Pharmacology of Alcohols

Flashcards covering ethanol metabolism, alcohol-drug interactions, withdrawal, alcoholism treatments, and methanol/ethylene glycol toxicity.

What is the most important alcohol of pharmacologic interest?

Ethanol

What central nervous system effects does ethanol possess?

Anxiolytic and sedative effects

Why do the pharmacologic benefits of ethanol not outweigh its usage?

Its toxic potential outweighs its benefits

What types of major problems are caused by alcohol abuse?

Major medical and socioeconomic problems

What two other alcohols are highlighted as having toxicologic importance?

Methanol and ethylene glycol

How many enzyme systems metabolize ethanol to acetaldehyde?

Two enzyme systems

What initial metabolite is produced when ethanol is oxidized by alcohol dehydrogenase or MEOS?

Acetaldehyde

What co-factor is required by alcohol dehydrogenase (ADH) enzymes?

$$\text{NAD}^+$$

Where in the body is alcohol dehydrogenase (ADH) primarily found?

In the liver

Which enzyme system accounts for the metabolism of low to moderate doses of ethanol?

Alcohol dehydrogenase (ADH)

What rate order kinetics does alcohol dehydrogenase (ADH) exhibit?

Zero-order kinetics

What is the clinical consequence of zero-order kinetics in ethanol metabolism via ADH?

It results in a fixed capacity for ethanol metabolism

What does the acronym MEOS stand for?

Microsomal ethanol-oxidizing system

At what blood ethanol concentration does MEOS contribute significantly to ethanol metabolism?

Blood ethanol levels higher than $100\,mg/dL$

What substrates/co-factors are utilized alongside ethanol in the MEOS pathway?

$$\text{NADPH} + \text{O}_2$$

What co-factor products are generated alongside acetaldehyde by MEOS oxidation?

$$\text{NADP}^+ + \text{H}_2\text{O}$$

Into what compound is acetaldehyde rapidly metabolized?

Acetate ($\text{CH}_3\text{COO}^-$)

Which enzyme converts acetaldehyde to acetate?

Aldehyde dehydrogenase

Where is aldehyde dehydrogenase located cellularly and tissue-wise?

It is a mitochondrial enzyme found in the liver and many other tissues

Which drug acts as an inhibitor of aldehyde dehydrogenase?

Disulfiram

What metabolic steps and enzyme inhibitors are illustrated in this diagram of ethanol oxidation?

Ethanol converts to Acetaldehyde via ADH (inhibited by Fomepizole) or MEOS, and Acetaldehyde converts to Acetate via Aldehyde dehydrogenase (inhibited by Disulfiram)

What is the chemical formula for Ethanol given in the metabolism pathway?

$$\text{CH}_3\text{CH}_2\text{OH}$$

What is the chemical formula for Acetaldehyde?

$$\text{CH}_3\text{CHO}$$

What is the chemical formula for Acetate?

$$\text{CH}_3\text{COO}^-$$

Which metabolic step converts $\text{NAD}^+$ to $\text{NADH}$ during ethanol breakdown?

Both the conversion of Ethanol to Acetaldehyde by ADH and Acetaldehyde to Acetate by Aldehyde dehydrogenase

What drug selectively inhibits Alcohol Dehydrogenase?

Fomepizole

How can interactions between ethanol and other drugs cause clinical effects?

By altering the pharmacokinetics or pharmacodynamics of the second drug

How does prolonged alcohol intake without liver damage affect the biotransformation of other drugs?

It can enhance their metabolic biotransformation

Ethanol induces which specific hepatic enzyme family?

Hepatic cytochrome P450 enzymes

Which over-the-counter medication has an increased risk of hepatotoxicity when taken with chronic alcohol?

Acetaminophen

Chronic consumption of how many alcoholic drinks per day increases the risk of acetaminophen hepatotoxicity?

Three or more drinks per day

Why does chronic ethanol intake increase acetaminophen-induced hepatotoxicity?

Because of increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites

What do FDA regulations require on over-the-counter products containing acetaminophen?

A warning about the relation between ethanol consumption and acetaminophen-induced hepatotoxicity

According to the acetaminophen metabolism pathway, which cytochrome P450 enzymes produce reactive toxic intermediates?

