vasodilators Flashcards
hockerman
what are the vasodilators that regulate membrane potential?
K+ channel agonists/openers (minoxidil, diazoxide)
adenosine
they reduce voltage-gated Ca2+ channel activity
what is the MOA of K+ channel agonsits?
K+ flux sets the membrane potentional –> The longer K+ channels are open, the closer the membrane potential is to the K+ equilibrium potential –> the harder it is to depolarize the membrane enough to open voltage-gated Ca2+ channel
what is minoxidil?
K+ channel opener and potent vasodilator activated in vivo by sulfotransferase 1A1
effective in severe, drug resistant forms of HTN
what drugs are used concurrently with minoxidil?
loop diuretics
beta blockers
what are the SE of minoxidil?
hypertrichosis
what is diazoxide?
K+ channel opener and potent vasodilator used IV to treat acute HTN or severe drug resistant form of HTN
what is the MOA of diazoxide in hypoglycemia?
inhibits release of insulin from pancreatic beta-cells, which treats hypoglycemia secondary to hyperinsulinemia
what is adenosine?
nucleoside given IV that binds to A1 receptor (GPCR)
increases conduction of a K+ channel to induce relaxation and hyperpolarization
what are the indications of adenosine?
coronary stress test
supraventricular arrhythmias
how does the vascular smooth muscle hyperpolarize?
via adenosine
G-beta, gamma binds and activates G-protein activated inwardly rectifying K+ channel (GIRK) –> conducts K+ efflux –> membrane hyperpolarizes
what vasodilators stimulate nitric oxide production?
organic nitrates/nitrites
hydralazine
human type B natriuretic peptide (BNP)
sacubitril
what is eNOS?
isoform of nitric oxide synthase that is located in vascular endothelium
activated by Ca2+-CAM
where does nitric oxide diffusion take place?
vascular smooth muscle (directly relaxes sm)
where is guanylate cyclase located?
vascular smooth muscle
what did nitric oxide use to be called?
endothelial derived relaxing factor (EDRF)
what is a partial inhibitor of acetylcholine?
L-NMMA
what drug relaxes smooth muscle via nitric oxide?
acetylcholine
how does smooth muscle relax via nitric oxide?
nitric oxide binds to heme iron prosthetic group in guanylate cyclase –> stimulates the production of cGMP and activates protein kinase G (cGKI)
how does protein kinase G relax smooth muscle?
Inhibition of L-type Ca2+ channels (Cav1.2)
stimulation of Ca2+- activated K+ channels (BKca)
decreased MLC phosphorylation (myosin phosphatase 1)
enhanced Ca2+ uptake into ER (phospholamban)
what are organic nitrates?
non-selective vasodilators that breakdown nitric oxide via bioactivation for acute or chronic administration
what are the types of organic nitrates/nitrites?
amylnitrite
glyceryl trinitrate (GTN)
pentaerythritol tetranitrate (PETN)
isosorbide dinitrate
isosorbide mononitrate
nitroprusside
what is PK of GTN?
3 minute half life
under 1% oral bioavailability
what is the PK of isosorbide dinitrate?
10 minute half life
20% oral bioavailability
what is the PK of isosorbide mononitrate?
280 minute half life
100% oral bioavailability
what are organic nitrates used for?
given sublingually for acute attacks of angina
given orally/transdermally for prolonged prophylaxis
tolerance occurs with continuous administration
what is sodium nitroprusside (SNP)?
vasodilator (veins and arterioles) given IV for acute management of HTN crisis and severe decompensated HF
what is the metabolism of sodium nitroprusside?
metabolized in erythrocytes to nitric oxide, 4 CN-, and cyanmethemoglobin
limits duration of treatment due to cyanide exposure
what is rhodanase?
enzyme that converts CN- to be less toxic
what is the effects of CN-?
inhibits oxidative metabolism
can lead to lactic acid accumulation
what is the MOA of hydralazine?
