Toxicology

01 Toxicology Principles

Medical toxicology applies pharmacokinetic and pharmacodynamic principles to the unique context of overdose, where drug concentrations far exceed therapeutic ranges. Dose-response relationships in poisoning are often non-linear: at supratherapeutic doses, metabolic pathways saturate, protein binding sites are overwhelmed, and elimination shifts from first-order to zero-order (saturation) kinetics, meaning the body eliminates a fixed amount per unit time rather than a fixed fraction.

Pharmacokinetics in Overdose

Enhanced Elimination — Overview

When endogenous clearance is overwhelmed, extracorporeal or pharmacological methods can accelerate drug removal. The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup provides evidence-based recommendations for when to initiate dialysis in poisoning.

Key Dose-Response Concepts

The toxic dose varies by substance and patient factors (age, hepatic/renal function, co-ingestants, tolerance). LD50 (lethal dose for 50% of a population) is a research metric with limited bedside utility. MLD (minimum lethal dose) is more clinically relevant. For acetaminophen, the toxic threshold is generally ≥150 mg/kg in a single ingestion. For many substances, the dose-response curve becomes sigmoidal — once a threshold is exceeded, toxicity escalates rapidly. Co-ingestants frequently shift dose-response curves leftward (lower threshold) through pharmacokinetic or pharmacodynamic interactions.

Initial Assessment of the Poisoned Patient

The approach to the undifferentiated poisoned patient follows a structured framework: 1. Stabilize: ABCs, IV access, cardiac monitoring, pulse oximetry. 2. Identify the toxidrome: vital signs, pupil size, skin moisture, bowel sounds, mental status, neuromuscular exam (tone, reflexes, clonus). 3. Obtain history: substance, dose, time, route, intent (accidental vs intentional), co-ingestants, medication list, past psychiatric history. 4. Targeted labs: BMP (AG, glucose, renal function), LFTs, APAP level, salicylate level, ethanol level, VBG/ABG, lactate, osmolality (for OG), pregnancy test, ECG (QRS/QTc), urinalysis (crystals, fluorescence under Wood lamp for EG). Urine drug screens (UDS) are of limited clinical utility — they have a high false-positive and false-negative rate, detect drug classes rather than specific agents, and should never delay empiric treatment.

Anion Gap & Osmolar Gap

02 Toxidrome Recognition

A toxidrome is a constellation of signs and symptoms that suggests a specific class of poisoning. Rapid toxidrome identification narrows the differential and directs empiric therapy before laboratory confirmation. The five classic toxidromes plus serotonin syndrome and neuroleptic malignant syndrome form the foundation of clinical toxicology assessment.

Classic Toxidromes

Anticholinergic Mnemonic

Cholinergic Mnemonics

Serotonin Syndrome — Hunter Criteria

Serotonin syndrome requires exposure to a serotonergic agent PLUS at least one of the following:

Treatment: Discontinue serotonergic agents. Benzodiazepines for agitation. Cyproheptadine 12 mg load PO, then 4 mg PO q6h (serotonin antagonist). Active cooling for hyperthermia. Avoid antipyretics (hyperthermia is muscular, not hypothalamic). Severe cases may require intubation and paralysis with non-depolarizing agents.

Neuroleptic Malignant Syndrome (NMS)

NMS results from dopaminergic blockade (antipsychotics, metoclopramide, or abrupt withdrawal of dopaminergic agents in Parkinson disease). Cardinal features: hyperthermia (often > 40°C), lead-pipe rigidity, altered mental status, autonomic instability (tachycardia, labile BP, diaphoresis). Labs: CK markedly elevated (often > 1000 U/L), leukocytosis, metabolic acidosis, elevated LDH and transaminases. Develops over days (slower onset than serotonin syndrome).

Treatment: Stop offending agent, aggressive IV fluids, active cooling, dantrolene 1–2.5 mg/kg IV q6h (skeletal muscle relaxant), bromocriptine 2.5 mg PO TID (dopamine agonist). Monitor CK and renal function for rhabdomyolysis.

Differentiating Serotonin Syndrome vs NMS vs Anticholinergic

03 Terminology & Abbreviations

Foundational toxicology abbreviations used throughout this reference. A comprehensive master list is provided in Section 30.

04 Decontamination

GI decontamination aims to reduce absorption of ingested toxins. The window for efficacy is narrow, and interventions must be weighed against aspiration risk, patient cooperation, and substance identity. No decontamination method has been shown in randomized trials to improve clinical outcomes, so decisions are made based on the toxicity of the ingested substance and the time since ingestion.

Activated Charcoal (AC)

Dose: 1 g/kg (adult typical dose 50–100 g) as a single dose. Most effective when given within 1–2 hours of ingestion, though may be considered later for substances with delayed absorption (extended-release formulations, anticholinergic agents that slow GI motility).

Multiple-Dose Activated Charcoal (MDAC)

MDAC (25–50 g q2–4h) enhances elimination of substances that undergo enterohepatic recirculation or have prolonged GI absorption. Proven benefit for: carbamazepine, dapsone, phenobarbital, quinine, and theophylline. Requires a protected airway and active bowel sounds. Sorbitol should be given with only the first dose to avoid electrolyte disturbances.

Whole Bowel Irrigation (WBI)

GoLYTELY (polyethylene glycol electrolyte solution) at 1.5–2 L/hr via NG tube in adults (500 mL/hr in children) until rectal effluent is clear. Indications: body packers (drug-filled packets), sustained-release or enteric-coated preparations, iron or lithium ingestion (not adsorbed by charcoal), late presentations where charcoal is no longer effective. Contraindications: bowel obstruction, perforation, ileus, hemodynamic instability, unprotected airway.

