1. Alcohol Toxicology

2. Ethanol Ethanol is the alcohol constituent of “alcoholic” beverages
The most commonly abused intoxicating substance and co-ingestant with other drugs in suicide attempts
Ethanol is a common solvent for both prescribed and over-the-counter medications
Also serve as the diluent for many household products such as mouthwashes, colognes, perfumes, and extracts
“Proof”……is the term used to describe the ethanol content of alcoholic beverages
Alcohol proof is a measure of how much ethanol (alcohol) is contained in an alcoholic beverage. The term was originally used in the United Kingdom and was defined as 7/4 times the alcohol by volume (ABV). The UK now uses the ABV standard instead of alcohol proof. In the United States, alcoholic proof is defined as twice the percentage of ABV.

3. Ethanol
Serious neurologic, GI, nutritional, & psychiatric disease accompany chronic alcoholism. 6% of annual deaths may be attributable to alcohol
Abuse is highly associated with major trauma (motor vehicle collisions, fires, burns, falls)
Also associated with domestic violence, child abuse, and suicide

4. Ethanol….properties
Ethanol also commonly called alcohol, spirits, ethyl alcohol, and drinking alcohol
It is a volatile, flammable, colorless liquid with a strong chemical odor. Clear and colorless liquid at R.T
Low molecular weight (46.05 Daltons)
Highly miscible in water
Low solubility in lipids and dense tissue (bone)

5. Does not bind significantly to plasma proteins
Rapid, passive diffusion through membranes

6. Ethanol….absorption
80% of ingested alcohol is absorbed from the small intestine…….small amount is absorbed from mouth, esophagus, and stomach
In healthy adult, peak absorption occurs within min why ??
Depends on the several characteristics:
food, product characteristic (wine faster than distilled spirits)
age, gender, weight,, and other factors (GI motility, blood flow and gastric emptying)

7. Factors Affecting Ethanol Absorption
GI motility
increased: gastric ulcer, chronic gastritis, cholinergics
decreased: nausea, shock, anticholinergics
GI blood flow
increased: warm liquids or food, stress, chronic gastritis
decreased: exercise, sympathomimetics, other stimulants
Gastric emptying
increased: gastrectomy, carbonated drinks
decreased: gastric fibrosis, emotional disturbances, size and composition of food in stomach, smoking

8. Ethanol distribution Cells Serum 82% H2O 95% H2O EtOH
Serum ethanol is 5 – 15% higher than whole blood ethanol
Mildly polar, water soluble…..Vd 0.6L/Kg. Enter the CNS
For an equivalent oral dose, women have higher peak conc? (lower water content)
BAC = Blood Alcohol Concentration (serum EtOH conc.)

9. Ethanol….metabolism
A typical non-tolerant adult……metabolized 7-10g of ethanol/hour (one drink); BAC decrease 15-20mg/dl/hr
Tolerant individuals may metabolize ethanol faster 30-40mg/dl/hr
Pathway…….??
~90% of ethanol is metabolized in the liver, small amount excreted unchanged by the kidney, the lungs (breath alcohol), & sweat glands
Follows zero-order kinetics…….

11. Concentration-Time Relationship of Ethanol
* Reminder: 100 mg/dL = 0.1%w/v = 21.7 mmol/L
Concentration-Time Relationship of Ethanol
140
drinking
Peak BAC
120
episode
rapid distribution
100
zero-order
elimination rate
Plasma Ethanol, mg/dL 80 60
Absorption Phase
Post-Absorption Phase 40 20 1 2 3 4 5 6
Time After Initiation of Drinking, hr

12. Ethanol
NAD+
Alcohol
Dehydrogenase
(ADH)
NADH
Some metabolism of ethanol occur in the stomach in men but smaller amount in women…gender-related differences in BAC
Acetaldehyde

13. Ethanol
NAD+
Alcohol
Dehydrogenase
NADH
Acetaldehyde
Oxidation of acetaldehyde is blocked by disulfuram……drug used to treat alcoholism……. N, V, abdominal pain, flushing, headache and dizziness (also genetic variations)
Aldehyde
Dehydrogenase
(ALDH)
NAD+
NADH
Acetic acid

14. Ethanol NAD+ Alcohol Dehydrogenase NADH Acetaldehyde Aldehyde NAD+
Acetic acid
Thiokinase
CoA + ATP
Acetyl CoA
Via kreb’s cycle
CO2+ H2O

