Poisoning and Drug Overdose¶

Chapter 470 | Harrison's 22e · Part 14 – Poisoning, Overdose & Environmental · Chapter 470

Key Clinical Points¶

The core principle of toxicology is that 'the dose makes the poison' (Paracelsus).
Over 5 million poison exposures occur annually in the US; 84% of serious or fatal cases involve pharmaceuticals.
Clinical diagnosis relies on a combination of history, physical examination, and toxicologic laboratory evaluations.
History must include: time, route, duration, circumstances (location, intent), substance name/amount, and patient's medical/psychiatric history.
Physical examination focuses on vital signs, respiratory status, and neurological assessment (e.g., dyskinesia, dystonia, myoclonus).
Poisonings are categorized by physiological state: Stimulated, Depressed, Discordant, or Normal.
Management follows a structured approach: Supportive Care → Prevention of Further Absorption → Enhancement of Elimination → Antidotes.
Anticholinergic toxicity is treated with Physostigmine (unless contraindicated by asthma or non-anticholinergic cardiovascular toxicity).
Antipsychotic and Cyclic antidepressant overdoses may cause QRS prolongation, requiring treatment with sodium bicarbonate.

EPIDEMIOLOGY¶

• Exposure Statistics: ◦ Over 5 million poison exposures occur annually in the United States. ◦ Pharmaceuticals are involved in 47% of all exposure cases and 84% of serious or fatal poisonings. ◦ Non-pharmaceutical exposures commonly involve household cleaning substances and cosmetics/personal care products. • Demographics & Context: ◦ Most cases are acute, accidental (unintentional), occur in the home (>90%), and frequently involve children <6 years of age. ◦ Fatalities are primarily driven by: 1. Intentional self-harm (suicide) involving pharmaceuticals; 2. Complications from opioids and other psychoactive drugs of abuse (e.g., fentanyl, xylazine). • Clinical Context: ◦ Carbon monoxide is a leading cause of death from poisoning, but it is often underrepresented in hospital statistics as patients are typically deceased upon discovery. ◦ "Body packing" (conceering illicit drugs in the body cavity) should be suspected in cases involving recent travel from foreign countries or arrests for criminal activity.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Core Principle: ◦ "The dose makes the poison" (Paracelsus). • Factors Influencing Severity: ◦ Individual responses vary due to: genetic polymorphism, enzymatic induction/inhibition by other xenotherapeutics, or acquired tolerance. ◦ Severity depends on: route of exposure, chemical/physical properties of the poison, mechanism of action, and the functional reserve of the target organ (influenced by age and pre-existing disease).

CLINICAL FEATURES¶

• History: ◦ Essential data: Time, route, duration, circumstances (location, intent), name/amount of substance. ◦ Clinical context: Severity and time of onset, nature/severity of symptoms, and first-aid measures provided. ◦ Patient background: Medical/psychiatric history, occupation, and social relationships. • Physical Examination: ◦ Primary focus: Vital signs, respiratory system, and neurological status. ◦ Neurological exam: Must document neuromuscular abnormalities (dyskinesia, dystonia, fasciculations, myoclonus, rigidity, tremors). ◦ Assessment for trauma or underlying illnesses.