Gastric Lavage

Rarely indicated in modern practice. Considered only within 1 hour of a life-threatening ingestion when charcoal alone is insufficient. Requires intubation for airway protection if mental status is depressed. Large-bore orogastric tube (36–40 Fr in adults). Complications: aspiration, esophageal perforation, laryngospasm, electrolyte disturbances. Not recommended routinely — American Academy of Clinical Toxicology/European Association of Poisons Centres position statement (2004).

Syrup of Ipecac

No longer recommended in any setting. Removed from OTC shelves in 2010. Induces vomiting via local gastric irritation and CTZ stimulation but offers no proven outcome benefit, delays definitive care, and poses aspiration risk. Not recommended by AAP, AACT, or EAPCCT.

05 Enhanced Elimination

Urinary Alkalinization

Sodium bicarbonate infusion (150 mEq NaHCO3 in 1 L D5W at 200–250 mL/hr) targeting urine pH 7.5–8.0. Ion trapping of weak acids in the renal tubule prevents reabsorption and enhances excretion. Effective for:

Hemodialysis

Hemodialysis removes toxins by diffusion across a semipermeable membrane. Ideal properties for dialyzable substances: MW < 500 Da, Vd < 1 L/kg, protein binding < 80%, water soluble. EXTRIP-recommended indications:

Other Modalities

CRRT (continuous renal replacement therapy): used when intermittent HD is not tolerated hemodynamically. Lower clearance rates but continuous removal; useful for lithium (prevents rebound). Exchange transfusion: rarely used; may be considered for severe methemoglobinemia in infants or massive hemolysis. ECMO: bridge therapy for refractory cardiotoxicity from beta-blockers, calcium channel blockers, or TCA poisoning when conventional vasopressors and antidotes fail.

Charcoal Hemoperfusion

Blood is passed over a charcoal cartridge that directly adsorbs toxin. Historically used for theophylline and carbamazepine, but largely replaced by standard intermittent HD due to availability, cost, and fewer complications (charcoal hemoperfusion causes thrombocytopenia, hypocalcemia, and cartridge saturation). May still be considered when HD is insufficient for large molecular weight or highly protein-bound substances.

Practical Considerations for Dialysis in Poisoning

06 Acetaminophen Toxicity

Acetaminophen (APAP) is the most common cause of acute liver failure in the United States and the most frequent drug involved in intentional overdose. At therapeutic doses, APAP is metabolized primarily by glucuronidation (40%) and sulfation (20–40%). A small fraction (< 5%) is oxidized by CYP2E1 to the reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine), which is rapidly detoxified by glutathione. In overdose, glucuronidation and sulfation pathways saturate, shunting more drug through CYP2E1. Glutathione stores deplete when < 30% of normal, and unconjugated NAPQI binds hepatocyte proteins, causing centrilobular necrosis.

Rumack-Matthew Nomogram

Phases of Acetaminophen Toxicity

N-Acetylcysteine (NAC) Protocols

NAC is nearly 100% effective at preventing hepatotoxicity when started within 8 hours of ingestion. Efficacy decreases with later initiation but NAC still provides benefit even in established hepatotoxicity (improved outcomes in ALF). Two-bag modified IV protocols (300 mg/kg over 20–21 hours) are increasingly used to reduce anaphylactoid reactions associated with the rapid first infusion.

NAC Anaphylactoid Reaction Management

Anaphylactoid reactions to IV NAC occur in 10–20% of patients, most commonly during the first (loading) infusion. These are non-IgE-mediated histamine release reactions, NOT true anaphylaxis. Risk factors: low initial APAP level (drug not present to bind NAC), history of asthma or atopy, rapid infusion rate. Management: stop the infusion temporarily, administer diphenhydramine 25–50 mg IV and/or ondansetron 4 mg IV for nausea. For bronchospasm: inhaled albuterol. For severe reactions: epinephrine 0.3 mg IM. Restart the infusion at a slower rate once symptoms resolve. NAC should NOT be permanently discontinued for anaphylactoid reactions in patients who need it — the risk of untreated APAP toxicity far outweighs the risk of the infusion reaction.

Repeated Supratherapeutic Ingestion (RSI)

Chronic or repeated supratherapeutic APAP ingestion cannot be plotted on the Rumack-Matthew nomogram. Risk assessment relies on: APAP level (any detectable level with symptoms warrants NAC), AST/ALT (if elevated, start NAC regardless of APAP level), and clinical risk factors (chronic alcohol use, CYP2E1 inducers, malnutrition/glutathione depletion, fasting). Start NAC if APAP level > 20 mcg/mL or if AST is elevated. Continue NAC until APAP is undetectable and AST is trending down or normal.

King's College Criteria — Liver Transplant Referral

Massive Ingestion (> 500 mg/kg)

Very large ingestions may overwhelm standard NAC dosing. Features suggesting massive ingestion: very early (< 4 hours) metabolic acidosis, markedly elevated lactate, early coma, initial APAP level > 500 mcg/mL. Consider doubling the NAC infusion rate and early nephrology consultation for possible hemodialysis (APAP is dialyzable, MW 151 Da, Vd 0.9 L/kg, low protein binding). Extended-release APAP may have a second peak; check a second level at 8–10 hours.

07 Salicylate Toxicity

Salicylate poisoning produces a characteristic mixed acid-base disturbance: early respiratory alkalosis (direct stimulation of the medullary respiratory center) followed by anion gap metabolic acidosis (uncoupling of oxidative phosphorylation, accumulation of organic acids). The combination of respiratory alkalosis + AG metabolic acidosis on ABG is nearly pathognomonic for salicylate toxicity.

