Alcohols

Question 1

Ethanol

Absorption

Answer 1

• Rapidly absorbed by passive diffusion from the stomach, small intestine and colon
• Rate of absorption from the stomach is influenced by food content
• Distribution is rapid, with tissue levels approaching those of the blood
• [Ethanol] that any organ receives is proportional to the blood flow to that organ
• Because the brain receives a high blood flow, high levels are achieved rapidly
• The placenta is permeable to ethanol

Question 2

Ethanol

Metabolism

Answer 2

• 90% oxidized by the liver via “first pass” metabolism
  
  • Limited and exhibits zero order kinetics d/t depletion of NAD
• Small but consistent portion eliminated through the lungs
  
  • Ratio between exhaled air and blood alcohol is 1/2100
  • Basis for the breathalyzer test
• A portion is metabolized by GI tract
  
  • Significant male/female differences
    
    • Females have less ADH in the digestive tract
      
      • ↑ Vulnerability of females to the acute and chronic effects of ethanol
    • Body water content of females < males
      
      • Given dose ⇒ higher BAC in females
      • Contributes to the higher ethanol concentration in females

Question 3

Ethanol

Biochemical Breakdown

Answer 3

• Major path: alcohol dehydrogenase in liver cytosol
  
  • ADH converts ethanol → acetaldehyde
  • Acetaldehyde → acetate by aldehyde dehydrogenase
  • Acetate → water and CO2 by peripheral tissues
  • Both enzymes utilize NAD⁺
    
    • 1M of ethanol → acetate ⇒ 2 M NADH produced
  • Altered NADH/NAD⁺ ratio has important clinical consequences
  • NADH → NAD⁺ by ETC and by lactate dehydrogenase
    
    • Action of LDH converts pyruvate → lactate
    • ↑ Lactic acid in the blood competes with urate for elimination ⇒ ↑ blood uric acid levels
  • ↑ NADH/ NAD⁺ ⇒ ⊗ gluconeogenesis by removing pyruvate
    
    • Important in the drinker who is not eating or vomiting and has used up glycogen stores
  • Two conditions together ⇒ hypoglycemia
  • Rarely, ~ 48 hrs after EtOH cessation ⇒ alcoholic ketoacidosis
    
    • D/t body’s starvation response ⇒ ↓ insulin and ↑ glucagon
    • Causes the body to use fatty acids as a source of energy ⇒ ketoacidosis
• Minor path: microsomal ethanol oxidizing system (MEOS) [cyp450]
  
  • Km for cytosolic ADH 0.05-30 mM (0.0002 to 0.14%)
  • Km of MEOS ~ 30 mM
  • MEOS not active below blood ethanol levels of ~ 100 mg/dL or 0.1%
  • ↑ BAC ⇒ NAD⁺ depletion ⇒ further ↑ BAC ⇒ MEOS metabolism
  • MEOS induced by chronic ingestion of ethanol
    
    • Partially responsible for tolerance
    • System also responsible for metabolism of several other drugs ⇒ drug interactions

Question 4

Ethanol Metabolism

Genetic Variability

Answer 4

• Alcohol dehydrogenase
  
  • Homodimers or heterodimers exist ⇒ six possible subunits ⇒ many isozymes
  • Considerable racial differences
  • If variant ⇒ ↑ ADH activity ⇒ ± ↑ alcoholism
  • If variant ⇒ ↑ ADH speed ⇒ protective for alcoholism d/t rapid acetaldehyde accumulation
  • Acetaldehyde causes a flushing reaction
• Also significant genetic variation in aldehyde dehydrogenase
  
  • ~50% of Asians have inactive aldehyde dehydrogenase
  • When they consume alcohol, high [acetaldehyde] occur