DIFFERENTIAL DIAGNOSIS¶

• Physiological State Classification (Table 470-1): ◦ Stimulated: Sympathomimetics, Ergot alkaloids, Methylxanthines, Monoamine oxidase inhibitors, Thyroid hormones, Anticholinergics, Antihistamines, Antipsychotics, Antispasmodics, Belladonna alkaloids, Cyclic antidepressants, Mushrooms and plants, Hallucinogens, Cannabinoids (marijuana), LSD and analogues, Mescaline and analogues, Phencyclidine and analogues, Withdrawal syndromes. ◦ Depressed: Sympatholytics (α-Adrenergic antagonists, β-Adrenergic blockers), ACE inhibitors, Angiotensin receptor blockers, Antipsychotics, Calcium channel blockers, Cardiac glycosides, Cyclic antidepressants, Cholinergics (Acetylcholinesterase inhibitors, Muscaric agonists, Nicotinic agonists), Opioids, Analgesics, GI antispasmodics, Heroin, Sedative-hypnotics, Alcohols, Anticonvulsants, Barbiturates, Benzodiazepines, GABA precursors, Muscle relaxants, Other agents, GHB products, Xylazine. ◦ Discordant: Asphyxiants, Cytochrome oxidase inhibitors, Inert gases, Irritant gases, Methemoglobin inducers, Oxidative phosphorylation inhibitors, AGMA inducers, Alcohol (ketoacidosis), Ethylene glycol, Iron, Methanol, Salicylate, Toluene, CNS syndromes (Extrapyramidal reactions, NMS, Serotonin syndrome), Strychnine, Membrane--active agents, Antihistamines/Antipsychotics (some), Carbamazepine, Local anesthetics, Quinoline antimalarials. ◦ Normal: Nontoxic exposure, Psychogenic illness, "Toxic time-bombs" (Slow absorption/distribution: Anticholinergics, Carbamazepine), Concretion formers, Dilantin Kapseals, Drug packets, Enteric-coated pills, Lomotil, Sustained-release pills, Valproate, Toxic metabolites (Acetaminophen, Carbon tetrachloride, Cyanogenic glycosides, Ethylene glycol, Methanol, Methemoglobin inducers, Mushroom toxins, Organophosphate insecticides, Paraquat), Metabolism disruptors (Antineoplastic agents, Antiviral agents, Colchicine, Hypoglycemic agents, Immunosuppressive agents, MAO inhibitors), Metals, Other oral anticoagulants (Warfarin).

DIAGNOSTIC APPROACH¶

Initial Assessment: Focus on vital signs, respiratory status, and neurological exam.
History Gathering: Obtain details on substance, amount, route, and time of exposure (query family/paramedics if patient is non-communicative).
Identification of Unknowns: ◦ Use label imprint codes or chemical product labels. ◦ Consult reference texts, databases, manufacturers, or regional poison centers (800-222-1222). ◦ Review Safety Data Sheets (SDS) for occupational exposures.
Specialized Consultation: Contact medical toxicologists or poison centers for unfamiliar substances or novel psychoactive drugs.

MANAGEMENT & TREATMENT¶

Supportive Care: ◦ Airway protection. ◦ Oxygenation/ventilation. ◦ Treatment of arrhythmias. ◦ Hemodynamic support. ◦ Correction of temperature abnormalities. ◦ Correction of metabolic derangements. ◦ Prevention of secondary complications.
Prevention of Further Poison Absorption: ◦ Gastrointestinal decontamination (e.g., multiple-dose activated charcoal).
Enhancement of Poison Elimination: ◦ Alteration of urinary pH. ◦ Chelation. ◦ Hyperbaric oxygenation. ◦ Extracorporeal removal: Hemodialysis, Hemoperfusion, Hemofiltration, Plasmapheresis, Exchange transfusion, Continuous venovenous hemofiltration (CVVH).
Administration of Antidotes: ◦ Specific agents based on toxidrome (e.g., Physostigmine for anticholinergics; Sodium bicarbonate for QRS prolongation in antipsychotic/cyclic antidepressant overdose).
Prevention of Reexposure: ◦ Adult education. ◦ Child-proofing. ◦ Naloxone distribution. ◦ Linkage to harm reduction services.
Follow-up: ◦ Notification of regulatory agencies. ◦ Psychiatric referral.

KEY PEARLS & HIGH-YIELD POINTS¶

• Severity of Physiological Stimulation (Table 470-2): ◦ Grade 1: Anxious, irritable, tremulous; vitals normal; diaphoresis, flushing or pallor, mydriasis, and hyperreflexia sometimes present. ◦ Grade 2: Agitated; may have confusion or hallucinations but can converse and follow commands; vitals mildly to moderately increased. ◦ Grade 3: Delirious; unintelligible speech, uncontrollable motor hyperactivity; markedly increased vitals; tachyarrhythmias possible. ◦ Grade 4: Coma, seizures, cardiovascular collapse. • Anticholinergic Toxidrome (Table 470-4): ◦ Causes: Antihistamines (Diphenhydramine, doxylamine, pyrilamine), Belladonna alkaloids (Atropine, hyoscyamine, scopolamine), Mushrooms and plants (Amanita muscaria/pantherina, henbane, jimson weed, nightshade). ◦ Features: Dry skin/mucous membranes, decreased bowel sounds, flushing, urinary retention; myoclonus and picking activity. ◦ Treatment: Physostigmine (Contraindicated in asthma or non-anticholinergic cardiovascular toxicity). • Antipsychotic Toxicity (Table 470-4): ◦ Causes: Chlorpromazine, olanzapine, quetiapine, thioridazine. ◦ Features: Depression, miosis, anticholinergic effects, extrapyramidal reactions, tachycardia; may cause QRS prolongation. ◦ Treatment: Sodium bicarbonate for ventricular tachydysrhythmias with QRS prolongation; magnesium, isoproterenol, and overdrive pacing for Torsades de Pointes. Avoid class IA, IC, and III antiarrhythmics. • Cyclic Antidepressant Toxicity (Table 470-4): ◦ Causes: Amitriptyline, doxepin, imipramine. ◦ Features: Depression, seizures, tachycardia, conduction delays (increased PR, QRS, JT, QT), ventricular tachydysrhythmias. ◦ Treatment: Hypertonic sodium bicarbonate or hypertantum saline for QRS prolongation; IV emulsion may be beneficial. Avoid class IA, IC, and III antiarrhythmics.

