Nitric oxide (NO)

Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the haeme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide produces selective pulmonary vasodilation.

Nitric oxide appears to increase the partial pressure of arterial oxygen (PaO₂) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, nitric oxide can improve oxygenation (as indicated by significant increases in PaO₂).

Nitric oxide chemically reacts with oxygen to form nitrogen dioxide.

Nitric oxide has an unpaired electron, which makes the molecule reactive. In biological tissue, nitric oxide may form peroxynitrite with superoxide (O₂-), an unstable compound which may cause tissue damage through further redox reactions. In addition, nitric oxide has affinity to metalloproteins and may also react with SH-groups in protein forming nitrosyl compounds. The clinical significance of the chemical reactivity of nitric oxide in tissue is unknown. Studies show that nitric oxide exhibits pulmonary pharmacodynamic effects at intra-airway concentrations as low as 1 ppm.

The pharmacokinetics of nitric oxide has been studied in adults. Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with haemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhaemoglobin to produce methaemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhaemoglobin to transiently form nitrosylhaemoglobin, which is converted to nitrogen oxides and methaemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhaemoglobin to produce methaemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate.

Methaemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. Methaemoglobin concentrations increase during the first 8 hours of nitric oxide exposure. The mean methaemoglobin levels remained below 1% in the placebo group and in the 5 ppm and 20 ppm nitric oxide groups, but reached approximately 5% in the 80 ppm nitric oxide group. Methaemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of te group. The average time to reach peak methaemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients; but one patient did not exceed 7% until 40 hours.

Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidny at rates approaching the rate of glomerular filtration.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Acute toxicity is related to anoxia resulting from elevated methaemoglobin levels.

Nitric oxide is genotoxic in some test systems. No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 h/day for up to two years. Higher exposures have not been investigated.

No reproduction toxicity studies have been conducted.