Drugs & Chemicals Poisoning

2. Drugs & Chemicals Poisoning By Dr. Jamshidi

3. Management of overdose and poisoning

4. General- evaluation • Rcognition of poisoning • Identification of agents involved • Assessment of severity • Prediction of toxicity

5. General- management • provision of supportive care • prevention of poison absorption • Enhancement of elimination of poison • Administration of antidotes

6. Supportive care • A: First, the airway should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed. • B: Breathing should be assessed by observation and oximetry and, if in doubt by measuring arterial blood gases patients with respiratory insufficiency should be intubated and mechanically ventilated

7. Supportive care • C:Circulation should be assessed by continuous monitoring of: • - pulse rate • - blood pressure • -urinary output • An intravenous line should be placed and blood drawn fro serum glucose and other routine determinations • Dextrose to treat hypoglycemia (0.5gm/kg)

8. Supportive care • Vital signs, mental status, and pupil size • Pulse oximetry, cardiac monitoring, ECG • Protect airway • Intravenous access • cervical immobilization if suspect trauma • Rule out hypoglycaemia • Naloxone for suspected opiate poisoning

9. History • Pill bottles • Alcohol • Drug history including access • Remember OTC drugs • Suicide note • National Poisons Information Centre (09694)

10. Examinations • Drug Physiologic excitation : anticholinergic sympathomimetic central hallucinogenic agents drug withdrawal • Physiologic depression cholinergic (parasympathomimetic) sympatholytic opiate, or sedative-hypnotic agents, or alcohols • Mixed state – polydrugs, hypoglycemic agents, tricyclic antidepressants, salicylates, cyanide

11. Drug detection

12. Drug levels

13. Preventing absorption Gastric lavage • Not in unconscious patient unless intubated (risk aspiration) • Flexible tube is inserted through the nose into the stomach • Stomach contents are then suctioned via the tube • A solution of saline is injected into the tube • Recommended for up to 2 hrs in TCA & up to 4hrs in Salicylate OD Induced Vomiting • Ipecac - Not routinely recommended • Risk of aspiration

14. CONTRAINDICATION OF EMESIS Corrosives and volatile poisons Comatose patients Heart disease patients Pregnant women Kerosene : may cause aspiration pneumonia Convulsant patients

15. Preventing absorption Activated charcoal • Adsorbs toxic substances or irritants, thus inhibiting GI absorption • Addition of sorbitol →laxative effect • Oral: 25-100 g as a single dose • Repetitive doses useful to enhance the elimination of certain drugs: -theophylline -phenobarbital - carbamazepine - aspirin -sustained-release products

16. Preventing absorption not effective for: - cyanide -mineral acids -caustic alkalis - organic solvents -iron, ethanol, methanol poisoning, lithium

17. Elimination of poisons Renal elimination • Medication to stimulate urination or defecation may be given to try to flush the excess drug out of the body faster Forced alkaline diuresis • Infusion of large amount of NS+NAHCO3 • Used to eliminate acidic drug that mainly excreted by the kidney eg salicylates • CAUTIONS • Serious fluid and electrolytes disturbance may occur • Need expert monitoring

18. Elimination of poisons Hemodialysis or haemoperfusion: • Reserved for severe poisoning • Drug should be dialyzable i.e. protein bound with low volume of distribution • may also be used temporarily or as long term if the kidneys are damaged due to the overdose.

19. Hemoperfusion

20. Antidotes • Does an antidote exist? • Does actual or predicted severity of poisoning warrant its use? • Do expected benefits of therapy outweigh its associated risk? • Are there contraindications?