15. Ethanol
NAD+
Alcohol
Dehydrogenase
NADH
Fatty Liver
In chronic alcoholics this pathway increases the NADH/NAD+ ratio……generate an excess of reducing agents in the liver……development of lactic acidosis and alcoholic ketoacidosis
Acetaldehyde
Aldehyde
Dehydrogenase
NAD+
NADH
Fibrosis
Acetic acid
CoA
Cirrhosis
Acetyl CoA
Via kreb’s cycle
CO2+ H2O

16. Mechanisms underlying hepatic disease resulting from heavy ethanol
Increase in NADH during ethanol oxidation….limit the rate of ethanol metabolism AND
Enzymes requiring NAD+ are inhibited…..lactate and acetyl CoA accumulates (also produced in quantity from ethanol-derived acetic acid)
This supports fatty acid synthesis and the storage and accumulation of TGs. Ketone bodies accrue, exacerbating lactic acidosis
Ethanol induces CYP2E1 and is metabolism by the CYP2E1 pathway limiting regeneration of reduced glutathione…..enhances oxidative stress

17. Mechanism of toxicity
Like sedative-hypnotic ethanol is a CNS depressant
Although almost every neurotransmitter system is affected…..do not appear to have specific receptor
Interacts with and become integrated into the lipid bilayer of cell membranes…….increase membrane “fluidity” and thereby interfere with normal cellular function (very high conc.)
Ethanol seems to potentiate the activity of GABA by interacting with GABAa-receptor chloride channel

18. Mechanism of toxicity
Alcohol also appears to inhibit glutamate function at the NMDA (N-methyl-D-aspartate) receptor…..alcoholic ”blackouts” (period of memory loss with high intoxication)
Tolerance!! For instance, NMDA receptor up-regulate following chronic exposure.....decreased ethanol effect
GABA & NMDA receptors though to be involved in the withdrawal seizures
AMPA receptors are largely resistant to alcohol

19. Drug-drug interactions
Acute intoxication: may block the metabolism of drugs such as benzodiazepine, barbiturates, phenytoin, tricyclic antidepressants; also synergistic effects with sedative hypnotic agents
Chronic intoxication: stimulates microsomal enzymes (cytP450) and increase metabolism of isoniazid, phenytoin, tolbutamide, warfarin, & acetamenophen
Disulfiram effects

20. Parietal lobe
Frontal lobe
Occipital lobe
Temporal lobe
cerebellum
Medulla

21. Clinical symptoms
BAC
Brain
Mild
Decreased inhibitions
Slight visual impairment
Increase confidence %
Frontal lobe
Moderate
Ataxia
Slurred speech
Decreased motor skills
Diplopia
Altered equilibrium %
Parietal lobe
Occipital
cerebellum
Sever
Vision impairment
Disequilibrium
Stupor %
Diencephalon
Fatal
Miosis, decrase BP, HR and Temp.; Respiratory failure, coma
More than 0.5%
Medulla

22. Clinical presentation of intoxication
CNS (prominent):
low BAC associated with euphoric feeling, disinhibited actions;
at high BAC cause depression, slurred speech, altered perception of the environment, impaired judgement, ataxia, nystagmus
Higher levels….respiratory depression, coma
GI: acute intoxication (N, V, abdominal pain); chronic intoxication (esophagitis, gastritis, ulcer disease, pancreatitis, fatty infiltration of the liver, alcoholic hepatitis, cirrhosis)

23. Clinical presentation of intoxication
Alcohol inhibits gluconeogensis……hypoglycemia
Hypoglycemia may develop 6-36h after acute alcohol consumption; & may be associated with malnutrition in chronic alcoholism
Some malnourished patients develop alcoholic ketoacidosis characterized by ion gap metabolic acidosis
Vasodilatation (contributes to hypothermia)
Recovery from acute ethanol poisoning is usually rapid, if liver and kidneys are healthy

24. Clinical presentation of intoxication
Ethanol interferes with thiamine (vitamin B1) absorption and ethanol-induced hepatic disease leads to decreased thiamine storage
…….Wernicke-Korsakoff syndrome (diplopia, blurred vision, ataxia, confusion, & psychosis)
Tolerance and dependence (psychological & physical)
Alcohol withdrawal in tolerant individuals: characterized by hyperadrenergic state (tremor, anxiety, headache, N, V, flushed skin, diaphoresis, tachycardia, HTN, insomnia & hallucinations)

