ion channel modulators, NO and H2S Flashcards
nifedipine
- calcium channel blocker (L-type voltage sensitive)
- treats hypertension and angina
- relaxes the muscles of the heart and blood vessels
amiloride
inhibits renal epithelial Na+ channels
treat hypertension and heart faliure
phenytoin
modulates voltage sensitive Na+ channels
treats siezures
ethosuximide
inhibits T-type calcium channels in thalamic neurones = treats siezures
nicorandil
opens ATP sensitive K+ channels
treatment for diabetes
ion channel modulators
stick to an ion channel and open/close it - they don’t act on a particular receptor
K+ channel openers
nicorandil and minoxidil
K+ channel blockers
glimepride
what does nicorandil do
stimulates production of cGMP which stimulates PKG - reduces Rho kinase activity - less calcium sensitivity
PKG - acts of K+ channels - more efflux and hyper polarisation - relaxation
the effect of nicorandil as a vasodilator is mainly attributed to
it nitrate properties
what does glimepride do
It lowers blood sugar by stimulating the release of insulin by pancreatic beta cells and by inducing increased activity of intracellular insulin receptors
what was a side effect of minodixidil
increase hair growth
how is glimpride metabolised
First, the medication is metabolized to M1 metabolite by CYP2C9. M1 possesses about 1⁄3 of pharmacological activity of glimepiride, yet it is unknown if this results in clinically meaningful effect on blood glucose. M1 is further metabolized to M2 metabolite by cytosolic enzymes. M2 is pharmacologically inactive. Excretion in the urine is about 65%, and the remainder is excreted in the feces.
what does eNOS stand for
endothelial nitric oxide synthase
what does iNOS require/
denovo synthesis - takes a few hours to be expressed
what are the NOS
gasotransmitters
nNOS: neurotransmission
long-term potentiation
coordination between neuronal activity and blood flow
pain modulation
eNOS: cardiovascular EDRF
endothelial
- regulation of vascular tone
- inhibiton of SMC proliferation
- inhibition of platelet aggregation
iNOS - inflammation and host defence
inducible
-cytoxicity against bacteria viruses and other microorganisms
excess production of NO in endothelium/vascular smooth muscle leads to
hypotension (septic shock)
inadequate production of NO in endothelium/vascular smooth muscle leads to
atherogenesis, thrombosis (e.g. hypercholesterolaemia, diabetes mellitus)
what physiological role does NO play in platelets
limitation of adhesion and aggregation
what physiological role does NO play in CNS
neuroransission, long term potentiation, plasticity (memory, appetite, penile errection)
excess production of NO in CNS leads to
excitotoxicity - ischemic stroke, Huntingtons disease, AIDs dementia
what physiological role does NO play in PNS
Neurotransmissionn - gastric emptying, penile errection
inadequate production of NO in PNS leads to
hypertrophic pyloric stenosis, errectil disfunction
how do nitric oxide donor work to help treat angina?
they cause blood vessels to dilate so chest pain is released
examples of nitric oxide donors
amyl nitrite and GTN
angina
inc HR, contract, after and preload - inc O2 consumption
Vasospasm, fixed stenosis, thrombosis - decreased coronary blood flow
what does adding a spacer to an NSAID allow you to do? example
allows you to add another group to the drug
eg - aspain - spacer - NO releasing group
How do NSAIDs cause topic irritation and direct epithelial damage?
COX1 is inhibited and so cannot synthesis PGE2 fro arachondonic acid - hence decreased mucus and bicarbonate secretions nd decreased blood flow - acid damage in the epithelium as no mucus to protect or bicarbonates to neutralise
How do NSAIDs cause topic irritation and direct epithelial damage?
COX1 is inhibited and so cannot synthesis PGE2 fro arachondonic acid - hence decreased mucus and bicarbonate secretions nd decreased blood flow - acid damage in the epithelium as no mucus to protect or bicarbonates to neutralise
what could NO releasing aspirin do?
help to reduce gastric bleeding?
what is beetroot packed full of and how does this help vasodilation
beetroot is packed full of nitrate - breaks down and acidified - you get NO produced -
how many ways are there to make H2S endogenously
4
what pathologies would decrease with H2S perturbed bioavailability
diabetes, Coronary artery disease, pulmonary hypertension, ichemia and repercussion injury, renal failure and atherosclerosis
what would increase with perturbed H2S
toxic shock, rheumatoid atheritis pancreatitis
H2S pro proliferation factors
Kate channel, T-CA2+ channel, oxidative stress, AKT
H2S pro apoptosis factors
NF-kB, cell cycle related kinases, cell death related genes, oxidative stress, MAPK
what determines whether H2S kills or rescues cells
how it is administered
does H2S have a target
mitochondria can use sulphide as an inorganic sulphur source - Used as substrate – take off electrons – bipass complex 1 and 2 - passed alont ETC – get ATP
how do you target mitochondria
Matrix inside – highly negatively charged
Something – v lipophilic
