1. Specific Toxins Part I

2. Acids Examples –Toilet bowl cleaner –Rust remover –Phenol (carbolic acid) –Hydrochloric acid Severe burning of stomach Absorption, systemic acidemia

3. Acids Loss of airway = most immediate threat Secure airway against edema IV with LR, NS for volume loss Emesis, gastric lavage contraindicated Dilution with water, milk NOT recommended

4. Alkalis Examples –Drain cleaner –Washing soda –Ammonia –Lye (sodium hydroxide) –Bleach (sodium hypochlorite) Severe burning of esophagus, stricture formation

5. Alkalis Loss of airway = most immediate threat Secure airway against edema IV with LR, NS for volume loss Emesis, gastric lavage contraindicated Dilution with water, milk NOT recommended

6. Hydrocarbons Examples –Kerosene –Gasoline –Lighter fluid –Turpentine –Furniture polish

7. Hydrocarbons Signs/Symptoms –Choking, coughing, gagging –Vomiting, diarrhea, severe abdominal pain –Chemical pneumonitis, pulmonary edema If the patient is coughing, aspiration has occurred

8. Hydrocarbons Signs/Symptoms –Euphoria, confusion/anxiety, seizures –Increased myocardial irritability, arrhythmias (adrenergic agents may cause V-fib) –Liver damage, hypoglycemia

9. Hydrocarbons Management –100% oxygen with good humidification –IV tko –Monitor ECG –Drug therapy D 50 W for hypoglycemia Diazepam for seizures Antiarrhythmics

10. Hydrocarbons Inducing emesis controversial –Should NOT be induced with low viscosity hydrocarbons

11. Hydrocarbons If ingestion has occurred recently, emesis probably should be induced with: –Halogenated hydrocarbons (carbon tetrachloride) –Aromatic hydrocarbons (toluene, xylene, benzene) –>1cc/kg gasoline, kerosene, naptha –Petroleum products with toxic additives (lead tetraethyl, pesticides)

12. Hydrocarbons Seek advice of medical control and poison control center

13. Methanol methyl alcohol wood alcohol wood naphtha

14. Methanol Sources –Industry –Household solvents –Paint remover –Fuel, gasoline additives –Canned heat –Windshield washer antifreeze

15. Methanol Toxic dose –Fatal oral: 30-240ml –Minimum: 100 mg/kg –Example Windshield washer fluid 10% Methanol 10 kg child needs only 10 cc to be toxic

16. Methanol Mechanism of toxicity –Methanol slowly metabolized to formaldehyde –Formaldheyde rapidly metabolized to formic acid Acidosis Ocular toxicity

17. Methanol Metabolism O C O H H + _ HO C O H Formic Acid C H O H Formaldehyde HO H H H C Methanol Alcohol dehydrogenase Aldehyde dehydrogenase

18. Methanol Overdose Presentation –Inebriation –Gastritis –Osmolar gap (osmolar gap as little as 10mOsm/L is consistent with methanol poisoning)

19. Methanol Overdose Presentation –Latent period of up to 30 hours –Severe anion gap metabolic acidosis –Visual disturbances, blindness (“standing in a snowstorm”) –Seizures –Coma –DEATH

20. Methanol Management –High concentration oxygen –IV tko –ECG monitor –if < 30 minutes lavage or induce emesis (if not done then it is probably useless)

21. Methanol Management –Sodium Bicarbonate –Folic acid 50mg IV every 4 hours Helps convert formic acid to CO 2, H 2 O –Give specific antidote

22. Methanol The specific antidote for methanol toxicity 10% EtOH solution in D5W 7.5 ml/kg loading dose and 1.5 ml/kg/hr maintenance 100 proof (50%) EtOH 1.5 ml/kg loading dose and 0.3 ml/kg/hr maintenance

23. Ethanol Metabolism H H H C HO H H CC H O H H H C HO C O H H H C Krebs Cycle Ethanol Acetic Acid Acetaldehyde Alcohol dehydrogenase Aldehyde dehydrogenase

24. Methanol Alcohol dehydrogenase EthanolMethan ol Acetic Acid CO 2 + H 2 O + Energy Urine

25. Methanol Specific antidote –Fomepizole (4-methylpyrazole) –Inhibits alcohol dehydrogenase –Produces same end result as ethanol without causing intoxication

26. Ethylene Glycol Antifreeze (95% ethylene glycol) Tastes sweet Kids, animals like taste/drink large quantities

27. Ethylene Glycol Mechanism of toxicity –Metabolized via alcohol dehydrogenase to glycoaldehyde then to glycolic, glyoxylic, and oxalic acids –Acids lead to anion gap metabolic acidosis –Oxalate binds with calcium Forms crystals causing tissue injury Produces hypocalcemia

