Alcohol

Question 1

What are the possible health benefits of alcohol

Answer 1

Moderate alcohol consumption may provide some health benefits, such as: Reducing your risk of developing and dying from heart disease. Possibly reducing your risk of ischemic stroke (when the arteries to your brain become narrowed or blocked, causing severely reduced blood flow). Possibly reducing your risk of diabetes.

Question 2

What is a standard drink

Answer 2

Question 3

What defines moderate drinking

Answer 3

up to 1 drink per day for women and up to 2 drinks per day for men.

Question 4

What defines binge drinking

Answer 4

5 drinks for men in 2 hours. For women it is 4 drinks in 2 hours.

Question 5

Ethanol pharmacokinetics

Answer 5

Ethanol is a small water-soluble molecule that is rapidly absorbed from the GI tract. The presence of food in the gut delays absorption by slowing gastric emptying.

Distribution is rapid, with tissue levels approximating the concentration in blood. Ethanol Vd = 0.5-0.7L/kg, approximately the total body water. Women tend to have a higher peak concentration, in part because they have a lower total body water content.

Excretion: >90% of alcohol consumed is oxidized in the liver, the remainder is excreted through the urine and lung

Question 6

Biotransformation of alcohol

Answer 6

The Biotransformation of alcohol is noteworthy for several reasons. First, some people have genetic mutation that affect alcohol metabolism. Second, the rate of metabolism can change depending on the amount and frequency of alcohol consumption. Third, certain drugs used to treat chronic, excessive drinking work to inhibit alcohol biotransformation.

Question 7

Steps of alcohol metabolism

Answer 7

1. Step 1 - Ethanol to Acetaldehyde

At low ethanol concentrations, the primary pathway for alcohol metabolism is alcohol dehydrogenase (ADH) in the liver. It is also in the brain and stomach. ADH converts EtOH to Acetaldehyde. A byproduct of this reaction is NADH

At high ethanol concentrations, a secondary pathway, the Microsomal Ethanol Oxidizing System (MEOS) is used, also converts EtOH to Acetaldehyde.

2. Step 2 - Acetaldehyde to Acetate

Aldehyde Dehydrogenase converts Acetaldehyde to Acetate. Acetate is broken down to CO2 and water. This reaction also uses NAD+ and also produces NADH.

Question 8

SX of Aldehyde Dehydrogenase deficiency

Answer 8

Some people have a genetic deficiency in mitochondrial Aldehyde Dehydrogenase. Up to a third of east Asians (Chinese, Japanese, and Korean) develop high acetaldehyde concentrations with EtOH consumption. This results in flushing.

Question 9

Order of alcohol metabolsim

Answer 9

Alcohol is unique in that it has zero order and first order kinetics. If ADH is metabolizing EtOH it is a zero order kinetics. Once ADH is saturated (~0.03% or 30 mg/dL), the reaction is first order kinetics.

Question 10

Conversion of alcohol volume

Answer 10

The conversion is - 1 mg/mL = 100 mg/dL = 100mg/100 ml = 0.1g/100 ml = 0.10%

Question 11

Blood Alcohol Concentration (BAC) and clinical effects in nontolerant individuals

Answer 11

Question 12

How does tolerance work in alcoholics?

Answer 12

upregulation of the Microsomal Ethanol-Oxidizing System]

Question 13

EtOH effect on the CNS

Answer 13

Actually, there is no EtOH “receptor”. Basically, it affects a large number of membrane proteins that participate in signaling

Acute EtOH enhances the action of GABA and GABAA receptors (consistent with GABA-mimetics ability to intensify the effects of alcohol and GABA antagonist attenuating the effects). EtOH also inhibits the ability of glutamate to open the cation channel associated with the NMDA subtype of glutamate receptors. Alcohol induced “blackouts” (periods of memory loss that accompany high levels of alcohol) my results from inhibition of NMDA receptor.

Question 14

EtOH impact on the heart

Answer 14

Consumption of moderate amounts of EtOH (100 mg/dL) depresses myocardial contractility.