Reference Tables¶

TABLE 470-1 Differential Diagnosis of Poisoning Based on Physiologic State STIMULATED Sympathetics¶

Harrison's 22e, p.3704

STIMULATED	DEPRESSED	DISCORDANT	NORMAL
Sympathetics Sympathomimetics Ergot alkaloids Methylxanthines Monoamine oxidase inhibitors Thyroid hormones Anticholinergics Antihistamines Antiparkinsonian agents Antipsychotics Antispasmodics Belladonna alkaloids Cyclic antidepressants Mushrooms and plants Hallucinogens Cannabinoids (marijuana) LSD and analogues Mescaline and analogues Mushrooms Phencyclidine and analogues Withdrawal syndromes Barbiturates Benzodiazepines Ethanol GHB products Opioids Sedative-hypnotics Sympatholytics	Sympatholytics α-Adrenergic antagonists 1 α-Adrenergic agonists 2 ACE inhibitors Angiotensin receptor blockers Antipsychotics β-Adrenergic blockers Calcium channel blockers Cardiac glycosides Cyclic antidepressants Cholinergics Acetylcholinesterase inhibitors Muscarinic agonists Nicotinic agonists Opioids Analgesics GI antispasmodics Heroin Sedative-hypnotics Alcohols Anticonvulsants Barbiturates Benzodiazepines GABA precursors Muscle relaxants Other agents GHB products Xylazine	Asphyxiants Cytochrome oxidase inhibitors Inert gases Irritant gases Methemoglobin inducers Oxidative phosphorylation inhibitors AGMA inducers Alcohol (ketoacidosis) Ethylene glycol Iron Methanol Other alcohols Salicylate Toluene CNS syndromes Extrapyramidal reactions Hydrocarbon inhalation Isoniazid Lithium Neuroleptic malignant syndrome Serotonin syndrome Strychnine Membrane-active agents Amantadine Antiarrhythmics Antihistamines Antipsychotics Carbamazepine Cyclic antidepressants Local anesthetics Opioids (some) Quinoline antimalarials	Nontoxic exposure Psychogenic illness “Toxic time-bombs” Slow absorption Anticholinergics Carbamazepine Concretion formers Extended-release phenytoin sodium capsules (Dilantin Kapseals) Drug packets Enteric-coated pills Diphenoxylate-atropine (Lomotil) Opioids Salicylates Sustained-release pills Valproate Slow distribution Cardiac glycosides Lithium Metals Salicylate Valproate Toxic metabolite Acetaminophen Carbon tetrachloride Cyanogenic glycosides Ethylene glycol Methanol Methemoglobin inducers Mushroom toxins Organophosphate insecticides Paraquat Metabolism disruptors Antineoplastic agents Antiviral agents Colchicine Hypoglycemic agents Immunosuppressive agents MAO inhibitors Metals Other oral anticoagulants Salicylate Warfarin

TABLE 470-2 Severity of Physiologic Stimulation and Depression in Poisoning and Drug Withdrawal Physiologic Stimulation…¶

Harrison's 22e, p.3705

Physiologic Stimulation
Grade 1	Anxious, irritable, tremulous; vital signs normal; diaphoresis, flushing or pallor, mydriasis, and hyperreflexia sometimes present
Grade 2	Agitated; may have confusion or hallucinations but can converse and follow commands; vital signs mildly to moderately increased
Grade 3	Delirious; unintelligible speech, uncontrollable motor hyperactivity; moderately to markedly increased vital signs; tachyarrhythmias possible
Grade 4	Coma, seizures, cardiovascular collapse
Physiologic Depression