Clinical Features by Severity

The Done nomogram is historically referenced but has significant limitations and is no longer recommended for clinical decision-making. Unlike the Rumack-Matthew nomogram, it does not reliably predict toxicity, particularly for chronic ingestions. Serial levels and clinical status are more useful.

Treatment

Chronic Salicylate Toxicity

Chronic salicylate poisoning occurs in elderly patients on long-term aspirin therapy with declining renal function, or those inadvertently taking multiple salicylate-containing products. It is far more dangerous than acute ingestion because: the drug has already distributed into the CNS, serum levels may be only moderately elevated (30–60 mg/dL) despite severe clinical toxicity, and diagnosis is frequently delayed (average 72 hours from symptom onset to correct diagnosis). Presentation mimics sepsis or encephalopathy: confusion, tachypnea, tachycardia, fever, and metabolic acidosis. Mortality in chronic salicylism is 25% compared to < 2% in acute ingestion, largely due to diagnostic delay. Maintain a high index of suspicion in elderly patients with unexplained AG metabolic acidosis and altered mental status. Treatment is the same as for acute toxicity, but thresholds for hemodialysis are lower: consider dialysis for any chronic poisoning with neurologic symptoms regardless of level.

08 NSAID & COX-2 Overdose

NSAID overdose is generally benign in most cases. The majority of patients develop only mild GI symptoms (nausea, vomiting, epigastric pain) and recover with supportive care alone. Serious toxicity is rare but may include seizures, renal failure, and metabolic acidosis with massive ingestion.

Specific NSAID Considerations

Treatment is supportive: IV fluids, GI decontamination with activated charcoal if presenting within 1–2 hours of a potentially significant ingestion, benzodiazepines for seizures, and monitoring renal function. Most patients can be observed for 4–6 hours and discharged if asymptomatic with normal labs.

Renal Complications of NSAID Overdose

NSAIDs inhibit prostaglandin-mediated afferent arteriolar vasodilation, reducing renal blood flow. In overdose, acute kidney injury may develop within 24–72 hours, particularly in patients with pre-existing renal impairment, volume depletion, or concurrent ACE inhibitor/ARB use. Monitor BUN, creatinine, and urine output in all significant NSAID ingestions. Interstitial nephritis (typically with chronic use rather than acute overdose) presents with eosinophiluria, pyuria, and renal failure; may require corticosteroids. Renal papillary necrosis is a complication of chronic NSAID abuse rather than acute overdose. Treatment of NSAID-induced AKI: discontinue the NSAID, aggressive IV hydration with isotonic crystalloid, avoid further nephrotoxins, and monitor electrolytes (hyperkalemia from reduced potassium secretion is a risk).

Observation and Disposition

09 Opioid Overdose

Opioid overdose presents with the classic triad: CNS depression, respiratory depression, and miosis (pinpoint pupils). It remains the leading cause of poisoning death in the United States. The rise of illicitly manufactured fentanyl has dramatically altered the epidemiology and clinical course of opioid overdose.

Naloxone (Narcan)

Duration Mismatch & Renarcotization

Naloxone has a shorter duration of action (30–90 minutes) than most opioids. Renarcotization occurs when naloxone wears off while the opioid remains active. This is particularly dangerous with:

Chest Wall Rigidity — Fentanyl Analogues

Rapid IV administration of potent synthetic opioids (fentanyl, sufentanil, carfentanil) can cause wooden chest syndrome — severe truncal and chest wall rigidity making bag-mask ventilation impossible. Treatment: naloxone (high dose, 2–10 mg), and if ventilation cannot be achieved, succinylcholine 1–2 mg/kg IV or rocuronium 1 mg/kg IV followed by endotracheal intubation.

Complications of Opioid Overdose

Naloxone Infusion

For opioids with long duration of action (methadone, extended-release preparations), a continuous naloxone infusion may be necessary. Protocol: calculate 2/3 of the initial bolus dose that achieved adequate respirations and infuse that amount per hour. Example: if 2 mg IV was the effective bolus, infuse ~1.3 mg/hr (2/3 of 2 mg). Titrate to maintain RR ≥12 and adequate tidal volume. Monitor for renarcotization if infusion rate is too low, and for withdrawal symptoms (agitation, vomiting, diarrhea, tachycardia) if rate is too high.

10 Tricyclic Antidepressant Poisoning

TCAs (amitriptyline, nortriptyline, imipramine, desipramine) remain among the most lethal medications in overdose. Toxicity results from three primary mechanisms: sodium channel blockade (cardiac conduction delays), anticholinergic effects, and alpha-1 adrenergic blockade (hypotension). Death typically occurs from refractory ventricular arrhythmias or cardiovascular collapse.

ECG Findings — Critical for Risk Stratification

Treatment

Additional TCA Management

Observation: patients with TCA overdose require continuous cardiac monitoring for a minimum of 6 hours after the last abnormal ECG finding. If ECG is normal at 6 hours post-ingestion and patient is asymptomatic, the risk of subsequent cardiac toxicity is very low. Mental status changes alone (without ECG abnormalities) may persist longer due to anticholinergic effects and do not necessarily mandate prolonged cardiac monitoring.

11 Lithium Toxicity

Lithium has a narrow therapeutic index (0.6–1.2 mEq/L). Toxicity patterns differ significantly between acute ingestion (lithium-naive patient or single large ingestion) and chronic toxicity (gradual accumulation in a patient on lithium therapy). Chronic toxicity is more dangerous because lithium has already equilibrated into the CNS.

