Specific Toxins Part I

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

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

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

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

Hydrocarbons Examples Kerosene Gasoline Lighter fluid Turpentine Furniture polish

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

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

Hydrocarbons Management 100% oxygen with good humidification IV tko Monitor ECG Drug therapy D50W for hypoglycemia Diazepam for seizures Antiarrhythmics

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

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)

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

methyl alcohol wood alcohol wood naphtha Methanol methyl alcohol wood alcohol wood naphtha

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

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

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

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

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

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

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

Methanol Management Sodium Bicarbonate Folic acid 50mg IV every 4 hours Helps convert formic acid to CO2, H2O Give specific antidote

Methanol ETHANOL 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

Ethanol Metabolism H C O C H O H O C Ethanol Acetaldehyde Acetic Acid Alcohol dehydrogenase C H O Acetaldehyde Aldehyde dehydrogenase H O C Acetic Acid Krebs Cycle

Alcohol dehydrogenase Methanol X Ethanol Methanol Alcohol dehydrogenase Acetic Acid Urine CO2 + H2O + Energy

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

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

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

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

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

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

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)

Cyanide

But first… A little review of biochemistry and biophysics

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.

Organisms capture and store the energy they need in the form of... Adenosine Triphosphate (ATP) 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.

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

The Krebs Cycle In mitochondria Requires oxygen Strips H+ and electrons off of acetate, leaving CO2 Sends the H+ and electrons to the electron transport chain

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 O2, making H2O 36 ATP produces per glucose molecule

Oxidative Phosphorylation NAD NADH2 ADP + Pi ATP FAD FADH2 Ox. Cyt. b Red. Cyt. b ADP + Pi ATP Ox. Cyt. c Red. Cyt. c Ox. Cyt. a Red. Cyt. a ADP + Pi ATP Red. Cyt. a3 Ox. Cyt. a3 2H+ H2O 1/2O2

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.

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

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

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

Cytochrome A3 Cytochrome a 1/2 O2 2e- Fe3+ Fe2+ 2e- 2H+ H2O

Cyanide Toxicity Cytochrome a 1/2 O2 2e- X CN- Fe3+ Fe2+ 2e- 2H+ H2O

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

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

Cyanide Antidote Kit Amyl nitrite, Sodium nitrite Sodium thiosulfate Oxidize iron in hemoglobin from Fe2+ to Fe3+ (methemoglobinemia) Methemoglobin binds cyanide, removing it from cells Sodium thiosulfate Provides rhodonase with sulfide anion Speeds conversion of cyanide to thiocyanate

Cyanide Antidote Kit Cytochrome a Fe2+ NO2 - Fe3+ CN- SCN- 2e- Fe3+ H2O

Cyanide Antidote Kit Amyl nitrite, sodium nitrite Sodium thiosulfate 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

Salicylates

Salicylates Examples Uses Aspirin Oil of wintergreen Analgesics Antipyretics Anti-inflammatories Platelet function inhibitors

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

Aspirin Toxicity 2H NAD NADH2 Heat ADP + Pi FAD FADH2 Ox. Cyt. b Red. Cyt. b Heat ADP + Pi X Ox. Cyt. c Red. Cyt. c Ox. Cyt. a Red. Cyt. a Heat ADP + Pi X Red. Cyt. a3 Ox. Cyt. a3 2H+ H2O 1/2O2

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.

Suspect in any child with sudden onset of tachypnea Salicylates Clinical Presentation: Acute Toxicity Coma Seizures Hypoglycemia Hyperthermia Pulmonary edema Vomiting Lethargy Hyperpnea Respiratory alkalosis Metabolic acidosis Suspect in any child with sudden onset of tachypnea

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

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

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

Acetaminophen

Acetamophen Examples Tylenol Tempra Datril Uses Analgesic Antipyretic

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

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

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

Acetaminophen Minimum toxic dose Adult: 7 grams Child: 140 mg/kg Onset of symptoms is slow, initially non-specific Stage Time Symptoms I 1/2 to 24h Anorexia, NV, malaise, diaphoresis II 24 to 48h Abdominal pain, liver tenderness, increased liver enzymes, oliguria III 72 to 96h Peak enzyme abnormality, Increased bilirubin and PT IV 4d to 2wk Resolution or progressive hepatic failure

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

MUCOMYST Acetaminophen The specific antidote for acetaminophen toxicity. MUCOMYST

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

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.