Toxicology

1. Toxicology Dr DuniaAlhashimi Consultant pediatrician

2. Important areas to be covered • Activated charcoal, mechanism of action, indications, contraindications • Carbon monoxide Poisoning, signs and management • Ethylene glycol, common forms, signs and symptoms, • Hydrocarbons, types, Mgt

3. Common medications: • Paracetamol, Elimination, S&S, Mgt, Acute vs chronic • TCA ingestion, S&S, Mgt • Salicylates, S&S, Mgt • Antihypertensives • Antihistamines • Multivitamins • Iron tablets • Caustic injury, types, Mgt • Organophosphorus poisoning

4. Household chemicals • Detergents • Antiseptics • Silica gel • Mercury thermometers • Drain cleaner • Mothballs • Bleach • Rat poison • Nail polish remover • Ammonia • Window cleaner • Oven cleaner • Dettol

5. Q1 • A 10kg 14 month old boy is brought to the A&E by his parents. His parents claim that he possibly ingested paracetamol, as six 500mg tablets were found to be missing from the family’s paracetamol container. This possible ingestion occurred within a 60-min window efore their presentation to the Emergency department. Which of th following is the most appropriate management action? • Measure plasma paracetamol levels • Administer ipecauanha to induce emesis • Perform a gastric lavage • Adminster N-acetyl cysteine • Administer activated charcoal

6. Q1 Ans E: Administer activated charcoal • The most appropriate management in this instance would be to administer activated charcoal, to limit further absorption of paracetamol, Inducing emesis with ipecuanha is now generally contraindicated. Measurement of plasma paracetmol level is useful only after 4 hours of ingestion. A gastric lavage maybe beneficial, but when you are given these five choices it would not be the first choice of treatment. N-acetylcysteine would not be the first line of treatment either.

7. Q2 • The nomogram is used to determine when a patient is give N-acetyl cysteine is administered in patients even if their levels are below the nomogram line. Which one of the following is not a risk factor? • Alcoholism • patient on isoniazide • pt on cimetidine • fasting • malnutrition

8. Q2 Ans: C • If the serum level falls between the two nomogram lines, consider giving NAC if the patient is at increased risk for toxicity; e.g. the patient is alcoholic, malnourished or fasting or is taking drugs that induce P-450 2E1 activity (e.g. isoniazide INH); after multiple or subacute overdoses; or the patient is considered uncertain or unreliable.

9. Prescott Nomogram

10. High Risk • Increased oxidation • Chronic alcohol use • Drugs • Reduces glutathione stores • Malnutrition • Eating disorders • Chronic liver disease

11. Q3 • A 3 year old boy was found with a empty packet of extended-release paracetamol tablet. The parents claim that he took 8 500mg tablet. You are called in the emergency and decide to do a drug level. When is the best time to do a paracetamol drug level in the patients • Immediately as the dose is very high • A level stat and one after 4 hours • A level 4 hours after ingestion • A level 8 hours after ingestion • A level 8 hours and another after 12 hours

12. Q3 Ans:E • After ingestion of extended release tablets, which are designed for prolonged absorption, there may be a delay before the peak paracetamol level is reached. This can also occur after co-ingestion of drugs is reached. In such circumstances, repeat the serum paracetamol level at 8 hours and possible after 12 hours.

13. Q4 • Which statement is true regarding liver toxicity from paracetamol overdose? • It is likely because paracetamol plasma half-life is approximately 2 to 3 hours. • It usually is evident 12 to 24 hours after ingestion • For a given toxic plasma level, children have a higher incidence of hepatic aminotransferase elevation than adults have. • Hepatic toxicity results from N-acetyl-p-benzoquinonemime (NAPQ1) • Diet, nutritional status, and age are not related to liver toxicity.

14. Q4 Ans: D • Liver toxicity results when NAPQ1, a reactive intermediary, is formed by cytochrome P-450 activity. Glutathione conjugates NAPQ1 to nontoxic conjugates. In an overdose, glutathione is depleted, and NAPQ1 binds covalently with hepatocytes to produce hepatic necrosis.

