Alcohol

Question 1

Answer 1

Question 2

Factors Affecting Ethanol Absorption

Answer 2

1. Concentration of ethanol
2. Blood flow at site of absorption
3. Irritant properties of ethanol
4. Rate of ingestion
5. Type of beverage
6. Food

Absorption of ethanol from the duodenum and jejunum is much more rapid than from the stomach; hence the rate of gastric emptying is an important determinant of the rate of absorption of orally administered ethanol.

Question 3

Food Effect

Answer 3

Rate of metabolism is greater in fed,well- nourished persons

FOOD

• Delays gastric emptying
• Slows absorption rate
• Boosts rate of alcohol metabolism

AFTER FOOD

• Return to zero concentration is earlier
• Hepatic first-pass metabolism is greater

EAT BEFORE AND DURING ALCOHOL USE !!

Question 4

Alcohol Distribution

Answer 4

• In tissue in proportion to H₂O content
• Body H₂O men = 70%, women =55%
• Vd men > women

Question 5

Answer 5

• Alcohol as a nutrient has a caloric value of about 7 Kcal per gram.
• Unlike carbohydrates and fat, which can be stored and utilized in time of need (e.g. fasting), alcohol is not stored and remains in the body water until eliminated.
• While the metabolism of major nutrients is under hormonal control e.g. insulin/glucagon and other hormones, there is little hormonal regulation to pace the rate of alcohol elimination.
• The liver oxidizes alcohol in order to remove it from the body

Question 6

Answer 6

* In the first step, alcohol dehydrogenase (ADH) in the cytosol acts to form acetaldehyde.

• In the next step mitochondrial aldehyde dehydrogenase (ALDH) converts the aldehyde to acetate.
• Each step requires NAD⁺ which is reduced to NADH.
• The limited ability of the liver to oxidize the NADH back to NAD⁺ limits alcohol metabolism to about 7-8g per hour or about 120 mg/kg per hour.

-That is less than one standard drink per hour.

• After drinking on an empty stomach the BAC declines by 10-15 mg/100 ml/hour.
• Food boosts the rate of elimination to about 15-20 mg/kg/hour.
• A microsomal cytochrome P450, CYP2E1, contributes to alcohol metabolism at BACs >0.08%.
• The CYP2E1 may have a role in the interaction of alcohol with other drugs.
• The cytochrome is induced by chronic alcohol consumption, thereby increasing the clearance of its substrates with the potential to activate certain drugs or toxins (for example acetaminophen).
• With acute alcohol use there may be reduced clearance of some drugs as the alcohol competes with the drugs for oxidation by the CYP2E1 (for example warfarin & phenytoin).
• Alcoholics (in the absence of liver disease) often display an increased rate of blood alcohol clearance.

-This metabolic tolerance is in part due to the induction of CYP2E1 by alcohol.

•CYP2E1 has a lower affinity (higher Km) for alcohol compared with ADH and becomes more important in alcohol metabolism when blood-alcohol concentration exceeds 60 mg/100 mL.

Question 7

Alcohol Clearance

Answer 7

Question 8

Genetic Variation in the Metabolism of Ethanol

Answer 8

• Genetic polymorphisms in ADH and ALDH may alter the rate of alcohol metabolism.
• Three isoforms of ADH are responsible for 70% of the ethanol metabolizing capacity at BACs of 22mM (~ 0.01g/dl).

-These ADH forms are the rate–limiting step in alcohol metabolism, reducing the BAC by ~4-5 mM (0.015-0.020 g/dl) per hour.

• Consumption of one “standard drink” will result in a BAC of ~ 0.015-0.020 g/dl.
• There are polymorphisms that result in potentially more rapid alcohol metabolism with transiently higher blood acetaldehyde concentrations.

-These persons may be at lower risk for heavy drinking and alcohol problems.

•Genetic variations of ALDH influence the aldehyde breakdown.

