Exam 5 - Vasodilators Hockerman Flashcards by Rehman Hameed

3 K+ channel agonists/opener drugs

minoxidil
diazoxide
adenosine

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minoxidil can lead to what rare condition?

hypertrichosis

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minoxidil is activated in vivo by what enzyme?

sulfotransferase 1A1

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minoxidil is given _____ for HTN

orally (topically for hair growth)

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diazoxide is given _____ to treat acute HTN

a. orally
b. topically
c. IV
d. subQ

c. IV

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diazoxide is given _____ for hypoglycemia secondary to hyperinsulinemia

a. orally
b. topically
c. IV
d. subQ

a. orally

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what drug inhibits release of insulin from pancreatic beta cells?

a. minoxidil
b. diazoxide
c. adenosine

b. diazoxide

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what kind of receptor is the A1 receptor that adenosine binds to?

GPCR

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which is given IV during a coronary stress test?

a. minoxidil
b. diazoxide
c. adenosine

c. adenosine

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what does GIRK channel stand for?

G-protein activated inwardly rectifying K+ channel

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which G protein subunit(s) binds and activates GIRK, leading to K+ efflux and membrane hyperpolarization?

beta, gamma subunits

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which nitric oxide synthase (NOS) isoform is important for this lecture?

a. nNOS
b. iNOS
c. eNOS

c. eNOS

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where is nitric oxide produced and what is it activated by?

vascular endothelium; Ca2+-CAM

(idk what that stands for)

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NOS is in the vascular endothelium, and NO diffuses to the vascular _____ _____

smooth muscle

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eNOS is found in which cells of the vasculature?

endothelial

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NO is a key activator of _____ _____ found in vasc sm muscle

guanylate cyclase

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__________ relaxes smooth muscle via NO

a. phenylephrine
b. acetylcholine
c. hemoglobin
d. L-NMMA

b. acetylcholine

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where does NO bind in guanylate cyclase to stim production of cGMP and activating protein kinase G?

heme iron prosthetic group

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what AA is a precursor to NO?

arginine

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4 ways protein kinase G relaxes smooth muscle

-inhib of L-type Ca2+ channels
-stim of Ca2+-activated K+ channels
-dec MLC phosphorylation
-enhanced Ca2+ uptake into ER

(all of these add up to vasodilatory effect of PKG)

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protein kinase G relaxes smooth muscle via inhib of which Ca2+ channels?

a. CaV1.2
b. BKca
c. myosin phosphatase 1
d. phospholamban

a. CaV1.2

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protein kinase G relaxes smooth muscle via stimulation of which channel?

a. CaV1.2
b. BKca
c. myosin phosphatase 1
d. phospholamban

b. BKca

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protein kinase G decreases MLC phosphorylation via which enzyme?

a. myosin phosphatase 1
b. myosin phosphatase 2
c. myosin phosphatase 3
d. myosin phosphatase 4

a. myosin phosphatase 1

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protein kinase G phosphorylates _____ to enhance Ca2+ uptake into the ER

a. CaV1.2
b. BKca
c. myosin phosphatase 1
d. phospholamban

d. phospholamban

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true or false: organic nitrates require functional endothelium

false

organic nitrates are __________ vasodilators a. selective b. non-selective

b. non-selective

which has the highest oral bioavailability and half-life? a. GTN (glyceryl trinitrate) b. ISDN (isosorbide dinitrate) c. 5-ISMN (isosorbide mononitrate)

c. isosorbide mononitrate (bioavailability: GTN < 1%, ISDN 20%, 5-ISMN 100% half life: GTN 3 min, ISDN 10 min, 5-ISMN 280 min)

organic nitrates are given __________ in tx of acute attacks of angina, and __________ or __________ for prolonged prophylaxis

sublingually; orally; transdermally

what was the importance of the munitions workers from lecture?

Tells us about tolerance to glyceryl trinitrate. Workers would mix it by hand, get headaches, but became more tolerant through the week, then after being away for the weekend they would come back and get headaches again

what enzyme is important in GTN tolerance?

ALDH2 (aldehyde dehydrogenase 2)

why is GTN not as efficacious for Asian pts?

30-50% of Asians have at least one Lys 504 allele, which is less efficient in metabolizing GTN (this allele also accounts for alcohol intolerance)

what polymorphism is common in ALDH2 in regards to GTN?

Glu 504 Lys polymorphism (Glu 504 is 10X more efficient in metabolizing GTN)

bioactivation of ISMN and ISDN are ALDH2-__________ a. dependent b. independent

b. independent

methylglyoxal _____ vasorelaxation stimulated by ACh/NO

inhibits (higher conc of methylglyoxal leads to dec ACh relaxation)

sodium nitroprusside (SNP) is given IV for ?

acute management of hypertensive crisis and severe decompensated HF

what element is in the center of nitroprusside structure?

iron

true or false: SNP constricts veins and arterioles

false (dilates)

SNP is metabolized in erythrocytes to what 3 things?