Question 15

EtOH impact on smooth muscle

Answer 15

EtOH is a vasodilator. This is likely due to CNS effects (depression of the vasomotor center) and smooth muscle relaxation by acetaldehyde. In severe overdose, hypothermia (due to vasodilation) may be marked in cold environments. (For instance, having a few beers while ice fishing or walking home from the bar on a cold night or being a homeless alcoholic).

Question 16

Cause of most EtOH related deaths

Answer 16

EtOH related deaths are caused by liver disease, cancer, accidents, and suicide.

Question 17

MOA of EtOH liver disease

Answer 17

Alcoholic fatty liver is reversible, but may progress to alcoholic hepatitis and finally cirrhosis and liver failure. This is the leading cause of liver cirrhosis and liver transplantation in the US.

One way acute alcohol consumption causes liver disease is through a byproduct of metabolism, NADH. Increasing the NADH:NAD+ ratio favors fatty acid accumulation causing hepatic steatosis. Chronic alcohol consumption can lead to other nutritional problems including acetaldehyde accumulation, vitamin (thiamine) deficiency, and caloric replacement.

Question 18

Impact of EtOH on GI tract

Answer 18

Chronic alcohol ingestion is by far the most common cause of chronic pancreatitis in the Western world. EtOH is toxic to pancreatic acinar cells, alters pancreatic epithelial permeability and promotes the formation of protein plugs and calcium carbonate-containing stones.

Chronic alcoholics are prone to gastritis and increased susceptibility to blood and plasma protein loss during drinking. This can lead to anemia and protein malnutrition. Other damage to GI tract can result in diarrhea, weight loss, and multiple vitamin deficiencies.

Malnutrition form dietary deficiency and vitamin deficiencies due to malabsorption are common among alcoholics.

Question 19

EtOH toxicity on nervous system

Answer 19

Withdrawal syndromes are common for chronic alcohol drinkers and indicate physical dependence. Classically, these symptoms include hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe cases. (Delirium tremens is a rapid onset of confusion usually caused by withdrawal from alcohol)

Psychological dependence is characterized by a compulsive desire to experience the rewarding effects of alcohol and avoid the negative consequences of withdrawal

Tolerance and Dependence

Consumption of large amounts of alcohol over an extended period (years) often leads to neurological defects - general symmetric peripheral nerve injury starting with distal parasthesias of hands and feet. Other defects include gait disturbances, ataxia due to degeneration of the nervous system, dementia, and (rarely) demyelinating disease.

Question 20

What is Wernicke-Korsakoff syndrome

Answer 20

. It is characterized by paralysis of the external eye muscles, ataxia, and a confused state that can proceed to coma and death. It is associated with thiamin deficiency, but rarely seen independent of alcoholism. It can be difficult to diagnose from the acute confused state created by alcoholism intoxication or the features of withdrawal. A distinguishing feature of Wernicke’s encephalopathy is the longer duration of confusion and the relative absence of the agitation that would be expected during withdrawal.

All patients suspected of having Wernicke-Korsakoff syndrome should receive thiamine therapy. Often ocular signs, ataxia, and confusion improve upon thiamine administration. Most patients are left with a chronic disabling memory disorder known as Korsakoff’s psychosis.

Question 21

EtOH cardiovascular toxicity

Answer 21

Chronic consumption of large amounts of alcohol is associated with dilated cardiomyopathy with ventricular hypertrophy and fibrosis. Cellular changes include membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and up-regulation voltage dependent of Ca2+ channels.

Binge drinking is associated with atrial and ventricular arrhythmias. Patients undergoing alcohol withdrawal can develop arrhythmias due to abnormalities in K or Mg metabolism and enhanced catecholamine release. Seizures, syncope, and sudden death during alcohol withdrawal may be due to these arrhythmias.

Question 22

EtOH impact on blood

Answer 22

Alcohol can indirectly affect hematopoiesis through metabolic and nutritional effects and directly inhibit the cell proliferation in bone marrow.

The most common effect in chronic drinkers is mild anemia from folic acid deficiency. Iron deficiency anemia may result from GI bleeding.

