Pharmacology and Pharmacotherapy of Alcohol Use/Abuse Flashcards
PHARMACOKINETICS OF ALCOHOL
Absorption
10% from stomach, remainder from intestine
Peak 30-90 minutes
Limited by gastric emptying - Slowed by food
Alcohol increases acid release - Induce ulcers/GERD
Distribution
Distributed in total body water - (58% men, 48% women); Men dilute ethanol more
ALCOHOL ELIMINATION FOLLOWS ZERO ORDER KINETICS
Blood concentration profile
Elimination is zero order at or above 10-20 mg/dl - ADH rate limiting step
body eliminates drug at a predictable rate, regardless of plasma concentration
ALCOHOL IS METABOLIZED IN TWO IMPORTANT STEPS
Metabolism:
90% in liver
Alcohol dehydrogenase (ADH)
Microsomal Ethanol Oxidizing System (MEOS) - Only at high alcohol concentration; Involves CYP2E1; LOW affinity for alcohol
Aldehyde dehydrogenase (ALDH) Glucuronidation (0.5%-EtG test):
Test used to monitor alcohol
consumption – Too sensitive
Ethyl glucuronide has very long
T1/2
1) ALCOHOL IS METABOLIZED BY ALCOHOL DEHYDROGENASE
Enzyme is found in liver, brain and stomach
Men express higher levels of gastric ADH
Fomepizole (Antizol): ADH inhibitor - Alcohol can be used as well; Ethylene glycol, MeOH
poisoning; Slow formation of
formaldehyde and toxic metabolites; Liver has more time to further metabolize toxic metabolites
2) ACETALDEHYDE IS METABOLIZED BY ALDEHYDE DEHYDROGENASE
ALDH1B1 and ALDH2 isozymes are important for alcohol metabolism - 50% Asians only have ALDH2
SNP in ALDH2 reduces activity - ALDH22
Heterozygous ALDH22: Reduced metabolic activity; Flushing and increase skin temp; Can still consume ethanol
Homozygous ALDH2*2: Deficient in the ability to metabolize acetaldehyde; neurotoxic; Strong ”hangover”; Also alcoholic neuropathy
Disulfiram (Antabuse): Irreversible inhibitor; Effects persist up to 14day
ALCOHOL HAS MANY TARGETS AND ACTIONS
Ligand-gated ion channels: GABAA-receptors (allosteric activator of inhibitory neurotransmitters); NMDA receptor (inhibitor); Alpha7 nicotinic receptors
Neurotransmitter release: Opioids (enkephalins) - Dopamine; Serotonin, norepinephrine; Acetylcholine; Increases CNS and blood ACTH levels
BLOOD ALCOHOL LEVEL CAN BE DEPICTED IN DIFFERENT WAYS
0.10% is equal to 100 mg/dl or 22 mmol/l of blood alcohol
Mg%: Milligrams of ethyl alcohol in 100 millilitres (1dl) of blood: 0.1% = 100 mg/dl = (100mg%); USA, 80mg% = legal driving limit; Independent of behavioral tolerance
PHARMACOLOGICAL ACTIONS OF LOW LEVELS OF ALCOHOL
Euphoria, disinhibition (30- 60 mg/dl), talkative
Analgesia (60-90 mg/dl)
PHARMACOLOGICAL ACTIONS OF INTERMEDIATE LEVELS OF ALCOHOL
CNS stimulation (80-120 mg/dl): Mood swings, aggression
CNS depression (100-200 mg/dl): Slurred speech, ataxia, sedation, loss of motor control, irrational behavior.
