Vasodilators

Question 1

Vasodilator classes

Answer 1

-Cyclic GMP modulators
-K channel agonists
-endothelin receptor antagonists
-PGI2 analogs- IP receptor agonists

Question 11

Why does inc K channel opening relax vasc smooth muscle?

Answer 11

-K flux set membrane potential
-the longer K channels are open, the closer the membrane potential is to the K equilibrium potential
-the closer the membrane potential is to the K equilibrium potential, the harder it is to depolarize membrane enough to open gated Ca channels

Question 12

K channel agonists/openers

Answer 12

-minoxidil
-diazoxide
-adenosine?

-regulate membrane potential
-reduce Ca channel activity

Question 13

Minoxidil

Answer 13

-activated in vivo by sulfotransferase 1A1
-K opener
-use w loop diurtics and beta blockers
-potent
-effective in severe, drug resistant HTN
-cAMP PDE inhibition may be efficacy
-give orally or topically for hair growth
-hypertrichosis

Question 14

Diazoxide

Answer 14

-K-opener
-used IV to tx acute HTN
-very potent (resistnant HTN)
-inhibits release of insulin form pancreatic B cells
-used orally for hypoglycemia 2’ to hyperinsulinemia

Question 15

Adenosine

Answer 15

-binds A1 (GPCR)
-inc conductance of a K channel (hyperpolarization and relaxation)
-give IV coronary stress test
-also for supraventricular arrhythmias

Question 16

Hyperpolarization of vasc smooth muscle by adenosine

Answer 16

-A1 receptor
-G-protein activated inwardly rectifyin K channel
-Gby binds and activates GIRK-conducts K efflux and membrane hyperpolarization

Question 18

Drugs that stimulate nitric oxide production

Question 19

Nitric Oxide Synthase

Answer 19

-NOS in vascular endothelium
-NO diffuses to vasc smooth muscle
-nNOS
-iNOS
-eNOS in vasc endothelium activated by Ca-CAM

-exogenous NO can relax smooth muscle

Question 20

Nitric oxide-cyclic GMP pathway

Answer 20

-eNOS found in endothelial cells of vasculature
-NO referred to as EDRF
-guanylate cyclase found in vasc smooth muscle
-exogenously applies NO can directly relax smooth muscle

Question 21

Acetylcholine relaxes smooth muscle via NO

Question 22

Nitric oxide binds to

Answer 22

-heme in iron prosthetic group in guanylate cyclase
=stimulate production of cGMP and activating cGKI (protein kinase G)
-

Question 23

how does protein kinase G relax smooth muscle?

Answer 23

-inhibition of L-type Ca channels (Cav1.2)
-stimulation of Ca activated K channels (BKca)
-dec MLC phosphorylation (myosin phosphatase 1)
-enhanced Ca uptake in to ER (phospholamban

Question 24

Organic nitrates

Answer 24

-non-selective vasodilators
-breakdown to nitric oxide (bioactivation)
-dont require functional endothelium
-acute or chronic admin

Question 25

Organic nitrate drugs

Answer 25

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

Question 26

PK of organic nitrates

Answer 26

-GTN 3min <1% bioavailability
-ISDN 10 min 20%
-5-ISMN 280 min 100%

-give sublingually in tx of acute attacks of angina
-tolerance occurs w continuous administration

Question 27

Tolerance to glyceryl trinitrate

Answer 27

-munitions workers
-monday headaches
-slide 21 mech

Question 28

genetics of glycerol trinitrate

Answer 28

-glu504 polymorphism
-glu504 metabolize glycerol trinitrate
-lack of efficacy in large % of Asian population
-the lys 504 allele also accounts for alcohol intolerance as acetaldehyde metabolism also reduced

Question 29

Differences in activation of GTN and ISMN/ISDN

Question 30

mech of cell damage initiated by hyperglycemia

Answer 30

-AGE precursor methylglyoxal inhibits vasorelaxation stimulated by acetylcholine/nitric oxide

Question 31

Sodium nitroprusside (SNP)

Answer 31

-give IV for acute managemnet of HTN crisis and severe heart failure
-dilates veins and arterioles
-metabolized in erythrocytes to NO, 4CN, and cyanmethemoglobin (limits duration)
-CN can inhibit oxidative metabolism = lactic acid accumulation
-CN converted to less toxic SCN- by rhodanase, excreted via kidney
-may be used for detox

Question 32

Hydrazaline

Answer 32

-nitrate
-dilates arterioles preferentially
-can induce lupus-like syndrome
-give orally or IV
-combined w B-blocker, diuretic

