1. Management of overdose and poisoning Paula Jerrard-Dunne Pharmacology & Therapeutics 2006

2. General- evaluation recognition of poisoning recognition of poisoning identification of agents involved identification of agents involved assessment of severity assessment of severity prediction of toxicity prediction of toxicity

3. General- management provision of supportive care provision of supportive care prevention of poison absorption prevention of poison absorption enhancement of elimination of poison enhancement of elimination of poison administration of antidotes administration of antidotes

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

5. History Pill bottles Pill bottles Alcohol Alcohol Drug history including access Drug history including access Remember OTC drugs Remember OTC drugs Suicide note Suicide note National Poisons Information Centre * National Poisons Information Centre *

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

7. Drug detection

8. Drug levels

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

10. Preventing absorption Activated charcoal Adsorbs toxic substances or irritants, thus inhibiting GI absorption Adsorbs toxic substances or irritants, thus inhibiting GI absorption Addition of sorbitol → laxative effect Addition of sorbitol → laxative effect Oral: 25-100 g as a single dose Oral: 25-100 g as a single dose repetitive doses useful to enhance the elimination of certain drugs (eg, theophylline, phenobarbital, carbamazepine, aspirin, sustained-release products) repetitive doses useful to enhance the elimination of certain drugs (eg, theophylline, phenobarbital, carbamazepine, aspirin, sustained-release products) not effective for cyanide, mineral acids, caustic alkalis, organic solvents, iron, ethanol, methanol poisoning, lithium not effective for cyanide, mineral acids, caustic alkalis, organic solvents, iron, ethanol, methanol poisoning, lithium

11. 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. 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 Infusion of large amount of NS+NAHCO3 Used to eliminate acidic drug that mainly excreted by the kidney eg salicylates Used to eliminate acidic drug that mainly excreted by the kidney eg salicylates Serious fluid and electrolytes disturbance may occur Serious fluid and electrolytes disturbance may occur Need expert monitoring Need expert monitoring Hemodialysis or haemoperfusion: Reserved for severe poisoning Reserved for severe poisoning Drug should be dialyzable i.e. protein bound with low volume of distribution 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. may also be used temporarily or as long term if the kidneys are damaged due to the overdose.

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

13. Specific overdoses

14. Opiates Antidote – naloxone Antidote – naloxone MOA: Pure opioid antagonist competes and displaces narcotics at opioid receptor sites 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 I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg every 2-3 minutes as needed Lower doses in opiate dependence Lower doses in opiate dependence Elimination half-life of naloxone is only 60 to 90 minutes Elimination half-life of naloxone is only 60 to 90 minutes Repeated administration/infusion may be necessary Repeated administration/infusion may be necessary S/E BP changes; arrhythmias; seizures; withdrawal S/E BP changes; arrhythmias; seizures; withdrawal

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

16. Tricyclic antidepressants PHARMACOLOGY — PHARMACOLOGY — TCAs have several important cellular effects, including inhibition of: 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 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

17. TCAD overdose clinical features Arrhythmias Arrhythmias - widening of PR, QRS, and QT intervals; - widening of PR, QRS, and QT intervals; heart block; VF/VT heart block; VF/VT Hypotension Hypotension Anticholinergic toxicity Anticholinergic toxicity - hyperthermia, flushing, dilated pupils, - hyperthermia, flushing, dilated pupils, intestinal ileus, urinary retention, sinus tachycardia intestinal ileus, urinary retention, sinus tachycardia Confusion, delirium, hallucinations Confusion, delirium, hallucinations Seizures Seizures

18. Diagnosis History History Blood/urine toxicology screen Blood/urine toxicology screen Levels not clinically useful Levels not clinically useful

19. TCAD overdose -Treatment ABC – many require intubation ABC – many require intubation Consider gastric lavage if taken < 2hrs Consider gastric lavage if taken < 2hrs Activated charcoal Activated charcoal Treatment of hypotension with isotonic saline Treatment of hypotension with isotonic saline Sodium bicarbonate for cardiovascular toxicity Sodium bicarbonate for cardiovascular toxicity Sodium bicarbonate Sodium bicarbonate Alpha adrenergic vasopressors (norepinephrine) for hypotension refractory to aggressive fluid resuscitation and bicarbonate infusion Alpha adrenergic vasopressors (norepinephrine) for hypotension refractory to aggressive fluid resuscitation and bicarbonate infusionnorepinephrine Benzodiazepines for seizures Benzodiazepines for seizures

