Alcohol

Question 1

Alcohol is not very potent:

• Standard Dose:
• Consumption:

Answer 1

1. Standard “dose” is about 14 g:
   
   • 12 ounce beer
   • 5 ounce wine
   • 1.5 ounce 80 proof liquor
2. Consumption:
   
   • Blood alcohol concentration of 30 mg/deciliter
     
     • 30 mg%
     • 0.03% w/v
   • Equal to 7 mM

Question 2

Pharmacokinetics:

Absoprtion

Answer 2

• Small, water soluble molecule which is absorbed rapidly from GI tract after oral administration
  
  • Primarily absorbed from small intestine
• Rate of absorption influenced by:
  
  • ethanol concentration, rate of consumption and composition of gastric contents
  • Absorption is decreased if gastric emptying is delayed

Question 3

Pharmacokinetics:

Distribution

Answer 3

• Distributed to total body water (Vd = volume of total body water)
• Distribution depends on degree of tissue vascularization
  
  • ​amount of blood flow
• Freely membrane permeable
  
  • ​Including INTO the alveolae from the lung
    capillaries
  • This is the basis for the breathalizer test of expired air

​

Question 4

Metabolism/ Biotransformation:

General issues

Answer 4

• Significant first pass effect in liver
  
  • 90-98% of ethanol ingested is metabolized to acetaldehyde

Question 5

Alcohol Dehydrogenase Pathway (ADH):

Answer 5

1. Primary pathway for ethanol oxidation to acetaldehyde
   
   • rate limiting
2. Primarily in the liver, but also present in other tissues
3. Kinetics of ethanol elimination by this pathway are zero-order
   
   • 10 g/hr in 70 g person at the concentrations of ethanol consumed
   • since one drink is about 14g ⇒ 1.5 hours to metabolize the drink

Question 6

Microsomal Ethanol Oxidizing System (Mixed Function
Oxidase System) (MFOS):

Answer 6

• High Km - little contribution at concentrations below 100 mg/dl
  
  • low affinity
• Induced in alcoholics
  
  • CYP2E1 - influences metabolism of other drugs

Question 7

Acetaldehyde Metabolism:

Answer 7

1. Mitochondrial aldehyde dehydrogenase (ALDH)
2. Oxidizes acetaldehyde to acetate
3. Genetic polymorphisms
4. Inhibition by disulfiram

Question 8

Ethanol Metabolism: Consequences

Answer 8

Two major metabolic consequences

1. Increased NADH results in inhibition of TCA cycle
   
   • Reduced gluconeogenesis
   • Decreased oxidation of fats
2. Increased acetaldehyde
   
   • Generation of protein adducts
   • Decreased glutathione
   • Inhibits microtubules

Question 9

Mechanism of Action in the CNS:

Answer 9

1. Affects function of several ion channels
2. In particular, activates GABA receptor-ligand gated Cl-channel
3. Disturbs balance between excitatory and inhibitory neurotransmission

Question 10

Acute Effects of Ethanol in CNS:

Answer 10

Ethanol is a dose-dependent, CNS depressant:

• BAC: 50-100 (mg/dl) ⇒ Sedation, subjective “high,” increased reaction times
• BAC: 100-200 (mg/dl) ⇒ Impaired motor function, slurred speech, ataxia
• BAC: 200-300 (mg/dl) ⇒ Emesis, stupor
• BAC: 300-400 (mg/dl) ⇒ Coma
• BAC: > 500 (mg/dl) ⇒ Respiratory depression, death

Question 11

Consequences of Chronic Alcohol Consumption
Liver and GI tract

Answer 11

1. Liver
   
   • Steatosis - fatty liver
   • Hepatitis C - often co-morbid
   • Alcoholic cirrhosis - due to necrosis and chronic inflammation
2. GI Tract
   
   • Chronic gastritis
   • Pancreatitis
   • Diarrhea
   • Malabsorption of Vitamins

Question 12

Consequences of Chronic Alcohol Consumption:

Nervous System

Answer 12

1. Tolerance
   
   • Adaptive neuronal changes
   • Metabolic tolerance
2. Dependence
   
   • Psychological dependence - craving
   • Physical dependence - withdrawal is dangerous, can get seizures
3. Neurotoxicity
   
   • Neuralgias and peripheral nerve injury
   • Cerebral/Cerebellar Atrophy
   • Wernicke’s Encephalopathy
   • Korsakoff’s Psychosis
   • Psychiatric Disorders

Question 13

Teratogenic Effects / Fetal Alcohol Syndrome:

Answer 13

1. Associated with chronic maternal alcohol abuse
2. Characterized by:
   
   • retarded body growth
   • microcephaly
   • poor coordination
   • facial abnormalities
   • minor joint abnormalities
3. Mechanism of Teratogenic Effect
   
   • ​​direct inhibitory effect of ethanol or acetaldehyde on embryonic cellular proliferation
4. Severity ⇒ dose-dependent
   
   • minimum dose not known
   • advise abstinence

Question 14

Alcohol-Drug Interactions:

Answer 14

1. Effects of ethanol augmented by other CNS depressants
   
   • ​​Barbiturates; benzodiazepines; opiates; neuroleptics
2. Ethanol can also interfere with drug metabolism
   
   • Acute, high doses inhibit CYP2E1 mediated metabolism
   • Chronic ethanol induces CYP2E1 enzymes therefore accelerates metabolism of some drugs
3. Acetaminophen liver toxicity worse in alcoholic or during acute ethanol intoxication​

Question 15

Management of Acute Intoxication:

Answer 15

1. Goal ⇒ prevention of severe respiratory depression and aspiration of vomitus
2. Lethal concentration - generally above 400 mg/dl
3. Metabolic alterations may require treatment of hypoglycemia, ketosis and electrolyte imbalance

Question 16

Define alcohol withdrawal:

Answer 16

• Syndrome - agitation, anxiety, insomnia, seizures, mood swings
• Severity - proportional to degree and duration of alcohol abuse

Question 17

What are the objectives of drug therapy for alcohol withdrawal?

Answer 17

prevention of seizures, delirium and arrhythmias

• Benzodiazepines – Diazepam (Diastat® / Dizac™ / Valium®), Chlordiazepoxide (Librium®)
  
  • Gradual reduction of dose “tapering off”

Question 18

Pharmacotherapy of Alcoholism:

Answer 18

1. Naltrexone (Depade® / Re Via® / Vivitrol™)
   
   • Therapeutic Use - reduces “urge to drink”; increases control
   • Mechanism of Action - opioid receptor antagonist
   • Best together with psychosocial therapy
2. Acamprosate (Campral®)
   
   • Decreases drinking frequency and reduces relapse
   • Mechanism of action - GABA mimetic
   • Well tolerated - primary side effect is diarrhea
3. Disulfiram (Antabuse®)
   
   • Therapeutic Use - Aversion Therapy
   • Mechanism of Action - inhibition of aldehyde dehydrogenase
   • Pharmacologic Effects - acetaldehyde syndrome
   • Not very effective