109. Pharmacology of Alcohol Abuse

🔥🔥🔥 *Chronic Effects of Ethanol:* -Fetal Alcohol Syndrom (FAS)- FAS includes what 5 sxs?

-Intrauterine growth retardation -Microcephaly -Poor coordination -Underdevelopment of midfacial region -Minor joint abnormalities

*Drugs Used in Treatment of Alcohol Dependence:* What are 2 Additional agents not approved by the FDA specifically for ethanol dependence?

1. *Topiramate* 2. *Ondansetron*

*Chronic Effects of Ethanol:* -Coronary heart disease (CHD)- 1. Studies show that moderate alcohol consumption (1-3 drinks per day) prevents WHAT and reduces mortality more than in individuals who abstain or are heavy consumers of alcohol? 2. Ethanol raises serum levels of the cardioprotective WHAT cholesterol, inhibits some inflammatory processes that underlie atherosclerosis, and antioxidants (especially in red wine) may protect against WHAT

1. CHD, (this is now being questioned, however) 2. -high density lipoprotein (HDL) -atherosclerosis

🔥🔥🔥🔥 *Most Notable Chronic Effects of Ethanol:* 1. Increased risk for WHAT in the mouth pharynx esophagus and liver? 2. What happens to pregnant alcoholics babies?

1. Increased risk of cancer (mouth, pharynx, esophagus, and liver) 2. Fetal alcohol syndrome

*🔥🔥🔥🔥* *Topic 1 Summary:* 5. Ethanol's CNS depressions starts at what and extends to what 2 things? 6. is it scheduled? is it addictive? what can result upon discontinuation of chronic use? 7. Ethanol has notable acute effects on what 3 systems? 8. Ethanol has notable chronic effects on what 4 things?

5. Ethanol's CNS depression extends from sedation to coma and death. 6. -Though not a scheduled substance, -ethanol is addictive and -results in withdrawal syndrome upon discontinuation of chronic use. 7. Ethanol has notable acute effects on CNS, myocardium and vascular & g.i. smooth muscle. 8. Ethanol has notable chronic effects on CNS, liver, cardiovascular system and fetus.

*Drugs Used in Treatment of Alcohol Dependence:* 1. What is the MOA of *Ondansetron*? 2. Approved for the treatment of what? 3. does it work against alcohol dependence?

1. MOA: antagonizes 5-HT3 receptors 2. Approved for treatment of nausea and vomiting induced by chemotherapy, radiation, and postoperatively; ongoing clinical trials for reducing alcohol consumption 3. Preliminary findings suggest that ondansetron is effective in the treatment of early-onset alcoholics who respond poorly to psychosocial treatment alone (early-onset alcoholics are individuals with a severe, lifelong battle with the disease, multiple medical, psychological and social problems, and often a family history of alcoholism)

*Drugs Used in Treatment of Alcohol Dependence:* 1. What is the MOA of *Disulfiram*? 2. What 8 symptoms do you get? WHY? 3. How does it work?

1. MOA: irreversibly inhibits aldehyde dehydrogenase and causes extreme discomfort in patients who drink alcoholic beverages 2. -flushing, throbbing headache, nausea, vomiting, sweating, hypotension, confusion -due to the accumulation of aldehyde 3. Discourages ethanol use because of unpleasant effects with ethanol (negative reinforcement)

*Drugs Used in Treatment of Alcohol Dependence:* 1. What is the MOA of *Acamprosate*? (agonist of what? antagonist of what? 2. How does it work?

1. MOA: weak NMDA-receptor antagonist and GABAA receptor agonist (also affects serotonergic, noradrenergic, and dopaminergic systems) 2. Reduces short-term and long-term (more than 6 months) relapse rates when combined with psychotherapy

*Drugs Used in Treatment of Alcohol Dependence:* 1. What is the MOA of *Naltrexone*? 2. how does it work?

1. MOA: µ opioid receptor antagonist (long-acting) 2. Reduces the craving for alcohol and the rate of relapse to either drinking or alcohol dependence for the short term (12 weeks)

🔥🔥🔥🔥🔥🔥🔥🔥🔥🔥🔥🔥🔥 *Chronic Effects of Ethanol:* -Diuresis- 1. Do you have more or less diuresis with alcohol? WHY? 2. Do you have more or less diuresis with alcohol withdrawal? WHY? 3. What can #2 cause?

