Watts Pharmacology and Pharmacotherapy of Alcohol Use/Abuse Flashcards
How is alcohol absorbed in the body?
-10% is absorbed from the stomach, remainder is absorbed in the intestine
-Peak absorption occurs in 30-90 minutes
-Limited by gastric emptying (slowed by food)
-Alcohol increases acid release (induces ulcers and GERD)
How is alcohol distributed in the body?
-Distributed in total body water
-Men dilute ethanol more because men have a higher body water percentage compared to women (58% men, 48% women)
At what rate is alcohol eliminated?
-Elimination is zero order at or above 10-20 mg/dl
-ADH is rate-limiting step
How is alcohol metabolized?
-90% in the liver
-Alcohol dehydrogenase (ADH)
-Microsomal ethanol oxidizing system (MEOS)
-Aldehyde dehydrogenase (ALDH)
How does MEOS metabolize alcohol?
-Only at high alcohol concentration
-Involves CYP2E1
-LOW affinity for alcohol
Alcohol dehydrogenase clinical pearls
-Enzyme is found in liver, brain and stomach
-Men express higher levels of gastric ADH
Fomepizole mechanism of action
-ADH inhibitor
-Used to treat ethylene glycol and methanol intoxication by slowing it’s conversion into formaldehyde and toxic metabolites
-Liver then has more time to further metabolize the toxic metabolites
Aldehyde dehydrogenase clinical pearls
-ALDH1B1 and ALDH2 isozymes are important for alcohol metabolism
-50% of Asians only have ALDH2
-SNP in ALDH2 reduces activity (ALDH2*2)
Effects of having heterozygous ALDH2*2
-Reduced metabolic activity
-Flushing and increased skin temp
-Can still consume alcohol
Effects of having homozygous ALDH2*2
-Deficient in the ability to metabolize acetaldehyde
-Neurotoxic
-Strong “hangover”
-Also alcoholic neuropathy
Disulfiram clinical pearls
-Irreversible inhibitor
-Effects persist up to 14 days
-Only works for people whoa re very motivated
Which ligand-gated ion channels does alcohol target?
-GABAa-receptors (allosteric activators of inhibitory neurotransmitters)
-NMDA receptor (inhibitor)
-Alpha7 nicotinic receptors
Which neurotransmitters does alcohol release?
-Opioids (enkephalin)
-Dopamine
-Serotonin, norepinephrine
-Acetylcholine
-Increases CNS and blood ACTH levels
What is the legal blood alcohol limit to drive in the United States?
-80mg% or 0.08
-This is independent of behavioral tolerance (some people can operate normally with a blood alcohol limit of 0.08)
Pharmacological actions of low levels of alcohol
-Euphoria, disinhibition
-Analgesia
Pharmacological actions of intermediate levels of alcohol
-CNS stimulation (mood swings, aggression)
-CNS depression (slurred speech, ataxia, sedation, loss of motor control, irrational behavior)
Pharmacological actions of high/fatal levels of alcohol
-Coma-death
-Respiratory paralysis
-People can survive 1000-1500 mg/dl
Cardiovascular effects induced by acute use of alcohol
-Vasodilation
-Warm, flush
-Reduced blood pressure
-Increased heart rate (decreases at high doses)
Cardiovascular effects induced by moderate alcohol use
Reduced risk of coronary disease (not worth the adverse effects associated)
Cardiovascular effects induced by heavy/chronic use of alcohol
-Affects heart
-Cardiomyopathy
-Arrhythmias
-Hypertension
-Hemostasis
Physiological effects of alcohol consumption
-Hypothermia (moderate in men and can be lethal in cold temps and high doses)
-Increases HCl secretion in the GI tract (alcohol is a secretagogue)
-Chronic gastritis in alcoholics
-Appetite stimulant with low doses and appetite depressant with high doses
Long-term adverse effects to the liver from alcohol consumption
-Increase fat metabolism (promotes triglyceride synthesis from FFA)
-Fatty liver leading to cirrhosis is common in abusers
-Vitamin deficiencies; glutathione reduced leading to small intestine damage and diarrhea
-Can cause ascites, edema, effusions
Long-term adverse effects to the blood from alcohol consumption
-Mild anemia
-Gastritis -> chance of blood loss
-Alcohol related folic acid deficiency
Possible types of cancer that can occur from alcohol consumption
-Liver
-Along route of ingestion (mouth, larynx, esophagus, stomach)
Important drug-drug interactions associated with alcohol
-CNS depressants (opioids, antipsychotics, anti-histamines, sedative-hypnotics)
-Aldehyde dehydrogenase inhibitors (disulfiram, antimicrobials (metronidazole, cephalosporins), sulfonylureas hypoglycemics (tolbutamide))
-Acetaminophen
-Aspirin
What is the mechanism behind the interaction between alcohol and acetaminophen?
