Deadly Single Dose Agents

Article Author:
Michael Euwema
Article Editor:
Terrell Swanson
Updated:
9/18/2019 3:02:16 PM
PubMed Link:
Deadly Single Dose Agents

Introduction

Although the basics of evaluating and treating most unknown ingestants are well known, many overdoses require very specific treatment if the patient is to have any chance of survival.[1] Countless studies have been published supporting Dr. Gideon Koren's 1993 landmark article “Medications Which can Kill a Toddler with One Tablet or Teaspoonful” in the Journal of Toxicology.[2][3][4][5]While each has its own merits, most focus solely on pediatric overdoses and relatively few of them provide an exhaustive list or act as a “quick-reference” when dealing with real-time ingestions. 

Despite widespread public education, childproof containers, and other safety measures, accidental overdoses continue to occur.  In the United States, poison control centers receive over 2.2 million calls each year, 47% of which concern children less than six years of age.  Most pediatric accidental ingestions involve cosmetics and personal care products, followed by cleaning products, and then analgesics and prescription medications.  Adult overdoses usually are due to intentional ingestion of analgesics and sedative hypnotics. 

Following are the list of toxic drugs (in decreasing severity/difficulty of treatment) included in this summary: 

  1. Alpha-2 Adrenergic Agonists - Clonidine, Naphazoline, Oxymetazoline, Tetrahydrozoline
  2. Sulfonylureas - Chlorpropamide, Glyburide, Glipizide, Glimepiride
  3. Calcium Channel Blockers - Nifedipine, Verapamil, Diltiazem, Amlodipine, Nicardipine
  4. Beta Blockers - Metoprolol, Labetalol
  5. Tricyclic Antidepressants - Imipramine, Desipramine, Amitriptyline, Nortriptyline
  6. Opioids - Codeine, Hydrocodone, Methadone, Morphine, Heroin
  7. Anti-diarrheals - Lomotil (Diphenoxylate + Atropine), Loperamide
  8. Salicylates/Methyl salicylates - Bengay, Wintergreen Oil, Peptobismol, Tiger Balm
  9. Antipsychotics - Loxapine, Thioridazine, Chlorpromazine
  10. Antimalarials - Chloroquine, Hydroxychloroquine, Quinine
  11. Antiarrhythmics - Quinidine, Disopyramide, Procainamide, Flecainide
  12. Terpenoid (Camphor) - Analgesic, Anti-itch, and Cooling Gels, Vicks, Tiger Balm
  13. Non-alkaloidToxic Lignan - Podophyllin, Condylox
  14. Plant Toxin / Secondary metabolite - Colchicine
  15. Oral Acetylcholinesterase Inhibitors - Rivastigmine, Donepezil, Tacrine, Galantamine
  16. Methylxanthine - Theophylline: 1,3-dimethylxanthine
  17. Partial Opioid Agonist / Synthetics - Buprenorphine / Fentanyl
  18. Toxic Alcohols - Methanol, Ethylene Glycol
  19. Caustics / Household Products - Acidic or Alkaline household products, hydrofluoric acid, selenious acid, ammonia fluoride, Methacrylic acid (cosmetic glue), Naphthalene (moth balls)

Function

Toxicokinetics

1. Alpha-2 Adrenergic Agonists: Alpha-2 receptors mediate the transmission of neurotransmitters (acetylcholine & norepinephrine) across the synapse effectively antagonizing them

2. Sulfonylureas: Stimulates the pancreas to increase insulin production

3. Calcium Channel Blockers: Decrease cardiac inotropy and increase vasodilation; can also block insulin secretion in the setting of overdose which can directly affect the heart and thereby worsening shock

4. Beta Blockers: Direct action on the heart causing bradycardia (less severe in children); blockage of gluconeogenesis leading to hypoglycemia; central nervous system (CNS) depression (crosses blood-brain barrier due to high lipid solubility)

5. Tricyclic Antidepressants: Block fast sodium channels, leading to intraventricular conduction delay; wide QRS and right axis deviation on EKG

6. Opioids: Direct suppression of CNS respiratory center leading to hypoxic respiratory failure

7. Anti-diarrheals: Biphasic toxicity - first anticholinergic effects (Lomotil) and then a longer lasting opioid effect (Lomotil and Imodium)

8. Salicylates/Methyl salicylates: Direct stimulation of CNS respiratory center (respiratory alkalosis) then metabolic acidosis 