1. MORE: Alcohol inhibits the release of vasopression (antidiuretic hormone; causes reabsorption of water and concentration of urine) from the posterior pituitary gland, resulting in enhanced diuresis 2. Vasopressin release is increased during withdrawal resulting in water retention 3. dilutional hyponatremia

🔥🔥🔥🔥🔥 *Chronic Effects of Ethanol:* -Neurotoxicity- 1. WHAT causes the Paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death? 2. It is Associated with a deficiency in WHAT and rarely seen in the absence of alcoholism? 3. How do you treat this? 4. What cannot be fixed with #3? What is it called?

1. Wernicke-Korsakoff syndrome 2. Thiamine 3. Treatment with thiamine will improve ocular problems, ataxia, and confusion, but most patients are left with a chronic disabling memory disorder -known as Korsakoff's psychosis

*Topic 2 Summary:* What drug compliance is predictably low diminishing its contemporary use.

Disulfiram

*Topic 2 Summary:* What drug increases levels of aldehyde following ethanol consumption and produces unpleasant symptoms of hangover as discouragement for alcohol use.

Disulfiram

*Topic 2 Summary:* What drug inhibits metabolism of other drugs and some drugs have "disulfiram-like" effects.

Disulfiram

🔥🔥🔥🔥 In the USA, WHAT is the leading cause of liver cirrhosis and of the need for liver transplantation

chronic alcohol abuse *singular most important chronic effect* -Liver disease is the most common medical complication of alcohol abuse (15-30% of chronic heavy drinkers eventually develop severe liver disease) B O N U S ? ! ? 1. Primary effects are progressive: WHAT 3 things occur which lead to liver failure? 2. Accumulation of fat results from inhibition of both the tricarboxylic acid cycle and the oxidation of fat, in part, owing to the generation of excess WHAT produced 1. -*fatty infiltration of the liver* (also called alcoholic fatty liver, which is reversible), -*hepatitis*, and -*cirrhosis* 2. NADH

*Chronic Effects of Ethanol:* -Nervous System- 1. What is Delirium Tremens?

caused by ethanol withdrawal and is characterized by delirium, hallucinations, fever, and tachycardia

I'm not going to talk about this illustration. Talks about blood alcohol levels that produces impairments in driving

what ever this is

🔥🔥🔥 *Chronic Effects of Ethanol:* Chronic alcohol abuse during pregnancy can have teratogenic effects (apoptotic neurodegeneration), Causing WHAT?

*Fetal alcohol syndrome (FAS)*

*Drugs Used in Treatment of Alcohol Dependence:* What are 3 agents approved by the FDA for treatment of ethanol dependence?

1. *Naltrexone* 2. *Acamprosate* 3. *Disulfiram*

🔥🔥🔥🔥 *Most Notable Chronic Effects of Ethanol:* -CV System- What are the 6 problems that can occur?

-cardiomyopathy, -heart failure, -arrhythmias, -hypertension, -stroke, -coronary heart disease

3 decades ago osteopathic leader in Tulsa.

...nothing here

*Ethanol:* -Predictable Actions- 1. Will lean or obese people have lower blood alcohol levels? 2. What can happen to the CNS? 3. What does it do to the heart? vasculature? Myometrium? 4. Chronic exposure causes what 10ish things?

1. *Lean people will have lower blood alcohol levels than obese people because of volume of distribution.* 2. *CNS depression ranging from sedation to coma and death from respiratory paralysis.* 3. -*Acute exposure:* -depresses myocardial function, -dilates peripheral vasculature, -relaxes myometrium 4. *Chronic exposure causes:* -liver disease, -pancreatitis, -gastritis, -CNS toxicity, -withdrawal syndrome, -cardiomyopathy, -cardiac arrhythmias, -hypertension, -coronary artery disease, -fetal alcohol syndrome -and others.

*Ethanol:* -Distinguishing Characteristics- 1. Is it water soluble? 2. Slowly or rapidly absorbed from the GI tract? at how many minutes is the peak plasma levels in fasting? What slows absorption? 3. Is it able to get into the CNS? Why? 4. What are the 3 ways it is eliminated from the body? 5. Is it addictive? Is it a controlled substance? 6. does it need protein binding?

1. *Water soluble (Volume of distribution = Total body water)* 2. -*Rapidly absorbed from g.i. tract* -(Peak plasma levels in 30 minutes in fasting. -*Food slows absorption*.) 3. *Rapid CNS entry due to small molecular size.* 4. Eliminated via: -1) *Alcohol dehydrogenase pathway in liver,(and gut)* -2) *Microsomal Ethanol-Oxidizing System (MEOS)* (chronic alcohol use) and -3) Renal, respiratory, cutaneous excretion. (least important) 5. Addictive, but not a controlled substance. 6. nope. its hydrophilic

*Ethanol:* 1. What are the 4 categories it is in? 2. What is its MOA? (What are 2 receptors that it hits and what does it do to them?)