TABLE 470-3 Fundamentals of Poisoning Management Supportive Care Airway protection Oxygenation/ventilation Treatment of…¶

Harrison's 22e, p.3706

Supportive Care
Airway protection	Treatment of seizures
Oxygenation/ventilation	Correction of temperature abnormalities
Treatment of arrhythmias	Correction of metabolic derangements
Hemodynamic support	Prevention of secondary complications
Prevention of Further Poison Absorption
Enhancement of Poison Elimination
Multiple-dose activated charcoal administration Alteration of urinary pH Chelation Hyperbaric oxygenation	Extracorporeal removal Hemodialysis Hemoperfusion Hemofiltration Plasmapheresis Exchange transfusion Continuous venovenous hemofiltration (CVVH)
Administration of Antidotes
Prevention of Reexposure
Adult education	Notification of regulatory agencies
Child-proofing	Psychiatric referral
Naloxone distribution	Linkage to harm reduction services

TABLE 470-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings¶

Harrison's 22e, p.3711

PHYSIOLOGIC CONDITION, CAUSES	EXAMPLES	MECHANISM OF ACTION	CLINICAL FEATURES	SPECIFIC TREATMENTS
Anticholinergics
Antihistamines	Diphenhydramine, doxylamine, pyrilamine	Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors. At high doses, amantadine, diphenhydramine, orphenadrine, phenothiazines, and tricyclic antidepressants have additional nonanticholinergic activity (see below).	Physiologic stimulation (Table 470-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction.	Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and non- anticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias).
Antipsychotics	Chlorpromazine, olanzapine, quetiapine, thioridazine	Inhibition of α-adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. Some agents also inhibit sodium, potassium, and calcium channels.	Physiologic depression (Table 470-2), miosis, anticholinergic effects (see above), extrapyramidal reactions (see below), tachycardia	Sodium bicarbonate for ventricular tachydysrhythmias associated with QRS prolongation; magnesium, isoproterenol, and overdrive pacing for torsades des pointes. Avoid class IA, IC, and III antiarrhythmics.
Belladonna alkaloids	Atropine, hyoscyamine, scopolamine	Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors	Physiologic stimulation (Table 470-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction.	Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and non- anticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias).
Cyclic antidepressants	Amitriptyline, doxepin, imipramine	Inhibition of α-adrenergic, dopaminergic, GABA-ergic, histaminergic, muscarinic, and serotonergic receptors; inhibition of sodium channels (see membrane-active agents); inhibition of norepinephrine and serotonin reuptake	Physiologic depression (Table 470-2), seizures, tachycardia, cardiac conduction delays (increased PR, QRS, JT, and QT intervals; terminal QRS right-axis deviation) with aberrancy and ventricular tachydysrhythmias; anticholinergic toxidrome (see above)	Hypertonic sodium bicarbonate (or hypertonic saline) for ventricular tachydysrhythmias associated with QRS prolongation. Use of phenytoin is controversial. Avoid class IA, IC, and III antiarrhythmics. IV emulsion therapy may be beneficial in some cases.
Mushrooms and plants	Amanita muscaria and A. pantherina, henbane, jimson weed, nightshade	Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors	Physiologic stimulation (Table 470-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction.	Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and nonanticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias).
Depressed
Clonidine, guanabenz, tetrahydrozoline and other imidazoline decongestants, tizanidine and other imidazoline muscle relaxants	Stimulation of α-adrenergic 2 receptors leading to inhibition of CNS sympathetic outflow. Activity at nonadrenergic imidazoline binding sites also contributes to CNS effects.	Physiologic depression (Table 470-2), miosis. Transient initial hypertension may be seen.
Chlorpromazine, clozapine, haloperidol, risperidone, thioridazine	Inhibition of α-adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. Some agents also inhibit sodium, potassium, and calcium channels.	Physiologic depression (Table 470-2), miosis, anticholinergic effects (see above), extrapyramidal reactions (see below), tachycardia. Cardiac conduction delays (increased PR, QRS, JT, and QT intervals) with ventricular tachydysrhythmias, including torsades des pointes, can sometimes develop.