[PCOL and TOXICOLOGY] Alcohol, Caffeine and Nicotine

Ethanol (Ethyl alcohol)

Form of alcohol we use for drinking

Alcohol

Moderate amount relieves anxiety and provides feeling of euphoria

Known to be associated with acute and chronic illnesses

Alcohol dependence

inability to control drinking, devoting much time to getting and using alcohol, or recovering from its effects

Genetic and Environmental Factors

Factors affecting the complex disorders involving Alcohol Use

Alcohol

Water-soluble, rapid GI absorption

Peak blood levels: ~30 min (fasting)

Food: slows absorption (↓ gastric emptying)

Rapid distribution, blood ≈ tissue levels

Vd (volume of distribution): 0.5–0.7 L/kg (≈ total body water)

Women: ↑ peak levels (↓ body water, ↓ first-pass metabolism)

CNS: rapid entry, ↑ brain levels (↑ blood flow)

Crosses biologic membranes easily

Slower Absorption

Effect of Food on Alcohol absorption

Metabolism and Excretion of Alcohol

>90% metabolized in liver

Remainder: lungs, urine

Zero-order kinetics (fixed rate, not concentration-dependent)

Zero order kinetics

order of elimination of alcohol in the body

Breath Test of ALCOHOL

measures lung excretion (DUI basis)

≈ 10 oz beer, 3.5 oz wine, 1 oz spirits

Equivalence of 1 drink

Metabolism rate: 7–10 g/hr (~1 drink/hour)

1) Alcohol Dehydrogenase Pathway

2) Microsomal Ethanol-Oxidizing System

3) Acetaldehyde Metabolism

3 metabolic pathways of alcohol

Alcohol Dehydrogenase Pathway

• Primary metabolism pathway for ethanol

• Mainly in liver; also in brain, stomach

• Genetic variations in ADH → affect ethanol metabolism rate

Influences risk of alcohol abuse

• Men: more gastric ADH → lower blood alcohol

• Women: less gastric metabolism → ↑ blood alcohol

Men

Gastric ADH (men vs. women)

Men < Women

Between men and women, who has a more gastric metabolism and therefore have lower blood alcohol

Microsomal Ethanol-Oxidizing System

Cytochrome P450 system (uses NADPH)

Induced by chronic alcohol use or blood alcohol >100 mg/dL

↑ Ethanol metabolism & drug clearance

Generates toxic byproducts (risk with chronic use)

Acetaldehyde Metabolism

Aldehyde dehydrogenase (ALDH) → converts acetaldehyde → acetate

Disulfiram: inhibits ALDH → ↑ acetaldehyde → aversion reaction

Symptoms: flushing, nausea, vomiting, dizziness, headache

Other ALDH inhibitors:

Metronidazole, cefotetan, trimethoprim → disulfiram-like reaction

East Asians: genetic ALDH deficiency

Asian flush: high acetaldehyde → unpleasant symptoms

Protective against alcohol-use disorders

Disulfiram

inhibits ALDH → ↑ acetaldehyde → aversion reaction

East asians

They have genetic ALDH deficiency

General Effects of Chronic Alcohol Consumption

Affects vital organs

Needs higher concentrations vs. other drugs to cause toxicity

Tissue damage: ethanol + acetaldehyde + metabolic stress

General Effects of Chronic Alcohol Consumption

Oxidative stress, ↓ glutathione, mitochondrial damage

Dysregulated growth factors, ↑ cytokine-induced injury

Tolerance and Dependence: ALCOHOL

From CNS adaptation + ↑ ethanol metabolism rate

Cross-tolerance with sedative-hypnotics (GABA-facilitators)

Marked psychological & physical dependence

Liver: ALCOHOL

Most common medical complication

↓ gluconeogenesis → hypoglycemia

Progression: fatty liver (reversible) → hepatitis → cirrhosis → liver failure

More severe in women and those with hepatitis B/C

Women with Hepa B/C

Effects of alcohol on liver is more common on what persons with conditions

GI Tract: ALCOHOL

Irritation, inflammation, bleeding, scarring

Malabsorption + worsens nutritional deficiencies

↑ Risk of pancreatitis

CNS: ALCOHOL

Common: peripheral neuropathy

Thiamine deficiency → Wernicke-Korsakoff syndrome:

> Ataxia, confusion, extraocular muscle paralysis

> Prevent Korsakoff’s psychosis with parenteral thiamine

Withdrawal:

Mild: hyperexcitability

Severe: seizures, toxic psychosis, delirium tremens

Parenteral Thiamine

How to prevent Korsakoff's psychosis

Endocrine and electrolytes: ALCOHOL

Gynecomastia, testicular atrophy (steroid imbalance)