1. -Alcohol, -CNS Depressant, -Sedative-Hypnotic, -Anxiolytic 2. Mechanism of Action: -Affects large number of membrane proteins that participate in signaling pathways. -***GABAA receptor - enhances ability of GABA to open Cl channel*** -*NMDA receptor - Inhibits ability of glutamate to open cation channel.* -Other include - Kir3 channels, 5-HT 3 receptors, nucleoside transporters, Na/K ATPase, adenyl cyclase, phosphoinositide-specific phospholipase C

*Fomepizole:* (Antizol) -Predictable actions- 1. Delays the metabolism of what 2 things? Allowing for what? 2. Contraindicated with WHAT? WHY?

1. -Delays metabolism of methanol and ethylene glycol -while liver detoxifies these chemicals or while they are removed by hemodialysis. 2. -Contraindicated with ethanol -because it extends the ethanol half-life and prolongs its toxic effects.

*Chronic Effects of Ethanol:* -Immune system- 1. Is the Immune function in some tissues inhibited or triggered? WHAT organs? 2. WHAT can occur in the liver while predisposition to infections (e.g., in the lung) can worsen the morbidity and increase the mortality risk of patients with pneumonia

1. -Immune function in some tissues is inhibited (lung) -while pathologic, hyperactive immune function in other tissues is triggered (liver, pancreas) 2. Inflammatory damage

*Chronic Effects of Ethanol:* -Cardiomyopathy and heart failure- 1. Heavy and continued alcohol consumption is associated with a WHAT type of cardiomyopathy? with ventricular [hypertrophy or atrophy?] and fibrosis 2. Alcohol induces the following changes in heart cells: membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and up-regulation of voltage-dependent calcium channels

1. -dilated cardiomyopathy -Ventricle Hypertrophy 2. no question

*Chronic Effects of Ethanol:* -Esophagus- 1. Alcohol is a factor associated with esophageal dysfunction, What are 5 things that it can cause in the esophagus? 2. At high BAC, [increased or decreased?] peristalsis and [Increases or decreases?] lower esophageal sphincter pressure occur (may respond to proton-pump inhibitors and abstinence)

1. -esophageal reflux, -Barrett's esophagus, -traumatic rupture of the esophagus, -Mallory-Weiss tears, and -esophageal cancer 2. -decreased -decreases

*Chronic Effects of Ethanol:* -Nervous System- 1. Consumption of alcohol in high doses over an extended period of time results in WHAT and in physical and psychological WHAT? 2. Is there a limit to tolerance, especially the lethal dose? 3. Physical dependence is demonstrated by the elicitation of a WHAT when alcohol consumption is terminated; 4. What are the symptoms in #3? (4)

1. -tolerance (reduced behavioral or physiological response to the same dose of ethanol) -dependence 2. YES, only a relatively small increase in the lethal dose occurs with increasing alcohol use 3. withdrawal syndrome 4. -hyperexcitability in mild cases and -seizures, -toxic psychosis, and -delirium tremens in severe cases

🔥🔥🔥🔥 *Most Notable Chronic Effects of Ethanol:* -LIVER- 1. What percentage of chronic abusers develop severe liver disease? 2. What is the first liver change that occurs? That leads to what liver problem to occur? That leads to what liver problem to occur. That leads to the liver to finally have what?

1. 15-30% of chronic abusers develop severe liver disease 2. Alcoholic fatty liver → hepatitis → cirrhosis → liver failure

*Molecular Targets of Drugs of Abuse:* 1. How many classes are there? 2. What do the Class I's activate? 3. What do the Class II's bind to? 4. What do the Class III's bind ot? 5. What class is ethanol in?

1. 3 2. Class I: Activate GPCRs 3. Class II: Bind to ionotropic receptors and ion channels 4. Class III: Bind to Monoamine Transporters 5. Class II (check out the picture)

*Fomepizole:* (Antizol) -Distinguishing Characteristics- 1. How is it administered? sometimes simultaneously with what?

1. Administered intravenously and sometimes simultaneously with hemodialysis.

*Chronic Effects of Ethanol:* -Sexual function- 1. Initially does it case increased or decreased libido? 2. What can occur with excessive long term use?