20. Sodium Bicarbonate in TCA overdose Hypertonic sodium bicarbonate (NaHCO3) Hypertonic sodium bicarbonate (NaHCO3)sodium bicarbonatesodium bicarbonate - QRS widening >100 msec; ventricular - QRS widening >100 msec; ventricular arrhythmias, and/or refractory hypotension arrhythmias, and/or refractory hypotension ↑ serum pH promotes protein binding and ↓ free drug concentrations; narrows the QRS complex, ↑ systolic blood pressure, and controls ventricular arrhythmias ↑ serum pH promotes protein binding and ↓ free drug concentrations; narrows the QRS complex, ↑ systolic blood pressure, and controls ventricular arrhythmias 1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent NaHCO3) rapid IV push large bore IV then infusion if working 1 to 2 meq/kg (two to three 100 mL ampules of 8.4 percent NaHCO3) rapid IV push large bore IV then infusion if working reasonable goal pH is 7.50 to 7.55 then taper dose reasonable goal pH is 7.50 to 7.55 then taper dose S/E Volume overload, hypernatreamia, and metabolic alkalosis S/E Volume overload, hypernatreamia, and metabolic alkalosis

21. Special Cautions in TCAD overdose Class IA and IC antiarrhythmic agents are contraindicated eg quinidine;disopyramide, flecainide; propafenone Class IA and IC antiarrhythmic agents are contraindicated eg quinidine;disopyramide, flecainide; propafenone Class IB Lignocaine, phenytoin used Class IB Lignocaine, phenytoin used Phenytoin may precipitate arrhythmias Phenytoin may precipitate arrhythmias Magnesium may be useful Magnesium may be useful Flumazenil must not be given Flumazenil must not be given

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

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

24. Salicylate overdose Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes Inhibition of cyclooxygenase results in decreased synthesis of prostaglandins, prostacyclin, and thromboxanes Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting Stimulation of the chemoreceptor trigger zone in the medulla causes nausea and vomiting Direct toxicity of salicylate species in the CNS, cerebral edema, and neuroglycopenia Direct toxicity of salicylate species in the CNS, cerebral edema, and neuroglycopenia Activation of the respiratory center of the medulla results in tachypnea, hyperventilation, respiratory alkalosis Activation of the respiratory center of the medulla results in tachypnea, hyperventilation, respiratory alkalosis Uncoupled oxidative phosphorylation in the mitochondria generates heat and may increase body temperature Uncoupled oxidative phosphorylation in the mitochondria generates heat and may increase body temperature Interference with cellular metabolism leads to metabolic acidosis Interference with cellular metabolism leads to metabolic acidosis

25. Clinical features Early symptoms of aspirin toxicity include tinnitus, fever, vertigo, nausea, hyperventilation, vomiting, diarrhoea Early symptoms of aspirin toxicity include tinnitus, fever, vertigo, nausea, hyperventilation, vomiting, diarrhoeaaspirin More severe intoxication can cause altered mental status, coma, non-cardiac pulmonary oedema and death More severe intoxication can cause altered mental status, coma, non-cardiac pulmonary oedema and death

26. Metabolic abnormalities Stimulate the respiratory center directly, early fall in the PCO2 and respiratory alkalosis 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 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 Mixed respiratory alkalosis and metabolic acidosis with ↑ anion gap Arterial Ph variable depending on severity Arterial Ph variable depending on severity

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

28. Salicylate overdose - treatment directed toward increasing systemic pH by the administration of sodium bicarbonate directed toward increasing systemic pH by the administration of sodium bicarbonatesodium bicarbonatesodium bicarbonate IV fluids +/- vasopressors IV fluids +/- vasopressors Avoid intubation if at all possible ( ↑ acidosis) Avoid intubation if at all possible ( ↑ acidosis) Supplemental glucose (100 mL of 50 percent dextrose in adults) to patients with altered mental status regardless of serum glucose concentration to overcome neuroglycopaenia 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 Hemodialysis

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

30. Haemodialysis - indications Altered mental status Altered mental status Pulmonary or cerebral edema Pulmonary or cerebral edema Renal insufficiency that interferes with salicylate excretion Renal insufficiency that interferes with salicylate excretion Fluid overload that prevents the administration of sodium bicarbonate Fluid overload that prevents the administration of sodium bicarbonatesodium bicarbonatesodium bicarbonate A plasma salicylate concentration >100 mg/dL (7.2 mmol/L) A plasma salicylate concentration >100 mg/dL (7.2 mmol/L) Clinical deterioration despite aggressive and appropriate supportive care Clinical deterioration despite aggressive and appropriate supportive care