Question 33

hydralazine combo w ISDN in BiDil

Answer 33

-antioxidant activity potentiates vasodilatory activity of ISDN
-BiDil decreases mortality in black people w CHF

Question 34

Human type B Natriuretic peptide (BNP)

Answer 34

-cleaved by Neprilysin
-synthesized and secreted from heart muscle in response to inc blood volume
-binds to and activates membrane-bound gunaylate cyclase in vasc smooth muscle and endothelial cells

Question 35

BNP mech

Question 36

Sacubritril

Answer 36

-combo w ARB valsartan (entresto) ARNI
-oral BID
-prodrug activated by esterases
-prevents breakdown of BNP enhancing its action
-NOT USED W ACEi
-use to tx heart failure
-inhibitor of neprilysin (protease)

Question 37

Drugs that inhibit breakdown of cGMP/AMP: phosphodiesterase inhibitors

Answer 37

-amrinone (PDE3 cAMP)
-milrinone (PDE3 cAMP)
-dipyridamole (PDE5 cGMP)
-sildenafil (PDE5 cGMP)

Question 38

mech for controlling smooth muscle tone

Answer 38

-Ca channel pathway
-GPCR pathway:
-inc cAMP PDE3 makes cAMP to AMP

Question 39

Amrinone and milrinone

Answer 39

-give IV
-inotropic
-vasodilatory effect on smooth muscle
-used maily in CHF

Question 40

sildenafil (PDE5 inhibitors)(viagra)

Answer 40

-inhibit cGMP
-10 fold selectivity over PDE6 inhibition (retina)
-bluish vision
-lack of systemic vasodilation
-corpus cavernosum

Question 41

levitra (vardenafil)

Answer 41

-shorter time to onset than viagra
-more selective for PDE5 than viagra

Question 42

tadalafil (cialis)

Answer 42

-more selective than viagra
-longer duration of action

Question 43

PDE5 inhibitor contraindication

Answer 43

-DO NOT USE w organic nitrates
-precipitous drop in blood pressure
=both drugs inc cGMP accumulation
-cGMP also inhibits PDE3
=inc cAMP levels
-both stimulate vasodilation

Question 44

Vasodilators used in Pulmonary arterial HTN (PAH)

Answer 44

-endothelin antagonists
-PGI2 analogs
-guanylyl cyclase activators
-PDE5 inhibitors
-activin neutralizers

Question 45

endothelin signaling

Answer 45

-increased in PAH

Question 46

vasoconstrictor (endothelin) ANTAgonists

Answer 46

-Bosentan (Tracleer)
-Macitentan (Opsumit)
Ambrisentan (Letairis)

Question 47

Bosentan (traccleer) and Macitentan (opsumit)

Answer 47

-specific low MW
-endothelin receptor antagonists
-block both ETA (VSM and ETB (VSM + endothel receptor)

Question 48

Ambrisentan (letairis)

Answer 48

-blocks only ETA receptors
-approved for PAH

Question 49

Vasoconstrictor ANTAgonist contraindications (-sentan)

Answer 49

-contraindicated in pregnancy
-hepatotoxicity (bosentan)
-only available to females thru special programs

Question 50

Prostacyclin analogs

Answer 50

-PGI2 (epoprostenol; 3-5min t1/2) IV
-Treprostinil (Remodulin 4h) PO or IV
-Iloprost (Ventavis 30 min) inhalation
-selexipag (uptravi 6-13h) PO or IV
-tx PAH

Question 51

Allosteric activator of sGC

Answer 51

-Riociguat (adempas)
-for PAH
-potentiates the effect of NO
-stimulates sGC activity allosterically
-inc cGMP concentration in VSM

Question 52

Riociguat

Answer 52

-allosteric activator of sGC
-not combo w nitrates of PDE5s
-dont use if pregnant
-risk of hemorrhage
-substrate for P-gp, CYP1A1,3A
-only available to females thru special programs

Question 53

PDE5 inhibitors for PAH

Answer 53

-sildenafil and tadalafil are both indicated for PAH
-both thought to enhance effect of NO

Question 54

Sotatercept-CSRK (winrevair)

Answer 54

-activin type IIA-Fc
-binds/neutralizes activin and other TGF ligands
-for PAH
-reduces proliferation of vas smooth muscle cells
-reduces pulmonary vasc resistance
-inj SQ q3weeks

Question 55

Sotatercept-CSRK (winrevair) potential toxicities

Answer 55

-erythrocytosis
-thrombocytopenia
-bleeding
-terrtogen
-impaired fertility

-HA, rash, nosebleed, telangiectasia

Question 56

PAH