1. Alcohol, along with many drugs of abuse, have disinhibiting effects that may lead initially to increased libido, 2. but with excessive long-term use, alcohol can lead to a deterioration of sexual function

*Metabolism of Ethanol and Methanol:* -Alcohol Dehydrogenase pathway- 1. Acetaldehyde gets broken down by WHAT? 2. What does it get broken down into?

1. Aldehyde dehydrogenase 2. Acetic acid (then it is excreted)

*Chronic Effects of Ethanol:* -Arrhythmias- 1. Atrial or ventricle arrhythmias are associated with heavy and binge drinking? 2. also seen in what syndrome?

1. BOTH 2. Also present in patients undergoing alcohol withdrawal syndrome

*ALCOHOL-DRUG INTERACTIONS:* 1. Chronic ethanol consumption increases the levels of WHAT? 2. Acute ethanol may inhibit drug metabolism due WHAT 2 things? 3. If you take what type of drug with it? 4. Several drugs (e.g., metronidazole, cefotetan, trimethoprim) inhibit WHAT and can cause a disulfiram-like reaction if combined with ethanol

1. CYP450s (particularly 2E1) -Example: risk of acetaminophen-induced (at high therapeutic levels) hepatotoxicity is increased by chronic consumption of three or more drinks per day 2. to a decrease in enzyme activity or liver blood flow (e.g., phenothiazines, tricyclic antidepressants, and sedative-hypnotics) 3. Additive CNS depression with other CNS depressants (e.g., sedative-hypnotics) 4. aldehyde dehydrogenase

*Methanol:* (wood alcohol, methyl alcohol) -Distinguishing Characteristics- 1. Where is it absorbed? 2. Metabolism to formaldehyde is fast or slow? Why is that important?

1. Can be absorbed through skin, lungs and g.i. tract. 2. -Metabolism to formaldehyde is slow (6 - 30 hours) -providing an opportunity for intervention.

*Disulfiram:* (Antabuse) 1. What category is it in? 2. What is its MOA?

1. Category: Alcoholism treatment drug 2. MOA: Aldehyde dehydrogenase inhibitor

*Fomepizole:* (Antizol) 1. What 2 categories is it in? 2. What is its MOA?

1. Category: Antidote to Methanol and Ethylene Glycol Poisoning 2. MAO: Inhibits alcohol dehydrogenase

*Methanol:* (wood alcohol, methyl alcohol) 1. What 2 categories is it in? 2. What is its MOT (mechanism of toxicity)?

1. Category: Commercial solvent, Poison 2. Mechanism of Toxicity: Converted by alcohol dehydrogenase to formaldehyde

*Ethylene Glycol:* 1. What 3 categories is it in? 2. What is the MOT (mechanism of toxicity)?

1. Category: Industrial solvent, antifreeze, poison 2. Mechanism of Toxicity: Converted by alcohol dehydrogenase to toxic oxalic acid.

*Chronic Effects of Ethanol:* -Intestines- 🔥1. What can result in malabsorption of nutrients in the small intestine? 🔥2. Reversible alcohol damage can also result in WHAT 2 things? 🔥🔥3. Deficiencies in WHAT vitamins? (3) 4. Chronic alcohol consumption has been implicated in WHAT bone problem? 5. Alcoholics have lowered serum and brain levels of WHAT, which may contribute to a predisposition to brain injuries

1. Chronic diarrhea 2. weight loss and multiple vitamin deficiencies 3. B complex of vitamins (*particularly thiamine*), retinoids and carotenoids 4. osteoporosis 5. magnesium

*Acute Effects of Ethanol:* -Heart- 1. What does acutely moderate amounts of alcohol do to the heart?

1. Depression of myocardial contractility has been observed in individuals who acutely consume moderate amounts of alcohol (i.e., at BAC above 100 mg/dl)

*Topic 2 Summary:* 1. Drug treatment in acute ethanol toxicity is confined to doing what? 2. Drug therapy for detoxification involves using WHAT drugs and using them HOW?

1. Drug treatment in acute ethanol toxicity is confined to maintaining patient as ethanol is eliminated. 2. Drug therapy for detoxification involves substituting a long-acting sedative-hypnotic drug for alcohol and then gradually tapering the dose.

*Chronic Effects of Ethanol:* -Body temperature- 1. What happens to the body temperature? Do they sweat?

1. Due to increased cutaneous and gastric blood flow, sweating may occur while the internal body temperature falls

🔥🔥🔥🔥 *Topic 1 Summary:* 1. Is ethanol water soluble? does it distribute quickly? 2. What is the major route of elimination for ethanol? HOW?(what 2 enzymes) 3. Chronic and excessive use of ethanol initiates what elimination pathway? this pathway increases the risk for WHAT? 4. What is ethanol's CNS MOA? (what channels, whats the result?)