• Homozygotes with a nonfunctional ALDH (10% of Chinese, Japanese, and Koreans) have severe reactions following consumption of a single drink or less.
• The reaction is not unlike that seen in alcoholics treated with the aldehyde dehydrogenase inhibitor, disulfiram.
• In persons with this trait the risk for repetitive heavy drinking is nil.

•Heterozygotes for this trait have facial flushing with alcohol use and an enhanced sensitivity to beverage alcohol.

-They drink less alcohol than the general population but with repeated use they may be at greater risk for end-organ injury (esophageal cancer, perhaps caused by acetaldehyde).

• The inter-individual variations in CYP2E1 activity are related to environmental factors that include obesity, fasting, previous exposure to alcohol and drugs.
• CYP2E1 is induced by chronic exposure to alcohol.
• The increased rate of alcohol elimination seen in alcoholics during detoxification is due to CYP2E1 induction.
• Because this enzyme system also metabolizes other compounds, alcohol may alter their metabolism.
• As noted this system is susceptible to induction and inhibition either of which has the potential to influence the metabolism and actions of other compounds.

Question 9

Answer 9

Question 10

Alcohol metabolism leads to an increased […] ratio.

Answer 10

Alcohol metabolism leads to an increased NADH/NAD ratio.

• The ADH and ALDH reactions increase the cellular NADH/NAD+ redox ratio.
• Enzymes requiring NAD⁺ are inhibited.
• The change in the redox state occurs both in the cytoplasm as a result of ADH activity, and in the mitochondria as a result of the ALDH activity and is the result of a limitation in the ability of the cell to regenerate NAD⁺.
• Important reactions that are inhibited by the increase in the NADH/NAD+ redox ratio are:
• Glycolysis
• Citric acid cycle, ketogenesis favored
• Pyruvate dehydrogenase
• Lactate dehydrogenase
• Fatty acid oxidation

Question 11

Consequences of a low NADH/NAD Ratio

Answer 11

• Alcoholic hypoglycemia
• Alcoholic ketoacidosis
• Lactic acidosis
• Hepatic steatosis

Question 12

Alcoholic Hypoglycemia

Answer 12

• Alcoholic hypoglycemia occurs in people who drink heavily over a period of fasting.
• Fasting depletes hepatic glycogen stores.
• The increased ratio of NADH/NAD+ as a consequence of alcohol oxidation decreases gluconeogenesis from alpha-glycerophosphate, lactate and pyruvate and amino acids via oxaloacetate.
• The hypoglycemia may be severe but is rarely fatal.
• Monitoring of blood glucose concentrations in intoxicated persons is important because they may readily pass from intoxication into hypoglycemic coma.

Question 13

Alcoholic Ketoacidosis

Answer 13

• The increase in the NADH/NAD+ ratio as a consequence of alcohol metabolism may cause a ketoacidosis and a mild lactic academia.
• One pathway that is activated to reoxidize NADH is the reduction of pyruvate to lactate.
• Some lactate escapes the liver to the systemic circulation accounting for a mild lactic acidemia.
• Some of the excess acetate generated by alcohol metabolism condenses with itself to form acetoacetate which can be reduced to alpha-hydroxybutyrate a reaction which also consumes the reducing equivalents of NADH.
• Some acetoacetate is decarboxylated to acetone which together with β-hydroxybutyrate and acetoacetate are referred to as “ketone bodies.”
• The ketone bodies contribute to the metabolic acidosis experienced by some alcoholics.
• The lactic acid formed may compete with uric acid for renal tubular secretion causing an elevation of blood urate concentration.
• Additionally, acidosis reduces the solubility of uric acid for excretion.

-In persons susceptible to gout, increased blood uric acid may lead to an attack of gouty arthritis.

Question 14

Lipid Metabolism

Answer 14

• The ingestion of alcohol for just a few days, even in amounts that do not raise the BAC above 0.1% is associated with the accumulation of lipid in hepatic cells.
• The process is reversible with abstinence.
• The mechanisms are complex and include a decrease in fatty acid oxidation and an increase in triglyceride synthesis, both of which are a facilitated by the increase in the NADH/NAD+ ratio.

