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Drug Overdose (DO) Overview

Drug Overdose (DO) Overview. September, 2006 Intensive Care Unit United Christian Hospital. DO Evaluation. Motive (intentional Vs incidental) Co-morbidity Related Drug Time of exposure and presentation Co-ingestion Other poison, corrosives exposure/ injury Symptoms & Vital Signs (VS).

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Drug Overdose (DO) Overview

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  1. Drug Overdose (DO) Overview September, 2006 Intensive Care Unit United Christian Hospital

  2. DO Evaluation • Motive (intentional Vs incidental) • Co-morbidity • Related Drug • Time of exposure and presentation • Co-ingestion • Other poison, corrosives exposure/ injury • Symptoms & Vital Signs (VS)

  3. DO Evaluation • Co-morbidity CVS: HT, IHD, arrhythmia, CHF Resp: Chronic respiratory insufficiency Renal: CRF GI: liver impairment, chronic hepatitis Alcoholism Drug addiction

  4. DO Evaluation • Related Drug 1.Types (e.g.salicylates, CCB) 2.Amount (e.g. dose, concentration) 3.Single Vs Multiple dose 4.Formula, preparation e.g. liquid, dispersible, enteric-coated, sustained-release, IV 5.Time of exposure and presentation

  5. DO Evaluation • Co-ingestion: (Maybe >2 agents) 1.paracetamol + salicylates 2.paracetamol + opioids 3.alcohol + paracetamol 4.alcohol + sedatives • Other poison, corrosives exposure/ injury 1.Carbon monoxide 2.Dettol 3.Bleaching agents 4.通渠水

  6. DO Evaluation • Symptoms (Toxidrome: Toxicologic Syndrome) NEJM Volume 355:602-611 August 10, 2006 Number 6

  7. DO Evaluation • Hypothermia ethanol, sedatives, barbiturates, hypoglycaemics, opioids, carbon monoxide beta-blockers (BB) • Hyperthermia Cocaine, amphetamines, neuroleptics, anticholinergics, lithium, salicylates, sympathomimetics

  8. DO Evaluation • Hypotension CCB, BB, antihypertensives, barbiturates,TCA, opioids, ethanol, theophylline, diuretics • Hypertension Amphetamine, cocaine, sympathomimetics, MAOI, anticholinergics, phenothiazines

  9. DO Evaluation • Hyperventilation Amphetamine, cocaine, anticholinergics, ethanol, methaemoglobin inducers, salicylates, theophylline, isoniazid • Hypoventilation Barbiturates, opioids, colchicine, ethanol, sedative-hypnotics, TCA

  10. DO Evaluation • Bradycardia CCB, BB, digoxin, opioids • Tachycardia Amphetamine, cocaine, anticholinergics, sympathomimetics, theophylline, TCA

  11. DO Evaluation • Bedside blood glucose test • SpO2 • ECG • Serum chemistry blood gas, electrolytes (e.g. Na, K, iCa2+) R//LFT • CBP, clotting profile • Drug level • Toxicology screen (blood, urine, gastric fluid) • CXR/AXR

  12. Management • A,B,C • GI Tract Decontamination • Enhance Elimination • Antidotes

  13. GI Tract Decontamination • Emesis • Orogastric Lavage • Activated Charcoal • Whole Bowel Irrigation

  14. Emesis Seldom use, have Risk • Acute ingestion of potentially toxic substance ( < 1hr) • Only potentially useful in pre-hospital setting with long transport time to medical care

  15. Orogastric Lavage (GL) • Large-bore fenestrated orogastric tube (36-40 Fr) • Require protected airway • Amount of poison ingested is potentially life threatening • Within 60 minutes of ingestion (Except anti-cholinergic < 12 hr ingestion; salicylate < 24 hr ingestion)

  16. Orogastric Lavage • Contraindications: Caustic/ Corrosive ingestion Large foreign bodies or sharp objects Airway not protected Suspected UGI injury Hypoxia

  17. Activated Charcoal (AC) • One gram of activated carbon has the surface area (>400 m2) of approximately two tennis courts (260 m2) ! • Single Dose • Multiple Dose