Acute vs Chronic Lithium Toxicity

Severity Classification

ECG Findings in Lithium Toxicity

Lithium affects cardiac conduction at toxic levels. Common ECG findings include: T wave flattening or inversion (most common, present in up to 30% of patients on therapeutic lithium), ST segment depression, QTc prolongation, sinus node dysfunction (sinus bradycardia, sinoatrial block — lithium concentrates in the sinus node), and rarely first-degree AV block. Severe toxicity can cause complete heart block and ventricular arrhythmias. The Brugada-like pattern (ST elevation in V1–V3) has been reported with lithium toxicity and resolves with treatment. All patients with suspected lithium toxicity should receive continuous cardiac monitoring. Pre-existing cardiac disease and electrolyte abnormalities (hyponatremia, hypokalemia) increase the risk of lithium-induced arrhythmias.

Drug Interactions Precipitating Lithium Toxicity

SILENT Syndrome

The Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) describes persistent cerebellar dysfunction (ataxia, dysmetria, nystagmus, cognitive impairment) that persists after lithium levels normalize. Risk factors: prolonged exposure to toxic levels, chronic toxicity, delayed dialysis initiation, concurrent neuroleptic use. There is no specific treatment; deficits may be permanent.

Treatment

Fluid resuscitation: aggressive NS (lithium is handled like sodium by the kidney; volume depletion increases reabsorption). Hemodialysis indications: level > 4 mEq/L, significant neurologic symptoms regardless of level, renal impairment (cannot eliminate lithium), level > 2.5 mEq/L with symptoms and renal impairment. Check levels 6 hours post-dialysis — rebound is common and may necessitate repeat dialysis. Avoid: NSAIDs (reduce lithium clearance by 15–20%), ACE inhibitors, thiazide diuretics — all increase lithium reabsorption and worsen toxicity. Activated charcoal does NOT bind lithium.

12 SSRI/SNRI & Serotonin Syndrome

SSRIs (fluoxetine, sertraline, citalopram, escitalopram, paroxetine, fluvoxamine) and SNRIs (venlafaxine, duloxetine, desvenlafaxine) in isolated overdose are generally less toxic than TCAs, but they can cause serotonin syndrome, especially in combination with other serotonergic agents. Citalopram is notable for dose-dependent QTc prolongation.

Serotonin Syndrome — Hunter Criteria (Full Enumeration)

Prerequisite: exposure to a serotonergic agent within the past 5 weeks (includes MAOIs, SSRIs, SNRIs, TCAs, tramadol, fentanyl, dextromethorphan, linezolid, St. John's wort, tryptophan, MDMA, lithium, ondansetron, metoclopramide). Diagnosis requires meeting at least ONE of the following criteria:

Treatment of Serotonin Syndrome

Mild: Discontinue serotonergic agents, observation, benzodiazepines for agitation. Moderate: Cyproheptadine 12 mg PO load, then 4 mg PO q6h (up to 32 mg/day); benzodiazepines; active cooling for T > 38.5°C. Severe: ICU admission, intubation and sedation with benzodiazepines, neuromuscular paralysis with non-depolarizing agent (vecuronium/rocuronium) for refractory hyperthermia, aggressive IV cooling, cyproheptadine (may need NG tube). Avoid succinylcholine (hyperkalemia risk from rhabdomyolysis). Antipyretics are ineffective because hyperthermia is muscular in origin, not hypothalamic.

Specific SSRI/SNRI Agent Toxicity Profiles

NMS vs Serotonin Syndrome vs Anticholinergic Toxicity

See the differential table in Section 2. Key distinguishing features: serotonin syndrome has clonus (especially lower extremity) with hyperreflexia; NMS has lead-pipe rigidity with bradyreflexia; anticholinergic toxicity has dry skin and urinary retention. Serotonin syndrome develops over hours; NMS develops over days.

13 Antipsychotic Overdose

Antipsychotic toxicity differs between first-generation (typical) and second-generation (atypical) agents. All antipsychotics share dopamine D2 receptor antagonism; toxicity profiles diverge based on additional receptor pharmacology.

First vs Second Generation

QTc Prolongation & Torsades de Pointes Management

Neuroleptic Malignant Syndrome (NMS)

See Section 2 for full discussion. Treatment: stop offending agent, dantrolene 1–2.5 mg/kg IV q6h (maximum 10 mg/kg/day), bromocriptine 2.5 mg PO/NG TID, aggressive cooling, IV fluids, monitor CK and renal function. Mortality 5–20% even with treatment.

Extrapyramidal Symptoms (EPS)

Specific Agent Considerations

14 Methanol & Ethylene Glycol

The toxic alcohols (methanol, ethylene glycol) are relatively non-toxic as parent compounds — their danger lies in their metabolites, produced by alcohol dehydrogenase (ADH). The diagnostic hallmark is a combination of elevated osmolar gap (early, before metabolism) and elevated anion gap metabolic acidosis (later, as metabolites accumulate). The osmolar gap and anion gap are inversely related over time.

Osmolar Gap Calculation

Methanol

Sources: windshield washer fluid, industrial solvents, illicit spirits (moonshine). Methanol is metabolized by ADH to formaldehyde, then by aldehyde dehydrogenase to formic acid. Formic acid causes: optic nerve toxicity (visual blurring, scotomata, blindness — "snowfield vision"), basal ganglia necrosis (putaminal hemorrhage on CT), and profound AG metabolic acidosis. Latency period of 12–24 hours before symptom onset (longer if ethanol co-ingested). The minimum lethal dose is approximately 1 mL/kg of pure methanol (15–30 mL can be fatal without treatment).

Methanol Clinical Staging

Ethylene Glycol

Sources: antifreeze (sweet taste → accidental pediatric ingestion), coolants. Metabolized by ADH to glycolaldehyde → glycolic acid (major contributor to acidosis) → glyoxylic acid → oxalic acid. Oxalic acid binds calcium → calcium oxalate crystals (needle-shaped or envelope-shaped on urinalysis, deposited in renal tubules → acute renal failure). Also causes hypocalcemia (ionized calcium drop from oxalate binding), cranial nerve palsies, and myocardial depression.