Question 5

Ethanol

Drug Interactions

Answer 5

• Ethanol enhances CNS depression caused by sedative hypnotics, antidepressants, neuroleptics, sedating antihistamines, or narcotics
• Acutely, high [EtOH] compete with drugs also metabolized by cytochrome P450 system, such as phenytoin
• Chronic use of ethanol causes induction of hepatic metabolizing enzymes ⇒ ↑ the clearance of many drugs
  
  • Cyp450 induction ⇒ ↑ oxidative metabolism of APAP ⇒ ↓ threshold for acetaminophen-induced liver damage
  • Depleted stores of glutathione and damaged liver further enhances toxicity
  • Analgesics should be used with caution in alcoholics
• EtOH + other drugs that inhibit acetaldehyde dehydrogenase ⇒ unusual AEs
  
  • Drugs include metronidazole, cephalosporins, and oral hypoglycemic agents
  • Accumulation of acetaldehyde causes flushing

Question 6

Ethanol

CNS Mechanism

Answer 6

• Acute EtOH effects:
  
  • ↑ transmission @ inhibitory GABA A receptors
  • ↓ transmission @ excitatory NMDA glutamate receptors
    
    • Glutamate (via inhibitory interneuron) exerts a tonic inhibitory control over DA release in the nucleus accumbens
    • Ethanol ⇒ disinhibition ⇒ ↑ dopamine release
  • Acutely ethanol causes a depression of behavioral inhibitory centers in CNS ⇒ initial euphoria and exaggerated feeling of well-being
• Chronic EtOH effects:
  
  • After chronic EtOH consumption systems adapt
  • GABA A receptors become less responsive
  • ↑ Glutamate-sensitive Ca²⁺ channels
  • Removal of ethanol ⇒ rebound stimulatory effect ⇒ withdrawal sx

Question 7

EtOH

CNS Effects

Answer 7

• Acute effects
  
  • Ethanol is a CNS depressant
  • @ Lower concentrations ⇒ ⊗ polysynaptic influences ⇒ behavioral stimulation
    
    • Manifested as talkativeness and mild euphoria
  • @ Higher concentrations ⇒ ↓ neuronal activity ⇒ cerebellar dysfunction, etc.
    
    • Death can occur d/t respiratory depression
• Chronic effects
  
  • Key features are tolerance and physical dependence
  • Acute tolerance can occur after several hrs of drinking
    
    • Chronic alcoholics w/ long-term tolerance need much higher concentrations of ethanol for CNS effects
    • Tolerance d/t pharmacokinetic and pharmacodynamic factors
  • Physical dependence manifested as withdrawal sx when EtOH reduced or stopped
    
    • B/c CNS has adapted to presence of ethanol
    • [Ethanol] and duration of exposure determines extent of w/d sx
  • Many effects of long-term ethanol usage d/t
• *poor nutrition**
  
  • Thiamine ⇒ ∆ glucose metabolism
    
    • Cofactor for transketolase
      
      • Deficiency ⇒ ↓ ribose-5-℗ and NADPH
    • Cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase
      
      • Deficiency ⇒ ↓ ATP
  • Chronic ETOH induced thiamine deficiecy
    
    • Peripheral neuropathy
    • Brain damage, memory loss, sleep disturbances
    • ↑ Risk of seizures
    • Wernicke-Korsakoff syndrome:
    • Short-lived Wernicke encephalopathy (truncal ataxia, ophthalmoplegia)
    • ~80-90% also develop Korsakoff’s psychosis (persistent learning and memory problems)
  • Thiamine part of “cocktail” used to tx alcohol w/d

Question 8

Legal BAC Levels

Answer 8

Question 9

EtOH

Cardiovascular Effects

Answer 9

• Acute effects
  
  • Ethanol causes a generalized vasodilation
    
    • Due effect on CNS
    • Direct effect on smooth muscle by acetaldehyde
    • Ethanol consumption ⇒ hypothermia
  • Moderate amounts of ethanol ⇒ ↑ vasoconstrictive effect of catecholamines in the heart and the brain
    