9. Antipsychotics: Block post-synaptic dopamine receptors and the reticular activating system (also some serotonin antagonism)

10. Antimalarials: Sodium channel blockade; QRS widening

11. Antiarrhythmics: Sodium channel blockade; QRS widening

12. Terpenoid (Camphor): Topical rubefacient induces local hyperemia and warmth

13. Non-alkaloid Toxic Lignans: Interrupt cell mitosis by binding to tubulin and disrupting the microtubular network, thereby disturbing cellular protein assembly and leading to sepsis and multisystem organ failure

14. Plant Toxins/Secondary metabolites: Same as the lignan. Interrupt cell mitosis by binding to tubulin and disrupting the microtubular network, thereby disturbing cellular protein assembly and leading to sepsis and multisystem organ failure

15. Oral Acetylcholinesterase Inhibitors: Act on nicotinic and muscarinic receptors; cholinergic toxidrome

16. Methylxanthines: Inhibit phosphodiesterase enzymes which increase cAMP and cGMP to cause bronchodilation

17. Partial Opioid Agonist/Synthetics: Direct suppression of CNS respiratory center (one lick can be enough to be toxic in a child)[6]

18. Toxic Alcohols: Metabolized into toxic chemicals like aldehyde, organic acids, acetone

19. Caustics/Household Products: Direct mucosal and pulmonary damage (toxicity related to pH < 3 and > 13), methemoglobinemia (methacrylic acid), cyanide (metabolite of acrylonitrile)

Symptoms/Physical Findings/Labs/EKG

1. Alpha-2 Adrenergic Agonists: Opioid toxidrome, altered mental status

2. Sulfonylureas: Anorexia, weakness, prolonged hypoglycemia up to 18-24 hours, lethargy, seizure, coma, headache, confusion, irritability

3. Calcium Channel Blockers: Hyperglycemia, cardiovascular collapse, bradycardia, hypotension (verapamil and nifedipine worst)[7]

4. Beta Blockers: Bradycardia and hypotension (generally not as severe in children), hypoglycemia, seizures, reflex tachycardia, 2nd- and 3rd-degree heart block, Torsades de pointes

5. Tricyclic Antidepressants: Seizures, anticholinergic toxidrome, hypotension, metabolic acidosis, cardiac conduction abnormalities (QRS prolongation and prominent R in aVR, hypotension, CNS depression, tachycardia then torsades de pointes)

6. Opioids: Hypoxic respiratory failure, miosis, CNS depression

7. Anti-diarrheals: Initially anticholinergic toxidrome then opioid toxidrome; cardiac dysrhythmias, ataxia, irritability, hypokalemia, myopathy, neuropathy, AMS, ocular toxicity, ototoxicity[8]

8. Salicylates/Methyl salicylates: Nausea and vomiting, diaphoresis, hyperthermia, tinnitus, CNS depression, hyperventilation, primary metabolic acidosis, pulmonary edema, cerebral edema, coma

9. Antipsychotics: Seizures, anticholinergic toxidrome, prolonged QTc, wide QRS, tachycardia, hypotension

10. Antimalarials: Delirium, coma, dysrhythmias, seizures, prolonged QT, widened QRS, hypotension, hypoglycemia, visual disturbances (blurry, diplopia, altered color perception)

11. Antiarrhythmics: Nausea and vomiting, hypotension, QRS widening, heart block, hyperthermia, hypoglycemia, bradycardia, tachyarrhythmias, ventricular tachycardia/fibrillation, torsades de pointes

12. Terpenoid (Camphor): Respiratory suppression, status epilepticus, typical odor, GI distress, sense of warmth, CNS hyperactivity then depression

13. Non-alkaloid Toxic Lignan: GI symptoms, CNS changes (confusion, coma, delirium, hallucinations), pancytopenia

14. Plant Toxin / Secondary metabolite: Same as lignan. GI symptoms, CNS changes (confusion, coma, delirium, hallucinations), pancytopenia[9]

15. Oral Acetylcholinesterase Inhibitors: Increased level and duration of neurotransmitters

16. Methylxanthine: Vomiting, anxiety, agitation, seizures, ventricular dysrhythmias, hypotension, tachycardia

17. Partial Opioid Agonist/Synthetics: Opioid Toxidrome, agitation[10]

18. Toxic Alcohols: Confusion, vomiting, seizures, hypopnea, cyanosis, hypothermia, syncope

19. Caustics/Household Products: Drooling, perioral burns, respiratory distress, dysphagia, metabolic effects (methemoglobinemia, hemolysis, cyanide toxicity)

