Organic Nitrates and Vasodilators Flashcards
Minoxidil activated in vivo by ______________ 1A1
sulfotransferase
adenosine binds to _______ which is a _______
A1 receptor; GPCR
With sildenafil, there is lack of _____________
systemic vasodilation
Where is PDE5 expressed?
VSM of the lungs
What are viagra and cialis indicated for?
TREATMENT OF PULMONARY ARTERIAL HTN
hypertrichosis definition
excessive hair growth
Hyperpolarization of vascular smooth muscle:
A1 (adenosine receptor) and the ______
GIRK (G-protein activated inwardly rectifying K+ channel)
Mechanisms for controlling smooth muscle tone: contraction
- Ca2+ channels (L-type)
- intracellular Ca2+ stores
- increases Ca2+ in combination with calmodulin
- impacts myosin light kinase
- impacts myosin light chain
- myosin light chain is phosphorylated with actin
- CONTRACTION
diazoxide is a ________ vasodilator. Effective in _______, drug resistant forms of ______
potent; severe; HTN
Prostacyclin (PGI2) - Epoprostenol given _______
IV (produced in the endothelium)
Vasoconstrictor antagonists: ambrisentan
- blocks only ETa receptors
- approved for pulmonary arterial hypertension***
- contraindicated in pregnancy (class); hepatotoxicity (Bosentan)
Treprostinil (Remodulin) given _______
orally ; IV
The _____ allele accounts for alcohol __________ intolerance, as ___________ metabolism is also reduced
Lys 504 ; intolerance ; acetaldehyde
hydralazine is an ____________
organic nitrate
adenosine given ____ for ________
IV; coronary stress test (and supraventricular arrhythmias)
For minoxidil, _________ may contribute to its efficacy
cAMP PDE inhibition
Natrecor binds to and activates _______________ in vascular smooth muscle and endothelial cells
membrane-bound guanylate cyclase
Cyclic GMP modulators
- organic nitrates/nitrites
- PDE inhibitors
- natriuretic peptide
vasodilators
beta 2 agonists, CGRP, VIP
Prostacyclin analogs
- PGIs
- Treprostinil
- Iloprost
- Selexipag
Pharmacogenetics of Glycerol Trinitrate:
Likely accounts for the lack of efficacy of ____ in a large percentage of the ______ population
GTN ; Asian
sodium nitroprusside is metabolized in ____________ to ____, ____ and cyanomethemoglobin (limits duration of treatment)
erythrocytes ; NO, 4 CN
NOS stands for
nitric oxide synthase
sodium nitroprusside _________ veins and arteries
dilates
For sildenafil, the PDE 5 inhibitor is predominant in the ________________
corpus cavernosum
Natrecor (nesiritide) is a ______________
vasodilator (human type B natriuretic peptide)
Organic nitrate facts
non-selective vasodilators
breakdown to nitric oxide (bioactivation)
don’t require functional endothelium
acute or chronic administration
What is the most potent and specific inhibitor of cGMP PDE5?
sildenafil (viagra)
Organic nitrate/nitrite examples
amylnitrite
glyceryl trinitrate (GTN)
pentaerythritol tetranitrate (PETN)
isosorbide dinitrate
isosorbide mononitrate
nitroprusside
Pharmacokinetics of organic nitrates:
Given _________ in tx of acute attacks of ________
Given _______ or _______ for prolonged _________
Tolerance occurs with _________ administration
sublingually; angina
orally; transdermally; prophylaxis
continuous
hydralazine combined with ISDN in BiDil. Antioxidant activity potentiates ___________ activity of ISDN. BiDil _________ mortality in ___________ with CHF
vasodilatory ; decreases ; African-Americans
Ambrisentan is contraindicated in _________ patients
pregnant
How does protein kinase G relax smooth muscle?
Inhibition of L-type Ca2+ channels with
Cav1.2
Vasodilators that regulate membrane potential
reduce voltage-gated Ca2+ channel activity
diazoxide is used _________ to treat _________
intravenously; acute HTN
What to know about amrinone/milrinone?
- given IV
- direct positive inotropic effect on myocardium
- minimal chronotropic effect
- direct vasodilatory effect on vascular smooth muscle
riociguat (adempas) is a ________________
SMALL MOLECULE
prostacyclin analogs used to treat _____________
pulmonary arterial HTN
Examples of phosphodiesterase III inhibitors
- inamrinone
- milrinone
CN is converted to less toxic ____ by ___________, excreted via kidney
SCN- ; rhodanase
What drugs inhibit the break down of cGMP/AMP?
Phosphodiesterase inhibitors
eNOS is found in the ________ of the ________
endothelial cells; vasculature
diazoxide used _______ for ________ secondary to________
orally; hypoglycemia; hyperinsulinemia
Minoxidil can give a ______ vasodilation. Used in ______, drug resistant forms of ____
rapid/effective ; severe ; HTN
The isoform of NO, ______, in the vascular endothelium is activated by _______
eNOS; Ca2+ - CAM
diazoxide inhibits _________ from _________
release of insulin; pancreatic beta cells
What is the alternative mechanism of action for NO?
- covalent modification of PRTs by nitrosyl transfer from glutathione
- inhibition of Cav1.2 by GSNO***
- May also contribute to tolerance and endothelial dysfunction
What are viagra and cialis thought to enhance?