Treatment

15 Ethanol & Isopropanol

Acute Ethanol Intoxication

Management is primarily supportive: airway protection, glucose (check fingerstick — hypoglycemia is common, especially in children and malnourished adults), volume resuscitation, electrolyte correction, and observation until clinically sober. Serum ethanol levels do not reliably predict clinical status in chronic drinkers (tolerance). Life-threatening levels in non-tolerant adults generally > 400 mg/dL.

Wernicke Encephalopathy

Ethanol Toxicity by Blood Alcohol Concentration

Alcoholic Ketoacidosis (AKA)

Occurs in chronic alcoholics after a binge followed by vomiting and poor intake. Presents with AG metabolic acidosis, low or normal glucose (distinguishes from DKA), elevated beta-hydroxybutyrate, positive ketones, and volume depletion. The nitroprusside test for ketones may be negative because AKA produces predominantly beta-hydroxybutyrate (not acetoacetate, which the test detects). Treatment: D5NS (dextrose stimulates insulin, shifting metabolism from ketogenesis to glucose utilization; saline repletes volume), thiamine, electrolyte correction. Resolves within 12–24 hours with fluid and dextrose. Insulin is NOT indicated.

Isopropanol (Isopropyl Alcohol)

Sources: rubbing alcohol, hand sanitizer, windshield de-icer. Isopropanol is metabolized by ADH to acetone (NOT to an acid). Key features: ketosis without acidosis (fruity breath, positive serum ketones, but normal anion gap and normal pH), CNS depression proportional to dose, GI hemorrhagic gastritis. Treatment is supportive: airway protection, fluids, GI protection. Hemodialysis for severe intoxication (level > 400 mg/dL) or refractory hypotension, though rarely needed.

16 Sympathomimetics — Cocaine, Methamphetamine, MDMA

Cocaine

Cocaine blocks reuptake of norepinephrine, dopamine, and serotonin and also directly blocks sodium channels (local anesthetic effect). Toxicity includes: hypertensive emergency, acute coronary syndrome (even in young patients with normal coronaries — vasospasm), aortic dissection, stroke, seizures, and hyperthermia. Routes of use affect onset and duration: smoked/IV (onset seconds, duration 15–30 min, highest acute risk), insufflated (onset 5–10 min, duration 60–90 min), and oral/mucosal (onset 30–60 min, slowest). Body packers ("swallowers") ingest drug-filled packets for smuggling — packet rupture can cause massive cocaine toxicity with sudden death; management includes WBI with GoLYTELY and surgical consultation for obstructing or leaking packets.

Cocaine-Associated Rhabdomyolysis

Cocaine causes rhabdomyolysis through multiple mechanisms: direct myotoxicity, excessive muscular activity from agitation/seizures, ischemia from vasoconstriction, and hyperthermia. CK levels often exceed 10,000–100,000 IU/L. Management: aggressive IV crystalloid resuscitation targeting urine output 200–300 mL/hr, monitor for hyperkalemia and acute kidney injury, and consider NaHCO3 for urine alkalinization (target urine pH > 6.5) to prevent myoglobin precipitation in renal tubules.

Methamphetamine

Sympathomimetic toxidrome plus serotonergic effects at high doses. Longer duration than cocaine (half-life 10–12 hours vs 1 hour). Unique complications: severe dental decay ("meth mouth"), skin excoriations from parasitosis delusions ("crank bugs"), pulmonary hypertension with chronic use, cardiomyopathy. Treatment: benzodiazepines for agitation and sympathomimetic symptoms, active cooling for hyperthermia, antihypertensives as needed. Serotonin syndrome may occur with massive doses.

MDMA (Ecstasy/Molly)

MDMA causes massive serotonin release plus sympathomimetic effects. Three life-threatening complications: hyperthermia (serotonin syndrome mechanism — can reach 42°C, often in setting of exertion + warm environment), hyponatremia (SIADH + excessive free water intake — can cause cerebral edema, seizures, death), and serotonin syndrome. Treatment: aggressive cooling (evaporative, ice packs; dantrolene if rigid), benzodiazepines, cyproheptadine for serotonin syndrome, hypertonic saline (3% NaCl 100–150 mL bolus) for symptomatic hyponatremia with seizures.

Bath Salts (Synthetic Cathinones)

Mephedrone, methylone, MDPV — produce a combined sympathomimetic/serotonergic toxidrome. Excited delirium is a hallmark: extreme agitation, hyperthermia, diaphoresis, paranoia, superhuman strength, and sudden cardiac arrest. Treatment: aggressive sedation with benzodiazepines (large doses often required — diazepam 40–80 mg or midazolam 20–40 mg total), active cooling, IV fluids, ketamine 4 mg/kg IM for refractory agitation.

17 Cannabis, Hallucinogens & Novel Substances

Cannabinoid Hyperemesis Syndrome (CHS)

Cyclic vomiting in chronic cannabis users (typically daily use for ≥1 year). Classic features: severe episodic nausea/vomiting, relief with hot showers/baths (pathognomonic behavior), diffuse abdominal pain. Diagnosis of exclusion. Treatment: cessation of cannabis (only definitive therapy), topical capsaicin 0.075% cream applied to the abdomen (activates TRPV1 receptors, paradoxically relieves symptoms), haloperidol 5 mg IV (superior to ondansetron in studies), IV fluids.

