Block 5 - Alcohols Learning Objectives

Front 1

1.Describe the acute CNS actions of ethanol and discuss their relationship to blood alcohol levels.

Back 1

a. Ethanol is a CNS depressant. The stimulation that appears to occur initially when consuming ethanol is due to depression of inhibitory centers in the CNS.
b.The effects of ethanol on the CNS are more evident when blood alcohol concentration is rising than when it is falling. This is an example of acute tolerance.
c.Both sensory and motor activity are affected.
d.The “stages” of intoxication correlate to blood alcohol level and include:
i. Subclinical
ii. Euphoria
iii. Excitement
iv. Confusion
v. Stupor
vi. Coma
vii. Death (diaphragmatic blockade)

Front 2

2.Discuss current theories about the mechanism of action of ethanol in the CNS.

Back 2

a. Ethanol increases the activity of GABA by binding the GABA-A receptor and increasing GABA binding. Ethanol is not a GABA agonist; rather it potentiates the effect of GABA. GABA is inhibitory.
b. Ethanol also decreases the activity of glutamate pathways.

Front 3

3. Describe the pharmacokinetics of ethanol and why zero order elimination kinetics are important.

Back 3

a. Ethanol is absorbed via passive diffusion. It is mostly absorbed in the intestine, but some absorption from the stomach occurs.
b. Bioavailability is dose dependent. The bioavailability of alcohol in a “drink” is approximately 80%.
c. Peak blood concentrations occur in 30-60 minutes.
d. Ethanol is distributed throughout body water.
e. Approximately 98% of ethanol is eliminated by enzymatic oxidation via alcohol dehydrogenase, a microsomal mixed function oxidase (CYP 2E1), and catalase. It is eliminated by first order kinetics initially, and once saturation occurs zero order kinetics are observed. Alcohol dehydrogenase is saturated at an approximate blood concentration of 0.03%.

Front 4

4. Describe the toxicity of ethanol.

Back 4

a. Ethanol can lead to respiratory depression and death at high blood alcohol levels (0.45% BAC).
b. Ethanol has toxic effects on the liver. Transformation of NAD to NADH during ethanol metabolism decreases NAD, which decreases fatty acid oxidation. Increased NADH favors fatty acid accumulation. Engorgement of hepatocytes with fat, protein, and water occurs acutely and is exacerbated with chronic use. Chronic inflammation and damage to the liver occur with chronic use of ethanol, with subsequent necrosis and fibrosis leading to a cirrhotic liver. Other effects include increased lipid peroxidation, damage to mitochondria, and depletion of glutathione.
c. Ethanol also has teratogenic effects and can lead to fetal alcohol syndrome.

Front 5

5. Discuss the use of disulfiram and naltrexone in the treatment of chronic alcoholism.

Back 5

a. Disulfiram alters the intermediary metabolism of alcohol. This leads to a 5-10X increase in blood acetaldehyde levels when a patient taking disulfiram drinks alcohol. Acetaldehyde causes numerous unpleasant symptoms including a hot, flushed face, intense throbbing of the head and neck, and pulsating headache. Other symptoms experienced when combining disulfiram and alcohol include respiratory difficulties, nausea, copious vomiting, sweating, thirst, chest pain, considerable hypotension, orthostatic syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. These effects are elicited at even low volumes of alcohol and last between 30 minutes and several hours. A problem with this therapy is that most alcoholics are not deterred by the unpleasant effects and drink through them.

b. Naltrexone is an opiate receptor antagonist. It reduces the positive reinforcement of alcohol and reduces craving. It has been shown to prevent relapse to heavy drinking, but has been less effective at maintaining abstinence.

Front 6

6. Discuss the use of ethanol and fomepizole in the treatment of methanol and ethylene glycol poisoning.

Back 6

a. The products of methanol and ethylene glycol metabolism are toxic. Ethanol, methanol, and ethylene glycol are metabolized by the same enzymes, so ethanol can be used as a competitive inhibitor of methanol or ethylene glycol metabolism.
b. Fomepizole is an inhibitor of alcohol dehydrogenase and can also be used to inhibit metabolism of methanol and ethylene glycol and prevent poisoning. It has fewer acute side effects than ethanol, but is expensive.

Front 7

7. Discuss the interaction of acetaminophen and ethanol.

Back 7

a. Acetaminophen is metabolized by several pathways, and under normal conditions is mostly converted to a nontoxic metabolite (glucuronidation). However, even at normal doses some of the acetaminophen can be converted by CYP2E1 to a quinone type of reactive intermediate. This is usually not a problem because glutathione is available to rapidly transform (detoxify) the intermediate to mercapturate. Chronic alcohol consumption deplete glutathione stores and detoxification of the reactive quinone is deficient. The reactive quinone reacts with liver tissue to form tissue adducts and can lead to liver failure.
b. The risk of acetaminophen hepatoxicity is also increased by alcohol via induction of CYP2E1. Thus alcohol consumption prior to acetaminophen ingestion (not when both are present in the system simultaneously) increases risk.

Front 8

8. Discuss the dual effects of ethanol on the clearance of drugs metabolized by P4502E1.

Back 8

a. Ethanol may undergo drug interactions with other drugs that are metabolized by CYP2E1. However, the specific interaction depends on the BAC of the alcohol.
b. When BAC is high, ethanol is a competitive inhibitor of metabolism of other drugs (i.e. methanol and ethylene glycol).
c. When BAC is low, ethanol induces CYP2E1, causing increased metabolism of other drugs.