21. Specific overdoses

22. Opiates • Opiat poisoning • Antidote – naloxone • MoA: Pure opioid antagonist competes and displaces narcotics at opioid receptor sites • I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg every 2-3 minutes as needed • Lower doses in opiate dependence

23. Opiates • Elimination half-life of naloxone is only 60 to 90 minutes • Repeated administration/infusion may be necessary • Side Effects • BP changes; arrhythmias; seizures; • withdrawal syndrome

24. Benzodiazepines Benzodiazepine poisoning Antidote – flumazenil • MoA: Benzodiazepine antagonist • IV administration 0.2 mg over 15 sec to max 3mg • S/E : arrhythmias; convulsions • C/I concomitant TCAD; status epilepticus • Should not be used for making the diagnosis • Benzodiazepines may be masking/protecting against other drug effects

25. Tricyclic antidepressants • PHARMACOLOGY — • TCAs have several important cellular effects, including inhibition of:     -Presynaptic neurotransmitter reuptake    -Cardiac fast sodium channels    -Central and peripheral muscarinic acetylcholine receptors    -Peripheral alpha-1 adrenergic receptors    -Histamine (H1) receptors    -CNS GABA-A receptors

26. TCAD overdoseclinical features • Arrhythmias - widening of PR, QRS, and QT intervals; - heart block Hypotension • Anticholinergic toxicity - hyperthermia - flushing -dilated pupils -intestinal ileus -urinary retention - sinus tachycardia • Confusion, delirium, hallucinations • Seizures

27. TCAD overdose Diagnosis • History • Blood/urine toxicology screen

28. TCAD overdose -Treatment • many require intubation • Consider gastric lavage if taken < 2hrs • Activated charcoal • Treatment of hypotension with isotonic saline • Sodium bicarbonate for cardiovascular toxicity • Alpha adrenergic vasopressors (norepinephrine )Benzodiazepines for seizures

29. Sodium Bicarbonate in TCA overdose • Hypertonic sodium bicarbonate (NaHCO3) - QRS widening >100 msec -ventricular arrhythmias -refractory hypotension • ↑ serum pH promotes protein binding and ↓ free drug concentrations

30. Sodium Bicarbonate in TCA overdose • reasonable goal pH is 7.50 to 7.55 then taper dose • S/E: • Volume overload • hypernatreamia • metabolic alkalosis

31. Special Cautions in TCAD overdose • Class IA and IC antiarrhythmic agents are contraindicated eg: • quinidine • Disopyramide • Flecainide • propafenone • Class IB Lignocaine, phenytoin used • Phenytoin may precipitate arrhythmias • Magnesium may be useful • Flumazenil must not be given

32. Salicylate overdose • Aspirin (acetylsalicylic acid) • Methyl salicylate (Oil of Wintergreen) • 5 ml = 7g salicylic acid • Herbal remedies • Fatal intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children

33. Salicylate levels • -Rapidly absorbed • -peak blood levels usually occur within one hour but delayed in overdose 6-35 hrs plasma salicylate concentration • Measure @ 4 hrs post ingestion & every 2 hrs until they are clearly falling • Most patients show signs of intoxication when the plasma level exceeds 40 to 50 mg/dL (2.9 to 3.6 mmol/L)

34. Salicylate overdose • 1- Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes • 2- Stimulation of the chemoreceptor trigger zone in the medulla causes: • nausea and vomiting • 3- Activation of the respiratory center of the medulla results in: • tachypnea, hyperventilation, respiratory alkalosis • 4- Uncoupled oxidative phosphorylation in the mitochondria generates heat and may increase body temperature • 5- Interference with cellular metabolism leads to metabolic acidosis

35. Clinical features • Early symptoms of aspirin toxicity include: • tinnitus • Fever • Vertigo • Nausea • Hyperventilation • Vomiting • diarrhoea More severe intoxication can cause: • altered mental status, coma • non-cardiac pulmonary edema and death

36. Metabolic abnormalities • Stimulate the respiratory center directly, early fall in the PCO2 and respiratory alkalosis • An anion-gap metabolic acidosis then follows, due to the accumulation of organic acids, including lactic acid and ketoacids • Mixed respiratory alkalosis and metabolic acidosis with ↑ anion gap • Arterial Ph variable depending on severity