28. Ethylene Glycol Toxic dose –Approximate lethal oral dose: 1.5ml/kg –Example 10 kg child needs 15ml for lethal dose

29. Ethylene Glycol Overdose Presentation (first 3-4 hours) –Patient may appear intoxicated –Gastritis, vomiting –Increase in osmolar gap –No initial acidosis

30. Ethylene Glycol Overdose Presentation (after 4-12 hours) –Anion gap acidosis –Hyperventilation –Seizures, coma –Cardiac conduction disturbances, arrhythmias –Renal failure –Pulmonary, cerebral edema

31. Ethylene Glycol Management –Lavage if within 2 hours –Sodium bicarbonate –Fomepizole or ethanol –Folic acid, pyridoxine, thiamine (enhance metabolism of glyoxylic acid to nontoxic metabolites)

32. Cyanide

33. But first… A little review of biochemistry and biophysics

34. Staying alive requires energy... The natural tendency of the universe is for things to become more disorderly. This trend toward disorder is called entropy. Complex systems (including us) don’t tend to last long, unless… They have a constant supply of energy to combat entropy.

35. Organisms capture and store the energy they need in the form of... The “currency” cells use to pay off the energy debt built up fighting entropy. Formed by capturing energy released as the cell breaks down large molecules through glycolysis and the Krebs Cycle. Adenosine Triphosphate (ATP)

36. Glycolysis In cytoplasm Does not require oxygen Breaks glucose molecule into two pyruvic acid molecules Net gain of 2 ATP If oxygen absent, pyruvate converted to lactate If oxygen present, pyruvate changed to acetate (acetyl-CoA) and sent to Krebs Cycle

37. The Krebs Cycle In mitochondria Requires oxygen Strips H + and electrons off of acetate, leaving CO 2 Sends the H + and electrons to the electron transport chain

38. Electron Transport/Oxidative Phosphorylation In mitochondria Electrons pass down a series of carriers--losing energy as they go It’s like a series of waterfalls Energy is released and stored as ATP Electrons and H + bind to O 2, making H 2 O 36 ATP produces per glucose molecule

39. Oxidative Phosphorylation NADNADH 2 2H FADFADH 2 Ox. Cyt. bRed. Cyt. b Ox. Cyt. cRed. Cyt. c Ox. Cyt. aRed. Cyt. a Red. Cyt. a3Ox. Cyt. a3 1/2 O 2 2H + H2OH2O ADP + P i ATP

40. Putting It All Together Cells have to have energy to stay alive. Cells get energy by breaking down glucose in two phases: glycolysis and the Krebs Cycle. Glycolysis yields 2 ATP and pyruvate. Pyruvate is changed to acetate (acetyl-CoA) and sent to the Krebs Cycle. The Krebs Cycle strips hydrogen and electrons off acetate and feeds them into the electron transport chain. Movement of electrons down the transport chain releases energy which is trapped as ATP. At the end of the chain, the electrons combine with hydrogen and oxygen to form water.

41. Cyanide Chemical, plastic industries Metallurgy, jewelry making Blast furnace gases Fumigants, pesticides Present in various plants –apples, pears, apricots, peaches, bitter almonds

42. Cyanide Acrylonitrile is metabolized to cyanide Nitroprusside (Nipride) if given too long is metabolized to cyanide Acetonitrile in some fingernail glues has caused pediatric deaths Cyanide is so common that all mammals have an enzyme called rhodonase that detoxifies cyanide by converting it to thiocyanate

43. Cyanide Mechanism of Toxicity –Chemical asphyxiant –Inhibits functioning of cytochrome a3 –Stops electron transport, oxidative phosphorylation –Blocks aerobic utilization of oxygen

44. Cytochrome A3 Fe2 + Fe3 + 2H + 2e - 1/2 O 2 H2OH2O Cytochrome a

45. Cyanide Toxicity Fe2 + Fe3 + 2H + 2e - 1/2 O 2 H2OH2O Cytochrome a CN -

46. Cyanide Clinical Presentation –Variable onset speed with different forms –Headache, nausea, dyspnea, confusion –Rapid, weak pulse –Bright-red venous blood –Syncope, seizures, coma –Agonal respirations, bradycardia, cardiovascular collapse

47. Cyanide Management –Treat all cases as potentially lethal –Support oxygenation, ventilation –ECG –IV tko –Cyanide Antidote Kit

48. Cyanide Antidote Kit Amyl nitrite, Sodium nitrite –Oxidize iron in hemoglobin from Fe 2+ to Fe 3+ (methemoglobinemia) –Methemoglobin binds cyanide, removing it from cells Sodium thiosulfate –Provides rhodonase with sulfide anion –Speeds conversion of cyanide to thiocyanate

49. CN - Cyanide Antidote Kit Fe3 + Fe2 + 2H + 2e - 1/2 O 2 H2OH2O Cytochrome a Fe2 + Fe3 + CN - NO 2 - SCN -

50. Cyanide Antidote Kit Amyl nitrite, sodium nitrite –Only be used in serious cyanide poisonings –Can induce life-threatening tissue hypoxia secondary to methemoglobinemia Sodium thiosulfate –Can be used by itself –Is relatively benign

