Vasodilators Flashcards by Julie Peceny

Cyclic GMP modulators

organic nitrates/nitrites
PDE inhibitors
vasoactive peptides

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Vasodilators

Cyclic GMP modulators

K+ channel agonists

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Isoforms of nitric oxide synthase

nNOS, iNOS, eNOS

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What aa is NO generated from

arginine

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Where is NOS?

in the vascular endothelium

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Where does NO diffuse to?

diffuses to the vascular smooth muscle

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Where is eNOS found

in the endothelial cells of the vasculature

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Guanylate cyclase is found

in the vascular smooth muscle

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Exogenously applied NO can directly do what?

relax smooth muscle

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Prostacyclin inhibits

platelet aggregation

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What does aceylcholine do?

relaxes smooth muscle: increases Ca2+ which activates NOS

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NO binds to

heme iron prosthetic group in guanylate cyclase

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NO binding stimulates what?

production of cGMP and activating protein kinase G

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How does protein kinase G relax smooth muscle?

inhibition of L-type Ca2+ channels
stimulation of Ca2+ activated K+ channels
decreased MLC phophorylation
Enhanced Ca2+ uptake into the ER

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Organic nitrates are

non-selective vasodilators

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Organic nitrates breakdown to

nitric oxide (by aldehyde dehydrogenase)

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Organic nitrates don’t require

functional endothelium

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Orgnaic nitrates can be administered how?

acute or chronic administration

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Three most important nitrates/nitrites used extensively in the US

Glyceryl trinitrate (GTN)
Isosorbide dinitrate
Isosorbide mononitrate

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Why is amylnitrite not used much?

drug of abuse

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Organic nitrate used in Europe

Pentaerythritol Tetranitrate (PETN)

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Active ingredient in SEMTX/C4 (explosive)

Pentaerythritol Tetranitrate

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Why do some populations not respond as well to Glycerol Trinitrate?

Glu504 Lys polymorphism in ALDH-2
Glu504 is 10X more efficient in metabolizing GTN
30-50% of Asian population has at least one Lys504 allele

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Likely accounts for the lack of efficacy of GTN in a large percentage of the Asian population

30-50% of the asian population has at least one Lys504 allele

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Lys504 allele also accounts for

alcohol intolerance in asian populations

Prostacyclin analogs (vasodilators)

PGI2 (epoprostenol) - IV Treprostinil (Remodulin) - Oral, IV Iloprost (Ventavis) - Inhalation

Prostacyclin analogs used to treat

pulmonary arterial hypertension

Hydralazine

dilates arterioles preferentially; appears to interfere with release of Ca2+ from the ER; can induce a lupus-like syndrome

BiDil

Isosorbidide (ISDN) + Hydralazine | antioxidant activity potentiates vasodilatory activity of ISDN

Who does BiDil decrease mortality in?

in African Americans with CHF

Sodium Nitroprusside given

given IV for acute management of severe hypertensive crisis and severe decompensated heart failure

What does sodium nitroprusside do?

dilates veins and arterioles

How is sodium nitroprusside metabolized?

metabolized in erythrocytes in No, 4CN-, and cyanmethemoglobin (limits duration of treatment)

CN- can inhibit

oxidative metabolism - lactic acid accumulation

CN- converted to

less toxic SCN- by rhodanase, excreted via kidney

Sodium thiosulfate or hydroxocobalamin may be used for

detoxification

Riociguate (Adempas) is an

allosteric activator of sGC

Riociguate (Adempas) is used for

pulmonary hypertention

What does riociguate do?

potentiates the effect of NO stimulates sGC activity allosterically increases cGMP concentration in vascular SM

Contraindications for riociguate

not combined with nitrates or PDE5 inhibitors contraindicated in pregnancy risk of hemorrhage

Riociguate is a substrate for

P-gp, CYP1A1, CYP3A

Alternative mechanism of action for NO

covalent modification of proteins by nitrosyl transfer from glutathione

Phosphodiesterase (PDE3) inhibitors

(In)Amrinone | Milrinone

Phosphodiesterase (PDE5) inhibitors

Dipyridamole | Sildenafil

Amrinone/Milrinone

given intravenously direct positive inotropic effect on myocardium minimal chronotropic effect direct vasodilatory effect on vascular SM

Amrinone/Milrinone used mainly in

CHF (acute treatment)

Sildenafil is a potent and specific inhibitor of

cGMP PDE5

Sildenafil has 10 fold selectivity over

inhibition of PDE6 (retina)

What can sildenafil cause

blueish vision

Sildenafil has 400 fold selectivity over

inhibition of PDE3 (CV)

Sildenafil has a lack of

systemic vasodilation

PDE5 is predominant in the

corpus cavernosum

PDE6 is in the

retina

Selective PDE5 inhibitors

Tadalafil (Cialis) Vardenafil (Lefitra) Sildenafil (Viagra)

Levitra compared to Viagra

shorter time to onset than Viagra | more selective for PDE5 than Viagra

Cialis compared to Viagra

more selective for PDE5 than Viagra | longer duration of action than Viagra or Levitra

Where is human type B natriuretic peptide synthesized?

synthesized and secreted from heart muscle in response to increased blood volume

Natrecor (nesiritide) is given and used in?

given IV in acutely decompensated heart failure

Natrecor (nesiritide) does what?

binds to and activates membrane-bound guanylate cyclase in vascular smooth muscle and endothelial cells

Vasoconstrictors

angiotensin, alpha1-agonists, endothelin

Vasodilators

beta2-agonists, CGRP, VIP

What does increasing K+ channel opening do to vascular SM?

relaxes vascular smooth muscle

Which ion sets the membrane potential?

K+ flux sets the membrane potential

What happens the longer K+ channels are open?

the closer the membrane potential is to the K+ equilibrium potential

What happens 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+ channels

K+ channel agonists/openers

Minoxidil | Diazoxide

Minoxidil activated by

activated in vivo by sulfotransferase

Minoxidil used with

loop diuretics and beta blockers

Minoxidil is a

very potent vasodilator - effective in severe, drug resistant forms of hypertension

What contributes to Minoxidil's efficacy?

cAMP PDE inhibition

How is Minoxidil given?

given orally (or topically to promote hair growth)

How is Diazoxide used?

intravenously to treat acute hypertension | orally for hypoglycemia secondary to hyprinsulinemia

Diazoxide is a

very potent vasodilator - effective in severe drug resistant forms of hypertension

Diazoxide inhibits

release of insulin from pancreatic beta cells

Adenosine binds to

alpha1 receptor-a GPCR

What does adenosine do

increases conductance of a K+ channel - hyperpolarization and relaxation

How is adenosine given?

given IV - during coronary stress tests

Describe the vasodilation mechanism of adenosine.

Gbetay on the A1 (adenosine) receptors binds and activates GIRK; conducts K+ efflux and membrane hyperpolarization

GIRK stands for

G-protein activated inwardly rectifying K+ channel

Vasodilators Flashcards

(79 cards)