Question 15

Effects of Alcohol on CNS

Answer 15

• Alcohol is a CNS depressant not unlike other depressants such as benzodiazepines and barbiturates.
• There are anti-anxiety actions and behavioral disinhibitions over a wide range of dosages.
• Signs of intoxication vary from expansive and vivacious affect to uncontrolled mood swings and emotional outbursts with violent behavior.
• Most CNS functions are progressively impaired as the state of general anesthesia is approached.
• There is little margin between anesthetic actions and lethal respiratory depression caused by alcohol.

Question 16

Neuropharmacological Features of Central Nervous System Actions of Alcohol

Answer 16

• Acute alcohol intoxication causes cellular changes in the brain that last for hours, while chronic alcohol use induces widespread neuroadaptation in the nervous system that may last a lifetime.
• There are changes in gene expression, cellular function, brain circuits, and ultimately behavior.

Question 17

Acute Molecular Effects of Alcohol

Answer 17

• Increased dopamine release (associated with reward)
• Increased GABA receptor activity (associated with anxiolysis, sedation, and motor incoordination)
• Decreased glutamate receptor activity
• The normal balance between excitatory and inhibitory influences is altered by alcohol. There is enhanced inhibitory neurotransmission or depressed excitatory neurotransmission.

Question 18

Chronic Molecular Effects of Alcohol

Answer 18

Chronic alcohol consumption causes neuroadaptation that opposes the effects of acute alcohol use. These adaptations include:

• Decreased dopamine release and increased dopamine receptor expression
• Decreased GABA receptor expression
• Increased glutamate release
• Increased NMDA receptor expression.

Question 19

Alcohol at the GABA_A Channel

Answer 19

•Acts with GABA to increase the duration of GABA_A channel opening, net result more Cl- enters and hyperpolarizes the neuron.

Question 20

Alcohol Intoxication DSM

Answer 20

RECENT INGESTION

BEHAVIORAL or PSYCHOLOGIC CHANGES ONE or MORE

• Slurred speech
• Incoordination
• Unsteady gait
• Nystagmus
• Impairment of memory or attention
• Stupor or coma

-Progresses to marked generalized loss of coordination

Question 21

Behavioral Effects

Answer 21

• Signs of intoxication typical of CNS depression occur in most people after 2-3 drinks on an empty stomach.
• These effects are most obvious at 30-60 minutes after ingestion, i.e., when the BAC peaks.
• Like general anesthetic agents, alcohol depresses all areas and functions of the brain.
• Similar to most CNS depressants, alcohol initially produces an excitement stage as depression of higher inhibitory centers releases the normal mechanisms that control social functioning and behavior.

-It is for this reason that alcohol is often described as a disinhibitor or euphoriant.

• The polysynaptic structures of the reticular activating system and the cortex are particularly sensitive to the presence of alcohol.
• The higher integrative areas of the brain are affected first.
• Thought processes, fine discrimination, judgment and motor function are then impaired sequentially.
• These effects may be observed with a BAC of 0.05% (50 mg/dl) or lower.
• Specific behavioral changes are difficult to predict and depend to a large extent on the environment and the personality of the individual.
• As the BAC increases to 0.1%, errors in judgment are frequent, motor systems are impaired and responses to complex auditory and visual stimuli are altered.
• The ability to perform tasks requiring divided attention, like driving, is impaired.
• Ataxia is noticeable and is characterized by difficulty in walking and staggering as the BAC approaches 0.15-0.2%.
• Reaction times are increased and the person may become loud, incoherent, and emotionally unstable.
• Violent behavior also characterizes the condition.