Question 23

EtOH impact on Endocrine System and Electrolyte Balance

Answer 23

Chronic alcohol use can lead to gynecomastia and testicular atrophy suggesting a steroid hormone imbalance.

Chronic liver disease in alcoholics may have disorders of fluid and electrolytes balance, including ascites, edema, and effusions. These may be related to decreased protein synthesis and portal hypertensison, alterations in whole body K+ (from vomiting and diarrhea), secondary aldosteronism (which can lead to muscle weakness).

Some alcoholics develop hypoglycemia due to impaired hepatic gluconeogenesis. Some develop ketosis due to excessive lipolytic factors (increased cortisol and growth hormone).

Question 24

EtOH impact on immune system

Answer 24

Alcohol suppresses immune response in multiple ways: the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, reduced function and number of T cells.

Chronic heavy alcohol use predisposes one to the development of infections, especially of the lung.

Question 25

What cancers are associated with EtOH

Answer 25

High risk tissues are the mouth, pharynx, larynx, esophagus, and liver. Some evidence for an increase in breast cancer.

Why would this be? Alcohol itself does not appear to be a carcinogen, but it may carry carcinogens from the fermentation process. Coupled with altered liver activity during alcohol consumption, the effects of those carcinogens could be enhanced.

Question 26

Impact of EtOH on fetus

Answer 26

Intrauterine growth retardation

Microcephally

Poor coordination

Underdevelopment of midfacial region (appearing as a flattened face)

Minor joint abnormalities

Question 27

What is the min ammount that can cause fetal alcohol syndrome

Answer 27

here is no “safe” number of drinks during pregnancy; 2.5 oz of alcohol may be sufficient for Fetal Alcohol Syndrome.

Question 28

MOA of fetal alcohol syndrome

Answer 28

The fetal liver has little alcohol dehydrogenase, so metabolism is minimal. In animal models, it seems ethanol triggers apoptotic neurodegeneration to negatively impact the nervous system.

Question 29

Alcohol drug interactions

Answer 29

cohol consumption can impact the metabolism of other drugs. Chronic alcohol consumption at high levels (3 or more drinks/day) can induce the hepatic Cytochrome P450s. This can: 1) lead to enhanced metabolism of drug to an inactive form and result in sub-therapeutic levels, 2) prevent metabolism of a drug, leading to higher (potentially toxic) levels or 3) causes a normally non-toxic drug to metabolized to a toxic compound.

Alcohol can be additive with other sedative-hypnotics and is why these drugs should not be taken with alcohol.

Alcohol can potentiate the effects of vasodilators and oral hypoglycemic agents. Also, it enhances the antiplatelet action of aspirin.

Question 30

Alcohol and acetaminophen

Answer 30

Normally, acetaminophen gets metabolized by Phase II reactions (Glucuronidation and Sulfation). When the substrates for those reactions get depleted (by high acetaminophen doses) and CYP2E1 and CYP3A4 get up-regulated (by alcohol consumption). Acetominophen undergoes the Phase I reaction. That can produce reactive toxic intermediates that cause liver cell death. This is an important reason for not taking acetaminophen for a headache that results from excessive alcohol consumption.

Question 31

Genetics and alcoholism

Answer 31

Polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase (read: poor metabolism and worse “hangover”) seem to protect against alcoholism.

Candidate gene products that increase the likelihood of alcoholism include dopamine D2 and D4 receptors, beta1 subunit of GABAA receptor, tyrosine hydroxylase (involve in dopamine, norepinephrine, epinephrine synthesis), and neuropeptide Y.

Question 32

Major concerns during EtOH withdrawal and strategy

Answer 32

Seizures

Delirium

Arrhythmias

Major tools: Potassium, Magnesium, and Phosphate balance in accordance with kidney function. Thiamine therapy is initiated in all cases.

Drug treatment for detoxification

Substitute a long acting sedative-hypnotic drug for alcohol

Gradually reduce the drug concentrations (“taper”)

Question 33

Best drugs for detox

Answer 33

Sedative-hypnotics. What are good sedative-hypnotics? Basically, any benzodiazepine will work. Choice will depend on pharmacokinetic or economic considerations.