Synthetic Cannabinoids (K2/Spice)

Full agonists at CB1/CB2 receptors (unlike THC, which is a partial agonist) — much more potent and dangerous than natural cannabis. Effects: severe agitation, psychosis, seizures, tachycardia, hypertension, acute kidney injury (some formulations), coagulopathy (brodifacoum-contaminated batches — treat with vitamin K). Treatment: benzodiazepines, supportive care.

PCP (Phencyclidine)

NMDA receptor antagonist. Produces dissociative state with: vertical nystagmus (nearly pathognomonic), agitation, violence, analgesia (may not respond to pain compliance), rhabdomyolysis, seizures, hyperthermia. Treatment: benzodiazepines for agitation and seizures, physical restraint with caution (risk of death from rhabdomyolysis with prolonged struggle), active cooling, IV fluids for rhabdomyolysis, monitor CK and renal function.

Other Substances

18 Carbon Monoxide Poisoning

Carbon monoxide (CO) binds hemoglobin with 240× the affinity of oxygen, forming carboxyhemoglobin (COHb) and shifting the oxyhemoglobin dissociation curve leftward (impaired O2 unloading to tissues). CO also binds myoglobin and mitochondrial cytochrome oxidase, directly impairing cellular respiration. Sources: house fires (most common), space heaters, car exhaust in enclosed garages, charcoal grills indoors, gas-powered generators, propane-powered forklifts, and methylene chloride (paint stripper — metabolized to CO in the liver, causing delayed and prolonged COHb elevation).

COHb Levels and Symptoms

Cherry-red skin is classically described but is an unreliable and late finding, more often seen postmortem. Pulse oximetry is unreliable in CO poisoning — COHb is read as oxyhemoglobin by standard pulse oximeters, showing falsely normal SpO2. Co-oximetry (ABG with co-oximetry) is required.

CO Elimination Half-Lives

HBO Indications

Evidence is mixed, but generally accepted indications include: loss of consciousness (at any time during exposure), COHb > 25% (some use > 20%), pregnancy (fetal hemoglobin has higher CO affinity), cardiac ischemia or arrhythmia, persistent neurologic symptoms despite 100% O2, and severe metabolic acidosis. HBO may reduce delayed neuropsychiatric sequelae (DNS — cognitive impairment, personality changes, parkinsonian features appearing 2–40 days after exposure).

Delayed Neuropsychiatric Sequelae (DNS)

DNS affects 10–30% of CO-poisoned patients, typically presenting 2–40 days after apparent recovery. Features include: cognitive impairment (memory deficits, difficulty concentrating), personality changes (irritability, depression), parkinsonian features (gait disturbance, masked facies), and demyelination visible on MRI (periventricular white matter changes, globus pallidus lesions). Risk factors for DNS: loss of consciousness during exposure, COHb > 25%, age > 36, prolonged exposure duration. HBO therapy may reduce DNS incidence, though evidence remains debated. There is no specific treatment once DNS develops; symptoms may partially resolve over months but can be permanent in up to 25% of affected patients.

Special Populations in CO Poisoning

Methemoglobinemia

While not strictly CO poisoning, methemoglobinemia is an important environmental/drug-induced hemoglobinopathy. Methemoglobin (Fe3+) cannot bind oxygen. Causes: dapsone, benzocaine/lidocaine (topical anesthetics), nitrites, aniline dyes, nitrobenzene. Symptoms correlate with MetHb level: <15% typically asymptomatic; 15–20% chocolate-brown blood (does not turn red with O2 exposure), cyanosis unresponsive to supplemental O2; 20–50% dyspnea, headache, tachycardia; >50% seizures, coma, cardiovascular collapse; >70% lethal. Treatment: methylene blue 1–2 mg/kg IV over 5 minutes (acts as electron carrier, reducing MetHb to Hb via NADPH-methemoglobin reductase). Contraindicated in G6PD deficiency (causes hemolytic crisis). Pulse oximetry is unreliable — tends to read ~85% regardless of actual saturation at high MetHb levels.

19 Organophosphate & Nerve Agent Poisoning

Organophosphates (OPs) irreversibly inhibit acetylcholinesterase (AChE), causing accumulation of acetylcholine at muscarinic, nicotinic, and CNS synapses. Sources: agricultural pesticides (malathion, parathion, chlorpyrifos), nerve agents (sarin, VX, novichok). The OP-AChE bond "ages" over time (hours to days depending on agent), becoming irreversible and resistant to oxime reactivation.

Clinical Presentation — Cholinergic Crisis

Muscarinic effects (SLUDGE/DUMBBELSS — see Section 2): salivation, lacrimation, urination, defecation, GI cramping, emesis, bronchospasm, bronchorrhea, miosis, bradycardia. Nicotinic effects: fasciculations, muscle weakness, paralysis (including respiratory muscles), tachycardia, hypertension. CNS effects: anxiety, seizures, coma, central apnea.

Intermediate Syndrome

Occurs 24–96 hours after acute exposure, after initial cholinergic crisis has resolved. Characterized by weakness of proximal muscles, neck flexors, respiratory muscles, and cranial nerve-innervated muscles. Mechanism: persistent AChE inhibition at nicotinic junctions. May require prolonged ventilatory support. Not prevented by atropine or pralidoxime.

Organophosphate-Induced Delayed Neuropathy (OPIDN)

Occurs 1–3 weeks after exposure. Distal sensorimotor polyneuropathy from inhibition of neuropathy target esterase (NTE). Presents as stocking-glove numbness progressing to weakness and ataxia. May be permanent. Not prevented by antidotes.

