Pharmacology of NO Flashcards
How is NO generated endogenously?
NO is generated from the oxidation of the guanidine group of arginine. Arginine is oxidized to citrulline in the process.
What is NO also known as?
EDRF
What is the main endogenous source of NO?
Endothelium
What are the isoforms of NO synthase?
NOS-1 and NOS-3 are constituitive
NOS-2 is inducible
What is the action of NO?
NO interacts with the heme moiety of soluble guanyl cyclase which converts GTP to cGMP production which causes its cytoprotective effects as well as vasodilation
What are the possible negative effects of NO on proteins?
It can nitrosylate proteins on Tyr and Cys residues as it is a free radical -> this is very BAD
How is NO inactivated?
Nitric oxide undergoes both oxidative and reductive reactions resulting in the formation of a variety of oxides of nitrogen including N2O and the most stable end product, NO3-
What inactivates NO?
Hemoglobin
Free Radical Superoxide
Glutathione
What are some of the NO inhibitors?
Arginine Analogs
Inhibitors of NO synthesis
Scavengers of NO - heme is a scavenger
What are the benefits of NO?
The beneficial effects include smooth muscle relaxation, vasodilation, immune regulation, anesthetic and anti-athlerosclerotic responses.
What is the toxicity of NO?
NO can generate nitrogen derivatives that are highly reactive and unstable, interact with numerous proteins, lipids, nucleic acids and metabolize.
Thus, these reactive species alter the physiologic disposition of cells and tissues and mediate several physiologic and pathologic effects.
What can increase plasma NO levels?
Dietary L-arginine consumption increases
List 3 drugs that spontaneously or enzymatically breakdown in the body to release NO.
a. Nitroglycerine
b. Isosorbide dinitrate (sublingual/oral)
c. Amyl nitrates ( volatile rapid acting)
What are NO donors?
Denitration of such drugs as the nitroglycerin result in the formation of NO which is responsible for the smooth muscle relaxation.
What are some of the therapeutic uses of NO?
a. Selective pulmonary vasodilation
b. Treatment of newborn with persistent pulmonary hypotension
c. Beneficial effects in cardiopulmonary bypass in adults, congestive heart disease, primary pulmonary hypertension, pulmonary edema, lung transplantation and sickle cell crisis
What is the interaction of NO with sildenafil (Viagra®)?
It leads to excessive formation of cGMP and smooth muscle relaxation that can lead to severe hypotension
What is the function of NO upon endothelial injury?
NO counteracts the vasoconstriction process upon injury
What happens with decreased NO levels in the plasma?
Decreased NO levels in blood vessels may result in an increase in blood pressure.
What is the effect of NO on WBCs?
NO is also a potent inhibitor of the white cells adhesion to the endothelial surface. It decreases the release of adhesion molecules such as the E-selectin on the endothelial surface.
What is the effect of NO on reperfusion injury?
NO has been shown to protect against ischemic and reperfusion injury.
What is the effect of NO on pulmonary hypertension?
Nitric oxide improves cardiopulmonary function in adults with pulmonary hypertension and is approved for this indication
What is the effect of NO on the airway?
Nitric oxide also relaxes airway smooth muscle and acts as a bronchodilator.
What are NO levels like in septic shock?
Increased
What is the effect of NO on platelets?
Nitric oxide is a potent inhibitor of platelet adhesion, activation, aggregation and regulates the release of serotonin, growth factors and thromboxane from platelets.
What is the effect of NO on fibrinolysis?
NO also indirectly enhances fibrinolysis by inhibiting the release of antiplasmin from the platelets.
What is the role of NO in organ transplant patients?
- Nitric oxide acts as a cytoprotective agent and prevents cellular and platelet adhesion
- Dietary arginine supplements are helpful in the management of transplantation patients.
Which of the following agents is not an inhibitor of nitric oxide synthesis?
A. Hemoglobin
B. 5-Methylthiocitrulline
C. 7-Nitroindazole
D. N-Nitro-L-Arginine methyl ester (L-NAME)
E. Hydralazine
E. Hydralazine
A cardiovascular patient was treated with nitrates to relieve chest pain. He also developed pulmonary hypertension and the physician deceided to treat him with sildenafil. The patient developed severe hypotension. What is the likely cause of this problem?
A. Inhibition of phosphodiesterasce by sildenafil and increased nitric oxide levels.
B. sildenafil increases muscle contraction
C. sildenafil decreases muscle relaxation
D. sildenafil counteracts the effects of NO
E. sildenafil inhibits nitric oxide
A. Inhibition of phosphodiesterasce by sildenafil and increased nitric oxide levels.
NO MOA
Covalent modification of proteins
NO ROA
Inhalation
NO Indication
ACS
NO SE
Vasodilation
Nitroglycerine MOA
NO donor
Nitroglycerine ROA
Sublingual
Nitroglycerine Indication
Pulmonary Artery Hypertension
Nitroglycerine SE
Hypotension
Hydralazine MOA
NO donor, vasodilator
Hydralazine ROA
Oral
Hydralazine Indication
Hypertension
Hydralazine SE
Headache, nausea, vomiting, hypotension
Sildenafil MOA
Phosphodiesterase Inhibitor
Sildenafil ROA
Oral
Sildenafil Indication
Hypertension
Erectile Dysfunction
Sildenafil SE
Hypotension, drug interactions
L-Arginine MOA
NO Donor
L-Arginine ROA
Oral
L-Arginine Indication
ACS, Vascular disease
L-Arginine SE
Hypotension
