vasodilators

Question 1

what are the vasodilators that regulate membrane potential?

Answer 1

K+ channel agonists/openers (minoxidil, diazoxide)
adenosine
they reduce voltage-gated Ca2+ channel activity

Question 2

what is the MOA of K+ channel agonsits?

Answer 2

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

Question 3

what is minoxidil?

Answer 3

K+ channel opener and potent vasodilator activated in vivo by sulfotransferase 1A1
effective in severe, drug resistant forms of HTN

Question 4

what drugs are used concurrently with minoxidil?

Answer 4

loop diuretics
beta blockers

Question 5

what are the SE of minoxidil?

Answer 5

hypertrichosis

Question 6

what is diazoxide?

Answer 6

K+ channel opener and potent vasodilator used IV to treat acute HTN or severe drug resistant form of HTN

Question 7

what is the MOA of diazoxide in hypoglycemia?

Answer 7

inhibits release of insulin from pancreatic beta-cells, which treats hypoglycemia secondary to hyperinsulinemia

Question 8

what is adenosine?

Answer 8

nucleoside given IV that binds to A1 receptor (GPCR)
increases conduction of a K+ channel to induce relaxation and hyperpolarization

Question 9

what are the indications of adenosine?

Answer 9

coronary stress test
supraventricular arrhythmias

Question 10

how does the vascular smooth muscle hyperpolarize?

Answer 10

via adenosine
G-beta, gamma binds and activates G-protein activated inwardly rectifying K+ channel (GIRK) –> conducts K+ efflux –> membrane hyperpolarizes

Question 11

what vasodilators stimulate nitric oxide production?

Answer 11

organic nitrates/nitrites
hydralazine
human type B natriuretic peptide (BNP)
sacubitril

Question 12

what is eNOS?

Answer 12

isoform of nitric oxide synthase that is located in vascular endothelium
activated by Ca2+-CAM

Question 13

where does nitric oxide diffusion take place?

Answer 13

vascular smooth muscle (directly relaxes sm)

Question 14

where is guanylate cyclase located?

Answer 14

vascular smooth muscle

Question 15

what did nitric oxide use to be called?

Answer 15

endothelial derived relaxing factor (EDRF)

Question 16

what is a partial inhibitor of acetylcholine?

Answer 16

L-NMMA

Question 17

what drug relaxes smooth muscle via nitric oxide?

Answer 17

acetylcholine

Question 18

how does smooth muscle relax via nitric oxide?

Answer 18

nitric oxide binds to heme iron prosthetic group in guanylate cyclase –> stimulates the production of cGMP and activates protein kinase G (cGKI)

Question 19

how does protein kinase G relax smooth muscle?

Answer 19

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)

Question 20

what are organic nitrates?

Answer 20

non-selective vasodilators that breakdown nitric oxide via bioactivation for acute or chronic administration

Question 21

what are the types of organic nitrates/nitrites?

Answer 21

amylnitrite
glyceryl trinitrate (GTN)
pentaerythritol tetranitrate (PETN)
isosorbide dinitrate
isosorbide mononitrate
nitroprusside

Question 22

what is PK of GTN?

Answer 22

3 minute half life
under 1% oral bioavailability

Question 23

what is the PK of isosorbide dinitrate?

Answer 23

10 minute half life
20% oral bioavailability

Question 24

what is the PK of isosorbide mononitrate?

Answer 24

280 minute half life
100% oral bioavailability

Question 25

what are organic nitrates used for?

Answer 25

given sublingually for acute attacks of angina given orally/transdermally for prolonged prophylaxis tolerance occurs with continuous administration

Question 26

what is sodium nitroprusside (SNP)?

Answer 26

vasodilator (veins and arterioles) given IV for acute management of HTN crisis and severe decompensated HF

Question 27

what is the metabolism of sodium nitroprusside?

Answer 27

metabolized in erythrocytes to nitric oxide, 4 CN-, and cyanmethemoglobin limits duration of treatment due to cyanide exposure

Question 28

what is rhodanase?

Answer 28

enzyme that converts CN- to be less toxic

Question 29

what is the effects of CN-?

Answer 29

inhibits oxidative metabolism can lead to lactic acid accumulation

Question 30

what is the MOA of hydralazine?

Answer 30

dilates arterioles preferentially appears to interfere with release of calcium from the ER may prevent nitric oxide oxidation

Question 31

what are the effects of hydralazine?