Treatment

Carbamate vs Organophosphate Poisoning

20 Heavy Metals

Lead Poisoning

Arsenic Poisoning

Acute: profuse watery diarrhea ("rice water"), abdominal pain, hypotension, multi-organ failure, QTc prolongation. Chronic: Mees lines (transverse white lines on nails), peripheral neuropathy, skin changes (rain-drop pattern hyperpigmentation, keratoses), increased cancer risk (lung, bladder, skin). Diagnosis: 24-hour urine arsenic (> 50 mcg/L is elevated; specify inorganic arsenic — seafood causes false elevation). Treatment: BAL (dimercaprol) 3–5 mg/kg IM q4h for severe acute poisoning, then transition to succimer (DMSA) PO for continued chelation. Unithiol (DMPS) is an alternative chelator.

Mercury

Iron Poisoning

Ingestion of ≥20 mg/kg elemental iron is potentially toxic; ≥60 mg/kg is potentially lethal. Five stages:

Treatment: WBI for large ingestions (iron not adsorbed by charcoal). Deferoxamine 15 mg/kg/hr IV (maximum 6–8 g/day) for serum iron > 500 mcg/dL, significant symptoms, or clinical deterioration. Classic finding: "vin rosé" urine (pinkish-orange discoloration from ferrioxamine complex). Stop deferoxamine when urine color normalizes, symptoms resolve, and AG closes.

Thallium

Colorless, odorless, tasteless — historically used as rat poison and in homicides. Presents with GI symptoms followed by painful ascending neuropathy and alopecia (7–14 days post-ingestion, pathognomonic). Treatment: Prussian blue (ferric hexacyanoferrate) 250 mg/kg/day PO in divided doses — binds thallium in the GI tract and interrupts enterohepatic recirculation. MDAC may augment elimination.

21 Envenomation

Pit Viper (Crotalid) Envenomation

Rattlesnakes, copperheads, and cottonmouths account for >95% of venomous snakebites in the US. Venom contains hemotoxins, cytotoxins, and myotoxins causing local tissue destruction, coagulopathy (thrombocytopenia, hypofibrinogenemia, elevated PT/INR), and compartment syndrome.

Coral Snake

Elapid envenomation with neurotoxic venom (postsynaptic nicotinic acetylcholine receptor blockade). Delayed toxicity is the hallmark — symptoms may not appear for 6–18 hours but then progress rapidly to bulbar weakness, diplopia, dysphagia, and respiratory paralysis. Once paralysis develops it is NOT reversible with antivenom. Antivenom (Pfizer Coral Snake Antivenin) must be given prophylactically if a confirmed coral snake bite with fang marks is identified, even if asymptomatic. 4–6 vials IV. Red-on-yellow rule (North America only): "red on yellow, kill a fellow; red on black, venom lack."

Spider & Scorpion Envenomation

Marine Envenomation

Box jellyfish (Chironex fleckeri): tentacle contact causes excruciating pain, cardiovascular collapse, and death within minutes in severe cases. Remove tentacles with vinegar rinse (inactivates undischarged nematocysts). Antivenom available in Australia. Stonefish: intense pain from dorsal spine envenomation; hot water immersion (45°C for 30–90 minutes) denatures heat-labile toxin; stonefish antivenom for severe cases. General principle: hot water immersion for most marine stings (denatures thermolabile proteins in venom).

Snakebite Management Pearls

22 Caustic Ingestions

Caustic ingestion causes direct chemical injury to the GI mucosa. Alkalis (pH > 12: NaOH, KOH, bleach, drain cleaners, button batteries) cause liquefactive necrosis — deep penetrating injury through esophageal wall. Acids (pH < 2: HCl, H2SO4, battery acid) cause coagulative necrosis — eschar formation limits depth of penetration; preferentially injure the stomach (acid passes quickly through the esophagus due to taste). Alkalis are generally more dangerous to the esophagus; acids to the stomach.

Critical Management Principles

Zargar Classification (Endoscopic)

Endoscopy timing: within 12–24 hours of ingestion (ideally within 12 hours). Avoid between 5–15 days post-ingestion (highest perforation risk due to weakened tissue). Grade IIb and higher require ICU admission, surgical consultation, and close monitoring for perforation. Long-term complications include esophageal stricture (may require repeated dilation or esophageal replacement), increased lifetime risk of esophageal squamous cell carcinoma (1000-fold increased risk with alkali injury), and pyloric stenosis after acid ingestion.

Specific Caustic Agents

Button Battery Ingestion

23 Cardiac Drug Toxicity

Beta-Blocker Overdose

Presents with bradycardia, hypotension, heart block, and hypoglycemia (especially propranolol). Propranolol also causes sodium channel blockade (QRS widening) and seizures. CNS-penetrant agents (propranolol, labetalol) are most lethal.

Calcium Channel Blocker Overdose

Dihydropyridine CCBs (nifedipine, amlodipine) cause vasodilation with reflex tachycardia. Non-dihydropyridine CCBs (verapamil, diltiazem) cause bradycardia, heart block, and negative inotropy. Both cause severe hypotension and hyperglycemia (blocked pancreatic insulin release) in overdose.

Digoxin Toxicity

Classic features: GI (nausea, vomiting, anorexia), visual disturbances (yellow-green halos — xanthopsia), and nearly any arrhythmia (classically atrial tachycardia with AV block or bidirectional VT). Hyperkalemia is a marker of severity (Na/K-ATPase inhibition prevents cellular K+ uptake).

Sodium Channel Blocker Toxicity (General)

Drugs with sodium channel blocking properties: TCAs, cocaine, class IA/IC antiarrhythmics (flecainide, procainamide), propranolol, diphenhydramine, carbamazepine, lamotrigine. ECG hallmark: QRS widening. Treatment: NaHCO3 1–2 mEq/kg IV bolus (sodium loading + alkalemia), targeting QRS < 120 ms and serum pH 7.45–7.55.

