This causes reduced cardiac output and hypotension, which may result in brain ischemia. A delayed return of symptoms have been reported. This results following a recurrence of increased carboxyhemoglobin levels; this effect may be due to a late release of carbon monoxide from myoglobin, which subsequently binds to hemoglobin. Cytochrome oxidase
Another mechanism involves effects on the mitochondrial respiratory enzyme chain that is responsible for effective tissue utilization of oxygen. Carbon monoxide binds to cytochrome oxidase with less affinity than oxygen, so it is possible that it requires significant intracellular hypoxia before binding. This binding interferes with aerobic metabolism and efficient adenosine triphosphate synthesis. Cells respond by switching to anaerobic metabolism, causing anoxia, lactic acidosis, and eventual cell death. The rate of dissociation between carbon monoxide and cytochrome oxidase is slow, causing a relatively prolonged impairment of oxidative metabolism. Central nervous system effects
The mechanism that is thought to have a significant influence on delayed effects involves formed blood cells and chemical mediators, which cause brain lipid peroxidation (degradation of unsaturated fatty acids). Carbon monoxide causes endothelial cell and platelet release of nitric oxide, and the formation of oxygen free radicals including peroxynitrite. In the brain this causes further mitochondrial dysfunction, capillary leakage, leukocyte sequestration, and apoptosis. The result of these effects is lipid peroxidation, which causes delayed reversible demyelination of white matter in the central nervous system known as Grinker myelinopathy, which can lead to edema and necrosis within the brain. This brain damage occurs mainly during the recovery period.
The distribution of alleles is uneven amongst ethnic groups. A large number of medications are potent inhibitors of CYP2D6. Some types of medications known to inhibit CYP2D6 include certain SSRIs and tricyclic antidepressants, some antipsychotics, and the commonly available antihistamine diphenhydramine. Therefore, the potential of interactions exists between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers. Dextromethorphan is also metabolized by CYP3A4. N-demethylation is primarily accomplished by CYP3A4, contributing to at least 90% of the MEM formed as a primary metabolite of dextromethorphan.A number of other CYP enzymes are implicated as minor pathways of dextromethorphan metabolism. CYP2D6 is more effective than CYP3A4 at N-demethylation of dextromethorphan, but since the average individual has a much lower CYP2D6 content in the liver compared to CYP3A4, most N-demethylation of dextromethorphan is catalyzed by CYP3A4. Chemistry
Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. As its pure form, dextromethorphan occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydrobromide salt is water-soluble up to 1.5 g/100 mL at 25 °C. Dextromethorphan is commonly available as the monohydrated hydrobromide salt, however some newer extended-release formulations contain dextromethorphan bound to an ion-exchange resin based on polystyrene sulfonic acid. Dextromethorphans specific rotation in water is +27.6° (20 °C, Sodium D-line). Synthesis
Several routes exist for the synthesis of Dextromethorphan.