15. N-acetylcysteine • Most effective within 8 hours • Precursor for glutathione production • Can cause anaphylactoid reactions • Consider starting before paracetamol result if: • Presenting > 8 hrs & >150mg/kg taken • Staggered overdose

16. Patient X • 15 year old girl who presents after taking 24 paracetamol over a period of 24 hours • No drug history • Fit and well • Blood level 20mg/l

17. Staggered overdose.(www.pharmweb.net) • In patients who have taken several overdoses of paracetamol over a short period of time, the plasma paracetamol concentration will be more difficult to interpret as the treatment graph relates to a single acute ingestion. • Such patients should be considered as at serious risk and considered for treatment with N-acetylcysteine (NAC). • They can be discharged after NAC treatment or 24 hours from the last paracetamol dose provided they are asymptomatic and the International Normalised Ratio (INR), plasma creatinine and ALT are normal.

18. PARACETAMOL DEADLY PITFALLS • The Prescott Nomogram High Risk Line • Staggered Overdoses • Management of late presentation • Recheck U&E, LFT, INR after N-acetylcysteine

19. Q5 • A mother brings in her 1-year-old after he drank from a Dettol bottle. What is the most common cause of mortality after Dettol ingestion? • Neurological depression • Aspiration pneumonia • Gastric strictures • Uncontrolled seizures • Hypoglycemia

20. Q5 Ans: B • Dettol liquid (chloroxylenol 4.8%, pine oil and isopropyl alcohol) is a commonly used household disinfectant. • Labeled nonpoisonous, • Serious complications were reported in up to 8% of cases of ingestion • included aspirations with gastric content resulting in pneumonia, • cardiopulmonary arrest, bronchospasm, adult respiratory distress syndrome • severe laryngeal edema with upper airways obstruction. • "Burning" in the mouth and throat with nausea and vomiting. Later contaminated skin becomes erythematous and there is redness, swelling and superficial ulceration in the mouth and upper alimentary tract. The larynx may also be involved leading to breathlessness and stridor.

21. Q6 • Which of the following ingestions could be seen with an increased anion gap? • Paracetamol • Isopropanol • Ethylene glycol • Ethylene dibromide • Methane

22. Q6 Ans: C • The etiologies of metabolic acidosis with elevated anion gap can be recalled with the mnemonic MUD-PILES: • Methanol, Uremia,Diabeticketoacidois, paraldehyde, Iron, Isoniazid or Inhlaants, Lactic Acidosis, Ethylene glycol or chronic Ethanol abuse, Salicylates or Solvents. • In paracetamol poisoning metabolic acidois is uncommon. • Isopropyl alcohol results in high srumkeones with little or no acidosis

23. Q7 • Ethylene glycol poisoning is characterized by all of the following except: • Metabolic acidosis • Increased anion gap • Hypocalemia • Hypomagnesemia • Hypokalemia

24. Q7 Ans: E • Metabolic acidosis with increased anion gap is suggestive of methanol and ethylene glycol ingestion. Ethylene glycol toxicity results from its metabolite oxalate, which chelates calcium ion to form insoluble calcium oxalate crystals and results in hypocalcaemia. Hyopmagmasemia usually occurs with hypocalcemia. However, hyperkalemia results from muscle necrosis, the development of acute tubular necrosis and renal failure, and metabolic acidosis.

25. Q8 • A 13-year-old girl comes to the A&E with a history of ingesting a bottle of diphenhydramine (Benadryl) tablets. Which of the following signs and symptoms would be expected on examining the patient? • Sweating, lacrimation, salivation, miosis, an blurred vision. • Lethargy, slow respiration, hypotension, and lured vision. • Agitation, tachycardia, sweating, and mydriasis • Flushed face, agitation, dry mucous membrane, and dilated pupils • Headache, tachycardia, tachypnoea, cherry red mucous membrane, and dim vision.