1. Ethanol is a small water soluble that quickly distributes to any place that water goes. 2. -Ethanol's major route of elimination is hepatic metabolism -by alcohol dehydrogenase followed by aldehyde dehydrogenase. 3. -Chronic and excessive use of ethanol initiates a secondary microsomal elimination pathway -that increases possibility of drug-drug interactions. 4. Ethanol's CNS MOA is modification of chloride and sodium ion channels resulting in diminished nerve transmission

*Metabolism of Ethanol and Methanol:* 1. Alcohol dehydrogenase breaks methanol to what? 2. #1 is toxic to alot of things what organ is specifically sensitive to it? What does it cause in this organ?

1. Formaldehyde 2. - retina -blindness

*Chronic Effects of Ethanol:* -Neurotoxicity- Degenerative changes of the nervous system occur with chronic alcohol abuse and include the 3 symptoms?

1. Generalized symmetric peripheral nerve injury, which begins with distal parathesias of the hands and feet 2. Gait disturbances and ataxia 3. Dementia and demyelinating disease (rare)

*Disulfiram:* (Antabuse) -Predictable Actions- 1. What does it produce in the presence of ethanol? (7) 2. Why does it have limited use? 3. What is another problem with this drug? what are some examples?

1. In presence of ethanol produces: flushing, throbbing headache, nausea, vomiting, diaphoresis, hypotension, confusion. 2. Compliance is often low leading to limited use. 3. -Metabolism of other drugs (in addition to ethanol) is impaired by disulfiram. -These include: phenytoin, oral anticoagulants, acetaminophen, cephalosporins, first generation sulfonylureas and isoniazid.

*Topic 3 Summary:* 1. Methanol is metabolized to toxic WHAT? 2. Ethylene glycol is metabolized to toxic WHAT? 3. Metabolism of methanol and ethylene glycol is slowed by WHAT? 4. Delaying metabolism of toxic alcohols permits treatment HOW?

1. Methanol is metabolized to toxic formaldehyde. 2. Ethylene glycol is metabolized to toxic oxalate. 3. Metabolism of methanol and ethylene glycol in slowed by fomepizole. 4. Delaying metabolism of toxic alcohols permits elimination by natural elimination and hemodialysis

*Mechanisms of Action of Ethanol and Other Drugs of Abuse:* 1. What is one of the major ethanol receptors? 2. Where does ethanol attach to #1? 3. What does ethanol do to it? 4. What 2 effects does it have on DA neurons? 5. Why do we care about DA?

1. Note that GABAA is a major ethanol receptor. (Note the diversity of receptors targeted by ethanol) 2. The GABAA receptor is probably an allosteric receptor like the benzodiazepines, z-compounds or barbiturates. 3. Each of these receptors are ionotrophic receptors that modify ionic conduction through cell membranes. 4. excitation and disinhibition 5. Thought to be the cause of tolerance, dependence, and addiction (CRAVINGS for DA) -note the diversity of receptors targeted by ethanol

*Topic 2 Summary:* Drug treatment of ethanol dependence may include what 3 drugs. WHAT are their MOAs?

1. Opiate antagonists (Naltrexone) 2. Glutamate antagonism and GABA agonism (Acamprosate) 3. Acetaldehyde dehydrogenase inhibition (Disulfiram)

*Disulfiram:* (Antabuse) -Distinguishing Characteristics- 1. is it poorly or well absorbed from the g.i. tract? 2. What does it do in the absence of ethanol? 3. How long does it require until full action?

1. Rapidly and completely absorbed from g.i. tract. 2. Has little effect in absence of ethanol, then effects are actions of acetaldehyde and my last 30 minutes to several hours. 3. Requires up to 12 hours for full action.

he skipped over this probably just read it *Acute Effects of Ethanol:* -CNS- Alcohol affects many proteins that participate in signaling pathways, including WHAT 3 things?

1. Receptors for amines, amino acids, opioids, and neuropeptides 2. Enzymes (Na+/K+-ATPase, adenylyl cyclase, phosphoinositide-specific phospholipase C) 3. Ion channels (NMDA and GABA receptors)

*Treatment of Acute Ethanol Intoxication:* 1. What should you support? 2. What should you prevent? consider what drugs? 3. What should you give if any suspicion of additional drugs? 4. What should you replace if hypovolemic? 5. What drug should you give if convulsing? 6. What 3 things should you also replace? 7. What should you do if the pt is violent?

