Stage Three of the Five stages of inebriation, ca.1863–1868, by Charles Percy Pickering<unk>  is metabolized by a normal liver at the rate of about 8 grams of pure ethanol per hour. 8 grams or is one British standard unit. An "abnormal" liver with conditions such as hepatitis, cirrhosis, gall bladder disease, and cancer is likely to result in a slower rate of metabolism. Ethanol is metabolised to acetaldehyde by<unk>  dehydrogenase (ADH), which is found in many tissues, including the gastric mucosa. Acetaldehyde is metabolised to acetate by acetaldehyde dehydrogenase (ALDH), which is found predominantly in liver mitochondria. Acetate is used by the muscle cells to produce acetyl-CoA using the enzyme acetyl-CoA synthetase, and the acetyl-CoA is then used in the citric acid cycle. As drinking increases, people become sleepy, or fall into a stupor. After a very high level of consumption, the respiratory system becomes depressed and the person will stop breathing. Comatose patients may aspirate their vomit (resulting in vomitus in the lungs, which may cause "drowning" and later pneumonia if survived). CNS depression and impaired motor co-ordination along with poor judgment increases the likelihood of accidental injury occurring. It is estimated that about one-third of<unk> -related deaths are due to accidents and another 14% are from intentional injury. In addition to respiratory failure and accidents caused by effects on the central nervous system,<unk>  causes significant metabolic derangements. Hypoglycaemia occurs due to ethanol's inhibition of gluconeogenesis, especially in children, and may cause lactic acidosis, ketoacidosis, and acute kidney injury. Metabolic acidosis is compounded by respiratory failure. Patients may also present with hypothermia. Mechanism In the past,<unk>  was believed to be a non-specific pharmacological agent affecting many neurotransmitter systems in the brain. However, molecular pharmacology studies have shown that<unk>  has only a few primary targets. In some systems, these effects are facilitatory and in others inhibitory. Among the neurotransmitter systems with enhanced functions are: GABAA, 5-HT3 receptor agonism (responsible for GABAergic (GABAA receptor PAM), glycinergic, and cholinergic effects), nicotinic acetylcholine receptors. Among those that are inhibited are: NMDA, dihydropyridine-sensitive L-type Ca2+ channels and G-protein-activated inwardly rectifying K+ channels.<unk>  is also converted to a lipid metabolite phosphatidylethanol by phospholipase D2 and this metabolite is shown to bind directly to and regulate ion channels. The result of these direct effects is a wave of further indirect effects involving a variety of other neurotransmitter and neuropeptide systems, leading finally to the behavioural or symptomatic effects of<unk> . The order in which different types of<unk>  are consumed ("Grape or grain but never the twain" and "Beer before wine and you'll feel fine; wine before beer and you'll feel queer") does not have any effect. GABAA receptors Ethanol binding to GABAA receptor Many of the effects of activating GABAA receptors have the same effects as that of ethanol consumption. Some of these effects include anxiolytic, anticonvulsant, sedative, and hypnotic effects, cognitive impairment, and motor incoordination. This correlation between activating GABAA receptors and the effects of ethanol consumption has led to the study of ethanol and its effects on GABAA receptors. It has been shown that ethanol does in fact exhibit positive allosteric binding properties to GABAA receptors. However, its effects are limited to pentamers containing the δ-subunit rather than the γ-subunit. GABAA receptors containing the δ-subunit have been shown to be located exterior to the synapse and are involved with tonic inhibition rather than its γ-subunit counterpart, which is involved in phasic inhibition. The δ-subunit has been shown to be able to form the allosteric binding site which makes GABAA receptors containing the δ-subunit more sensitive to ethanol concentrations, even to moderate social ethanol consumption levels (30mM). While it has been shown by Santhakumar et al. that GABAA receptors containing the δ-subunit are sensitive to ethanol modulation, depending on subunit combinations receptors could be more or less sensitive to ethanol. It has been shown that GABAA receptors that contain both δ and β3-subunits display increased sensitivity to ethanol. One such receptor that exhibits ethanol insensitivity is α3-β6-δ GABAA. It has also been shown that subunit combination is not the only thing that contributes to ethanol sensitivity. Location of GABAA receptors within the synapse may also contribute to ethanol sensitivity.
Alcohol intoxication
Hepatic encephalopathy
Drug withdrawal
Traumatic brain injury
Nicotine withdrawal
Wernicke encephalopathy
Alcohol withdrawal syndrome
Meningitis