31. Paracetamol Widely available Widely available Potential toxicity underestimated 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 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 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 Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity unless appropriately treated

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

34. Clinical features Stage I (0.5 to 24 hours) Stage I (0.5 to 24 hours) No symptoms; N&V Malaise No symptoms; N&V Malaise Stage II (24 to 72 hours) Stage II (24 to 72 hours) Subclinical elevations of hepatic aminotransferases (AST, ALT) Subclinical elevations of hepatic aminotransferases (AST, ALT) right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT), total bilirubin, and oliguria and renal function abnormalities may become evident right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT), total bilirubin, and oliguria and renal function abnormalities may become evident Stage III (72 to 96 hours) Stage III (72 to 96 hours) Jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis hypoglycemia, lactic acidosis, renal failure 25%, death Jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis hypoglycemia, lactic acidosis, renal failure 25%, death Stage IV (4 days to 2 weeks) Stage IV (4 days to 2 weeks) Recovery phase that usually begins by day 4 and is complete by 7 days after overdose Recovery phase that usually begins by day 4 and is complete by 7 days after overdose

35. Paracetamol overdose The risk of toxicity is best predicted by relating the time of ingestion to the serum paracetamol concentration The risk of toxicity is best predicted by relating the time of ingestion to the serum paracetamol concentration The dose history should not be used as studies have found no correlation The dose history should not be used as studies have found no correlation Peak serum concentrations reached within 4 hrs following overdose of immediate-release preparations 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 May be delayed with extended releases preparations or drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingested Check level at >= 4 hrs Check level at >= 4 hrs

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

37. N-acetylcysteine Antidote – MOA: a glutathione precursor Antidote – MOA: a glutathione precursor Limits the formation and accumulation of NAPQI Limits the formation and accumulation of NAPQI Powerful anti-inflammatory and antioxidant effects Powerful anti-inflammatory and antioxidant effects IV infusion or oral tablets (also oral methionine) 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 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 Beyond 8 hours, NAC efficacy progressively decreases S/Es nausea, flushing, urticaria, bronchospasm, angioedema, fever, chills, hypotension, hemolysis and rarely, cardiovascular collapse S/Es nausea, flushing, urticaria, bronchospasm, angioedema, fever, chills, hypotension, hemolysis and rarely, cardiovascular collapse

39. 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 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 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

40. Indications for liver transplantation Liver transplantation is life-saving for fulminant hepatic necrosis Liver transplantation is life-saving for fulminant hepatic necrosis The indications for liver transplantation are: The indications for liver transplantation are: 1 - Acidosis (pH < 7.3), or 1 - Acidosis (pH < 7.3), or 2 - PT > 100 sec 2 - PT > 100 sec 3 - Creatinine > 300 mcg/l 4 - Grade 3 encephalopathy (or worse) It is better to contact the local liver transplant centre earlier than this. It is better to contact the local liver transplant centre earlier than this. Grossly abnormal prothrombin times should trigger referral: Grossly abnormal prothrombin times should trigger referral: PT > 20 sec at 24 hr PT > 20 sec at 24 hr PT > 40 sec at 48 hr PT > 40 sec at 48 hr

41. Alcohol poisoning Clinical features of acute alcohol poisoning include: Clinical features of acute alcohol poisoning include: Ataxia and anaesthesia leading to accidental injury Ataxia and anaesthesia leading to accidental injury Dysarthria and nystagmus Dysarthria and nystagmus Drowsiness which may progress to coma Drowsiness which may progress to coma Inhalation of vomit which can be fatal & should be prevented Inhalation of vomit which can be fatal & should be prevented Hypoglycaemia in children and some adults Hypoglycaemia in children and some adults Check BM stix and give 50% glucose i.v. if required Check BM stix and give 50% glucose i.v. if required

42. Coma (alcohol induced) In cases of alcohol induced coma exclude: In cases of alcohol induced coma exclude: 1. Coincident head injury 2. Hepatic failure 3. Meningitis 4. Wernicke’s encephalopathy 5. Other associated drug ingestion A blood test will confirm substantial levels of alcohol A blood test will confirm substantial levels of alcohol Rule out alcoholic hypoglycaemia Rule out alcoholic hypoglycaemia The airway and circulation must be maintained The airway and circulation must be maintained But glucose- containing fluids may precipitate Wernicke's encephalopathy But glucose- containing fluids may precipitate Wernicke's encephalopathy Thiamine should given to all Thiamine should given to all Intravenous naloxone has reversed coma in a proportion of cases Intravenous naloxone has reversed coma in a proportion of cases