
-stimulation of ca activated K channels
Are organic nitrates selective or non-selective
non-selective
Know structure for organic nitrates
organic nitrate drug names
Amylnitrate
GTN
PETN
ISDN
ISMN
Nitroprusside
Which organic nitrate has the shortest half life
GTN
which organic nitrate has the largest t1/2 and best oral bioavailability
ISMD
how is GTN activated inn vivo
enzyme called ALDH 2 (aldehyde dehydrogenase2 ) in mirochondria activates NO
How is tolerance to organic nitrate generated
- once NO is generated, we develop a disulfide on dehydrigenase
-Lipoic acid reduces disulfide on ALDH-2 to active form - With persistent or chronic administration of organic nitrate, we run out of reducing enzymes , so we can not generate active form.
-once we take a break from the nitrate to regenerate the enzymes, it can be efficacious again
Why is GTN not as efficacious in Asians
Most asians have LYS 504 instead of glutamate.
Glutamate is 10X more efficient at metabolizing GTN
