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

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 30-120min 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 Serum 95% H 2 O Cells 82% H 2 O 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. Absorption PhasePost-Absorption Phase * Reminder: 100 mg/dL = 0.1%w/v = 21.7 mmol/L Concentration-Time Relationship of Ethanol 0123456 0 20 40 60 80 100 120 140 Time After Initiation of Drinking, hr Plasma Ethanol, mg/dL zero-order elimination rate Peak BAC rapid distribution drinking episode

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

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

14. Ethanol Acetaldehyde Acetic acid Acetyl CoA NAD+ NADH NAD+ NADH Alcohol Dehydrogenase Aldehyde Dehydrogenase CO 2 + H 2 O CoA + ATP Via kreb’s cycle Thiokinase

15. Ethanol Acetaldehyde NAD+ NADH NAD+ NADH Alcohol Dehydrogenase Aldehyde Dehydrogenase Fatty Liver Fibrosis Cirrhosis Acetic acid Acetyl CoA CO 2 + H 2 O CoA Via kreb’s cycle 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

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 GABA a -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

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. Frontal lobe Parietal lobe Occipital lobe cerebellum Medulla Temporal lobe

21. Clinical symptomsBACBrain Mild Decreased inhibitions Slight visual impairment Increase confidence 0.05-0.1%Frontal lobe Moderate Ataxia Slurred speech Decreased motor skills Diplopia Altered equilibrium 0.1-0.3%Parietal lobe Occipital cerebellum Sever Vision impairment Disequilibrium Stupor 0.3-0.5% Occipital cerebellum 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 1. Serum ethanol concentration (BAC): variation in kinetic and tolerance make difficulty to associate conc. to clinical findings BAC 80-100mg/dl…..intoxication BAC >400mg/dl associated with fatalities 2. Serum osmolarity 3. Exhaled air ethanol analyzer “breathalyzers” (accurate it not vomiting within 15-30min) 4. Saliva ethanol assay: estimate BAC 5. Serum glucose

26. Treatment Mild/moderate acute intoxication: hydration Severe acute intoxication: airway/breathing 1. Circulation: hypovolemia Tx with fluids 2. Altered mental status…naloxone, dextrose, thiamine (DONT cocktail) 3. Sod. Bicarbonate to correct lactic acidosis 4. GI decontamination not indicated (rapid abs.) unless other drug ingestion is suspected 5. Activated charcoal poorly adsorb alcohol but may be given if other drugs or toxins were ingested 6. Hemodialysis if symptoms are sever and extremely high BAC (> 0.4%)

27. Treatment Withdrawal syndrome: 1. Prevent seizures, delirium, arrhythmias 2. 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 CH 3 OH Formaldehyde (particular odor) CH 2 O ADH Formic acid CHOOH CO2 + H2O NAD+ NADH + H+ ALDH NAD+ NADH + H+ Competitive inhibition by ethanol Causes metabolic acidosis and follows zero-order kinetics with a half-life 2-24 hours Very reactive compound with a brief half-life of less than two minutes

30. Management of poisoning 1.Support respiration 2.Suppression of metabolism by alcohol dehydrogenase to toxic metabolites (fomepizole, or ethanol i.v) 3.Alkalinization to counteract metabolic acidosis 4.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 H3CCH OH CH3 H3CCH O CH3 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 (500-600mg/dl)