Upregulation of CYP2E1 leads to an increase of NAPQI toxic metabolites
How do you treat someone who is suffering from toxicity associated with concurrent alcohol and acetaminophen use?
Treat with n-acetylcysteine to detoxify NAPQI
Why can aspirin not be used with alcohol?
Increased ulcers and GI bleeds
How do you manage acute alcohol intoxication?
-Prevent respiratory depression by keeping them awake and make sure they do not aspirate vomit
What are signs of fetal alcohol syndrome?
-Facial dysmorphology
-Low birth weight
-Decreased brain size
-Mental retardation
What are the teratogenic effects of alcohol?
-Fetal alcohol syndrome
-Lower testosterone and sperm quality
Alcohol withdrawal symptoms
-Anxiety
-Insomnia
-Seizures/tonic-clonic convulsions
-Nausea/vomiting
-Tactile hallucinations/delirium tremens
Treatment for alcohol withdrawal
-Benzodiazepines
-Phenytoin for seizures
-Electrolytes
-Alpha2-adrenergic partial agonists (clonidine, guanfacine)
Why are alpha2-adrenergic partial agonists used for the treatment of alcohol withdrawal?
-Alcohol desensitizes alpha2-ARs
-Withdrawal increases NE responses
What are examples of cues that can trigger relapse?
-Glass of alcohol
-Favorite bar
-Mood (stress, anxiety, depression)
What are the three FDA approved treatments for alcoholism?
-Disulfiram (antabuse)
-Acamprosate (Campral)
-Naltrexone (Revia)
Disulfiram mechanism of action
Aldehyde dehydrogenase inhibitor
Disulfiram side effects
-Flushing
-Throbbing
-Headache
-Nausea and vomiting
-Sweating
-Hypotension
-Confusion
What is an important counseling point regarding disulfiram?
Patients should be alcohol-free for 24 hours before initiating therapy
Acamprosate mechanism of action
-NMDA receptor antagonist/GABA agonist
-Reduced relapse and prolonged abstinence
Naltrexone mechanism of action
-Opioid receptor antagonist
-Prevents relapse and people who do relapse are in better control
What population of patients responds better to naltrexone?
Patients with a mutation in the alanine118glycine gene
Three important off-label drugs used for the treatment of alcoholism
-Topiramate (Topamax)
-Baclofen
-Varenicline (Chantix)
Topiramate clinical pearls
-Inhibits glutamate signaling, enhances GABA signaling
-Similar in mechanism to Acamprosate
-Approved for epilepsy and migraine
-Encouraging results in two trials for alcoholism
Baclofen clinical pearls
-Stimulates GABAb receptors
-Approved for treating spasticity
-Reduces anxiety and craving
-High doses reduced drinking in several small trials for alcoholism
-Not better than placebo in double blind trials
Varenicline clinical pearls
-Nicotinic acetylcholine receptor partial agonist
-Approved for smoking cessation
-Human tests for alcoholism underway