dilates arterioles preferentially
appears to interfere with release of calcium from the ER
may prevent nitric oxide oxidation
what are the effects of hydralazine?
lupus-like syndrome
how is hydralazine administered?
oral or IV
what is BNP?
human type B natriuretic peptide
vasodilator that binds to and activates membrane-bound guanylate cyclase in vascular smooth muscle and endothelial cells
wha tis neprilysin?
enzyme that cleaves BNP
how is BNP synthesized and secreted?
from heart muscle in response to increased blood volume
what is sacubitril?
inhibitor of neprilysin (protease) and prodrug activated by esterases that prevents to breakdown of BNP
what is the indication of sucubitril?
heart failure
what is CI with sacubitril?
not used with ACE inhibitors
what are phosphodiesterase inhibitors?
vasodilators that inhibit the break down of cGMP/AMP
what drugs are PDE3 inhibitors?
amrinone
milrinone
what drugs are PDE5 inhibitors?
diypyridamole
sildenafil (viagra)
tadalafil (Cialis)
vardenafil (levitra)
what are the inotropic and chronotropic effects of amrinone/milrinone?
direct positive inotropic effect on myocardium
minimal chronotropic effect
what are amrinone and milrinone?
cAMP PDE inhibitors
direct vasodilators given IV for acute treatment of chronic HF
what is the selectivity of sildenafil?
10 fold and 4000 fold inhibition of PDE5 over PDE6 (retina) and PDE3 (CV) respectively
lack of systemic vasodilation
what are the SE of sildenafil?
blurred vision
where PDE5 predominantly located?
corpus cavernosum
what is the PK of levitra?
faster onset and more selective for PDE5 than viagra
what is the PK of cialis?
more selective for PDE5 than viagra
longer duration than viagra or levitra
what are the CI of PDE5 inhibitors?
organic nitrates due to both drugs increasing the accumulation of cGMP which drops BP substaintly
what are vasodilator drugs used in pulmonary arterial HTN?
endothelin antagonists
PG12 analogs
guanylyl cyclase activators
PDE5 inhibitors
activin neutralizers
how does PAH affect endothelin signaling?
increases it
what is MOA of bosentan (Tracleer) and macitentan
specific low MW endothelin receptor antagonists that block both Eta (VSM) and ETb (VSM and endothel) receptors
what is MOA of ambrisentan?
endothelin receptor antagonist
blocks only ETa receptors
what is the CI of endothelin receptor antagonists?
pregnancy
hepatotoxicity (bosentan)
what is the indication of endothelin receptor antagonists?
pulmonary arterial hypertension (PAH)
what is the MOA of smooth muscle relaxation?
Activation of GPCRs –> increases cAMP –> activates PKA –> inactivates MLCK –> reducing muscle contraction and promoting smooth muscle relaxation
what is the PK of prostacyclin analogs?
PG12 –> half life 3 to 5 minutes; IV
treprostinil –> half life 4 hours: oral/IV
iloprost –> half life 30 minutes; inhalation
selexipag –> half life 6-13 hours; oral/IV
what drugs are prostacyclin analogs?
PG12 (epoprostenol)
treprostinil (remodulin)
iloprost (ventavis)
selexipag (uptravi)
what is the MOA of prostacyclin analogs?
relax pulmonary vascular SM
what is the indication of prostacyclin analogs?
PAH
what is riociguat?
adempas
allosteric activator of sGC and substrate for P-gp, CYP1A1/3A
used for pulmonary HTN
what are the effects of riociguat?
potentiates the effect of NO
stimulates sGC activity allosterically
increase cGMP concentration in VSM
what are the CI of riociguat?
nitrates
PDE inhibitors
pregnancy
what is the warning of riociguat?
risk of hemorrhage
where is PDE5 located?
vascular smooth muscle of lungs
why are viagra and cialis indicated for PAH?
they enhance vasodilatory effects of nitric oxide