Pharmacology Of Alcohol

Alcohol refers to compounds with a hydroxyl group, that is, an oxygen and hydrogen (-OH) bonded to a carbon atom. Beverage alcohol consists of etha-nol, which occurs naturally as a fermentation product of sugars and grains. The ethyl alcohol molecule is hydrophilic and affects all cells of the body.

Alcohol is absorbed from the stomach and the proximal part of the small bowel. Ninety-five percent of alcohol is metabolized in the liver by alcohol dehydrogenase (ADH), which converts alcohol to the toxic substance acetaldehyde. The stomach contains at least three isoenzymes of alcohol dehydrogenase. Women have less gastric ADH and may therefore metabolize alcohol less efficiently. If gastric emptying is slowed, as with ingestion of food or with drugs having anticholinergic properties, more metabolism of alcohol by gastric ADH occurs, resulting in a lower blood alcohol concentration (Wedel, Pieters, Pikaar, & Ockhuizen, 1991). Alternatively, aspirin and cimetidine inhibit gastric ADH and may lead to an increased blood alcohol concentration.

The principal route of metabolism of alcohol is through the ADH pathway, which eliminates approximately one drink (13 g of alcohol) per hour. The major product is the toxic substance acetaldehyde. Acetaldehyde is further broken down to acetic acid via the enzyme aldehyde dehydrogenase (ALDH), and subsequently goes through the citric acid cycle to become carbon dioxide and water. Both ADH and ALDH possess several distinct isoenzymes that may reflect a genetic predisposition to alcoholism. Another pathway for oxidation, the microsomal ethanol-oxidizing system (MEOS), is induced by chronic ingestion of alcohol. An increase in the activity of the MEOS pathway can increase the rate of elimination by 50-70%. The MEOS may be responsible for the increased metabolic tolerance seen in chronic alcoholics for other hypnotic/ sedative drugs, as well as for alcohol.

One action of ethanol is the disruption of the phospholipid molecular chain in the nerve cell membrane. The result is an increased "fluidity" of the membrane. This disturbance in the structure of the membrane affects the functional protein system (enzymes, receptors, and ionophores), which is attached to the membrane. For example, adenylate cyclase and monoamine oxidase activity are lower in alcoholics than in controls. Adenylate cyclase is important in the formation of cyclic adenosine monophosphate (cAMP), which in turn influences metabolism within the cytoplasm. Of particular interest is the finding that adenylate cyclase remains inhibited in alcoholics 12-48 months following abstinence (Tabakoff et al., 1988).

More important than the disruption of the cell membrane is the effect of alcohol on the gamma-aminobutyric acid (GABA) system and glutamate system of the brain. The brain has three types of GABA receptors: A, B, and C. GABA A receptors are the targets for alcohol, benzodiazepines, barbituates, and neurosteroids. Stimulation of the GABA receptor by the binding of these compounds causes an ion channel to open temporarily and emit chloride ions into the cell. Alcohol enhances the influx of chloride ion, and the result is sedative and anxiolytic effects. Chronic use of alcohol down-regulates the GABA system, and the neuron eventually becomes dependent on alcohol to enable GABA to function. If alcohol is withdrawn, the opening of the chloride ion channel fails, because GABA is no longer capable of performing the task secondary to the cell, having adapted to the role of alcohol. Thus, the cell becomes hyperexcitable, leading to irritability, insomnia, hypertension, tachycardia, and possibly hallucinations and seizures.

The second major neurotransmitter system involving alcohol is the glutamate system, and in particular the glutamate receptor N-methyl-D aspartate (NMDA). Ethanol is a potent inhibitor of the NMDA receptor and most likely blocks NMDA-stimulated calcium uptake. The NMDA receptor is involved in memory formation, neuronal excitability, and seizures. Alcohol's acute actions on this receptor leads to sedative, amnestic, and anxiolytic effects. However, when alcohol is withdrawn, the NMDA receptor becomes abnormally excited, and seizure activity and hypoxic damage may result.

Low doses of alcohol activate the norepinephrine system via the reticular activating system in the brainstem. This action stimulates behavior and arousal, and as the concentration of alcohol in the brain increases, the dopamine pathways in the mesolimbic system assume importance as a reward center. This system, which involves the ventral tegmental area and projections to the nucleus accumbens, is the same system activated by opiates and stimulants.

It has also been demonstrated that individuals with family histories that are positive for alcoholism show increased beta-endorphin release and in-

creased euphoria after drinking alcohol. Similarly, serotonin function might predispose to alcoholism, as evidenced by the fact that some alcoholics have been found to have reduced serotonergic function and, although inconsistent, some serotonin medications have attenuated drinking behavior (Dackis & O'Brien, 2002; Pettinati, 2001)

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