Pharmacology and Pharmacotherapy of Alcohol Use/Abuse

Question 1

PHARMACOKINETICS OF ALCOHOL

Answer 1

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

Question 2

ALCOHOL ELIMINATION FOLLOWS ZERO ORDER KINETICS

Answer 2

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

Question 3

ALCOHOL IS METABOLIZED IN TWO IMPORTANT STEPS

Answer 3

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

Question 4

1) ALCOHOL IS METABOLIZED BY ALCOHOL DEHYDROGENASE

Answer 4

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

Question 5

2) ACETALDEHYDE IS METABOLIZED BY ALDEHYDE DEHYDROGENASE

Answer 5

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

Question 6

ALCOHOL HAS MANY TARGETS AND ACTIONS

Answer 6

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

Question 7

BLOOD ALCOHOL LEVEL CAN BE DEPICTED IN DIFFERENT WAYS

Answer 7

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

Question 8

PHARMACOLOGICAL ACTIONS OF LOW LEVELS OF ALCOHOL

Answer 8

Euphoria, disinhibition (30- 60 mg/dl), talkative
Analgesia (60-90 mg/dl)

Question 9

PHARMACOLOGICAL ACTIONS OF INTERMEDIATE LEVELS OF ALCOHOL

Answer 9

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.

Question 10

PHARMACOLOGICAL ACTIONS OF HIGH/FATAL LEVELS OF ALCOHOL

Answer 10

Coma-Death (300-500 mg/dl): Respiratory paralysis; People have survived (1000-1500 mg/dl)

Question 11

CARDIOVASCULAR EFFECTS INDUCED BY ALCOHOL - acute

Answer 11

 Vasodilation: Warm, flush; Reduced blood pressure; Increase heart rate - Decrease at high dose

Question 12

CARDIOVASCULAR EFFECTS INDUCED BY ALCOHOL - moderate use

Answer 12

Reduced risk of coronary disease - HDL ↑

Question 13

CARDIOVASCULAR EFFECTS INDUCED BY ALCOHOL - heavy/chronic use

Answer 13

Affects heart
 Cardiomyopathy
Arrhythmias (binge drinking)
Hypertension (5% of all cases)
Hemostasis

Question 14

PHYSIOLOGICAL EFFECTS OF ALCOHOL CONSUMPTION - thermoregulation

Answer 14

 Hypothermia: Moderate in man; Possible lethal with cold temp and large dose

Question 15

PHYSIOLOGICAL EFFECTS OF ALCOHOL CONSUMPTION - gastro-intestinal

Answer 15

 EtOH is a secretagogue - increases HCl secretion; Chronic gastritis in alcoholics
 Appetite stimulant (low dose)
 Appetite depressant (high dose)

Question 16

ALCOHOL CONSUMPTION CAUSES LONG-TERM ADVERSE EFFECTS - liver

Answer 16

 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

Question 17

ALCOHOL CONSUMPTION CAUSES LONG-TERM ADVERSE EFFECTS - blood

Answer 17

 Mild anemia
 Gastritis -> chance of blood loss
 Alcohol related folic acid deficiency

Question 18

ALCOHOL CONSUMPTION CAUSES LONG-TERM ADVERSE EFFECTS - cancer

Answer 18

 Liver
 Along route of ingestion - mouth, larynx, esophagus, stomach

Question 19

ALCOHOL HAS SEVERAL IMPORTANT DRUG-DRUG INTERACTIONS

Answer 19

CNS depressants
aldehyde dehydrogenase inhibitors
acetaminophen
aspirin

Question 20

CNS depressants

Answer 20

 Opioids,
 antipsychotics
 anti-histamines, sedative-hypnotics

Question 21

Aldehyde Dehydrogenase Inhibitors

Answer 21

 Disulfiram
 Antimicrobials (Metronidazole, Cephalosporins)
 Sulfonylureas hypoglycemics (Tolbutamide)

Question 22

Acetaminophen

Answer 22

 Increases toxic metabolite (i.e. NAPQI)
 Alcohol upregulates CYP2E1
 Treat with n-acetylcysteine to detoxify NAPQI

Question 23

Aspirin

Answer 23

Increased uclers, GI bleeding

Question 24

ALCOHOL IS TOXIC

Answer 24

Acute Intoxication management
 Prevent respiratory depression
 Aspiration of vomit

Question 25

ALCOHOL IS TERATOGENIC

Answer 25

Teratology
 Fetal Alcohol Syndrome (FAS)
– Facial dysmorphology
– Low birth weight
– Decreased brain size
– Mental retardation
– Lower testosterone and sperm quality

Question 26

ALCOHOL ABUSE AND DEPENDENCE IS WIDESPREAD

Answer 26

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

Question 27

ALCOHOL CESSATION CAUSES WITHDRAWAL

Answer 27

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

Question 28

ALCOHOL CESSATION CAUSES RELAPSE

Answer 28

Cue triggered: Glass of alcohol; Favorite bar; Mood - Stress, anxiety, depression

Question 29

THERE ARE THREE FDA APPROVED TREATMENTS FOR ALCOHOLISM

Answer 29

disulfiram
acamprosate
naltrexone

Question 30

Disulfiram (antabuse):

Answer 30

Aldehyde dehydrogenase inhibitor
 Causes flushing, throbbing, headache, N&V, sweating, hypotension, confusion
 Patients should be alcohol free for 24 hrs (Some OTCs contain alcohol!)

Question 31

Acamprosate (Campral):

Answer 31

NMDA receptor antagonist/GABA agonist
 Reduced relapse and prolong abstinence

Question 32

Naltrexone (Revia):

Answer 32

Opioid receptor antagonist
 Prevents relapse and people who do relapse are in better control

Question 33

NALTREXONE IS MORE EFFECTIVE IN PATIENTS WITH A SNP IN THE MU OPIOID RECEPTOR GENE

Answer 33

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

Question 34

THREE IMPORTANT OFF-LABEL DRUGS USED FOR TREATMENT OF ALCOHOLISM

Answer 34

topiramate
baclofen
varenicline

Question 35

Topiramate (Topamax):

Answer 35

Inhibits glutamate signaling, enhances GABA signaling
– Similar in mechanism to Acamprosate
– Approved for epilepsy and migraine
– Encouraging results in two trials for alcoholism.

Question 36

Baclofen:

Answer 36

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

Question 37

Varenicline (Chantix):

Answer 37

nicotinic acetylcholine receptor partial agonist
– Approved for smoking cessation
– Human tests for alcoholism underway