Pulmonary Vasodilators

Question 1

Classify the pulmonary vasodilators

Answer 1

INHALED

• Nitric Oxide
• Prostaglandin I2 (Epoprostenol)
• Oxygen

NON-INHALED

• Sildenafil
• Tadalafil
• Milrinone

Question 2

How is Nitric Oxide administered for the treatment of pulmonary hypertension

Answer 2

INOMax - proprietary system

Administered as part of an inspired gas admixture

Fraction measured in tens of ppm

Question 3

How is Epoprostenol (PGI2) administered for the treatment of pulmonary hypertension

Answer 3

Can be intravenous but usually nebulized as part of a solution with a glycine buffer using a continuous ultrasonic nebulizer

Question 4

Why does Epoprostenol require glycine buufer

Answer 4

Requires glycine buffer and sodium hydroxide because its pKa is 4.4 and spontaneous hydrolysis of the drug occurs in aqueous solution at normal pH

The reconstituted mixture has a pH of 12

Question 5

What is the mechanism of action of Nitric Oxide

Answer 5

Increased Nitric oxide –> Activation guanylate cyclase –> increase cGMP –> smooth muscle relaxation

Question 6

How is endogenous secretion of nitric oxide initiated

Answer 6

Acetylcholine (PSNS) binds M3 receptors on endothelial cell membrane –> Gq coupled –> IP3 –> Ca induced Ca release from SR –> Ca-Calmodulin –> NO production.

Question 7

List the Muscarinic receptors

- name each of their 2nd messenger systems and functions

Answer 7

M1 - Gq (IP3) —> Cognitive/memory/seizures

M2 - Gi (- AC) —> Mainly cardiac and eyes

M3 - Gq (IP3) —> Mainly Lungs, GIT, eyes, urogenital

M4 - Gi (- AC) —> Inhibits ntmtr release CNS / Dopamine

M5 - Gq (IP3) —> facilitates dopamine release

Question 8

What are the routes of administration of oxygen

Answer 8

1. Inhaled
2. IV (ECMO)
3. External (hyperbaric oxygen therapy)

Question 9

What is the mechanism of action of oxygen

Answer 9

Increases ATP by acting as a substrate for aerobic metabolism of glucose

Question 10

How does O2 cause vasodilatation of the pulmonary vasculature

Answer 10

It prevents vasoconstriction of the pulmonary vasculature by averting hypoxic pulmonary vasoconstriction

Question 11

List the Oral and IV drugs used for pulmonary vasodilatation

Answer 11

Oral
- Sildenafil

IV
- milrinone

Question 12

Differentiate the mechanisms of action of milrinone vs sildenafil

Answer 12

Sildenafil - PDE 5 inhibitor

–> Increase cGMP in vascular smooth muscle –> pulmonary vasodilation

Milrinone - PDE 3 inhibitor

–> Increase cAMP in vascular smooth muscle –> inhibition of MLCK –> relaxation vascular smooth muscle –> pulmonary vasodilatation

Question 13

Compare the metabolism of milrinone and sildenafil

Answer 13

Sildenafil –> CYP3A4 –> active metabolite with 50% activity of sildenafil

Milrinone –> Renal

Question 14

Describe the clinical effects of sildenafil and milrinone

Answer 14

Pulmonary vasodilation
Hypotension
Reflex tachycardia
Headache
Priapism

Question 15

How does the function of milrinone differ from sildenafil

Answer 15

Milrinone
–> Improves myocardial contractility
Propensity for arrhythmias