Organic Nitrates and Vasodilators Flashcards
Two main types of vasodilators presented in the lecture
Cyclic GMP modulators
K+ Channel Agonists
Three types of cyclic GMP modulators
Organic Nitrates/Nitrites
PDE Inhibitors
Vasoactive Peptides
How is Nitric Oxide made?
Conversion of L-Arginine into L-citruline+NO by Nitric Oxide synthase
Three isoforms of Nitric Oxide Synthase
nNOS (Neuronal)
iNOS (Inducible)
eNOS (Endothelial)
How is eNOA activated?
Ca-CAM
How does endothelial NOS influence skeletal muscle?
the NO diffuses out to the vascular smooth muscle
How does NO lead to protein Kinase G
NO binds heme prosthetic group of Guanylate Cyclase, stimulating the production of cGMP and activating protein kinase G.
How does cGMP activation influence cell activity?
It dephosphorylates Myosin LC, causing muscle relaxation
Where is eNOS? where is Guanylate Cyclase?
eNOS – Endothelial cells of vasculature
GC – Vascular smooth muscle
Four ways that Protein Kinase G relaxes smooth muscle
- Inhibition of L-type Ca Channels
- Stimulation of Ca activated K Channels
- Decreases MLC P-ation
- Enhanced Ca uptake into the ER
In an experiment, phenylephrine is applied to a normal vascular tissue sample, then acetylcholine afterward. What do you see?
Phenylephrine causes increase in tension that is released by acetylcholine
In an experiment, phenylephrine is applied to a vascular tissue sample with no endothelium, then acetylcholine afterward. What do you see?
Phenylephrine still increases tension, but acetylchoine can no longer release it
In an experiment, phenylephrine is applied to a normal vascular tissue sample soaked in L-NMMA, then acetylcholine afterward. What do you see?
Same as without L-NMMA EXCEPT the drop following acetylcholine exposure is smaller
(NMMA is a competitive inhibitor of NOsynthase)
In an experiment, first hemoglobin, then phenylephrine is applied to a normal vascular tissue sample, then acetylcholine afterward. What do you see?
Contraction, but no relaxation
NO complexes with the heme iron
Three important given organic nitrates
Glycerol trinitrate (GTN) Isosorbide dinitrate (ISDN) Isosorbide mononitrate (5-ISMN)
Of the three given organic nitrates, rank from most to least half life and bioavailablily
5-ISMN, ISN
How are nitrates typically given in acute angina patients?
Sublingually
Risk of continuous administration of nitrates?
Tolerance
What do Organic Nitrates vasodilate?
Both Veins and Arteries
What happens to Organic nitrates after you take them?
They are broken down to NO by aldehyde dehydrogenase
Important nitrite listed?
Amylnitrite
Liquid – Inhaled Drug
“Poppers”
Molecularly speaking, how does GTN tolerance happen?
GTN requires use of ALDH2 to generate the active thionitrate intermediate. ALDH2 is regenerated by oxidizing reduced lipoic acid. Eventually, theres not enough reduced lipoic acid sitting around, so ALDH2 isn’t remade, so the active form of ALDH2 isn’t made.
Mutation that might make GTN ineffective?
Glu 504 Lys polymorphism
Difference between GTN, ISMN, and ISDN activation?
Very similar
GTN and ISDN look like they both use mitochondrial and cytoplasmic ROS, which ISMN only used cytoplasmic
Three important types of Prostacyclin analogs
PGI2 (epoprostenol)
Treprostinil
Iloprost
Which prostacyclin analog has the longest half life? shortest?
Longest – Treprostinil (Remodulin) at 4 hours
Shortest – PGI2 at 3-5 minutes
What are prostacyclin analogs used for?
Treatment of pulmonary arterial hypertension
What is Hydralizine?
An organic nitrate that dilates arterioles preferentially
Appears to interfere with Ca release from theER
Hydralizine associated risks (2)
- Can induce a lupus-like syndrome
2. when combined with ISDN, increased likelihood of mortality in African Americans with CHF
Indications for Sodium Nitroprusside?
Given IV for acute management of HYPERTENISVE CRISIS and SEVERE DECOMPENSATED HEART FAILURE
Sodium Nitroprusside works on…
Veins and Arterioles
How does Sodium Nitroprusside work?
Metabolized in RBCs to NO and Cyanide
This is why it can only be given acutely
CN can be converted to SCN by….
Rhodanase
What is Riociguat? How does it work?
An allosteric activator of GC used to treat Pulmonary HTN.
1) Potentiates NO activity
2) Stimulates GC allosterically
Overall – Increased cGMP concentration in vascular SM
Who should never get Riociguat?
Folks taking nitrates, PDE5 inhibitors
Pregnant Women
Riociguat is a substrate for…
P-gp, CYP1A1, 3A
What is the alternative mechanism of NO that may play a role?
Covalent modification of proteins by a nitrosyl transfer
Contributes to tolerance and endothelial dysfxn
Phosphodiesterase 3 inhibitors
(In)Amrinone
Milrinone
What do Phosphodiesterase 3 inhibitors do
make cAMP last longer
List phosphodiesterase 5 inhibitors
Dipyridamole
Sildenafil
What do Phosphodiesterase 5 inhibitors do
Make cGMP last longer
Important details for cAMP Phosphodiesterase inhibitors
Given IV
Direct positive inotropic effect on myocardium
Direct vasodilatory effect on vascular smooth muscle
cAMP Phosphodiesterase inhibitors are given in treatment of…
CHF (acute treatment)
Common name for Sildenafil
Viagra
Name three selective PDE 5 inhibitors
Tadalafil (Cialis)
Vardenafil (Levitra)
Sildenafil (Viagra)
Why is there blueish vision for some folks with PDE5 inhibitors
also can activate some PDE6 in the retina
Compare Levitra and Viagra
Shorter time to onset than Viagra
More selective for PDE5
Compare Cialis and Viagra
More selective for PDE5 than Viagra
Longer duration of action than Viagra or Levitra
What is Natrecor?
A Human type B natriuretic Peptide analog used to treat acutely decompensated HF
How does Natrecor work?
Synthesized and secreted from heart muscle in response to increased blood volume.
Binds to/activates membrane bound guanylate cyclase in vascular smooth muscle and endothelial cells
Describe how the vasodilators influence cell channels.
Vasodilators use camp->PKA or cGMP->PKG to promote potassium channel opening. This allows the membrane potential to approach the K potential, making it harder to depolarize and open up the Voltage gated Ca channels.
Classic examples of a K+ Channel Agonist
Minoxidil
Diazoxide
Why give Minoxidil?
Given with loop diuretics + beta blockers for HTN
Given topically to promote hair growth
Why give Diazoxide?
Used IV to treat acute, severe/drug resistant HTN
Also given for hypoglycemia secondary to hyperinsulinemia
What does Adenosine do?
Binds to A1 receptor a GPCR
Increases the conductance of the K+ channel
Given for CORONARY STRESS TEST
How does adenosine dilate vessels?
Adenosine Receptor (A1) is activated and turns on the GIRK channel to conduct K+ efflux, causing membrane hyperpolarization