Issues of Concern

Treatment / Management (currently recommended antidotes listed first)

1. Alpha-2 Adrenergic Agonists: Naloxone (antidote); supportive care, airway protection, respiratory support, atropine, IV fluids, vasopressors

2. Sulfonylureas: Octreotide (antidote); serial glucose monitoring, glucagon, GI decontamination, IV dextrose bolus (can overstimulate the pancreas and cause rebound hypoglycemia), 24-hour observation

3. Calcium Channel Blockers: High Dose Insulin/euglycemic therapy (antidote); other antidotes (weaker evidence) such as lipid emulsion, IV calcium, methylene blue (amlodipine), ECMO for cardiovascular collapse, atropine, cardiac pacing, pressors[11][12]

4. Beta Blockers: Glucagon (antidote); monitoring, vasopressors, cardiac pacing, whole bowel irrigation, calcium 

5. Tricyclic Antidepressants: Sodium Bicarb/Lipid Emulsion (antidotes); aggressive ABCs, urine alkalinization, activated charcoal, benzodiazepines (may rapidly deteriorate)

6. Opioids: Naloxone (antidote); supportive care, airway protection, respiratory support, 24 hours observation for longer acting opioids

7. Anti-diarrheals: Naloxone (antidote); fluids, airway support, supportive care

8. Salicylates/Methylsalicylates: Sodium bicarbonate (antidote); urine alkalinization, supportive care, activated charcoal, dialysis. May require long observation (may not peak until 24 hours)

9. Antipsychotics: Sodium bicarbonate (antidote); supportive care, benzodiazepines, cardiac monitoring, GI decontamination

10. Antimalarials: Sodium bicarbonate (antidote); ECMO, supportive care, benzodiazepines, cardiac monitoring, glucose, (severe – epinephrine, intubation, gastric lavage)

11. Antiarrhythmics: Sodium bicarbonate (antidote); supportive care, cardiac monitoring, intravenous fluid bolus

12. Terpenoid (Camphor): Supportive Care; benzodiazepines, airway monitoring, remove chemical if possible

13. Non-alkaloid Toxic Lignan: Supportive care; remove topicals, GI decontamination 

14. Plant Toxin/Secondary metabolite: Supportive Care; remove topicals, GI decontamination

16. Methylxanthine: Supportive care; IV Fluids, benzodiazepines, antiemetics, activated charcoal, inotropes

17. Partial Opioid Agonist/Synthetics: Narcan (antidote); supportive care, airway protection, respiratory support

18. Toxic Alcohols: Ethanol, fomepizole (antidote); supportive care, specific treatment depends on type of alcohol

19. Caustics/Household Products: (multiple specific treatments) supportive care, airway protection, dilution, cyanide kit, methylene blue

Clinical Significance

Although there is little primary research into poisonings, there are numerous case reports and summary articles on the topic.  Novel therapies are being devised and tested all the time; for example, methylene blue in amlodipine overdose and “old” therapies such as ECMO are being used more often and with greater success.[13][14]  In treating patients be sure to liberally utilize the regional poison control center to ensure the use of the latest therapies and best management available. Toxicologists are always standing by to assist. Also, numerous web resources, such as UpToDate and eMedicine, and textbooks, such as Goldfrank, provide very specific and current treatment protocols. Observation and supportive care are sufficient for most toxic ingestions, but some, like these highly dangerous substances, require specific treatment and a knowledgeable clinician.

Enhancing Healthcare Team Outcomes

Although identification and proper management of toxic ingestions are vital skills for emergency and acute care clinicians, one cannot forget those that support our mission both before arrival and after treatment and discharge.  Caring for these complicated overdoses is a daunting task, especially for the pre-hospital personnel as well as those providing aftercare.  Numerous studies and articles are now focusing on reducing unnecessary ER visits for minor ingestions [15] as well as on patient safety and proper mental health or substance abuse referrals.  More evidence-based research is needed on how to prevent recidivism, and more collaborative programs need to be developed to provide clear pathways to recovery for the patient's that have intentionally overdosed. As the U.S. opioid crisis has been given federal attention (and funding to address is) - now is the time to capitalize on the national momentum to improve our comprehensive care of these patients.  Now is also the time to build our care teams when these patients present to the ER.  A collaboration of EMS, ED providers, clinical Pharmacologists, Poison Control, Intensivists, Mental Health providers, and Addiction specialists are needed for this type of patient's journey to full recovery.