Question 22

Lethal Range for BAC

Answer 22

• The lethal range for the BAC concentration, in the absence of other CNS depressants, is between 0.4-0.5 percent.
• Persons with higher BACs have survived.
• Death from acute alcohol overdose is rare as compared to the frequency of death resulting from the combination of alcohol with other CNS depressants.
• Death occurs as a result of depressant effects on the medulla causing respiratory failure.
• In emergent situations alcohol can be removed from the body with hemodialysis.

Question 23

AUD Blackouts

Answer 23

• Intoxicated but not drowsy or stuporous
• New memories not recorded during intoxication
• Duration of a few hours
• Permanent retrograde amnesia for period of intoxication
• Mechanism not understood
• No implications regarding prognosis of alcoholism

Question 24

Alcohol Coma: Clinical Features

Answer 24

• Life threatening: not well appreciated
• Lethal BAC about 360 mg/dl
• Often complicated by other drug ingestion
• Kills by respiratory depression or by complicating states:
• subdural hematoma
• hypoglycemia
• meningitis
• pancreatitis
• pneumonia
• UGI hemorrhage
• hypothermia
• hepatitis
• portosystemic encephalopathy

Question 25

Diuretic Effects of Alcohol

Answer 25

•The diuretic effects of alcohol are primarily related to suppression of the release of antidiuretic hormone from the posterior pituitary gland and related secondarily to the increased fluid intake associated with drinking.

Question 26

Other CNS Effects

Answer 26

•WKS consists of two separate syndromes probably caused by deficiencies of the B complex vitamins.

• Mental confusion, cranial nerve palsy’s, and incoordination characterize Wernicke’s encephalopathy. A high percentage of patients with Wernicke’s encephalopathy develop Korsakoff’s psychosis.
• Korsakoff’s psychosis is a debilitating syndrome characterized by learning and memory problems. There is both retrograde and anterograde amnesia. The latter is most striking.
• Thiamine helps improve brain function in early WKS.

•The peripheral neuropathy of alcoholism is due to direct neural effects of alcohol along with concomitant nutritional deficiencies (folate and thiamine).

Question 27

GI Effects

Answer 27

• Alcohol has diverse effects on the gastrointestinal tract.
• The irritant effect together with stimulation of gastric acid production is associated with the development acute and chronic gastritis with a fair frequency of bleeding.
• Gastric and/or duodenal ulceration is common. In high doses, vomiting may occur independently of any local irritation.
• Alcohol abuse is associated with the development of both acute and chronic pancreatitis by mechanisms that are not understood.
• Heavy users of alcoholic beverages may also have esophagitis and an increase incidence of carcinoma of the pharynx, larynx, and esophagus.
• Upper gastrointestinal hemorrhage is a major contributor of the morbidity and mortality of acute and chronic alcoholism.
• Mallory Weiss tears occur at the gastroesophageal junction as a consequence of vomiting.
• Varices are dilated gastric and/or esophageal veins that shunt blood from the obstructed portal system to the inferior vena cava.
• The varices serve as the major route of portal venous return as the cirrhotic process in the liver obstructs blood flow through the organ.
• Variceal rupture is a life threatening event.

Question 28

Liver Effects

Answer 28

• Alcohol ingestion poses a risk of liver injury that is, in part, proportional to the dose and duration of use.
• The liver injury is manifest in three ways: hepatic steatosis, hepatitis and cirrhosis.
• The causal and temporal relationships between the steatosis and hepatitis and the development of cirrhosis are not well understood.
• Thus cirrhosis may occur without evidence of steatosis or hepatitis.
• Fat accumulates in hepatocytes in response to alcohol use, even when the amounts taken are insufficient to raise the BAC to 0.1%.
• The process is reversible with abstinence unless fibrosis has begun.
• With continued heavy use of alcohol the fibrotic process begins.
• Alcoholic hepatitis is an inflammatory process characterized by swelling and necrosis of the hepatocytes secondary to the accumulation of normally exported water and fat.
• Microscopically there is the accumulation of polymorphonuclear white blood cells around degenerating hepatocytes.
• The hallmark of alcoholic cirrhosis is the formation of Mallory bodies.
• Cirrhosis is the final and irreversible stage of a slow and insidious process.
• Its development is unpredictable. Only 10-15% of persons ingesting 160 g/d alcohol for 10-20 years develop cirrhosis.
• The disease is more common in women.
• The pathogenesis of the process begins with the development of hepatic fibrosis which ultimately destroys the normal hepatic architecture.
• There is accompanying liver dysfunction and impaired hepatic circulation. Both have dire consequences for the individual.