Long acting means less dosing and built in tapering. If liver disease then short acting

Anti-convulsants . Alcohol withdrawal is a major cause of seizures in adults. Gabapentin and Topamax (Topiramate) are administered to reduce seizures.

Antipsychotic medications . These are administered to control hallucinations or for patients that have a history of psychosis that makes them irritable or aggressive.

Question 34

WHAT DRUGS HELP TREAT ALCOHOLISM?

Answer 34

Disulfiram, naltrexone, acamprosate

Question 35

Disulfiram MOA

Answer 35

Disulfiram - this drug inhibits aldehyde dehydrogenase causing Acetaldehyde to build up. Not surprisingly, in the absence of alcohol consumption, there is little effect. However, within 30 minutes of alcohol consumption the patient experiences flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion.

It is rapidly absorbed from the GI tract, but 12 hours are required for its full action. It’s elimination rate is slow and may persist for several days after the last dose.

Disulfiram inhibits the metabolism of other drugs including phenytoin, oral anticoagulants, and isoniazid. Some non-prescription medicines contain EtOH, and patients should not use those.

Question 36

Acamprosate MOA

Answer 36

Acamprosate - antagonist of excitatory neurotransmitters (e.g. NMDA) in the CNS. It is approved for reducing alcohol cravings for those in recovery. It is most effective for those who have be abstinent for several days to two weeks. There is no effect on withdrawal symptoms.

Question 37

Role of psychosocial therapy

Answer 37

These programs are moderately successful with ~50% relapsing in the first year. Alcoholics Anonymous (AA - www.aa.org) is one of the most recognizable programs.

The psychosocial therapies treat underlying problems, usually depression and anxiety disorders. If these are not addressed, the detoxified alcoholic will likely relapse.

Question 38

Common alcohols that arent EtOH

Answer 38

Methanol (MeOH) and Ethylene glycol.

Question 39

Metabolism of methanol

Answer 39

Methanol is converted to the toxic metabolites formaldehyde and formate by alcohol dehydrogenase and aldehyde dehydrogenase. By inhibiting alcohol dehydrogenase, fomepizole or ethanol will reduce the formation of toxic metabolites.

Question 40

Sx of methanol poisoning

Answer 40

The characteristic symptom is a visual disturbance of described as “being in a snowstorm”. Blurred vision with a clear sensorium suggests the diagnosis of MeOH poisoning. Breath and urine may smell like formaldehyde. Toxicity is due to the metabolites, so there is often a delay of 30 hours after ingestion for symptoms to appear. Other late signs include changes in the retina, bradycardia, prolonged coma, seizures, and resistant acidosis and imply a poor prognosis. Usually, death is due to cessation of respiration.

Question 41

TX for methanol poisoning

Answer 41

There are three modalities of treatment of MeOH poisoning.

1. suppress metabolism by blocking alcohol dehydrogenase (administer EtOH or fomepizole)

2. dialysis to enhance removal of methanol and toxic products

3. alkalinization to counteract metabolic acidosis.

Question 42

Where is ethylene glycol found

Answer 42

Ethylene glycol is used in anti-freeze solutions. Young children and animals can be attracted by the sweet taste. Again, the parent compound isn’t a problem, it’s the metabolites (aldehydes and oxalate).

Question 43

SX of ethylene glycol poisoning

Answer 43

There are three stages.

1. Within the first few hours, there is transient excitation followed by CNS depression.
2. After 4-12 hours, severe metabolic acidosis develops from the metabolites.
3. Final stage is renal insufficiency due to oxalate in renal tubules.

Question 44

TX for ethylene glucol poisoning

Answer 44

Treatment (similar to MeOH), early EtOH infusion and hemodialysis. Fomepizole is an alcohol dehydrogenase inhibitor that decreases toxic metabolites as well. Fomepizole can also be used in MeOH poisoning. Fomepizole is associated with headache, nausea, dizziness, and minor allergic reactions.