Pharm: Nitric Oxide Drugs Flashcards
What are the major pharmacologic actions of nitric oxide?
Smooth muscle relaxation
Decreased cell adhesion
Inflammatory response
What amino acid is digested to produce endogenous NO?
arginine
What enzymes synthesize NO?
Nitric oxide synthase family of enzymes (three isoforms)
Which NOS isoforms are inducible, which are constitutively active?
NOS-2 is inducible
NOS-1, NOS-3 are constitutive
Which NOS isoform is considered “bad” and is a target for drugs?
NOS-2 (the inducible isoform)
What is the affect of arginine analogs (ex: NMMA)?
Inhibition of the conversion of arginine to citrulline
decreased formation of NO
What is the pathway that NO acts on?
NO interacts with the guanyl cyclase which converts GTP to cGMP
This leads to vasodilation
How does glutathione affect vascular pathology?
In CVD and DM, glutathione levels are reduced. This leads to increased vascular pathology due to increased NO.
What are the targets for inhibiting NO?
1) L-arginine derivatives (L-NMMA, L-NAME)
2) Inhibit NOS synthesis
3) Inhibit binding of arginine to NOS
4) NO scavengers
What are the beneficial effects of NO?
Smooth muscle relaxation Vasodilation Immune regulation Anesthetic effects Anti-atherosclerotic responses
What are the pathological effects of NO?
Production of free radicals
Nitrosation
Irritant effects
How is BP affected by NO levels?
Decreased NO levels may result in an increased BP
What is the mechanism of action of sildenafil (viagra)?
Inhibition of phosphodiesterase
Increases cGMP levels (by preventing conversion to GMP) leading to increased relaxation
Describe the interaction between sildenaphil and nitrates
Strong adverse reaction that can cause severe hypotension.
Both drugs result in increased cGMP levels leading to relaxation
What is the effect of NO on ischemic and reperfusion injury?
NO has been shown to protect against ischemic and reperfusion injury
Describe the NO treatment for pulmonary hypertension
Inhaled to improve cardiopulmonary function
Essentially a low dose of viagra (INOmax)
What are the NO levels in septic shock?
NO levels are markedly increased in septic shock.
LPS induces NOS-2 to produce NO, leads to hypotension and shock
What effect does NO have on platelet function?
NO is a potent inhibitor of platelet adhesion, activate and aggregation
NO also regulates release of 5HT, growth factors and TXA from platelets
What role does NO play for organ transplant patients?
NO is cytoprotective, prevents cellular and platelet adhesion.
Dietary arginine supplements are helpful for transplant patient management
What are the most widely used NO donor drugs?
Nitrates
Denitrated to release NO, cause smooth muscle relaxation
What are the 4 categories of NO donor drugs?
Ultra short (fastest acting)
Short
Intermediary
Long (slowest acting)
What are the major side effects associated with NO drugs?
Hypotension
What are the main NO donor drugs?
Nitroglycerine
Hydralazine
L-Arginine