    • In pts with stable angina, ethanol ⇒ ↓ duration of exercise required to cause angina
  • Acutely ethanol ⇒ ↓ myocardial contractility
• Chronic effects
  
  • Heavy ethanol consumption caused cardiomyopathy
    
    • D/t thiamine deficiency + direct toxic effects
  • Heavy alcohol consumption ⇒ HTN (causes 5% of all HTN)
    
    • D/t thiamine deficiency
  • Both of these effects are reversible
  • Modest ethanol consumption ⇒ slight ↑ in survival
    
    • D/t ↑ HDL/LDL ratio

Question 10

EtOH

GI Effects

Answer 10

• Oral mucosa, esophagus, stomach, and small intestine exposed to higher concentrations of ethanol than the rest of the body
• Ethanol ↑ gastric secretions by several mechanisms both direct and indirect:
  
  • Direct effect includes release of gastrin
  • Indirect effects include psychological mechanisms and stimulation of sensory nerve endings in the gut
  • Secretion is rich in acid
  • Pts with peptic ulcer disease should not drink ethanol
• High concentrations of ethanol (80 proof/40%) cause direct gastric mucosal irritation
  
  • These concentrations also cause erosive gastritis
• Damage caused by aspirin is enhanced by ethanol
• Chronic use of excessive ethanol can cause either diarrhea or constipation
• Chronic ethanol predisposes pt to pancreatitis, d/t ↑ secretions and blockade of the pancreatic duct

Question 11

EtOH

Liver Effects

Answer 11

• Acute ingestion of ethanol has little long-term effect on the liver
• Chronic ingestion of ethanol can have profound effects
  
  • Accumulation of fat is an early event
    
    • D/t excess NADH accumulation ⇒ ⊗ oxidation of fatty acids and fatty acid utilization
  • Fatty liver → alcoholic hepatitis → cirrhosis → hepatic encephalopathy & other sequelae
    
    • Malnutrition can intensify these effects
  • Acetaldehyde formed is very reactive
    
    • Contributes to liver damage, enhanced lipid peroxidation, mitochondrial damage, depletion of glutathione
  • Acetaminophen toxicity is enhanced to d/t enzyme induction and depletion of glutathione

Question 12

EtOH

Renal Effects

Answer 12

EtOH ⇒ ↓ secretion of ADH ⇒ ↓ tubular reabsorption ⇒ ↑ Diuresis

Question 13

EtOH

Hematologic Effects

Answer 13

• Ethanol has direct toxic effects on the bone marrow ⇒ anemia
  
  • ↓ WBCs and platelets
• GI bleeding ⇒ iron deficiency
• Chronic alcoholism may be ass. w/ poor nutrition ⇒ folate deficiency ⇒ megaloblastic anemia
• Even w/o liver disease, chronic ethanol ingestion ⇒ ↑ blood cell volume (macrocytosis)

Question 14

EtOH

Teratogenic Effects

Answer 14

• Fetal alcohol syndrome consists of many dysfunctions including low IQ, microcephaly, and facial abnormalities
• Most frequent cause of teratogenically induced mental deficiency in the western world
• Even moderate drinking of ethanol is contraindicated in pregnancy

Question 15

EtOH

Endocrine Effects

Answer 15

• Colloquial aphrodisiac effect, likely d/t ↓ inhibition
  
  • Actually causes ↓ in sexual responsiveness
• Acute ingestion ⇒ rapid ↓ in testosterone d/t acute toxic effect on the testes
• Chronic ingestion in both men and women ⇒ disturbed hypothalamic-pituitary-gonadal function
  
  • In females ⇒ defeminization
    
    • Ovarian atrophy, loss of breast and pelvic fat accumulation and infertility
  • In post-menopausal women, moderate drinking ↑ estrogen levels
    