Due to the complexity and risk of patients exposed to these agents, an interprofessional approach will lead to the best outcomes. The nurse should assist the clinician in obtaining an accurate patient and family history, including making calls as necessary to family members and pharmacists. The specialty-trained toxicologist pharmacist should assist in evaluating drug-drug interactions, selection of antidotes, and providing guidance for care to the team. The clinician should consult a clinical toxicologist in most cases to assist in guiding evaluation and therapy. Often a mental health counselor is often involved as well. Only by working together as a team will these patients obtain the best care and chance for long-term survival. [Leve 5]


References

[1] The approach to the patient with an unknown overdose., Erickson TB,Thompson TM,Lu JJ,, Emergency medicine clinics of North America, 2007 May     [PubMed PMID: 17482020]
[2] Medications which can kill a toddler with one tablet or teaspoonful., Koren G,, Journal of toxicology. Clinical toxicology, 1993     [PubMed PMID: 8355317]
[3] Medications that can be fatal for a toddler with one tablet or teaspoonful: a 2004 update., Bar-Oz B,Levichek Z,Koren G,, Paediatric drugs, 2004     [PubMed PMID: 15035652]
[4] Small dose... big poison., Braitberg G,Oakley E,, Australian family physician, 2010 Nov     [PubMed PMID: 21301654]
[5] Deadly pediatric poisons: nine common agents that kill at low doses., Michael JB,Sztajnkrycer MD,, Emergency medicine clinics of North America, 2004 Nov     [PubMed PMID: 15474780]
[6] Fatal Fentanyl: One Pill Can Kill., Sutter ME,Gerona RR,Davis MT,Roche BM,Colby DK,Chenoweth JA,Adams AJ,Owen KP,Ford JB,Black HB,Albertson TE,, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 2017 Jan     [PubMed PMID: 27322591]
[7] Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil., Levine M,Boyer EW,Pozner CN,Geib AJ,Thomsen T,Mick N,Thomas SH,, Critical care medicine, 2007 Sep     [PubMed PMID: 17855820]
[8] Cardiac conduction disturbance after loperamide abuse., Marraffa JM,Holland MG,Sullivan RW,Morgan BW,Oakes JA,Wiegand TJ,Hodgman MJ,, Clinical toxicology (Philadelphia, Pa.), 2014 Nov     [PubMed PMID: 25345436]
[9] Colchicine poisoning: the dark side of an ancient drug., Finkelstein Y,Aks SE,Hutson JR,Juurlink DN,Nguyen P,Dubnov-Raz G,Pollak U,Koren G,Bentur Y,, Clinical toxicology (Philadelphia, Pa.), 2010 Jun     [PubMed PMID: 20586571]
[10] Adverse effects in children after unintentional buprenorphine exposure., Geib AJ,Babu K,Ewald MB,Boyer EW,, Pediatrics, 2006 Oct     [PubMed PMID: 17015570]
[11] Treatment for calcium channel blocker poisoning: a systematic review., St-Onge M,Dubé PA,Gosselin S,Guimont C,Godwin J,Archambault PM,Chauny JM,Frenette AJ,Darveau M,Le Sage N,Poitras J,Provencher J,Juurlink DN,Blais R,, Clinical toxicology (Philadelphia, Pa.), 2014 Nov     [PubMed PMID: 25283255]
[12] Intravenous lipid emulsion in the emergency department: a systematic review of recent literature., Cao D,Heard K,Foran M,Koyfman A,, The Journal of emergency medicine, 2015 Mar     [PubMed PMID: 25534900]
[13] Extracorporeal membrane oxygenation in the treatment of poisoned patients., de Lange DW,Sikma MA,Meulenbelt J,, Clinical toxicology (Philadelphia, Pa.), 2013 Jun     [PubMed PMID: 23697460]
[14] Methylene blue in the treatment of refractory shock from an amlodipine overdose., Jang DH,Nelson LS,Hoffman RS,, Annals of emergency medicine, 2011 Dec     [PubMed PMID: 21546119]
[15] Hickey CN,Mycyk MB,Wahl MS, Can a poison center overdose guideline safely reduce pediatric emergency department visits for unintentional β-blocker ingestions? American journal of therapeutics. 2012 Sep;     [PubMed PMID: 21192245]