25. Laboratory
Serum ethanol concentration (BAC): variation in kinetic and tolerance make difficulty to associate conc. to clinical findings
BAC mg/dl…..intoxication
BAC >400mg/dl associated with fatalities
Serum osmolarity
Exhaled air ethanol analyzer “breathalyzers” (accurate it not vomiting within 15-30min)
Saliva ethanol assay: estimate BAC
Serum glucose

26. Treatment Mild/moderate acute intoxication: hydration
Severe acute intoxication: airway/breathing
Circulation: hypovolemia Tx with fluids
Altered mental status…naloxone, dextrose, thiamine (DONT cocktail)
Sod. Bicarbonate to correct lactic acidosis
GI decontamination not indicated (rapid abs.) unless other drug ingestion is suspected
Activated charcoal poorly adsorb alcohol but may be given if other drugs or toxins were ingested
Hemodialysis if symptoms are sever and extremely high BAC (> 0.4%)

27. Treatment Pharmacotherapy of Alcoholism : Withdrawal syndrome:
Prevent seizures, delirium, arrhythmias
Detoxification with long-acting BZD (diazepam)
Pharmacotherapy of Alcoholism :
Naltrexone
Acamprosate
Disulfuram

28. Other Alcohols
Methanol
Sources- oral exposures, skin or inhalation: (perfumes, solvents, paint remover)
Elimination is by oxidation to formaldehyde, formic acid and CO2
Although methanol produces mainly inebriation, its metabolic products may cause visual disturbance (progress to blindness), metabolic acidosis due to formic acid production and death due to respiratory depression after a characteristic latent period of 6–30 hours

29. Methanol Metabolism Methanol CHOOH Formic acid CO2 + H2O
CH3OH
Methanol Metabolism
Competitive inhibition
by ethanol
NAD+
ADH
Very reactive compound with a brief half-life of less than two minutes
Causes metabolic acidosis and follows zero-order kinetics with a half-life 2-24 hours
NADH + H+
ALDH
Formic acid
CHOOH
CO2 + H2O
Formaldehyde (particular odor)
CH2O
NADH + H+
NAD+

30. Management of poisoning
Support respiration
Suppression of metabolism by alcohol dehydrogenase to toxic metabolites (fomepizole, or ethanol i.v)
Alkalinization to counteract metabolic acidosis
Hemodialysis to enhance removal of MeOH and toxic products (formate)

31. Ethylene Glycol
In antifreeze preparation and industrial solvent (sweet taste sometimes intentional ingestion for suicide or instead of EtOH)
Ethylene glycol is metabolized by alcohol dehydrogenase to glycoaldehyde, which is then metabolized to, glyoxylic, and oxalic acids
These acids, along with excess lactic acid, are responsible for the anion gap metabolic acidosis
Oxalate readily precipitates with calcium to form insoluble calcium oxalate crystals….precipitate in the renal tubules and kidney damage
Treated with fomepizole or ethanol, and hemodialysis

32. Figure 1. Calcium oxalate monohydrate crystals in unstained urine sediment from a dog with ethylene glycol intoxication. The crystals are elongate with pointed ends.

33. Isopropanol….the “blue heaven”
Isopropyl alcohol is used widely as a solvent, an antiseptic, and a disinfectant and is commonly available in the home as a 70% solution (rubbing alcohol)
It is often ingested by alcoholics as a cheap substitute for liquor
Isopropanol has 2-3 times the potency of ethanol and causes hypotension and CNS and respiratory depression more readily than ethanol
Not metabolized to toxic organic acids….does not produce a profound anion gap acidosis

34. Isopropanol
Approximately 20-50% of isopropanol is excreted unchanged by the kidney, while 50-80% is converted in the liver to acetone
Acetone is excreted primarily by the kidneys, with some excretion through the lungs
H3C CH OH
CH3 O
ADH

35. Symptoms GIT: pain, vomiting, gastritis with hematoemesis
Cardiovascular: arrhythmia, hypotension
Renal: hypotension may lead to renal failure
Metabolic acidosis may occur but is usually mild
Musculoskeletal: ataxia, myopathy (rare)
Respiratory: depressed function in overdose

36. Treatment ABCD Treat coma, hypotension, hypoglycemia,
There is no specific antidote. Fomepizole or ethanol therapy is not indicated
Hemodialysis should be considered when levels are extremely high ( mg/dl)