51. Salicylates

52. Examples –Aspirin –Oil of wintergreen Uses –Analgesics –Antipyretics –Anti-inflammatories –Platelet function inhibitors

53. Salicylates Mechanism of Toxicity –Direct stimulation of respiratory center, causing respiratory alkalosis –Irritation of gastrointestinal tract, causing decreased motility, pylorospasm, nausea, vomiting, hemorrhagic gastritis –Decreased prothrombin levels/platelet dysfunction, causing prolonged clotting times –Uncoupling of oxidative phosphorylation

54. Aspirin Toxicity NADNADH 2 2H FADFADH 2 Ox. Cyt. bRed. Cyt. b Ox. Cyt. cRed. Cyt. c Ox. Cyt. aRed. Cyt. a Red. Cyt. a3Ox. Cyt. a3 1/2 O 2 2H + H2OH2O ADP + P i Heat

55. Results of Oxidative Phosphorylation Uncoupling ATP production decreases, resulting in CNS and cardiovascular failure. Cells attempt to compensate by increasing the rate they process glucose anaerobically through glycolysis. Lactic and pyruvic acids accumulate, leading to metabolic acidosis. Hypoglycemia results as liver sugar stores are depleted. In absence of sugar cells begin to metabolize lipids, ketone bodies are produced, acidosis worsens. Energy normally trapped as ATP is wasted as heat, causing a rise in body temperature. The rise in body temperature accelerates metabolism, increasing tissue oxygen demand and worsening acidosis.

56. Salicylates –Vomiting –Lethargy –Hyperpnea –Respiratory alkalosis –Metabolic acidosis –Coma –Seizures –Hypoglycemia –Hyperthermia –Pulmonary edema Clinical Presentation: Acute Toxicity

57. Salicylates Clinical Presentation: Chronic Toxicity –Usually young children, confused elderly –Confusion, dehydration, metabolic acidosis –Higher morbidity, mortality than acute overdose –Cerebral, pulmonary edema more common

58. Salicylates Acute Toxicity Management –Oxygen, monitor, IV –GI tract decontamination –Activated charcoal –Replace fluid losses, but do NOT overload –Control hyperthermia

59. Salicylates Acute Toxicity Management –Bicarbonate for metabolic acidosis –D50W for hypoglycemia –Diazepam for seizures

60. Acetaminophen

61. Acetamophen Examples –Tylenol –Tempra –Datril Uses –Analgesic –Antipyretic

62. Acetaminophen Mechanism of toxicity –N-acetyl p-benzoquinonimine, normal product of acetaminophen metabolism, is hepatotoxic –Normally is detoxified by glutathione in liver –In overdose, toxic metabolite exceeds glutathione capacity, causes liver damage

63. Acetaminophen Metabolism APAP APAP-glucuronideAPAP- sulfate Urine N-acetyl-p-benzo- quinonimine Cysteine Congugates Urine Glutathione 28- 52% 45-55% 2- 4% P-450 MFO

64. Acetaminophen Toxicity APAP APAP-glucuronideAPAP- sulfate Urine Cysteine Congugates Urine Hepatocyte Protein Congugates Cell Death Glutathione N-acetyl-p-benzo- quinonimine

65. Acetaminophen Minimum toxic dose –Adult: 7 grams –Child: 140 mg/kg Onset of symptoms is slow, initially non-specific StageTimeSymptoms I1/2 to 24hAnorexia, NV, malaise, diaphoresis II24 to 48hAbdominal pain, liver tenderness, increased liver enzymes, oliguria III72 to 96hPeak enzyme abnormality, Increased bilirubin and PT IV4d to 2wkResolution or progressive hepatic failure

66. Acetaminophen Management –Induce emesis –Do NOT give activated charcoal –Give specific acetaminophen antidote

67. Acetaminophen The specific antidote for acetaminophen toxicity.

68. Mucomyst N-acetylcysteine l Another sulfur-containing amino acid l Substitutes for glutathione. l Allows continued detoxification of NAPBQI. l 140mg/kg initially followed by 70mg/kg every 4 hours 17 times. l Tastes, smells like rotten eggs l Mix with chilled fruit juice to decrease odor, taste

69. Can Mucomyst (NAC) Be Given If The Patient’s Gotten Activated Charcoal? AC and NAC are not given simultaneously AC is given in the first 4 hours. NAC is given after 4 hours. The effective dose of NAC is equal to the amount of APAP ingested. Patients receive a total dose of 1330 mg/kg, so most are over-treated. The reduction in NAC absorption caused by AC (8 to 39%) applies only to the first dose. So the potential total decrease in absorption is 4.5% A patient would have to ingest 1275 mg/kg for this to become a problem.