Question 29

Cardiovascular Effects

Answer 29

• Epidemiologic data indicate that daily moderate consumption of alcohol may decrease the risk of coronary heart disease (CHD).
• This benefit is abrogated by the risk of alcohol - induced cancers.
• Alcohol use is associated with an increase in blood pressure and heart rate and, on some occasions, arrhythmias.
• Alcohol is a vasodilator and this may have dire consequences for the acutely intoxicated or comatose individual in a cold environment.
• Chronic alcoholism on rare occasions produces a cardiomyopathy.

Question 30

Hematopoetic Effects

Answer 30

• Anemia seen in alcoholic persons is often multifactorial. It may be secondary to GI blood loss, vitamin deficiencies or bone marrow depression.
• Bleeding may be exacerbated by alcoholinduced thrombocytopenia and reduced hepatic synthesis of clotting factors.

Question 31

Alcohol and Cancer

Answer 31

• There is strong evidence that alcohol causes seven cancers. Epidemiologic evidence supports a causal association of alcohol consumption and cancers of the oropharynx, larynx, esophagus, liver, colon, rectum, and female breast. The evidence is strong for cancer of the mouth, pharynx, and esophagus (relative risk, ~4-7 for ≥ 50g/day). The relative risk for cancers of liver, colon and rectum is ~1.5 for ≥50 g/day. There appears to be a causal association between alcohol use and the listed cancers. There is no safe level of drinking. Or said differently: There is no dose of alcohol that confers a health benefit.
• For cancers of the mouth, larynx, pharynx and esophagus there is a well-recognized interaction of alcohol with smoking, resulting in a multiplicative effect on risk.
• The exact mechanisms as to how alcohol alone or in combination with smoking cause cancer are not fully understood. Alcohol enters cells readily and is converted to acetaldehyde, which can damage DNA and is a known carcinogen.
• Epidemiologic studies of alcohol and these seven cancers reveal some of the hallmarks of causality: dose- response relationship and the fact that the risk for esophageal, head and neck, and liver cancers the risk attenuates when drinking ceases. Alcohol attributable cancers make up 5.8% of all cancer deaths worldwide.

Question 32

Fetal Alcohol Spectrum Disorder

Answer 32

• FASD is a non-diagnostic term that is used to describe the broad range of adverse sequelae that can be seen in prenatally exposed offspring of heavily drinking women.
• When pregnant women drink, they put their offspring at risk for a wide range of physical, cognitive, and behavioral problems.
• Prenatal alcohol exposure is the leading preventable cause of birth

Question 33

FASD Epidemiology

Answer 33

• Occurs in ~ 5% of offspring of heavily drinking women
• Incidence is in the range of 0.5-7 per 1000 live births. Rates are higher in Native American and African American populations (maybe due to lower socioeconomic status).
• Other risk factors include: higher parity, older maternal age and binge drinking.
• The effects of heavy alcohol exposure on the developing fetus have long been known. But the term fetal alcohol syndrome (FAS) was introduced about 40 years ago. Since then, scientists have defined a broad range of effects caused by prenatal alcohol exposure.
• The teratogenic actions of alcohol occur along a continuum, i.e. they are proportional to dose and the timing of use with respect to the stage of fetal development.
• The consequences of maternal ingestion of alcohol can include miscarriage, still birth, low birth weight, slow postnatal growth, microcephaly, mental retardation and many other organic and structural abnormalities.