CYP2E1 and CYP3A4

Which non-toxic pathway converts acetaminophen using UDP?

Glucuronidation (producing Nontoxic glucuronide)

Which non-toxic pathway converts acetaminophen using ADP and $\text{SO}_3\text{H}$?

Sulfation (producing Nontoxic sulfate)

What molecule detoxifies reactive intermediates of acetaminophen via GSH-conjugation?

Glutathione (GSH)

What occurs when reactive toxic intermediates of acetaminophen react with nucleophilic cell macromolecules (Protein-SH)?

Liver cell death

In Figure 4-5, what product is formed downstream of GSH-conjugation of acetaminophen?

Mercapturic Acid Conjugate

What do the abbreviations GSH and SG stand for in Figure 4-5?

GSH stands for glutathione; SG stands for glutathione moiety

How does acute alcohol consumption affect the metabolism of other drugs?

It can inhibit metabolism due to decreased enzyme activity or decreased liver blood flow

Which three major classes of drugs interact with acute alcohol via pharmacokinetic inhibition?

Phenothiazines, tricyclic antidepressants, and sedative-hypnotic drugs

What pharmacokinetic mechanism causes acute alcohol to inhibit drug metabolism?

Decreased enzyme activity or decreased liver blood flow

What pharmacodynamic effect occurs when ethanol is combined with other central nervous system depressants?

Additive CNS depression

Combining ethanol with which specific drug class produces the most important additive CNS depression?

Sedative-hypnotics

What happens when individuals physically dependent on ethanol abruptly discontinue its use?

They develop a withdrawal syndrome

What early symptoms characterize alcohol withdrawal syndrome?

Insomnia, tremor, and anxiety

What severe, life-threatening complications can arise from ethanol withdrawal?

Seizures and delirium tremens

What clinical features characterize delirium tremens?

Delirium, agitation, autonomic nervous system instability, and low-grade fever

What peripheral symptoms are observed during alcohol withdrawal?

Nausea, vomiting, diarrhea, and arrhythmias

Based on the withdrawal timeline graph, during what days post-discontinuation do withdrawal seizures typically occur?

Days 1 to 4

According to the alcohol discontinuation timeline, when do alcoholic hallucinations peak?

Between days 1 and 4

According to the alcohol discontinuation timeline, when does Delirium Tremens occur?

Between days 2 and 9 post-discontinuation

What symptoms can persist up to 30-90 days following alcohol discontinuation?

Anxiety, insomnia, tremor, palpitations, nausea, and anorexia

What are the three core components in managing alcohol withdrawal symptoms?

1. Correction of electrolyte imbalance, 2. Administration of thiamine, 3. Administration of a sedative-hypnotic

Why is thiamine administered during the management of alcohol withdrawal?

As a standard component of management to prevent neurological complications

Which category of sedative-hypnotics is preferred for managing alcohol withdrawal?

Long-acting benzodiazepines

What are two examples of long-acting benzodiazepines used for alcohol withdrawal?

Diazepam and chlordiazepoxide

When are short-acting benzodiazepines preferred over long-acting ones for alcohol withdrawal?

When the patient has compromised liver function

What is an example of a short-acting benzodiazepine used for withdrawal in liver-compromised patients?

Lorazepam

How is alcoholism (alcohol dependence) characterized socio-medically?

As a complex socio-medical problem characterized by a high relapse rate

How many drugs have FDA approval for adjunctive treatment of alcohol dependence?

Three drugs

Which three drugs are FDA-approved for adjunctive treatment of alcohol dependence?

Disulfiram, naltrexone, and acamprosate

What three medications are classified under 'Drugs to treat alcohol dependence' in the provided flowchart?

Disulfiram, Naltrexone, and Acamprosate

What is the enzymatic mechanism of action of Disulfiram?

It blocks the oxidation of acetaldehyde to acetic acid by inhibiting aldehyde dehydrogenase

What compound accumulates in the blood if a patient on Disulfiram drinks alcohol?

Acetaldehyde

What clinical symptoms are caused by disulfiram-induced acetaldehyde accumulation?

Flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion

How quickly do symptoms of acetaldehyde accumulation appear after drinking alcohol on Disulfiram?

Within a few minutes

What type of behavioral response does Disulfiram induce in patients seeking to stop alcohol consumption?

A conditioned avoidance response

Why does a patient taking Disulfiram refrain from drinking alcohol?

To prevent the unpleasant effects of disulfiram-induced acetaldehyde accumulation

What class of drug is Naltrexone?

A long-acting opiate antagonist

What intervention should always accompany Naltrexone therapy for alcohol dependence?

Supportive psychotherapy

What did experimental animal studies show regarding opioids and alcohol consumption?

Small amounts of opioids increased alcohol drinking, whereas opioid antagonists inhibited self-administration of alcohol

How does Naltrexone's tolerability and reaction profile compare to Disulfiram?

Naltrexone is better tolerated and does not produce an aversive reaction

Why should the combination of Naltrexone and Disulfiram be avoided?

Because both drugs are potential hepatotoxins

What is Acamprosate?

An agent used in alcohol dependence treatment programs with a poorly understood mechanism of action

Which receptor systems does Acamprosate act upon molecularly?

GABA, glutamate, serotonergic, noradrenergic, and dopaminergic receptors

What clinical benefit does Acamprosate provide when combined with psychotherapy?

It reduces short-term and long-term (more than 6 months) relapse rates

For how long can Acamprosate reduce relapse rates when combined with psychotherapy?

Short-term and long-term (more than 6 months)

What are the primary clinical features of methanol intoxication?

Visual dysfunction, gastrointestinal distress, shortness of breath, loss of consciousness, and coma

Why is there a delay before severe toxic symptoms appear in methanol poisoning?

Because the conversion of methanol to its toxic metabolites is relatively slow

How long is the typical delay before severe toxicity appears after methanol ingestion?

6–30 hours

What is the first metabolite produced when methanol is oxidized by alcohol dehydrogenase?

Formaldehyde ($\text{H}_2\text{CO}$)

According to the methanol metabolism diagram, which enzyme converts Formaldehyde to Formate?

Aldehyde dehydrogenase

Through what pathway is Formate ($\text{HCOO}^-$) converted to $\text{CO}_2 + \text{H}_2\text{O}$?

A folate-dependent pathway

What specific end-stage toxicities are caused by formaldehyde and formic acid accumulation?

Severe acidosis and retinal damage

What inhibitor of alcohol dehydrogenase is promptly administered to reduce formaldehyde formation in methanol poisoning?

Fomepizole

How does ethanol work as a treatment for methanol toxicity?

It competitively inhibits alcohol dehydrogenase oxidation of methanol

By what administration route should Fomepizole or Ethanol be given during acute toxic alcohol poisoning?

Intravenously

How does industrial exposure to ethylene glycol typically occur?

By inhalation or skin absorption

What common product is associated with self-administration/ingestion of ethylene glycol?

Antifreeze products

What toxic metabolite is formed from ethylene glycol via alcohol dehydrogenase?

Oxalic acid

What major organ damages/complications are caused by oxalic acid formation?

Severe acidosis and renal damage (nephrotoxicity)

According to the toxic alcohols comparison diagram, what toxic product and clinical outcome arise from ADH acting on Ethylene Glycol versus Methanol?

Ethylene glycol produces Oxalic acid leading to Acidosis and nephrotoxicity; Methanol produces Formaldehyde/formic acid leading to Severe acidosis and retinal damage

Which two drugs are categorized for treating acute methanol or ethylene glycol intoxication in the provided flowchart?

Ethanol and Fomepizole

What medical intervention effectively removes ethylene glycol and its toxic metabolites from circulation?

Hemodialysis

Hemodialysis is recommended for patients with a serum ethylene glycol concentration above what threshold?

Above $50\,mg/dL$

Besides high serum concentration ($>50\,mg/dL$), what two clinical findings warrant hemodialysis in ethylene glycol toxicity?

Significant metabolic acidosis and significant renal impairment

What target enzyme do Fomepizole and Ethanol both inhibit to treat toxic alcohol poisonings?

Alcohol dehydrogenase