1. Respiratory support 2. Prevent aspiration; consider anti-emetics 3. Naloxone if any suspicion of additional drugs 4. Fluid replacement if hypovolemic 5. Short acting benzodiazepine (e.g., lorazepam) if convulsing 6. Thiamine (IM), glucose (IV), electrolytes, etc. 7. Consider sedation in violent patients

*Ethylene Glycol:* -Distinguishing Characteristics- 1. Why is this sometimes attractive to victims?

1. Sweet taste sometimes attractive to victims, especially children and animals.

*Ethylene Glycol:* -Predictable actions- 1. What are the 3 stages of toxicity? 2. How do you treat this?

1. Three stages of toxicity: -Transient excitation followed by CNS depression. -Severe metabolic acidosis -Deposition of oxalate crystals in kidney followed by renal insufficiency 3. Treat with supportive therapy and fomepizole.

*Acute Effects of Ethanol:* -Smooth Muscle- 1. Ethanol causes [Vasoconstriction or Vasodilation?] via what 2 mechanisms? 2. In severe overdose situations What does ethanol do to the body temperature? 3. What does it do to the Uterine muscle? What did it used to be used for?

1. Vasodilation, -likely due to CNS effects (depression of the vasomotor center) and -smooth muscle relaxation caused by the metabolite acetaldehyde 2. In severe overdose situations, ethanol can cause hypothermia caused by vasodilation (can cause death) 3. Ethanol causes uterine muscle relaxation and was used intravenously for suppression of premature labor before the introduction of more effective and safe medications (e.g., calcium blockers, magnesium ion, β2-adrenergic receptor agonists)

*Methanol:* (wood alcohol, methyl alcohol) -Predictable Actions- 1. What symptoms will you first get? 2. How do you know someone has severe poisoning when you are around them? 3. How do you treat this?

1. Visual disturbance 2. Formaldehyde odor on breath (severe poisoning) 3. Treat with supportive therapy and fompizole

*Drugs Used to Treat Ethanol Withdrawal Syndrome:* 1. Drug therapy for detoxification in severe cases involves substituting WHAT drug for alcohol and then gradually tapering the dose 2. What are the benefits of Long-acting benzodiazepines (chlordiazepoxide, clorazepate, diazepam)? What are the disadvantages? 3. When should Short-acting benzodiazepines (lorazepam, oxazepam) be used? 4. Tapering of sedative-hypnotic medications can occur over several weeks with complete alcohol detoxification requiring several months of abstinence for restoration of normal CNS function

1. a long-acting sedative-hypnotic 2. -Benefits: less frequent dosing and built-in tapering effect -Disadvantages: pharmacologically active metabolites may accumulate, especially in patients with compromised liver function 3. Rapidly converted to inactive metabolites and are useful in patients with liver disease 4. no question

*Chronic Effects of Ethanol:* -Blood- 1. Chronic drinkers may have mild anemia resulting from WHAT? 2. Iron deficiency anemia may result from WHAT?

1. alcohol-related folic acid deficiency 2. gastrointestinal bleeding

*Time Course of Events During Ethanol Withdrawal Syndrome:* 1. What are the 6 earliest signs and symptoms? 2. What 2 things are possible in severe syndromes? 3. how long can it persist for? 4. Delirium tremens typically develops HOW LONG after alcohol discontinuation?

1. anxiety, insomnia, tremor, palpitations, nausea, and anorexia 2. Can persist, in a milder form, for several months after alcohol discontinuation 3. 48-72 hours after alcohol discontinuation

*Drugs Used in Treatment of Alcohol Dependence:* 1. *topiramate* is approved for the treatment of what 2 things? 2. Does it work against alcohol dependence?

1. approved for the treatment of seizure disorders and migraine prophylaxis; ongoing clinical trials to test reduction of craving for alcohol 2. compared to placebo group, pts taking topiramate achieved more abstinent days and lower craving for alcohol

*Metabolism of Ethanol and Methanol:* 1. What inhibits the breakdown of ethanol and methanol? 2. What inhibits the breakdown of aldehyde dehydrogenase? 3. Methanol is metabolized to WHAT which is highly toxic?

1. fomepizole inhibits breakdown of ethanol and methanol via alcohol dehydrogenase 2. disulfiram inhibits breakdown of aldehyde dehydrogenase. 3. methanol is metabolized to the highly toxic formaldehyde.