NO radical 4 CN- cyanmethemoglobin (limits treatment duration)

why can sodium nitroprusside lead to lactic acidosis?

cyanide (CN-) is a product of metabolism and inhibits oxidative metabolism, so lactic acid accumulates

for sodium nitroprusside, CN- is converted to less toxic SCN- by __________, excreted via kidney (blank is a mitochondrial enzyme)

rhodanase

what 2 agents can be used for SNP detoxification?

sodium thiosulfate hydroxycobalamin (injectable B12) (for hydroxocobalamin, CN will bind to cobalt in middle of complex)

what drug can induce a Lupus-like syndrome?

hydralazine

what is the combo product of hydralazine + ISDN?

BiDil

true or false: BiDil (hydralazine + ISDN) increases mortality in African Americans with CHF

false (decreases)

which enzymes play key roles in the vasodilation mediated by glyceryl trinitrate? A. eNOS and soluble guanylyl cyclase B. ALDH2 and soluble guanylyl cyclase C. ALDH2 and membrane-bound guanylyl cyclase D. eNOS and membrane-bound guanylyl cyclase

b. ALDH2 and soluble guanylyl cyclase

where is human B type natriuretic peptide made?

in the ventricles

which drug is related to BNP and is given IV in acutely decompensated HF? a. nesiritide b. sacubitril c. GTN d. amrinone

a. nesiritide (brand name = Natrecor)

Natrecor (nesiritide) activates __________ guanylate cyclase a. soluble b. membrane-bound

b. membrane-bound

sacubitril drug class

neprilysin inhibitor

how does sacubitril work?

inhibits neprilysin to prevent breakdwon of BNP (enhances BNP action, as well as Ang II and bradykinin)

entresto is a combo of what two drugs?

sacubitril and valsartan

why is entresto given as a combo drug?

neprilysin isn't specific for breakdown of NP, also Ang II and bradykinin

entresto indication

HF (both HFrEF and HFpEF)

two PDE3 inhibitor drugs to know

amrinone milrinone

PDE3 is selective for _____ while PDE5 is selective for _____ a. cAMP; cGMP b. cGMP; cAMP

a. cAMP; cGMP

are amrinone/milrinone mainly used in acute or chronic CHF treatment?

acute

amrinone/milrinone route of administration a. oral b. IV c. subQ d. topical

b. IV

which is incorrect about amrinone/milrinone? a. has direct positive inotropic effect on myocardium b. given IV c. large chronotropic effect d. direct vasodilatory effect on vasc sm muscle

c. large chronotropic effect (minimal chronotropic effect)

why can sildenafil cause bluish vision?

it has 10 fold selectivity of PDE6, which is present in photoreceptors in the retina

3 selective PDE5 inhibitor drugs

sildenafil (Viagra) tadalafil (Cialis) vardenafil (Levitra)

true or false: tadalafil and vardenafil are more selective for PDE5 than viagra

true

vardenafil (Levitra) has a _____ time to onset than Viagra a. shorter b. longer

a. shorter

which has the longest duration of action? a. sildenafil b. tadalafil c. vardenafil

b. tadalafil

entresto should not be used with what drug class?

ACE inhibitors

what is the contraindication for PDE5 inhibitors and why?

CI: any PDE5 inhibitor with organic nitrates Reason: huge drop in BP, both inc accum of cGMP. cGMP also inhibits PDE3, increasing cAMP levels in vasc sm muscle. cGMP and cAMP both stimulate vasodilation

__________ signaling is increased in pulmonary arterial hypertension (PAH)

endothelin

3 vasoconstrictor/endothelin antagonist drugs

bosentan (Tracleer) macitentan (Opsumit) ambrisentan (Letairis)

endothelin antagonists indication

pulmonary arterial hypertension (PAH)

which has a contraindication of hepatoxicity? a. bosentan b. macitentan c. ambrisentan

a. bosentan

true or false: endothelin antagonists can be used in pregnancy

false

main difference between ambrisentan compared to bosentan and macitentan

ambrisentan blocks only ETa receptors while the other two block both ETa and ETb receptors

the endothelin ETa receptor is found in a. vasc sm muscle b. endothelium c. both

a. vasc sm muscle

the endothelin ETb receptor is found in a. vasc sm muscle b. endothelium c. both

c. both

how do prostacyclin analogs work for vasodilation?

they relax pulmonary vasc sm muscle (used for PAH)

what are the route of adminstration and half-lives of each prostacyclin analog drug? PGI2 (epoprostenol) treprostinil (Remodulin) iloprost (Ventavis) selexipag (Uptravi)

PGI2 -> IV; 3-5 min treprostinil -> oral, IV; ~4 hours iloprost -> inhalation; ~30 min selexipag -> oral; 6-13 hours

drug for pulmonary hypertension that is an allosteric activator of sGC (soluble guanylate cylclase) and can inc cGMP conc in vasc sm muscle

Riociguat (Adempas)

Riociguat should not be combined with nitrates or PDE5 inhibitors and is contraindicated in __________

pregnancy

Riociguat has a risk of __________

hemorrhage

Riociguat (allosteric sGC activator), is a substrate for what 3 things? (2 of them are cyps)

P-gp CYP1A1 CYP3A

sildenafil and tadalafil are both indicated for treatment of _____ due to enhanced vasodilatory effect of NO

PAH