  18. Activated Charcoal (AC) • Used in: 1. Enterohepatic Circulation: Digoxin, amitriptyline, phenobarbitone, dozepin 2. Theophylline, salicylates

  19. Activated Charcoal (AC) • Not bind well to: Lithium, strong acids and bases, and most inorganic minerals (examples of these are sodium, iron, lead), Alcohol (such as ethanol, methanol, isopropyl alcohol, and glycols), ammonia

  20. Single Dose AC • ~1 gram/ Kg • Adult dose: 60 to 90grams

  21. Multiple Dose AC • Phenobarbital, dapsone, theophylline, digoxin, phyentoin, carbamazepine, aspirin • SR products, Enteric-coated product, Concretion formation • Enterohepatic circulation, low proetin-binding, long half-life • Dose: 0.5g/kg Q2-6H (till “charcoal stools” and also depending on D.O. severity)

  22. AC Contraindications • I.O. • Ileus • GI perforation • Loss of airway protection

  23. Whole Bowel Irrigation (WBI) • mechanically flushing the ingestedpoison out of the gastrointestinal tract before it can be absorbed into the body • iso-osmolar solution of polyethylene glycol • Rate:1-2L per hour (minimally) • P.O. or R/T • Entire procedure usually takes 4 to 6 hours • Till rectal effluent clear

  24. Whole Bowel Irrigation (WBI) • Indicatios: • potentially toxic ingestion of substance that not well-absorbed by activated charcoal (e.g. Fe, Li, Pb, Zn) • Sustained release/ Enteric coasted preparation • Rising drug level despite GL/AC

  25. Whole Bowel Irrigation (WBI) • Contraindications: I.O. Ileus GI perforation GIB Compromised airway

  26. Enhance Elimination • Urinary alkalinization • Saline diuresis • Haemodialysis and haemoperfusion

  27. Urinary alkalinization • By ion trapping mechanism • Urine pH >7.5 • Method: Stat 1-2mEq/kg of NaHCO3 Continuous infusion NaHCO3 in D5 e.g. 1LD5+NaHCO3 150mmol+ 40mmol KCl Q8H Monitor serum pH, avoid >7.55 Maintain normokalaemia

  28. Urinary alkalinization • Salicylates • Methotrexate • Chlorpropamide • Phenobarbital

  29. Saline diuresis • Saline diuresis NOT equal to Forced diuresis • Forced diuresis: use diuretics to increase urinary elimination of toxin—generally NOT helpful • Saline diuresis For lithium

  30. Antidotes • Acetaminophen N-acetylcysteine • Benzodiazepine Flumazenil • Beta blockers Glucagon • Calcium blockers Calcium • Iron or Aluminum Deferroxamine • Isonizide (INH) Vit B6 • Methemoglobinemia Methylene bluce • Methanol Alcohol • Opioid Naloxone • TCA anti-depressants Sodium bicarbonate • Coumarin Vit K1

  31. Haemodialysis and haemoperfusion • Drug HD HP • Aspirin D* D • Lithium D/MD unknown • Phenobarbital D/MD D • Theophylline D D

  32. Haemodialysis and haemoperfusion • Not Useful in TCA Digoxin Valporic acid Dilantin

  33. Drug Overdose • Antipyretic & Analgesic • Antidepressants • Cardiovascular Medications • “Sleeping Pills” • Antipsychotics, Neuroleptics & Mood Stabilizers • Hypoglycaemic Agents • Anticonvulsants

  34. Antipyretic & Analgesic • Paracetamol • Salicylates • Non-Steroidal Anti-Inflammatory Drugs (NSAID)

  35. Case 1 • 28/F worked as clerk • Non-drinker Thin-built • Suicidal D.O. • Claimed took 10 tab panadol + 40 tab 靈芝丸at 03:00 attended AED 13:00 • Panadol level at 13:00 >150mcg/ml • NAC started, developed rash, so stopped NAC temporally , given anti-histamine and resumed NAC at slower rate

  36. Case 1 • INR 1.5--1.7-- > 2 AST rising trend • pH Normal • INR still on rising trend • AST > 3000 (peak) • Transferred to QMH liver transplant team • Responsive to medical Rx