37. Metabolic abnormalities • Metabolic acidosis increases the plasma concentration of protonated salicylate • thus worsening toxicity by allowing easy diffusion of the drug across cell membranes

38. Salicylate overdose - treatment • directed toward increasing systemic pH by the administration of sodium bicarbonate • IV fluids +/- vasopressors • Supplemental glucose (100 mL of 50 percent dextrose in adults) to patients with altered mental status regardless of serum glucose concentration to: overcome neuroglycopaenia • Hemodialysis

39. Alkalinization of plasma and urine • Alkalemia from a respiratory alkalosis is not a contraindication to sodium bicarbonate therapy • A urine pH of 7.5 to 8.0 is desirable • Blood gas analysis every two hours • Avoid severe alkalemia (arterial pH >7.60)

40. Haemodialysis - indications • Altered mental status • Pulmonary or cerebral edema • Renal insufficiency that interferes with salicylate excretion • Fluid overload that prevents the administration of sodium bicarbonate • A plasma salicylate concentration >100 mg/dL • Clinical deterioration despite aggressive and appropriate supportive care

41. Paracetamol • Widely available • Potential toxicity underestimated • Toxicity unlikely to result from a single dose of less than 150 mg/kg in child or 7.5 to 10 g for adult • Toxicity is likely with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period • Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity unless appropriately treated

43. Factors influencing toxicity • Dose ingested • Excessive cytochrome P450 activity due to induction by chronic alcohol or other drug use eg carbamazepine, phenytoin, isoniazid, rifampin • Decreased capacity for glucuronidation or sulfation • Depletion of glutathione stores due to malnutrition or chronic alcohol ingestion • Acute alcohol ingestion is not a risk factor for hepatotoxicity and may even be protective by competing with acetaminophen for CYP2E1

44. Clinical features • Stage I (0.5 to 24 hours) No symptoms • Stage II (24 to 72 hours) Subclinical elevations of hepatic aminotransferases (AST, ALT) -right upper quadrant pain -liver enlargement and tenderness -Elevations of prothrombin time (PT) -oliguria and renal function abnormalities may become evident

45. Clinical features • Stage III (72 to 96 hours) -Jaundice -confusion (hepatic encephalopathy) -marked elevation in hepatic enzymes -hyperammonemia lactic acidosis- - renal failure 25% - death • Stage IV (4 days to 2 weeks) Recovery phase that usually begins by day 4 and is complete by 7 days after overdose

46. Paracetamol overdose • The risk of toxicity is best predicted by relating the time of ingestion to the serum paracetamol concentration • Peak serum concentrations reached within 4 hrs following overdose of immediate-release preparations • May be delayed with extended releases preparations or drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingested • Check level at >= 4 hrs

47. Paracetamol overdose treatment • Activated charcoal within four hours of ingestion • May reduce absorption by 50 to 90 percent • Single oral dose of one gram per kilogram • Inhibits absorption of oral methionine

48. Activated Charcoal

49. N-acetylcysteine • Antidote – MOA: a glutathione precursor • Limits the formation and accumulation of NAPQI • Powerful anti-inflammatory and antioxidant effects • IV infusion or oral tablets (also oral methionine) • 150mg/Kg over 15 min; 50mg/Kg over next 4 hrs; 100mg/kg over next 16 hrs up to 36hrs • Beyond 8 hours, NAC efficacy progressively decreases • S/Es nausea, flushing, urticaria, bronchospasm, angioedema, fever, chills, hypotension, hemolysis and rarely, cardiovascular collapse

50. Paracetamol overdose treatment • At the end of NAC infusion, a blood sample should be taken for determination of the INR, plasma creatinine and ALT. • If any is abnormal or the patient is symptomatic, further monitoring is required and advice sought from the NPIS • Patients with normal INR, plasma creatinine and ALT and who are asymptomatic may be discharged from medical care. • They should be advised to return to hospital if vomiting or abdominal pain develop or recur