Alcohol

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🧬 Receptor activityPH

Mechanism of actionPH

Ethanol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes.
... Ethanol is known to affect a large number of membrane proteins that participate in signaling pathways such as neurotransmitter receptors, enzymes, and ion channels, and there is extensive evidence that ethanol interacts with a variety of neurotransmitters. The major actions of ethanol involve enhancing the inhibitory effects of gamma-aminobutyric acid (GABA) at GABAa receptors and blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate, an excitatory amine acid (EAA) receptor. Animal studies indicate that the acute effects of ethanol result from competitive inhibition of glycine binding to NMDA receptor and disruption of glutamatergic neurotransmission by inhibiting the response of the NMDA receptor. Persistent glycine antagonism and attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in tolerance to ethanol by enhancing EAA neurotransmission and NMDA receptor upregulation. The latter appears to involve selective increases in NMDA R2B subunit concentrations and other molecular changes in specific brain loci. The abrupt withdrawal of ethanol thus produces a hyperexcitable state that leads to the ethanol withdrawal syndrome and excitotoxic neuronal death. GABA-mediated inhibition, which normally acts to limit excitation, is eliminated during ethanol withdrawal syndrome and further intensifies this excitation. In addition, NMDA receptors function to inhibit the release of dopamine in the nucleus accumbens and mesolimbic structures, which modulate the reinforcing action of addictive xenobiotics such as ethanol. By inhibiting NMDA receptor activity, ethanol could increase dopamine release from the nucleus accumbens and ventral tegmental area and could thus create dependence. Chronic ethanol administration also results in tolerance, dependence, and an ethanol withdrawal syndrome, mediated, in part, by desensitization and or downregulation of GABAa receptors.
The development of alcoholic ketoacidosis (AKA) requires that a combination of physical and physiologic events occur. The normal response to starvation and depletion of hepatic glycogen stores is for amino acids to be converted to pyruvate. Pyruvate can serve as a substrate for gluconeogenesis, be converted to acetyl-CoA, which can enter the Krebs cycle or can be utilized in various biosynthetic pathways (eg, fatty acid, ketone bodies, cholesterol, and acetylcholine) ... Ethanol metabolism generates NADH, resulting in an excess of reducing potential. This high redox state favors the conversion of pyruvate to lactate, diverting pyruvate from being a substrate for gluconeogenesis. To compensate for the lack of normal metabolic substrates, the body mobilizes fat from adipose tissue and increased fatty acid metabolism as an alternative source of energy. This response is mediated by a decrease in insulin and an increased secretion of glucagon, catecholamines, growth hormone, and cortisol. Fatty acid metabolism results in the formation of acetyl-CoA and it combines with the excess acetate that is generated from ethanol metabolism to form acetoacetate. Most of the acetoacetate is reduced to beta-hydroxybutyrate due to the excess reducing potential or high redox state of the cell. Volume depletion interferes with the renal elimination of acetoacetate and beta-hydroxybutyrate, and contributes to the acidosis. An elevated lactate concentration may result from shunting from pyruvate or from hypoperfusion or infection that may coexist with the underlying ketoacidosis.
Adenosine may mediate many of the acute and chronic motor effects of ethanol on the brain. Ethanol, probably through its metabolite, acetate, prevents adenosine uptake, raising synaptic adenosine concentrations. Excessive stimulation of several adenosine receptors in the cerebellum may explain much of the motor impairment from low ethanol concentrations. In fact, animals made tolerant to ethanol develop cross-tolerance to adenosine agonists. In mice, adenosine receptor agonists increase ethanol-induced incoordination while adenosine antagonists decrease this intoxicating response.
Chronic ethanol (alcohol) administration has been associated with alterations in the binding and function of the gamma-aminobutyric acid (GABAA) receptor. To evaluate the mechanism underlying these changes, /the authors/ measured the steady state levels of the mRNAs for the alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6 subunits of the GABAA receptor after chronic ethanol administration to rats and ethanol withdrawal for 24 hr. The results indicated that chronic ethanol administration resulted in a 61% decline in the level of the GABAA receptor alpha 1 subunit mRNAs [3.8 and 4.3 kilobases (kb)] in the cerebral cortex in rats. The levels of the alpha 2 subunit mRNAs (6 and 3 kb) and the alpha 5 subunit mRNA (2.8 kb) were also reduced, by 61, 45, and 51%, respectively, whereas there was no change in the level of the alpha 3 subunit mRNA (3 kb). Furthermore, the ethanol-induced decrease in receptor mRNA levels persisted for 24 hr, after withdrawal of ethanol and returned to control values at 36 hr of withdrawal. alpha 1 mRNA levels in cerebellum also decreased by 28%. The level of the alpha 6 subunit mRNA, which selectively encodes Ro15-4513 binding sites, was found to be increased by approximately 76% in the cerebellum. Also, the photoaffinity labeling studies using [3H]Ro15-4513 indicated an increase in the levels of various protein components of the GABAA receptor, in the cerebellum and the cerebral cortex (e.g., 50- and 55-kDa proteins in the cerebellum and 41- and 50-kDa proteins in the cortex), after chronic ethanol treatment. The increase in alpha 6 mRNA in the cerebellum might be related to the increased labeling of the 55-kDa (approximately 56-kDa) protein and partially responsible for the increased binding ... . Because the alpha 6 subunit is not expressed in cortex, involvement of an as yet unknown subunit in this region cannot be ruled out. The effect of chronic ethanol treatment appears to be specific for GABAA receptor subunit mRNAs, because the same treatment did not alter the levels of glyceraldehyde-3-dehydrogenase mRNA or poly(A)+ RNA. In summary, these data indicate that chronic ethanol treatment results in an alteration in the regulation of expression of GABAA receptor subunit-encoding mRNAs, which could be due to alterations in transcription or mRNA stability.
For more Mechanism of Action (Complete) data for Ethanol (8 total), please visit the HSDB record page.

PharmacodynamicsPH

Alcohol produces injury to cells by dehydration and precipitation of the cytoplasm or protoplasm. This accounts for its bacteriocidal and antifungal action. When alcohol is injected in close proximity to nerve tissues, it produces neuritis and nerve degeneration (neurolysis). Ninety to 98% of ethanol that enters the body is completely oxidized. Ethanol is also used as a cosolvent to dissolve many insoluble drugs and to serve as a mild sedative in some medicinal formulations. Ethanol also binds to GABA, glycine, NMDA receptors and modulates their effects. Ethanol is also metabolised by the hepatic enzyme alcohol dehydrogenase.

Pharmacokinetics

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