  37. Paracetamol

  38. Paracetamol Only • Acetaminophen • Tylenol, Tempra, Datril (USA) • Panadol (UK, HK) 必理痛 • Progesic • Fortolin幸福止痛素

  39. Medications with Paracetamol • Saridon 散利痛 250mg paracetamol+65mg caffeine • Dologesic 325mg paracetamol+32.5mg dextropropoxyphene • Coltalin-ND, Coltalin cold tabs 幸福傷風素 325mg paracetamol+phenylephrine+chlorpheniramine, etc

  40. Paracetamol • International Union of Pure and Applied Chemistry (IUPAC) name: N-(4-hydroxyphenyl)acetamide Other chemical names: N-acetyl-para-aminophenol and para-acetyl-amino- phenol APAP • Chemical Formula: C8H9NO2

  41. Paracetamol • Pharmacokinetic data Absorption a) Peak serum levels i. 1-2hrs at therapeutic dose ii. 2-4hrs in overdose Bioavailability almost 100% Low protein binding

  42. Paracetamol • Metabolism (therapeutic dose): 90-95% hepatic t1/2: 2-3hrs in therapeutic doses 1. >90% non-toxic sulfate & glucuronide conjugates 2.<5% by cytochrome P450 2E1 to N-acetyl-para-benzoquinoneimine (NAPQI), strong oxidizing agent NAPQI is reduced by glutathione into non-toxic mercaptate conjugate

  43. Paracetamol • Metabolism (Overdose) 90-95% hepatic t1/2: prolonged in overdose 1. non-toxic sulfate & glucuronide conjugates pathway(Saturated) 2. Increase in NAPQI, depletes glutathione stores-->NAPQI accumulates-->hepatocellular centribular necrosis and renal injury

  44. Paracetamol • Factors favor NAPQI toxic pathway a) Enzyme inducers: smoking, barbiturates, phenytoin, INH, alcohol, carbamazepine b) Reduced glutathione stores: malnutrition, alcoholism, fasting, HIV, chronic disease, long-term use of paracetamol

  45. Paracetamol Overdose • Clinical presentation • Toxic dose >150mg/kg ; massive overdose >1g/kg Phase 1 (0.5-24h) minimal symptoms; metabolic acidosis in massive overdose Phase 2 (24-72h) RUQ pain, elevation of hepatic enzymes. 25% of hepatotoxic patients have impaired renal function Phase 3 (72-96h) marked hepatic dysfunction including hepatic encephalopathy. Death is related to hepatic failure Phase 4 (4-14 days) resolution of hepatic dysfunction

  46. Paracetamol Overdose Evaluation • History: Time of ingestion Amount ingested (150mg/kg potentially toxic) • Serum level: 4hrs post-ingestion/ as soon as possible thereafter Nomogram -Without NAC, 60% of those with initial drug level above toxic line will have aminotransferase > 1000IU/L

  47. Rumack and Matthew (Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876.)

  48. Treatment of Paracetamol D.O. • Gastric lavage Consider only for coingestants • Activated charcoal Only of benefit within 4 hours of ingestion 1gm/kg • N-acetylcysteine (NAC) Protection of NAC is 100% if given within 8 hrs of ingestion

  49. N-acetylcysteine (NAC) • Mechanism: Precursor for glutathione Increase non-toxic sulfation metabolism Prevent covalent binding of NAPQI to hepatocytes • Dose: (Load)150mg/ kg in 200ml-500ml D5 over 15min to 1 hr (then)50mg/kg in 500ml D5 over 4 hrs (then)100mg/kg in 1L D5 over 16 hrs

  50. N-acetylcysteine (NAC) • Paracetamol level above treatment line • All patients with potentially hepatotoxic overdose (> 150 mg/kg). Treatment can be stopped if paracetamol concentration is below standard treatment line (Level taken >/=4hr of ingestion & not extended release type) • All paracetamol ingestions who present late (>24 hours) with either detectable serum paracetamol or elevated tansaminases • All patients with evidence of severe toxicity or fulminant hepatic failure, regardless of time since overdose. Continue or start NAC 150mg/kg/day until recovery from encephalopathy or patient dies • Chronic large ingestions (>4g/day in adult), especially those who are high risk and deranged LFT

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