THE VASODILATORY EFFECT OF NO
Minoxidil used with ________ and _________
diuretics; beta blockers
Phosphodiesterase V inhibitor impacts
cGMP
Iloprost (Ventavis) given _______
inhalation
Minoxidil and diazoxide
K+ channel agonist/opener
riociguat (adempas) used for ________________
pulmonary arterial HTN
cGMP and cAMP stimulate ________ via distinct mechanisms
vasodilation
Gbetagamma binds and activates ______ to ______ & _____
GIRK; conduct K+ efflux; membrane hyperpolarization
Why does increasing K+ channel opening relax vascular smooth muscle?
K+ sets the membrane potential
the longer the 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 the membrane enough to open voltage-gated Ca2+ channels
Examples of selective PDE 5 inhibitors (3)
- tadalafil (cialis)
- vardenafil (levitra)
- sildenafil (viagra)
Types of Vasodilators
- cGMP modulators
- K+ channel agonists
- Endothelin antagonists
- PGI2 analogs
Natrecor given ___ in ___________
IV ; acutely decompensated HF
PDE5 inhibitors are contraindicated with _______ because
nitrates ; drop in BP (both drugs increase cGMP)
besides agonizing guanylyl cyclase, cGMP inhibits PDE3 which potentially increases cAMP levels in VSM cells
cGMP and cAMP stimulate vasodilation via distinct mechanisms
hydralazine _________ arterioles preferentially. Mechanism not clear. Appears to interfere with release of Ca2+ from _____
dilates ; ER
Vasoconstrictor antagonists: Bosentan and Macitentan facts
- specific, low MW
- endothelin receptor antagonists***
- block ETb (VSM + endothel) receptors
riociguat (adempas) potentiates the effect of _______ NO. This stimulates ____ activity allosterically and increases cGMP concentration in ______________
NO ; sGC ; vascular smooth muscle
NO used to be referred to as _____
EDRF (endothelial derived relaxing factor)
Mechanisms for controlling smooth muscle tone: relaxation
- G-protein coupled receptor (beta-2,IPR)
- increases cAMP (this can be blocked by PDE3 which causes increase in AMP)
- impacts myosin light chain phosphorylation
- causes relaxtion
sildenafil has __-fold selectivity over inhibition of _______
10 ; PDE 6 (retina)
CN can inhibit _______________
oxidative metabolism - lactic acid accumulation
vasoconstrictors
angiotensin, alpha-1 agonists, endothelin
hydralazine can induce _______-like syndrome
lupus
What is increased in pulmonary arterial HTN?
endothelin signaling
Ambrisentan is approved for____________
pulmonary arterial HTN
Compared to viagra, cialis:
- more selective for PDE 5
- longer duration of action than either viagra or levitra
Prostacyclin analogs are ____________. They ___________
vasodilators ; relax pulmonary smooth muscle
examples of vasoconstrictor antagonists
- bosentan (tracleer)
- macitentan (opsumit)
-ambrisentan (letairis)
How does protein kinase G relax smooth muscle?
Enhanced Ca2+ uptake in to ER with
phospholamban
How does protein kinase G relax smooth muscle?
Decreased MLC phosphorylation with
myosin phosphatase 1
Minoxidil generally given ________ or _______
orally; topically to promote hair growth
cGMP inhibitors, such as ________, can cause______ vision
sildenafil ; blueish
Examples of phosphodiesterase V inhibitors
- dipyridamole
- sildenafil
nitric oxide binds to the ______ group in ______, stimulating production of cGMP and activating ______
heme iron prosthetic; guanylate cyclase; protein kinase G (cGKI)
guanylate cyclase is found in the ________
vascular smooth muscle
Nitric oxide production occurs in the
endothelial layer of the muscle
Amrinone/milrinone is a ______ PDE inhibitor
cAMP
How does protein kinase G relax smooth muscle?
Stimulation of Ca2+ activated K+ channels with
BKca
hydralazine is given ______ or IV
orally
Differences in activation of GTN and ISMN/ISDN:
Bioactivation is _________
ALDH-2-independent
exogenously applied NO can directly __________
relax smooth muscle
Selexipag (Uptravi) given _______
orally
adenosine increases _________ of a K+ channel
conductance
-causes hyperpolarization and relaxation
Sodium nitroprusside (SNP) is a __________
vasodilator
Amrinone/milrinone used mainly in
CHF (acute treatment)
nitric oxide synthase is in the _________ and ___ diffuses to the _________
vascular endothelium; NO; vascular smooth muscle
Allosteric activator of sGC
riociguat (adempas)
Compared to viagra, levitra:
- shorter time to onset
- more selective for PDE5
Phosphodiesterase III inhibitor impact
cAMP
Sodium nitroprusside is given ___ for acute management of _______ and severe decompensated ____________
IV ; hypertensive crisis ; heart failure
ET receptors between ______ and ______
GPCR ; Calcium. Blocking the ET receptor blocks the increase in calcium and causes relaxation
Natrecor synthesized and secreted from ___________ in response to ________ blood volume
heart muscle ; increased
riociguat (adempas) is not combined with _______ or _____ inhibitors. It is ____________. There is risk of hemorrhage. It is a substrate for P-gp, CYP1A1, 3A
nitrates ; PDE5 ; contraindicated in pregnancy