26. Q8 Ans: D • Benadryl (diphenhydramine) is an anticholinergic agent. • Toxidrome: Hot as a hare, Blind as a bat, Dry as a bone, Red as a beet, and Mad as a hatter • A: anticholinesterase inhibitors or cholinergic agents (organophoshates) • B: narcotic overdose • C: sympathomimetic agents (amphetamines) • E: carbon monoxide poisoning

27. Common causes • Antidepressants-Tricyclics • Antihistamines • Atropine • Antipsychotics • Antispasmodics

28. Cholinergic • Brady/tachycardia • Confusion/reduced GCS • Pinpoint pupils • Seizures • Weakness • SLUDGE • Pulmonary oedema

29. SLUDGE • S sweating salivation • L lacrymation • U urinary frequency urgency • D diarrhoea • G gastrointestinal discomfort • E eyes pinpoint

30. Toxidromes

31. Q9 • A 2-year old is brought to the A&E by his mother, who says her son may have ingested a few CBZ (Tegretol) chewable tablets used by his sibling. Which of the following clinical findings would best support the possibility of an ingestion? • Vomiting • Confusion and excitation • Tachycardia • Hyperreflexia • Nystagmus

32. Q9 Ans: E • Dizziness, ataxia, and nystagmus with deviating pupils are the classic triad seen in CBZ toxicity. • Although vomiting, confusion and excitement, tachycardia, and hyperreflexia are all possible signs of toxicity, the are nonspecific.

33. Q10 • A grandmother brings in her 15-month-old toddler who may have swallowed one clonidine tablet (0.1mg) about 30minutes ago. The child is sitting quietly on her lap with heart rate (HR) 80 beats per minute, her blood pressure (BP) 130/80 mm Hg, and respiratory rate (RR) 20 breaths per minute. Which of the following would be the most appropriate management of this patient? • The patient can be discharged afte initial assessment • Look for other ingestants because hypertension is unlikely with a clonidine overdose • Nalaxone 0.1mg/kg IV boluis should be given because the patient is bradycardiac • Emesis should be immediately attempted with syrup of ipecac • Only supportive care and monitoring are needed because most patients recover in 12 to 24 hours

34. Q10 Ans: E • All children who are symptomatic after clonidine ingestion require admission, monitoring, and supportive care because symptoms may persist for up to 24 hours. • Although the toxic dose of clonidine is not known, significant toxicity has resulted with as little as 0.1mg 30 minutes after ingestion. • The central effects of clonidine predominate and cause tachycardia and hypotension, but initially there maybe peripheral α2 stimulation and reduced uptake of epinephrine, resulting in benign, transient paradoxic hypertension.

35. Q11 • A 2-year old who swallowed digoxin tablets is found to have bradycardia. An electrocardiogram (ECG) shows ventricular bigeminy. Which of the following is true? • ECG findings of T wave depression and scooped ST segment correlate with significant digoxin toxicity • Digoxin immune FAB (Digibind) is indicated for life-threatening dysrhythmias • There is a wide margin between therapeutic and toxic doses • Hyperkalemia is not affected by digoxin immune FAB (Digibind) therapy • Forced alkaline diuresis may increase renal excretion

36. Q11 Ans: B • Digoxin immune FAB (Digibind) is indicated for use in treating life-threatening digoxin-induced dysrhythmias and for hyperkalemia. The ECG finding of T wave depression and scooped ST segemntsar known as digitalis effect but do not indicate toxicity. Alkaline diuresis is not useful in digitalis elimination.

37. Q12 • Which of the following regarding caustic injury to the esophagus is true? • Acid burns are usually deeper than alkali burns in the esophagus and thus cause greater long-term complications • If there are no orophayngeal lesions, esophagoscopy is not required because esophageal burns are unlikely • Patients who ingest caustics appear to have an increased risk of esophageal carcinoma • Only 50% of all stricture formation results within 2 months of ingestion • About 10% of first-degree burns results in esophageal strictures

38. Q12 Ans: C • Drain pipe cleaners usually contain sodium hydroxide as their principal components. • Patients who ingest caustics have an increased risk of developing esophageal carcinoma. • In the esophagus, acid burns usually cause a superficial coagulation necrosis with eschar formation of the mucosa, which limits penetration of the injury. • However, bases causes liquefaction necrosis of the fat and protein involving the mucosa, submucosa, and muscle and penetrate deeply, causing the potential for greater tissue damage. • Oropharyngeal lesions do not predict esophageal burns as only a third of patients with oral lesions develop esophageal burns, and about 10% to 15% of those with esophageal burns have no oral lesions. • First degree burns do not develop strictures; 15% to 30% of second-degree do; and almost 100% of third-degree burns do

39. Q13 • A frantic mother calls you saying that her 2-year-old child just swallowed some household bleach. She gave him milk, which he drank without any drooling or vomiting. Which of the following is the most appropriate action to take? • Tell the mother to give her son syrup of ipecac immediately • Tell the mother to bring her child to the A&E for endoscopy to rule out esophageal strictures • Reassure the mother that it is a mild irritant and that her son will do fine as he has been drinking without problems • Warn the mother that because household bleach is an alkali, it can cause esophageal strictures even if oral lesions are not seen • Tell the mother to give her son antacid to buffer the effect of the bleach

40. Q13 Ans: C • Household bleach contains chlorine or sodium hypochlorin, which is a mild irritant and usually causes no tissue destruction. • Immediate dilution with water or milk is all that is required.

