A scale relating various degrees of functional impairment to blood alcohol levels in nonhabituated persons was constructed many years ago by Miles. At a blood alcohol level of 30 mg/dL, a mild euphoria was detectable, and at 50 mg/dL, mild incoordination. At 100 mg/dL, ataxia was obvious; at 200 mg/dL, there was confusion and a reduced level of mental activity; at 300 mg/dL, the subjects were stuporous; and a level of 400 mg/dL—accompanied by deep anesthesia—was potentially fatal. These figures are valid provided that the alcohol content in the blood rises steadily over a 2-h period.
For all practical purposes, once the absorption of alcohol has ended and equilibrium has been established with the tissues, ethanol is oxidized at a constant rate, independent of its concentration in the blood (about 150 mg alcohol per kilogram of body weight per hour, or about 1 oz of 90-proof whiskey per hour). Actually, slightly more alcohol is metabolized per hour when the initial concentrations are very high, and repeated ingestion of alcohol may facilitate its metabolism, but these increments are of little clinical significance. In contrast, the rate of oxidation of acetaldehyde does depend on its concentration in the tissues. This fact is of importance in connection with the drug disulfiram (Antabuse), which acts by raising the tissue concentration necessary for the metabolism of a certain amount of acetaldehyde per unit of time. The patient taking both disulfiram and alcohol will accumulate an inordinate amount of acetaldehyde, resulting in nausea, vomiting, and hypotension, sometimes so pronounced in degree as to be fatal. Certain other drugs—notably the sulfonylureas, metronidazole, and furazolidone—have effects like those of disulfiram but are less potent.
Alcohol acts directly on neuronal membranes in a manner akin to that of the general anesthetics. These agents, as well as barbiturates and benzodiazepines, are lipid-soluble and are thought to dissolve in the cell membranes (in direct relation to the degree of their lipid solubility). With continued ingestion of alcohol, the neuronal membranes ostensibly “rigidify” and become resistant to the fluidizing effect of alcohol (Chin and Goldstein; Harris et al). It is unlikely, however, that these changes in the physical properties of cell membranes are in themselves sufficient to alter cell function. Probably of equal importance are the effects of alcohol on membrane receptor systems that regulate ion channels, particularly chloride and calcium channels. One likely site that relates to the acute intoxicating effects of alcohol is a receptor for the inhibitory neurotransmitter GABA and its associated chloride-ion channel. Benzodiazepine antagonists appear to block the potentiation by alcohol of GABA-induced chloride flux. Like the GABA-chloride channel, the N-methyl-d-aspartate (NMDA) receptors, which transduce signals carried by glutamate (the major excitatory transmitter in the brain), are sensitive to extremely low concentrations of alcohol. There is also evidence that alcohol selectively potentiates serotonin receptor-ion currents, and the activity of this receptor has been implicated in alcoholand drug-seeking behavior and addiction.
The effect of chronic administration of alcohol is to increase the number of neuronal calcium channels in the cell membrane. Moreover, calcium channel blockers, given during chronic administration, prevent both the increase in neuronal calcium channels and the development of tolerance to alcohol (Dolin and Little). The significance of these findings has been demonstrated by Little and colleagues, who showed that calcium channel blockers, given to chronically intoxicated animals after withdrawal, prevent withdrawal convulsions.