Answer 31

lupus-like syndrome

Question 32

how is hydralazine administered?

Answer 32

oral or IV

Question 33

what is BNP?

Answer 33

human type B natriuretic peptide vasodilator that binds to and activates membrane-bound guanylate cyclase in vascular smooth muscle and endothelial cells

Question 34

wha tis neprilysin?

Answer 34

enzyme that cleaves BNP

Question 35

how is BNP synthesized and secreted?

Answer 35

from heart muscle in response to increased blood volume

Question 36

what is sacubitril?

Answer 36

inhibitor of neprilysin (protease) and prodrug activated by esterases that prevents to breakdown of BNP

Question 37

what is the indication of sucubitril?

Answer 37

heart failure

Question 38

what is CI with sacubitril?

Answer 38

not used with ACE inhibitors

Question 39

what are phosphodiesterase inhibitors?

Answer 39

vasodilators that inhibit the break down of cGMP/AMP

Question 40

what drugs are PDE3 inhibitors?

Answer 40

amrinone milrinone

Question 41

what drugs are PDE5 inhibitors?

Answer 41

diypyridamole sildenafil (viagra) tadalafil (Cialis) vardenafil (levitra)

Question 42

what are the inotropic and chronotropic effects of amrinone/milrinone?

Answer 42

direct positive inotropic effect on myocardium minimal chronotropic effect

Question 43

what are amrinone and milrinone?

Answer 43

cAMP PDE inhibitors direct vasodilators given IV for acute treatment of chronic HF

Question 44

what is the selectivity of sildenafil?

Answer 44

10 fold and 4000 fold inhibition of PDE5 over PDE6 (retina) and PDE3 (CV) respectively lack of systemic vasodilation

Question 45

what are the SE of sildenafil?

Answer 45

blurred vision

Question 46

where PDE5 predominantly located?

Answer 46

corpus cavernosum

Question 47

what is the PK of levitra?

Answer 47

faster onset and more selective for PDE5 than viagra

Question 48

what is the PK of cialis?

Answer 48

more selective for PDE5 than viagra longer duration than viagra or levitra

Question 49

what are the CI of PDE5 inhibitors?

Answer 49

organic nitrates due to both drugs increasing the accumulation of cGMP which drops BP substaintly

Question 50

what are vasodilator drugs used in pulmonary arterial HTN?

Answer 50

endothelin antagonists PG12 analogs guanylyl cyclase activators PDE5 inhibitors activin neutralizers

Question 51

how does PAH affect endothelin signaling?

Answer 51

increases it

Question 52

what is MOA of bosentan (Tracleer) and macitentan

Answer 52

specific low MW endothelin receptor antagonists that block both Eta (VSM) and ETb (VSM and endothel) receptors

Question 53

what is MOA of ambrisentan?

Answer 53

endothelin receptor antagonist blocks only ETa receptors

Question 54

what is the CI of endothelin receptor antagonists?

Answer 54

pregnancy hepatotoxicity (bosentan)

Question 55

what is the indication of endothelin receptor antagonists?

Answer 55

pulmonary arterial hypertension (PAH)

Question 56

what is the MOA of smooth muscle relaxation?

Answer 56

Activation of GPCRs --> increases cAMP --> activates PKA --> inactivates MLCK --> reducing muscle contraction and promoting smooth muscle relaxation

Question 57

what is the PK of prostacyclin analogs?

Answer 57

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

Question 58

what drugs are prostacyclin analogs?

Answer 58

PG12 (epoprostenol) treprostinil (remodulin) iloprost (ventavis) selexipag (uptravi)

Question 59

what is the MOA of prostacyclin analogs?

Answer 59

relax pulmonary vascular SM

Question 60

what is the indication of prostacyclin analogs?

Answer 60

PAH

Question 61

what is riociguat?

Answer 61

adempas allosteric activator of sGC and substrate for P-gp, CYP1A1/3A used for pulmonary HTN

Question 62

what are the effects of riociguat?

Answer 62

potentiates the effect of NO stimulates sGC activity allosterically increase cGMP concentration in VSM

Question 63

what are the CI of riociguat?

Answer 63

nitrates PDE inhibitors pregnancy

Question 64

what is the warning of riociguat?

Answer 64

risk of hemorrhage

Question 65

where is PDE5 located?

Answer 65

vascular smooth muscle of lungs

Question 66

why are viagra and cialis indicated for PAH?

Answer 66

they enhance vasodilatory effects of nitric oxide