    • ↑ Aromatase in peripheral tissues ⇒ ↑ conversion of androgenic precursors
    • ↑ Estrogen correlates with ↑ breast CA in these individuals
  • In men, ↓ testosterone synthesis + induction of aromatase ⇒ feminization in some pts
    
    • Loss in body hair, red palms (palmar erythema), red blood vessels radiating like a spider (spider angiomata) and gynecomastia
  • Liver damage⇒ ↓ androgenic precursor metabolism ⇒ ↑ conversion to estrogens by peripheral aromatase ⇒ accentuating the feminization

Question 16

Long-term EtOH Effects

Summary

Answer 16

Question 17

Alcohol Withdrawal

Answer 17

• Withdrawal sx
  
  • Autonomic hyperactivity: tremors, sweating, and nausea
  • Neuropsychiatric alterations:
• *agitation, anxiety, auditory disturbances, clouding of sensation, and disturbances in visual and tactile senses**
  
  • Occur within 24 hrs after the last drink, peak within 24-36 hrs and end by 48 hrs
• Delirium tremens: hallucinations, confusion, disorientation, impaired attention
  
  • Occurs within 48-72 hrs after the last drink
  • Peak at 4 days
• Acute withdrawal management
  
  • Pharmacotherapy replaces alcohol with a sedative drug that can be tapered in a controlled manner
  • Benzodiazepines are the drugs of choice because of the wide therapeutic index
    
    • In pts with severe cirrhosis, who metabolize long-acting benzodiazepines slowly, use short acting drugs to treat w/d
      
      • Short-acting drugs are lorazepam and oxazepam
      • Drugs are metabolized by conjugation
  • Supportive care including reduce environmental stimuli, rest, adequate nutrition including thiamine, monitor fluids
  • Hallucination can be tx with haloperidol
  • Benzodiazepines protect against convulsions and seizures
  • Beta-blockers and clonidine reduce many of the adrenergic manifestations

Question 18

Disulfiram (Antabuse)

Answer 18

• ⊗ Aldehyde dehydrogenase by chelating metal ions essential for its activity
  
  • Resulting “acetaldehyde syndrome” consists of facial flush, headache, hypotension, marked uneasiness, confusion, vomiting
    
    • Pts must be cautioned about other sources of ethanol
• ⊗ Activity of dopamine beta hydroxylase
  
  • Results in impaired cardiovascular reflexes ⇒ hypotension

Question 19

Naltrexone

Answer 19

Approved for treating alcoholism

Anti-craving activity d/t blockade of positive reinforcing effects of ethanol

Question 20

Acamprosate

(Campral)

Answer 20

• Modulates/normalize alcohol-disrupted brain activity
• Particularly in the GABA and glutamate neurotransmitter systems
• May elicit anti-craving action via prevention of conditioned responses to alcohol withdrawal

Question 21

Methanol Toxicity

Answer 21

• Methanol is an industrial solvent found in “canned heat” and windshield washing products
  
  • Metabolized by alcohol dehydrogenase
    
    • Methanol → formaldehyde → formic acid
  • Methanol and formate are much more potent toxins than ethanol
    
    • Essential to treat ASAP
• Most characteristic sx of methanol poisoning is a visual disturbance
• Fomepizole
  
  • ⊗ Alcohol dehydrogenase
• Ethanol has a higher affinity for ADH
  
  • Saturation of ADH w/ ethanol ⇒ ↓ formate production
• Other treatments are dialysis and alkalinization to counteract metabolic acidosis

Question 22

Ethylene Glycol Toxicity

Answer 22

• Used in antifreeze
  
  • Has a sweet taste which attracts young children
  • Also sometimes ingested as an ethanol substitute
• Metabolized by alcohol dehydrogenase to toxic aldehydes and oxalate
• Metabolic acidosis and renal insufficiency occur d/t deposition of oxalate crystals
• Fomepizole
  
  • ⊗ Alcohol dehydrogenase
• May use ethanol infusion and/or dialysis as required