CO competes with O2 for binding to Haemoglobin and causes a left shift of the
O2 Dissociation Curve.
Although CO has an affinity for Haemoglobin 200 times greater than that of oxygen,
hypoxia from this mechanism alone does not account for all the clinical and
biochemical manifestations of CO poisoning.
A biphasic pattern to CO poisoning has been shown in experimental animals (Langston:
Toxicology 1996). Initially, cerebral oxygen supply and utilisation is held
constant due to an increase in cerebral blood flow.
A secondary hypoxic phase is then caused by haemodynamic collapse. This seems
to be due to CO binding to myocardial myoglobin. Cardiac myoglobin binds three
times as much CO as skeletal muscle.
At the same time, CO also binds to intracellular haemoproteins such as the cytochrome
systems in mitochondria, leading to inhibition of oxidative phosphorylation.
Together with intracellular hypoxia, this in turn causes formation of toxic
free radical species and consequent endothelial damage.
CO also causes a several hundred fold increase in the release of nitric oxide
from platelets. Nitric oxide derived oxidants such as peroxynitrite (ONOO-)
can inactivate mitochondrial enzymes and further generate free radical species.
As a final pathway, leucocyte adherence to the cerebral microvasculature subsequently
leads to lipid peroxidation of cell membranes. Areas such as the globus pallidus,
the hippocampus and the sub-cortical white matter show particular vulnerability.