Fluid/electrolyte disorders: ascites, edema, effusions

Vomiting/diarrhea → K⁺ loss, secondary aldosteronism

↓ Gluconeogenesis → hypoglycemia

↑ Cortisol & GH → ketosis

Cardiovascular: ALCOHOL

↑ hypertension, anemia, dilated cardiomyopathy

Binge drinking → arrhythmias

Moderate ethanol (10–15 g/day) → ↑ HDL cholesterol

Potential coronary heart disease protection

Immune system: ALCOHOL

Dual effect: Immunosuppression + immune hyperactivity

Lungs:

↓ Alveolar macrophage function

↓ Granulocyte chemotaxis, ↓ T cells

Liver:

↑ Activity of Kupffer & stellate cells

↑ Cytokine production

↑ Risk of infections, esp. pneumonia

↑ Morbidity & mortality in respiratory infections

Cancer risk: ALCOHOL

↑ Risk: oral cavity, pharynx, larynx, esophagus, liver

Slight ↑ in breast cancer (women)

Acetaldehyde + Reactive Oxygen Species (ROS) - from CYP450 → DNA damage

No known safe threshold

Fetal Alcohol Syndrome

Teratogenic:

> Mental retardation, growth deficiency

> Microcephaly, midface underdevelopment

> Congenital heart defects

Caused by: DNA damage, altered folate metabolism, chronic inflammation

Acetaminophen (paracetamol)

Ethanol induces hepatic CYP450 enzymes, especially relevant for what drug

Acetaminophen (paracetamol)

Chronic alcohol use → ↑ risk of hepatotoxicity

↑ P450-mediated conversion → toxic metabolites

Risk at even therapeutic doses

Acute Alcohol Use

May inhibit drug metabolism

↓ enzyme activity

↓ liver blood flow

Affects drugs like:

Phenothiazines

Tricyclic antidepressants

Sedative-hypnotics

CNS Depressants: Alcohol Use

Additive CNS depression when combined with:

> Sedative-hypnotics

> Opioids

> Antihistamines (H1 blockers)

Can lead to respiratory depression, coma, death

Other interactions: ALCOHOL

Potentiates effects of non-sedative drugs:

Vasodilators

Oral hypoglycemics

Initial emergency Management of ALCOHOL

Prevent respiratory depression & aspiration of vomitus

Fatal level: >400 mg/dL blood alcohol concentration

Correct electrolyte & fluid imbalances

Administer glucose → treat hypoglycemia, ketoacidosis

Administer thiamine → prevent Wernicke-Korsakoff syndrome

Glucose

Initial emergency management for Alcohol when treating hypoglycemia and ketoacidosis

Thiamine

Initial emergency treatment of alcohol when treating Wernicke-Korsakoff Syndrome

Withdrawal Syndrome Risks: ALCOHOL

Symptoms:

Insomnia

Tremor

Anxiety

Delirium, delirium tremens

Nausea, vomiting, diarrhea, arrhythmias

Goal: prevent seizures, delirium, arrhythmias

Potassium

Magnesium

Phosphate

What needs to be corrected in supportive correction of Alcohol?

uses Thiamine

Long-acting Sedative Hypotonic

For pharmacologic alcohol management, we need to replace alcohol with what

Benzodiazepines

Chlordiazepoxide

Diazepam

3 long acting drugs of alcohol pharmacologic maangement

Diazepam

Used as alcohol's treatment for :

Built-in tapering effect

Risk of metabolite accumulation

short-acting benzodiazepines:

Lorazepam

Oxazepam

When an older adult has a liver disease, what is the alcohol medication suitable

Naltrexone

Used to treat alcoholism:

Class: Long-acting opioid antagonist

Mechanism: Blocks μ-opioid receptors

Benefits: Reduces relapse rates to drinking/alcohol dependence

Reduces craving

Considerations:

> Can cause dose-dependent hepatotoxicity

Caution: If abnormal serum aminotransferases

Do not combine with disulfiram (risk of liver toxicity)

Disulfiram

What should not be combined with Naltrexone because it can cause liver toxicity

μ-opioid receptors

Receptors blocked by Naltroxene

Long-acting

Is Naltroxene long acting or short acting?

