Drugs of Abuse 3: Alcohol Flashcards

Question

chronic effects due to alcohol

Answer 1

Dementia – Cortical atrophy/ volume cerebral white matter confusion (encephalopathy), oculomotor symptoms Ataxia – Cerebellar cortex degeneration - gait Wernicke-Korsakoff syndrome (due to thiamine deficiency) Wernicke’s encephalopathy – (hypothalamus/thalamus) Korsakoff’s psychosis – (deep brain e.g. hippocampus)

Answer 2

*alcohol needs NAD+ to be metabolised, but alcoholics use it all up for other processes in the liver. therefore it is not metabolised properly causing lipid and fat build up hence there is more ketosis and lactic acid build up. Fatty liver. In the liver, alcohol is primarily metabolized by cytosolic alcohol dehydrogenase (ADH) to acetaldehyde, which is further metabolized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). Both enzymes use NAD+ as a cofactor, producing a reducing equivalent NADH in both steps. Increased production of NADH was implicated in the disruption of many dehydrogenase-related reactions in the cytoplasm and mitochondria [i.e. the tricarboxylic acid cycle (TCA) and β-oxidation of fatty acids], thereby suppressing energy supply and fatty acid oxidation, which in turn results in alcoholic fatty liver. Cytochrome P450 2E1 (part of the microsomal ethanol oxidising system) leaks oxygen radicals as part of its operation and when they exceed the cellular defense systems they result in oxidative stress with its pathologic consequences. This is true when excess alcohol has to be metabolized, as in alcoholic steatohepatitis, or when CYP2E1 is confronted by an excess of ketones and fatty acids associated with diabetes, obesity, or both, resulting in nonalcoholic steatohepatitis. Alcohol related problems for Glycolysis – Glucose to pyruvate (requires 2 x NAD+), pyruvate into acetyl coA (requires 2 x NAD+), acetyl coA into Krebs Cycle (requires 6 x NAD+). With alcohol using up NAD+, then pyruvate must be converted to lactate to generate NAD+ for glycolysis. Acetyl coA unable to enter citric acid cycle are transformed to ketones.

Answer 3

acidosis and ketosis -> inflammatory changes -> hepatitis and cirrhoisis The oxidative stress caused by CYP2E1 induction and mitochondrial injury results in lipid peroxidation and membrane damage. In addition, the acetaldehyde produced by the oxidation of ethanol has toxic effects, decreasing the activity of key enzymes, and markedly reducing oxygen use in mitochondria damaged by long-term ethanol consumption. The impaired oxidation capacity of the mitochondria may, in turn, interfere with the oxidation of acetaldehyde leading to a vicious circle of progressive acetaldehyde accumulation and greater mitochondrial injury. Moreover, acetaldehyde promotes cell death by depleting the concentration of reduced glutathione (GSH), inducing lipid peroxidation, and increasing the toxic effect of free radicals. Oxidative stress promotes inflammation, which is aggravated by an increase of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) in the Kupffer cells. Kupffer cells are a major source of cytokines. Acetaldehyde, the first metabolite of ethanol, can upregulate transcription of collagen I directly as well as indirectly by upregulating the synthesis of transforming growth factor-beta 1 (TGF-beta1).

Answer 4

Fibroblasts (connective tissue cells) – Supportive framework Hepatocyte regeneration- decreases Fibroblasts - increases Active liver tissue - decreases

Answer 5

decrease Mortality from coronary artery disease (Men 2-4 units/day); increase HDLs increase tPA levels/ platelet aggregation

Answer 6

the acetaldehyde produced leads to damage to gastric mucosa- which is carcinogenic

Answer 7

increase ACTH | decrease testosterone secretion

Answer 8

because symptoms peak as blood alcohol conc tends to 0

Answer 9

Nausea Irritant  Vagus  Vomiting center Headache Vasodilation Fatigue 1. Sleep deprivation, 2. ‘Rebound’ Restlessness and muscle tremors ‘Rebound’ Polyuria and polydipsia ↓ ADH secretion

Answer 10

Sleep Water drinking – does it help clear toxins (e.g. acetaldehyde?) Kidney Int 67 : 613 –621, 2005 – 15min water load is largely excreted Water mixed with an easily absorbed sugar is largely excreted