Question 4

Describe the mechanisms of action and potential adverse effects of inhaled nitric oxide and prostacyclin.

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College Answer

Most candidates were able to describe the mechanism of action of inhaled nitric oxide (iNO), however many demonstrated very little knowledge about prostacyclin and the adverse effects of both commonly used drugs. General statements about NO, it’s delivery and pharmacological effects did not attract marks candidates are encouraged to read the question and provide information specific to the question. Methaemoglobin and its effects were reasonably described with many understanding the rational for restricting the concentration of iNO (ppm) because of the risk of N02 formation. The knowledge related to prostacyclin was very limited. Such limited detail as to its mechanism of action prevented any discussion regarding any differences from iNO. Many reasonable answers to the iNO component were limited overall due to a paucity of knowledge and incorrect facts in the prostacyclin section


  Inhaled nitric oxide Prostacycline
  • Rapidly absorbed into pulmonary circulation
  • Induces guanylyl cyclase
  • Thus, increases the amount of cyclic GMP (cGMP) in the cytosol
  • Thus decreases the amount of cytosolic calcium ions available to sustain smooth muscle contraction
  • This results in vasodilation
  •  Binds to PGE receptors on platelets and vascular endothelial cells
  • These are G-protein coupled receptors
  • Binding the ligand therefore activates adenylyl cyclase and increases the intracellular concentration of cAMP
  • Increased cyclic AMP leads to decreased platelet activation and activates protein kinase A
  • PKA then phosphorylates and inhibits myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation
Adverse effects
  • Methaemoglobinaemia
  • Worsening hypoxia following abrupt withdrawal
  • Thrombocytopenia
  • Worsening lung injury due to NO2 production
  • Increased susceptibility to lung infections
  • Systemic vasodilation (half life is 1-2 minutes, enough to reach the systemic circulation)
  • Platelet inhibition, bleeding risk
  • Facial flushing
  • Tachycardia,
  • Inhibition of gastric acid secretion
  • Decreased gastric

This question focused only on the mechanisms of action and potential adverse effects, which means extensive digressions on other properties would not have earned any marks; but in case you might want to have a look at those, they are listed in the Part One Pharmacopoeia, as follows:

Inhaled Pulmonary Vasodilators
Name Nitric oxide Epoprostenol
Class Inhaled pulmonary vasodilator Inhaled pulmonary vasodilator
Chemistry A free radical with the formula NO Synthetic analogue of the naturally occurring eicosanoid prostacyclin (prostaglandin I2 or PGI2)
Routes of administration Administered as part of inspired gas mixture, usually as an admixture fraction measured in tens of ppm, via a proprietary system (INOMax) Can be intravenous, but usually nebulised as a part of a solution with a glycine buffer, using a continuous ultrasonic nebuliser
Absorption Absorbs rapidly into the pulmonary circulation via the lungs Absorbs rapidly into the pulmonary circulation via the lungs
Solubility As it dissociates in water, nitric oxide produces nitric acid (HNO3) which has a pKa of -1.3 Natural pKa is 4.4; requires a diluent which contains glycine and sodium hydroxide. The pH of the reconstituted drug mixture has a pH of around 12, because the drug tends to spontaneously hydrolyse in aqueous solution at a normal pH
Distribution VOD is impossible to measure, but is potentially very large. NO reacts with oxygen and water to produce nitrogen dioxide and nitrites, which then bind to haemoglobin and produce either nitrosylhaemoglobin or methaemoglobin, i.e. it can be described as "highly protein bound". 0.357L/kg
Target receptor Soluble guanylyl cyclase (which is induced by NO) Activates G protein-coupled PGE receptors on platelets and endothelial cells, which activates adenlyl cyclase and increases cAMP
Mechanism of action Inhibits vasoconstriction by increasing the amount of cyclic GMP (cGMP) in the cytosol, thus decreasing the amount of cytosolic calcium ions available to sustain smooth muscle contraction Increased cyclic AMP leads to decreased platelet activation and activates PKA, which phosphorylates and inhibits myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation
Metabolism One way or another, nitric oxide ends up as methaemoglobin and nitrate. Either it reacts with lung water, becoming nitrite (which reacts with oxyhemoglobin and generates methaemoglobin and nitrate) or it combines directly with oxyhaemoglobin, with the same results. If it encounters hypoxic blood, it can combine with deoxyhaemoglobin to create nitrosyl-haemoglobin, which then rapidly becomes methaemoglobin when it contacts oxygen. Degrades spontaneously as well as enzymatically into about sixteen major and minor metabolites
Elimination Nitrates are eliminated mainly in urine whereas methaemoglobin is metabolised in several hours into
haemoglobin by endogenic reductases. The nitrates excreted in urine represent over 70% of the inhaled NO
Half-life is about six minutes
Time course of action Onset of effect is seen within seconds Platelet inhibition effects last up to 2 hrs; smooth muscle vasodilation is very shortlived (comparable with half-life)
Clinical effects Apart from pulmonary vasodilation, there is methemoglobinaemia, hypotension (maybe some of it does leak into the systemic circulation, or maybe this the effect of depressed LV function, rebound hypoxia after abrupt withdrawal, thrombocytopenia (in as many as 10% of patients) and increased susceptibility to pulmonary infections probably due to NO2 formation and associated lung injury. Vasodilation (pulmonary as well as systemic); inhibition of platelet aggregation; facial flushing, tachycardia, bronchodilation, inhibition of gastric acid secretion, and decreased gastric
Single best reference for further information TGA (AusPAR) product information Flolan PI by GlaxoSmithCline


Siobal, Mark S. "Pulmonary vasodilators." Respiratory care 52.7 (2007): 885-899.