Acamprosate

Mechanism:

Weak NMDA-receptor antagonist

GABAA receptor activator

Affects serotonergic, noradrenergic, and dopaminergic systems

Pharmacokinetics:

Poor oral absorption, worsened by food

Renally eliminated

No significant drug-drug interactions

Adverse Effects:

Mostly gastrointestinal

Contraindication: Severe renal impairment

GI problems

+

Affects: Serotonin, Dopamin, Adrenaline

Adverse effect of Acamprosate

Poor oral absorption

Effect of FOOD to acamprosate

Patients with severe renal impairment

Acamprosate is contraindicated for patients with

Disulfiram

Mechanism: Inhibits aldehyde dehydrogenase, causing acetaldehyde buildup

Reaction with alcohol causes:

Flushing

Throbbing headache

Nausea, vomiting

Sweating

Hypotension, confusion

Kinetics:

Rapidly & completely absorbed

Slowly eliminated → effects last several days post-dose

Drug Interactions:

Inhibits metabolism of phenytoin, oral anticoagulants, isoniazid

> Avoid alcohol-containing medications

Hepatic Risk: Can raise hepatic transaminases

Slow elimination

(can last several days)

Describe the elimination of Disulfiram

phenytoin

oral anticoagulants

isoniazid

(avoid: Alcohol containing)

Disulfiram inhibits metabolism of what drugs

Alcohol containing medications

when using disulfiram, what medications need to be avoided

Throbbing headache

Nausea, vomiting

Sweating

Hypotension, confusion

Adverse effects of Disulfiram

Increase Disulfiram

Increase Acetaldehyde

correlational relationship of

Disulfiram and Acetaldehyde

Methanol (Wood Alcohol)

Sources: Solvents, windshield fluids

Absorption: Skin, respiratory, GI

Formaldehyde

Formic acid

CO₂

Toxic Forms of Metabolites of Methanol

Causes Visual dysfunction, GI distress, SOB, coma

(nahilo > sumakit tiyan > nakatulog)

Methanol (Wood Alcohol): Adverse Effects

Stabilize: Support respiration

Prevent toxic metabolism:

Fomepizole – alcohol dehydrogenase inhibitor

IV ethanol – competes with methanol for ADH

Eliminate toxins:Hemodialysis

Correct acidosis:Alkalinization

Treatments of Methanol Poisoning

Fomepizole

An alcohol dehydrogenase inhibitor used as treatment for methanol poisoning

IV Ethanol

Treatment for methanol poisoning that acts as a competition for the methanol

Ethylene Glycol

Uses: Antifreeze, industrial solvents

Risks: Sweet taste attracts children, pets

Toxic Metabolites: Toxic aldehydes and oxalate

Aldehyde

Oxalate

Toxic Metabolites of Ethylene Glycol

Stages of Ethylene Glycol Toxicity

1) Excitation → CNS depression (first few hours)

2) Severe metabolic acidosis (4–12 hours)

3) Delayed renal insufficiency

Fomepizole

IV ethanol

Hemodialysis

3 treatments of Ethylene Glycol

Nicotine and Caffeine

Health Risks:

have high incidences of cardiovascular, respiratory, and neoplastic diseases.

Addiction & Dependence:

Both substances can lead to addiction and dependence.

Acute toxicity of Caffeine and Nicotine

Excessive CNS stimulation: tremor, insomnia, nervousness

Cardiac stimulation: arrhythmias

Nicotine

Respiratory paralysis at high doses

Severe toxicity in small children who ingest nicotine-containing products (gum, patches, or vaping solutions)

Nicotine

Mechanism of Action:

Selective agonist of the nicotinic acetylcholine receptor

Withdrawal:

Mild withdrawal symptoms: irritability, anxiety, sleep disturbances

Highly addictive: relapse is common after cessation attempts

Nicotine Substitution

Medications (Varenicline, Bupropion, Rimonabant)

Treatment for Nicotine Addiction

Nicotine Substitution

Chewed, inhaled, or transdermal nicotine delivery systems help reduce dependency by slowing absorption.

Varenicline

Partial agonist at α4β2 nicotinic receptors; may impair driving and is associated with suicidal ideation.

Bupropion

Antidepressant approved for smoking cessation, most effective when combined with behavioral therapy.

Rimonabant

A cannabinoid receptor agonist (used off-label for smoking cessation).

Caffeine

Methylxanthine family member with pronounced CNS effects.

Cortical arousal: increases alertness and defers fatigue.

Heart: CAFFEINE

Positive chronotropic (heart rate) and inotropic (force of contraction) effects.

Symptoms: CAFFEINE

Symptoms include lethargy, irritability, and headaches.

Esmosol

A treatment for caffeine

A short-acting β-blocker used as an antidote.

Quinolone antibiotics

inhibit caffeine metabolism.