Question 34

Disorders Under the FASD Rubric

Answer 34

•FAS – This diagnosis requires a characteristic pattern in in-utero exposed children

• Craniofacial abnormalities
• Pre-and/or postnatal stunting of growth
• CNS dysfunction
• Partial FAS-There is history of exposure to alcohol. Some signs and symptoms of FAS are present but not all three of the characteristics noted in the previous bullet.
• Alcohol related birth defects (ARBD) – These children have congenital defects associated with alcohol exposure that include dysplastic kidneys, ptosis, atrial and ventricular septal defects and neurosensory loss.
• Alcohol-related neurodevelopmental disorder (ARDN) – These alcohol- exposed children have normal growth and lack the facial stigmata of FAS. Included in this disorder are central nervous system abnormalities, as well as cognitive and behavioral problems.

Question 35

Facial Dysmorphology of FAS

Answer 35

• Short palpebral fissures
• Smooth philtrum
• Thin upper lip

Question 36

Women and Alcohol

Answer 36

• Women are more vulnerable than men to many of the adverse effects of alcohol use.
• With the ingestion of equivalent amounts of alcohol women achieve higher BACs than men in part due to lesser amounts of gastric ADH and a smaller volume of distribution related to lower body water content.
• Women are also more susceptible than men to alcohol-related organ damage and to trauma resulting from traffic crashes.
• Alcohol use is more prevalent among men than women in the U.S.
• Men are more likely to become alcohol dependent than women.
• Compared to men, women develop alcohol-induced liver disease over a shorter period of time and after consuming less alcohol.
• Women are more likely than men to develop alcoholic hepatitis and to die of cirrhosis.

Question 37

Long Term Alcohol Use AUD

Answer 37

• CRAVING
• TOLERANCE
• CYP2E1 Induction
• Neuroadaptation
• Lethal BAC unchanged

• WITHDRAWAL

Question 38

Tolerance to Chronic Alcohol

Answer 38

• Tolerance is defined as diminished behavioural or physiologic response to the same dose of alcohol.
• Acute tolerance can be demonstrated following a single exposure to alcohol.
• Chronic tolerance develops in the long-term heavy drinker in part due to induction of the CYP2E1 system.
• Tolerance also reflects the development of neuroadaptive CNS changes that reduce the response to the drug after repeated administration.
• Chronic (heavy) alcohol use induces widespread neuroadaptation in the nervous system that may last a lifetime.
• There are changes in gene expression, cellular function, brain circuits, and ultimately behavior.
• A resetting of homeostatic mechanisms that maintain the balance of inhibitory and excitatory brain mechanisms that keep the body in balance produces the adaptation that follows repetitive drug use.
• A person in this adapted state requires continued administration of the drug to maintain normal function.
• If administration of the drug is stopped abruptly or the dose is reduced substantially, another imbalance is produced, which may result in the development of a withdrawal syndrome.
• High tolerances develop in some persons. In these persons the BAC must be approximately doubled to produce the desired CNS effects.

-This degree of tolerance is much less than that observed in those who take opiate drugs where a tolerance of 10-30 fold may be seen.

•While tolerance develops to some of the CNS effects of alcohol, there is only a minor increase in the BAC associated death.

Question 39

Withdrawal

Answer 39

• Psychological and physical dependence are characteristic of chronic alcohol use.
• Psychological dependence is characterized by craving and drug-seeking behavior following abstinence.
• Physical dependence is demonstrated by the development of a withdrawal syndrome following abstinence.
• The clinical manifestations of alcohol withdrawal are divided into early and late effects.
• The signs and symptoms of withdrawal occur between a few hours and up to 48 hours after relative or absolute abstinence.
• Peak effects occur around 24-36 hours.
• Anticonvulsant therapy for seizure management is rarely required and it is not used in prophylaxis.
• The withdrawal syndrome associated with alcohol is more life-threatening than that associated with opioids.
• Management is directed toward protecting and calming the person while identifying and treating underlying medical problems.