🔥🔥🔥 *Chronic Effects of Ethanol:* -Stomach- 1. Heavy alcohol use can disrupt the gastric mucosal barrier and cause acute and chronic WHAT? 2. Beverages containing more than 40% alcohol have a direct toxic effect on gastric mucosa with clinical symptoms that include WHAT? WHAT meds relieve this?

1. gastritis 2. -acute epigastric pain -(relieved with antacids or histamine H2-receptor blockers)

*Chronic Effects of Ethanol:* -Endocrine system and electrolyte balance- 1. Possible unbalance of steroid hormones may cause WHAT 2 things? 2. Potassium level alterations, [hyper or hypo?] glycemia, and ketosis are possible in heavy drinkers

1. gynecomastia and testicular atrophy 2. -hypoglycemia

*Chronic Effects of Ethanol:* -Stroke- 1. Clinical studies indicate an [increased or decreased?] incidence of hemorrhagic and ischemic stroke in persons who drink more than 40-60 g of alcohol/day

1. increased

*Chronic Effects of Ethanol:* -Increased risk of cancer- 1. Chronic alcohol use increases the risk for cancer of the reactive oxygen species 5 places and may increase the risk of breast cancer in women (though alcohol is not a carcinogen) 2. _________________ and __.___.__. produced by increased CYP450 activity can damage DNA

1. mouth, pharynx, larynx, esophagus, and liver 2. -Acetaldehyde -reactive oxygen species

*Chronic Effects of Ethanol:* -Nervous System- 1. What is the Molecular mechanisms of tolerance and dependence? 2. Chronic exposure of animals to alcohol elicits many adaptive responses involving neurotransmitters and their receptors, ion channels, and enzymes that participate in signal transduction pathways: -Expression of __________ receptors and voltage-sensitive ________ channels are [Down or Up?]-regulated, which may underlie the seizures that accompany alcohol withdrawal syndrome 3. __________ receptors are [Down or UP?]-regulated, which leads to a continued hyperexcited state of the CNS during withdrawal 4. Alcohol affects local concentrations of opiods and what 2 NT, which are all involved in brain reward circuits (see below)

1. poorly known BUT animal studies offer up some hypotheses 2. -NMDA receptors -voltage-sensitive Ca2+ channels -up-regulated, 3. -GABAA receptors -down-regulated, which leads to a continued hyperexcited state of the CNS during withdrawal 4. - serotonin, opioids, and dopamine

*Acute Effects of Ethanol:* -CNS- 1. At moderate concentrations what does alcohol do? (2) 2. As concentrations of alcohol increase, individuals experience WHAT 4 things? 3. How fast does tolerance occur? So when are the CNS effects most marked? 4. What does #3 mean fro chronic drinkers? 5. Similar to other sedative-hypnotic agents, alcohol is a CNS depressant and at high BAC can induce WHAT 3 things?

1. sedation and relief of anxiety 2. slurred speech, ataxia, impaired judgment, and disinhibited behavior (typically called intoxication or drunkenness) 3. -Acute tolerance to alcohol can occur after a few hours of drinking, -so many of the CNS effects are most marked as the blood level is rising 4. For chronic drinkers who are tolerant to the effects of alcohol, higher concentrations are needed to elicit these CNS effects 5. Coma, respiratory depression, and death

*Drugs Used to Treat Ethanol Withdrawal Syndrome:* 1. Moderate forms of alcohol withdrawal syndrome, characterized by WHAT 3 THINGS, occur 6-8 hours after alcohol consumption is stopped and usually abate in 1-2 days 2. Major pharmacological objective is to prevent WHAT 3 THINGS and include electrolyte rebalancing and WHAT therapy

1. tremor, anxiety, and insomnia 2. -seizures, delirium, and arrhythmias -Thiamine

*Chronic Effects of Ethanol:* -Skeletal muscle- 1. Chronic ethanol consumption is associated with [increased or decreased?] muscle strength and [increased or decreased?] activity of creatine kinase in the plasma

1.- decreased muscle strength -increased activity of creatine kinase

A 52 y/o male is found unconscious at home and brought to the hospital by his wife. She states that he regularly drinks half a gallon of vodka daily and has suffered an alcohol withdrawal seizure in the past. She does not believe that he ever abused street or prescription drugs. His BAC on admission is 520 mg/dL (0.52 mg%). After admission to the hospital the patient begins to seize. Which drug is most clinically effective in this situation? A. Diazepam B. Disulfiram C. Flumazenil D. Fluoxetine E. Oxazepam

A. Diazepam

🔥🔥🔥 What is a leading cause of mental retardation and congenital malformation?

Alcohol

*Metabolism of Ethanol and Methanol:* What is the major pathway for ethanol metabolism?