41. Salicylate DEADLY PITFALL • Salicylate levels can continue to rise following admission (10% of cases) • Repeat levels every until peaked

42. Q14 • Which statement most accurately describes the effects of insecticides? • Carbamates create an irreversible bond with cholinesterase • Organophosphates stimulate the release of excessive amounts of acetylcholine at the synaptic junction • Insecticide poisoning can be confirmed by a rise in cholinesterase level in the blood • Humans have no biotransformation mechanism for metabolizinig (detoxifying) insecticides • Organophosphates inhibit the degradation of acetylcholine

43. Q14 Ans: E • Organophosphates exert their effect by interfering with the enzyme cholinesterase, which degrades acetylcholine but rather cause its accumulation by preventing degradation. • Insecticide poisoning causes cholinesterase levels to fall, and this test can be used to confirm the clinical impression of insecticide poisoning. • Humans are, in fact able to detoxify organophosphates by conjugation in the liver. • Carbamates form a reversible bond with cholinesterase. • In contrast, organophosphates irreversibly bind to cholinesterase via phosphorylation.

44. Q15 • Which statement most accurately characterizes the differences between organophosphate and carbamate poisoning? • Carbamate exposure is more common than organophosphate exposure • Carbamate poisoning is usually of shorter duration • Pralidoxime must be started sooner to be effective in carbamate poisoning • Only organophosphates are absorbed through the skim • Both answers B and C are correct.

45. Q15 Ans: B

46. Q16 • Which of the following statements concerning cholinergic poisoning treatment is most correct? • Pralidoxime is used to prevent irreversible deactivation of cholinesterase • Atropine restores the biologic activity of cholinesterase • The dose of atropine should not exceed 2 mg • Pralidoxime is more useful as a treatment for Carbamate exposure than for organophosphate exposure • Bronchorrhea must be treated by loop diuretics because atropine is ineffective for this

47. Q16 Ans: A • Pralidoxime reactivates cholinesterase by competing for the phosphate moiety of the organophosphate compound, thus releasing if from the cholinesterase enzyme. • Atropine counteracts the effects of acetylcholine excess but has no effect on the biological activity of cholinesterase. • There is no maximum dose of atropine in insecticide poisoning. • Rather, the dose is titrated to the patient’s clinical response. • Loop diuretics such as frusemide should be avoided in insecticide poisoning because they exacerbate already excessive urinary output. • Bronchorrhea generally is controlled with ventilation and atropine.

48. Q17 • A 22-month-old, 15-kg girl is found with an empty bottle of chewable vitamin tablets (15 mg of elemental iron per tablet). Although originally 100 tablets were in the bottle, the mother believes that at least 75 tables are found on the floor in the house. The child is asymptomatic when she comes to the ED 90minutes after the ingestion. Which of the following is the next most appropriate action? • Administer an immediate dose of activated charcoal and observe for 6 hours • Obtain a serum iron level, complete blood count, serum electrolytes, and liver function test and observe the patient for 6 hours in the ED • Obtain an abdominal radiograph, and if no iron tablets are seen, discharge the patient. • Administer syrup of ipecac and observe for 6 hours in the ED • Administer a desferoxamine challenge of 50mg/kg intramuscularly

49. Q17 Ans: B

50. Q18 • Which of the following regarding Naloxone (Narcan) is most correct? • It can be administered intravenously, intramuscularly, and endotracheally, but not intraosseously • It is often effective in reversing miosis associated with barbiturate overdose • It can reverse the respiratory depression of a clonidine overdose • It is effective with natural and semisynthetic opioids and is ineffective with synthetic opioid • It has agonist as well as antagonist effects at higher doses