Pharm - Lec#4 - Nitric Oxide

Question 1

Nitric Oxide (INOMAX)

• MOA
• route

Answer 1

Covalent modification of proteins

• inhalation

Question 2

Nitric Oxide (INOMAX)

• indications
• side effects

Answer 2

• Pulmonary Hypertension

- Vasodilation

Question 3

Nitroglycerine

• MOA
• route

Answer 3

NO donor

• sublingual

Question 4

Nitroglycerine

• indications
• side effects

Answer 4

ACUTE CORONARY SYNDROME

• hypotension

Question 5

Hydralazine

• MOA
• route

Answer 5

NO donor, vasodilator

• ORAL route

Question 6

Hydralazine

• indications
• side effects

Answer 6

• hypertension

SE:

• headache
• nausea
• vomiting
• hypotension

Question 7

Sildenafil (viagra)

• MOA
• route

Answer 7

MOA: phosphodiesterase inhibitor

Route - oral

Question 8

Sildenafil (viagra)

• indications
• side effects

Answer 8

Indications: hypertension

SE:

• hypotension
• drug interactions (if given with NITRATE)

Question 9

L- Arganine

• MOA
• Route

Answer 9

MOA: NO donor

Route: Oral

Question 10

L- Arganine

• Indications (2)
• Side effects

Answer 10

Indications:
ACS
Vascular Disease

SE: hypotension

Question 11

What causes the generation of NO in the macrophage?

What is it generated from?

Answer 11

exposure to bacterial LPS

• oxidation of the guanidine group of arginine

Question 12

Acetylcholine & Carbachol causes the endothelium to release _____

Answer 12

EDRF (NO)

Question 13

State the following for Nos1, Nos2, and Nos3:

1. other name
2. Tissue expression
3. Constitutive/inducible

Answer 13

NOS1:

• neuronal NOS (nNOS)
• NEURONAL epithelium
• constitutive

NOS2****
- iNOS
-macrophage, smooth muscle cells
- INDUCIBLE
(bad! associated with pathologic conditions)

NOS3:

• endothelial nos (eNOS)
• endothelial cells
• constitutive

Question 14

What NOS is only activated in pathologic states?

What causes this activation?

Answer 14

iNOS

• induced by LPS

Question 15

What is L- Arginine converted to generate NOS

What does it require as cofactors

Answer 15

L- Arginine to L - CITRULLINE

1. NADPH
2. FAD
3. THF

Question 16

Some nitric oxide donors such as oxygenated nitroprusside, spontaneously generates NO,

whereas others such as the _____ and organic ____ and _____ such as nitroglycerin require the presence of a THIOL compound such as cysteine.

Answer 16

furoxan
nitrates
nitrites

Question 17

What nitric oxide derivative is conveniently measured in SEPSIS?

Answer 17

NITRATE
(NO3-)

• MOST STABLE
• CONVENIENTLY MEASURED IN PATIENTS WITH SEPSIS!!!!
• iNOS –> due to lipopolysaccharide of bacteria

Question 18

Why are low levels of GLUTATHIONE related to increased vascular pathology in CV disease and diabetes?

Answer 18

low glutathione = HIGH NO

• increased NO results in greater hypotensive effects and INFLAMMATION
• contributes to vascular pathology

Question 19

What are the 4 inhibitors of NO?

Answer 19

1. L-arginine Derivatives (L-NMMA, L-NAME)
2. Inhibitors of nitric oxide synthase synthesis
3. Inhibitor of binding of arginine to NOs
4. Scavengers of NO

Question 20

Excess production of NO results in the generation of _____ which is toxic to cells

Answer 20

peroxynitrite

Question 21

State the 5 inhibitors of NO

Answer 21

1. L- NMMA
2. L- NAME
3. 7 - Nitroindazole
4. BBS-2
5. Hemoglobin!!

Question 22

What is a scavenger of NO that inhibits it?

Answer 22

HEMOGLOBIN!!!

Question 23

What are the beneficial and pathologic effects of NO?

Answer 23

The beneficial effects include smooth muscle relaxation, vasodilation, immune regulation, anesthetic and anti-athlerosclerotic responses.

The pathologic responses include free radical formation, nitrosylation of protein and irritant effects.

Question 24

What is particularly dangerous of taking Nitrates w/ sildenifil (viagra)

Answer 24

many patients are taking NITRATES & phosphodiesterase inhibitors like VIAGRA (sildenifil)

can generate severe hypotension AND SHOCK!!!!

(nitrates already lower BP, sildenifil increases this effect)

Question 25

How does NO generate smooth muscle relaxation?

Answer 25

NO -> bind GC by heme moiety--> convert GTP to cGMP --> DEPHOSPHORYLATION OF MYOSIN LIGHT CHAIN = relaxation!

Question 26

State the vascular effects of NP

Answer 26

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. NO has been shown to protect against ischemic and reperfusion injury. (TEST)

Question 27

State pulmonoary effects of NO How is it administered

Answer 27

- bronchodilator (used in kids for ARDS) - used for PULMONARY HTN!!! INHALATION

Question 28

What reduces the shock & hypotension caused by iNOS activated by bacterial LPS?

Answer 28

L-NMMA - High levels of NO and dysoxia result in severe ischemia and perfusion defects

Question 29

How does NO inhibit platelet function?1

Answer 29

1. inhibit adhesion, activation, aggregation - regulates the release of serotonin, growth factors and thromboxane from platelets 2. NO also indirectly enhances fibrinolysis by inhibiting the release of antiplasmin from the platelets.

Question 30

How does NO affect organ transplants?

Answer 30

Nitric oxide acts as a cytoprotective agent and prevents cellular and platelet adhesion - Dietary arginine supplements are helpful in the management of transplantation patients

Question 31

Which NOS (1,2,3) is responsible of the inflammatory affects experienced in diseases like IBD, arthritis, etc?

Answer 31

NOS 3 | - mediates ACUTE inflammation

Question 32

What is the most long acting NO donor?

Answer 32

Transdermal nitroglycerine 8-10 hours

Question 33

What is the MOA of NO?

Answer 33

Primarily produce smooth muscle relaxation by releasing endogenous NO which produces the following effects. A.Stimulates guanyl cyclase B.Increased production of cGMP C.Dephosphorylation of myosin

Question 34

What are the indications of NO?

Answer 34

Selective pulmonary vasodilation Treatment of newborn with persistent pulmonary hypotension (improves oxygenation) Beneficial effects in cardiopulmonary bypass in adults, congestive heart disease, primary pulmonary hypertension, pulmonary edema , lung transplantation and sickle cell crisis.