Alcohol Dehydrogenase Pathway

*Metabolism of Ethanol and Methanol:* -Alcohol Dehydrogenase pathway- 1. Where does it get broken down in the body? (3) what does it get broken down to? 2. What is acetaldehyde thought to be responsible for?

Alcohol Dehydrogenase Pathway: 1. Alcohol dehydrogenase in liver, stomach and brain converts ethanol to acetaldehyde 2. thought to be responsible for many symptoms of hangover.

A 50 y/o male alcoholic, unable to find any ethanol, ingests a large amount of methanol that he bought for his camp lantern. Which is the most likely consequence? A. Atrioventricular conduction defect B. Blindness C. Bronchospasm D. Delirium tremens E. Metabolic alkalosis

B. Blindness

*Chronic Effects of Ethanol:* -Hypertension- 1. What percent of HTN cases is alcohol responsible for?

Alcohol is responsible for 5% of cases of hypertension

WHAT is the most common neurologic abnormality of chronic alcoholics?

Generalized symmetric peripheral nerve injury, which begins with distal parathesias of the hands and feet

🔥🔥🔥🔥 *Most Notable Chronic Effects of Ethanol:* -CNS- 1. Changes to what 2 receptors? 2. What 2 things can occur from chronic alcohol use? (not symptoms) 3. What degenerative change can occur? 🔥4. What syndrome can occur?

CNS: 1. changes in GABAA and NMDA receptor expression 2. Tolerance and physical dependence 3. Degenerative changes - generalized symmetric peripheral nerve injury 4. Wernicke-Korsakoff syndrome

A 50 y/o male alcoholic, unable to find any ethanol, ingests a large amount of methanol that he bought for his camp lantern. Which pharmacologic treatment should be initiated to reduce metabolism of methanol to toxic metabolites? A. Disulfiram B. Ethanol C. Folic acid D. Fomepizol E. Thiamine

D. Fomepizol

🔥🔥🔥🔥 *Chronic Effects of Ethanol:* -Fetal Alcohol Syndrom (FAS)- How does the baby break down ethanol?

Ethanol crosses the placenta and the fetal liver has little or no alcohol dehydrogenase activity and must rely on the mother's liver for elimination

*Topic 2 Summary:* What drug inhibits alcohol dehydrogenase thereby diminishing rate of metabolism of ethanol and other alcohols.

Fomepizole

🔥🔥🔥 WHAT is the most common cause of both acute and chronic pancreatitis in the US?

Heavy alcohol use B O N U S ? ! ? 1. Alcohol has direct toxic effects on WHAT pancreatic cells, 2. Alcohol alters pancreatic [endothelial or epithelial?] permeability, 3. Alcohol promotes the formation of what 2 things in the pancreas? 1. pancreatic acinar cells 2. pancreatic epithelial permeability 3. protein plugs and calcium carbonate-containing stones

*Chronic Effects of Ethanol:* Does it increase or decrease the risk of cancer?

Increased risk of cancer

*Metabolism of Ethanol and Methanol:* 1. When is the microsomal Ethanol-Oxidizing system (MEOS) mostly in use? 2. #1 causes what to the Cytochrom P450 enzymes? this causes what? 3. What are the byproducts of MEOS? (2)

Microsomal Ethanol-Oxidizing System (MEOS): 1. During chronic ethanol consumption 2. cytochrome P450 enzymes (esp. CYP2E1) are induced causing increasing amounts of ethanol to be metabolized by MEOS. 3. Toxic byproducts (free radicals, oxidizing agents) are produced

*Chronic Effects of Ethanol:* -Neurotoxicity- What happens to the vision over several weeks of heavy alcohol consumption, with changes typically bilateral and symmetric (optic nerve degeneration may follow)

Painless blurring of vision

what drug can you take that is 80% ethanol without having to talk to your bishop?

Vicks NyQuil not a test question

There is a diversity of ethanol targets and their vulnerability to different concentrations. WHICH receptors are NOT vulnerable at fatal concentrations?

They are all vulnerable at fatal concentrations

Which receptor is most sensitive to ethanol? (get activated first with the lowest amount of blood alcohol)

potentiation of delta GABAa receptor

lets talk about some chronic effects. keep in mind that you are going to see a half a dozen slides that will describe a variety of chronic effects, I do not want you to use your synapses to memorize all those but I would like you to have in your notes; the diversity of chronic effects that occur as a result of ethanol. I will point out a couple that I think are particularly important. If he talked about something I will bold it and fire the card.

tough loss Robert