Question 40

Management of Withdrawal

Answer 40

• Oral or intravenous benzodiazepines are recommended for alcohol withdrawal management.
• These drugs should be used along with a structured assessment scale (the revised Clinical Institute Withdrawal Assessment for Alcohol or CIWA scale).
• The use of such a scale permits benzodiazepine dosing based on clinical condition and avoids the problems associated with fixed dosing of benzodiazepines.
• Use of the benzodiazepines is associated with a reduction of seizures and delirium.
• All benzodiazepines are effective though the longer acting ones may be superior in preventing seizures (lorazepam and others).

Question 41

Disulfiram

Answer 41

• (Antabuse) is an inhibitor of ALDH.
• When alcohol is taken after institution of disulfiram therapy, there is a noxious response thought to be related to the accumulation of acetaldehyde.
• The response is thought to serve as a disincentive to further alcohol use.
• Well-controlled trials of disulfiram do not show overall reductions in alcohol consumption. The fact that there were fewer drinking days for patients who returned to drinking suggests that disulfiram may benefit some AUD patients.
• Clinical trial data suggest that disulfiram use does not result in overall reductions in alcohol consumption. The fact that there were fewer drinking days for patients who returned to drinking suggests that disulfiram may benefit some AUD patients.

Question 42

Naltrexone

Answer 42

• an opioid receptor antagonist, blocks some of alcohol’s rewarding effects.
• Clinical trial data suggest that naltrexone reduces the risk for heavy drinking.
• The drug may be given orally or by injection of a long-acting form.

Question 43

Acamprosate

Answer 43

• an agonist analog of GABA, affects the activity of the excitatory neurotransmitter glutamate to reduce symptoms of abstinence.
• Acamprosate and naltrexone are used in conjunction with psychosocial co-interventions.
• Their use results in favorable alcohol consumption outcomes.
• Trials comparing these two medications did not establish a difference in outcomes between the two drugs.
• Acamprosate is given three times daily while naltrexone is given once daily.
• Acamprosate is contraindicated with severe renal impairment and oral naltrexone is contraindicated with acute hepatitis, liver failure, concurrent opioid use or an anticipated need for opioids.

Question 44

Alcohol Drug Interactions - Increased Drugg Effect

Answer 44

• Competitive inhibition of drug metabolism

• warfarin (increased INR)
• CYP P450 occupied with alcohol

• Additive CNS depression

• antihistamines
• barbiturates
• benzodiazepines
• opioids

Question 45

Alcohol Drug Interactions - Decreased Drug Effect after Chronic Alcohol (No Acute Alcohol)

Answer 45

• Increased drug metabolism

• CYP P-450 induced
• warfarin (decreased INR)

• CNS tolerance

• barbiturates
• general anesthetics
• tranquilizers

Answer 46

• Although ADH is responsible for the majority of ethanol metabolism, CYP2E1 accounts for about 10%.
• This constituent of the microsomal ethanol-oxidizing system can be altered by acute or chronic ethanol consumption.
• Competition between ethanol and other drugs (e.g., phenytoin and warfarin) that are metabolized by CYP2E1 is observed after acute consumption of ethanol.
• CYP2E1 is also induced by chronic consumption of ethanol, resulting in increased clearance of its substrates and increased susceptibility to certain toxins.
• The CYP P450 metabolism of warfarin to inactive metabolites is inhibited by the presence of alcohol.
• Warfarin action may be enhanced.
• Conversely CYP 2E1 induction with chronic alcohol use may enhance the toxicity of molecules metabolized to reactive intermediates.
• An example is acetaminophen.
• When alcohol is in the body it protects the liver from toxicity by diminishing the production of the toxic metabolite.
• However, shortly after the elimination of alcohol from the body, susceptibility to acetaminophen toxicity may be enhanced due to the alcohol-induced induction of CYP 2E1.