Question 17

 Describe the pharmacology of inhaled nitric oxide (NO).

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College Answer

Nitric Oxide (NO) is an inorganic colourless and odourless gas presented in cylinders containing 100/800 ppm of NO and nitrogen. Many candidates mentioned oxygen instead of nitrogen. The exposure of NO to oxygen is minimized to reduce formation of nitrogen dioxide and free radicals. Hence it is administered in inspiratory limb close to the endotracheal tube. Many candidates did not mention the contraindications/caution for NO use. Candidates generally did well in mentioning the impact on improving V/Q mismatch by promoting vasodilatation only in the ventilated alveoli and reducing RV afterload. Many candidates did not mention the extra cardio-respiratory effects. The expected adverse effects of NO were nitrogen dioxide related pulmonary toxicity, methemoglobinemia and rebound pulmonary hypertension on abrupt cessation. Pharmacokinetics of NO carried a significant proportion of marks. It was expected that the answers would involve mention of location of delivery of NO in inspiratory limb and reason behind it, the high lipid solubility and diffusion, the dose (5-20ppm), very short half-life of < 5 seconds and combination with oxyhemoglobin to produce methaemoglobin and nitrate. The main metabolite is nitrate which is excreted in urine.

Discussion

Class Pulmonary vasodilator
Chemistry A free radical with the formula NO
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); added into the gas mixture close to the ETT to minimise exposure to oxygen.
Absorption 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
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".
Target receptor Soluble guanylyl cyclase (which is induced by NO)
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.
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 dose.
Time course of action Onset of effect is seen within seconds
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
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.
Single best reference for further information TGA (AusPAR) product information

References

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