Vasodilators Flashcards
Cyclic GMP modulators
organic nitrates/nitrites
PDE inhibitors
vasoactive peptides
Vasodilators
Cyclic GMP modulators
K+ channel agonists
Isoforms of nitric oxide synthase
nNOS, iNOS, eNOS
What aa is NO generated from
arginine
Where is NOS?
in the vascular endothelium
Where does NO diffuse to?
diffuses to the vascular smooth muscle
Where is eNOS found
in the endothelial cells of the vasculature
Guanylate cyclase is found
in the vascular smooth muscle
Exogenously applied NO can directly do what?
relax smooth muscle
Prostacyclin inhibits
platelet aggregation
What does aceylcholine do?
relaxes smooth muscle: increases Ca2+ which activates NOS
NO binds to
heme iron prosthetic group in guanylate cyclase
NO binding stimulates what?
production of cGMP and activating protein kinase G
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
Organic nitrates are
non-selective vasodilators
Organic nitrates breakdown to
nitric oxide (by aldehyde dehydrogenase)
Organic nitrates don’t require
functional endothelium
Orgnaic nitrates can be administered how?
acute or chronic administration
Three most important nitrates/nitrites used extensively in the US
Glyceryl trinitrate (GTN)
Isosorbide dinitrate
Isosorbide mononitrate
Why is amylnitrite not used much?
drug of abuse
Organic nitrate used in Europe
Pentaerythritol Tetranitrate (PETN)
Active ingredient in SEMTX/C4 (explosive)
Pentaerythritol Tetranitrate
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
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
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
