Pharmacology of nitric oxide

Chemical properties and molecular structure

Otherwise known as nitrogen monoxide, it is a free radical with the formula NO (where the N and the O are joined by a double bond, i.e. N=O). At room temperature, it is colourless and non-flammable. One can synthesise this substance easily by combining nitrogen and oxygen at about 1000 degrees. It is often described as a product of combustion, and indeed is often seen in the company of combustants (eg. in the exhaust of petrol-burning internal combustion engines), but the reaction that produces it (N2 + O2 → 2NO) is not technically combustion because it's endothermic. In any case car exhaust is not the favoured industrial method of synthesis (that would be the oxidation of ammonia). Nitric oxide is inherently unstable; it degenerates into oxygen and nitrogen (albeit gradually in the absence of a catalyst).

Chemical Relatives

There are no specific "related" compounds to speak of. Nitric oxide, in contact with water, can produce nitrous acid:

4NO + O₂ + 2H₂O → 4HNO₂

Nitric oxide also reacts with atmospheric oxygen to generate nitrogen dioxide:

2NO + O₂ → 2NO₂

Which then converts into nitric acid:

2NO₂ + H₂O → HNO₂ + HNO₃

The nitrous acid also easily oxidises into nitric acid  (HNO₃).

This, needless to say, is sub-optimal.

Administration and absorption

This agent is inhaled; typically, one would not be awake for this (being ventilated for ARDS and probably paralysed). If some sort of dangerous madman were to acquire a sizeable quantity of concentrated NO and release it into the near vicinity of your head, you would get a hit of strong, sharp, sweet odour, which would be followed by the familiar burn of nitric acid filling your lungs. One can enjoy this experience easily by sucking on the exhaust fumes of an LPG-powered car, the exhaust of which contains as much as 1% NO.

The gas comes in a pressurised cylinder, under a brand name "INOmax". It contains 99.92% nitrogen and only 0.08% nitric oxide, or 800 parts per million (ppm). What a rip-off, you might think; did I just pay for a whole lot of pressurised nitrogen? Well, it needs to be that dilute, for convenience of administration. The highest concentration you would ever use is about 80ppm, which corresponds to a gas mixture of 90% whatever, and 10% Inomax.

Nitric oxide is rapidly absorbed into the systemic circulation through the lungs; however there it undergoes some significant modifications, which (for lack of a better term) can be described as "metabolism".

Metabolism and clearance

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.

The nitrate generated by this process is excreted in the urine in a manner which suggests that it is freely filtered by the glomerulus.

The methaemoglobin, normally only 1% or so of total haemoglobin, has been seen to rise to as high as 7% in nitric oxide therapy, giving rise to odd readings of the pulse oximeter (it shows 85%, irrespective of true oxygen saturation). The methaemoglobinaemia is mainly seen at inhaled concentrations in excess of 80ppm. A plateau level of methaemoglobin seems to be reached after about 12 hours of therapy.

So, the nitric oxide itself, reacting so rapidly with hemoglobin, is a transient tenant of the bloodstream, and has a very short halflife (measured in seconds), which means that virtually none of it arrives at the left atrium unchanged.

Mechanism of action

Nitric oxide is a potent vasodilator; it inhibits vasoconstriction by increasing the amount of cyclic GMP (cGMP) in the cytosol, thus decreasing the amount of cytosolic calcium ions available to sustain contraction.

Indications and contraindications

The chief indication for nitric oxide has been refractory hypoxic respiratory failure in ARDS. However, a good Cochrane analysis demonstrated no benefit in mortality, and a statistically insignificant benefit in the duration of ventilation and length of ICU stay. Oxygenation did improve, to be sure- but the effect was only significant in the first 24 hours of therapy. Thus, nitric oxide these days is seldom used. In the manufacturers brochure, it is recommended for use only in the neonatal population.

There are several contraindications.

• Left ventricular failure: NO seems to cause lots of adverse effects in this group of patients- particularly, pulmonary oedema. In fact, halfway through one study, the investigators had to start excluding CCF patients from the trial because of these effects.
• Left to right shunting: NO will decrease the pulmonary (and thus the RV) pressure, increasing the amount of blood shunted via a septal defect.
• Uncontrolled haemorrhage: Though there is no human evidence, in animal studies NO had been shown to increase bleeding times.
• Existing methaemoglobinaemia: obviously, it will get worse.

Additionally, one better wean this stuff off gradually. Sudden discontinuation results in a rebound hypoxia, due to pulmonary vasoconstriction; this can be so severe that it results in forward flow failure through the pulmonary circulation, and thus systemic hypotension.

Adverse effects

Nitric oxide is genotoxic. It damages DNA in a vicious, direct fashion. On top of that, the following adverse effects have been reported:

• Methemoglobinaemia, as abundantly discussed already
• 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)
• Increased susceptibility to pulmonary infections probably due to NO₂ formation and associated lung injury

Interactions

Nitric oxide doesn't really have enough time to interact with other drugs, as it is a short-lived substance.

However, it will have an additive effect with other drugs which cause methaemoglobinaemia, and this ought to be kept in mind.

Acute Toxicity and Overdose

As a small fraction of its normal metabolism is conversion into NO₂, one must be wary of NO₂ toxicity. This, in the context of inhaled NO, is manifested chiefly by a worsening lung injury. The answer is to turn off the gas.

Management of chronic toxicity

The methaemoglobinaemia may be treated by a few different ways. Infusing Vitamin C seems to be a safe method; methylene blue is another answer. One can also supplement normal haemoglobin by transfusing packed cells.