PHARMACOLOGICAL ACTIONS OF HIGH/FATAL LEVELS OF ALCOHOL
Coma-Death (300-500 mg/dl): Respiratory paralysis; People have survived (1000-1500 mg/dl)
CARDIOVASCULAR EFFECTS INDUCED BY ALCOHOL - acute
Vasodilation: Warm, flush; Reduced blood pressure; Increase heart rate - Decrease at high dose
CARDIOVASCULAR EFFECTS INDUCED BY ALCOHOL - moderate use
Reduced risk of coronary disease - HDL ↑
CARDIOVASCULAR EFFECTS INDUCED BY ALCOHOL - heavy/chronic use
Affects heart
Cardiomyopathy
Arrhythmias (binge drinking)
Hypertension (5% of all cases)
Hemostasis
PHYSIOLOGICAL EFFECTS OF ALCOHOL CONSUMPTION - thermoregulation
Hypothermia: Moderate in man; Possible lethal with cold temp and large dose
PHYSIOLOGICAL EFFECTS OF ALCOHOL CONSUMPTION - gastro-intestinal
EtOH is a secretagogue - increases HCl secretion; Chronic gastritis in alcoholics
Appetite stimulant (low dose)
Appetite depressant (high dose)
ALCOHOL CONSUMPTION CAUSES LONG-TERM ADVERSE EFFECTS - liver
Increase fat metabolism (promote triglyceride synthesis from FFA)
Fatty liver leading to cirrhosis is common in abusers
Vitamin deficiencies; glutathione reduced - Small intestine damage -> diarrhea
Can cause ascites, edema, effusions
ALCOHOL CONSUMPTION CAUSES LONG-TERM ADVERSE EFFECTS - blood
Mild anemia
Gastritis -> chance of blood loss
Alcohol related folic acid deficiency
ALCOHOL CONSUMPTION CAUSES LONG-TERM ADVERSE EFFECTS - cancer
Liver
Along route of ingestion - mouth, larynx, esophagus, stomach
ALCOHOL HAS SEVERAL IMPORTANT DRUG-DRUG INTERACTIONS
CNS depressants
aldehyde dehydrogenase inhibitors
acetaminophen
aspirin
CNS depressants
Opioids,
antipsychotics
anti-histamines, sedative-hypnotics
Aldehyde Dehydrogenase Inhibitors
Disulfiram
Antimicrobials (Metronidazole, Cephalosporins)
Sulfonylureas hypoglycemics (Tolbutamide)
Acetaminophen
Increases toxic metabolite (i.e. NAPQI)
Alcohol upregulates CYP2E1
Treat with n-acetylcysteine to detoxify NAPQI
Aspirin
Increased uclers, GI bleeding
ALCOHOL IS TOXIC
Acute Intoxication management
Prevent respiratory depression
Aspiration of vomit
ALCOHOL IS TERATOGENIC
Teratology
Fetal Alcohol Syndrome (FAS)
– Facial dysmorphology
– Low birth weight
– Decreased brain size
– Mental retardation
– Lower testosterone and sperm quality
ALCOHOL ABUSE AND DEPENDENCE IS WIDESPREAD
1 in 8 US adults meets alcohol use disorder criteria (12.7%)
Less than 8% get treatment
88,000 people die from alcohol-related deaths each year
ALCOHOL CESSATION CAUSES WITHDRAWAL
Anxiety, insomnia
Seizures/tonic clonic convulsions
Nausea/vomiting
Tactile hallucinations/delirium tremens
Treatment: benzodiazepines, phenytoin for seizures, electrolytes
α2-adrenergic partial agonists: Clonidine, guanfacine; Alcohol desensitizes α2-ARs; Withdrawal increases NE responses
ALCOHOL CESSATION CAUSES RELAPSE
Cue triggered: Glass of alcohol; Favorite bar; Mood - Stress, anxiety, depression
THERE ARE THREE FDA APPROVED TREATMENTS FOR ALCOHOLISM
disulfiram
acamprosate
naltrexone
Disulfiram (antabuse):
Aldehyde dehydrogenase inhibitor
Causes flushing, throbbing, headache, N&V, sweating, hypotension, confusion
Patients should be alcohol free for 24 hrs (Some OTCs contain alcohol!)
Acamprosate (Campral):
NMDA receptor antagonist/GABA agonist
Reduced relapse and prolong abstinence
Naltrexone (Revia):
Opioid receptor antagonist
Prevents relapse and people who do relapse are in better control
NALTREXONE IS MORE EFFECTIVE IN PATIENTS WITH A SNP IN THE MU OPIOID RECEPTOR GENE
Alanine118glycine mutation: N-terminal tail of mu opioid receptor; Changes asparagine amino acid -> aspartate (N40D); 3x higher potency for beta-endorphins
118G patients respond better to naltrexone
Prevalence: 40-50% Asians; 15-30% Europeans; 1-3% African American/Hispanic
Clear indication for precision/personalized medicine
THREE IMPORTANT OFF-LABEL DRUGS USED FOR TREATMENT OF ALCOHOLISM
topiramate
baclofen
varenicline
Topiramate (Topamax):
Inhibits glutamate signaling, enhances GABA signaling
– Similar in mechanism to Acamprosate
– Approved for epilepsy and migraine
– Encouraging results in two trials for alcoholism.
Baclofen:
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 trial
Varenicline (Chantix):
nicotinic acetylcholine receptor partial agonist
– Approved for smoking cessation
– Human tests for alcoholism underway