Intralipid Emulsion (ILE) Therapy

24 Cyanide Poisoning

Cyanide binds mitochondrial cytochrome oxidase a3, blocking the electron transport chain and halting aerobic metabolism. Cells switch to anaerobic glycolysis, producing profound lactic acidosis despite adequate oxygen delivery (PaO2 and SaO2 are normal). Sources: house fire smoke inhalation (most common — combustion of synthetic materials), industrial (electroplating, mining, laboratories), sodium nitroprusside infusion (releases cyanide), ingestion of cyanogenic plants (bitter almonds, cassava, apricot pits).

Clinical Features

Rapid onset: headache, confusion, seizures, cardiovascular collapse, death. Classic finding: bright red venous blood (cells cannot extract oxygen → high venous PO2). Bitter almond odor (only ~50% of population can detect due to genetic variation). In fire victims, suspect cyanide when: persistent lactic acidosis despite adequate oxygen delivery, COHb-corrected lactate > 8 mmol/L, or altered mental status disproportionate to COHb level.

Cyanide Toxicity by Exposure Route

Laboratory Findings

Treatment

25 Withdrawal Syndromes

Alcohol Withdrawal

Onset 6–24 hours after last drink. Spectrum: tremulousness (6–24h) → withdrawal seizures (12–48h) → alcoholic hallucinosis (12–48h) → delirium tremens (48–96h, mortality 5–15% if untreated). Monitor with CIWA-Ar (Clinical Institute Withdrawal Assessment — Alcohol, revised) — scores nausea, tremor, paroxysmal sweats, anxiety, agitation, tactile/auditory/visual disturbances, headache, orientation. CIWA ≥8 triggers treatment; ≥20 indicates severe withdrawal.

Benzodiazepine Withdrawal

Similar to alcohol withdrawal (both are GABA-A agonists) but more protracted. Onset depends on half-life of the specific agent: short-acting (alprazolam, lorazepam) → 1–2 days; long-acting (diazepam, clonazepam) → 3–7 days. Features: anxiety, insomnia, tremor, perceptual disturbances, seizures. Treatment: prolonged taper using a long-acting benzodiazepine (diazepam or chlordiazepoxide), reducing by 10–25% per week. Rapid cessation can be fatal.

Opioid Withdrawal

Extremely uncomfortable but rarely life-threatening (unlike alcohol/benzodiazepine withdrawal). Onset: short-acting (heroin) 8–24 hours; long-acting (methadone) 24–72 hours. Features: mydriasis (opposite of intoxication), lacrimation, rhinorrhea, yawning, diarrhea, piloerection ("goosebumps"), myalgias, abdominal cramps, insomnia. Monitor with COWS (Clinical Opiate Withdrawal Scale).

GHB Withdrawal

GHB withdrawal can be life-threatening and uniquely resistant to benzodiazepines. Onset: 1–6 hours after last use (very rapid). Features: tremor, tachycardia, hypertension, diaphoresis, psychosis, delirium, seizures. Treatment: high-dose benzodiazepines (may require enormous amounts), barbiturates (pentobarbital/phenobarbital) if refractory, propofol infusion for refractory cases. GHB withdrawal may last 5–15 days.

Baclofen Withdrawal

Abrupt discontinuation of baclofen (especially intrathecal pump failure) causes: seizures, spasticity rebound, psychosis, hyperthermia, rhabdomyolysis, and multi-organ failure mimicking NMS or malignant hyperthermia. Treatment: restart baclofen immediately (oral or via pump); benzodiazepines for seizures; cyproheptadine and dantrolene as adjuncts; ICU admission for severe cases.

Stimulant Withdrawal

Withdrawal from cocaine, amphetamines, and other stimulants is not life-threatening but causes significant dysphoria. The "crash" phase (hours to days) involves hypersomnia, increased appetite, psychomotor retardation, depression, and vivid dreams. The withdrawal phase (days to weeks) involves anhedonia, fatigue, intense cravings, and depression that may persist for months. Treatment is entirely supportive: safe environment, psychiatric evaluation for suicidal ideation, sleep hygiene, and outpatient substance use treatment referral. No pharmacotherapy has demonstrated consistent benefit for stimulant withdrawal, though modafinil and bupropion are sometimes used off-label for persistent fatigue and anhedonia.

Nicotine Withdrawal

Onset within 2–12 hours of last nicotine use. Features: irritability, anxiety, difficulty concentrating, increased appetite, insomnia, restlessness, depressed mood. Peak severity at 24–72 hours; most symptoms resolve within 2–4 weeks, but cravings may persist for months. Treatment: nicotine replacement therapy (patch, gum, lozenge, inhaler, nasal spray), varenicline (partial nicotinic agonist, most effective single agent), bupropion SR, or combination therapy. Acute nicotine poisoning (e-cigarette liquid ingestion in children) presents with cholinergic symptoms: vomiting, diarrhea, diaphoresis, followed by seizures and respiratory failure in severe cases.

Withdrawal Syndrome Comparison

26 Antidotes Master Table

27 Toxidrome Summary Table

28 Dialyzable Substances

Hemodialysis effectively removes substances that meet specific pharmacokinetic criteria. The ideal dialyzable toxin has: low molecular weight (< 500 Da, passes membrane pores easily), low volume of distribution (< 1 L/kg, drug remains in blood compartment), low protein binding (< 80%, free drug available for clearance), and high water solubility.

*Protein binding for salicylates and valproic acid is concentration-dependent; binding decreases (and free fraction increases) in overdose, making dialysis more effective than predicted from therapeutic-level pharmacokinetics.

Substances NOT Effectively Dialyzed

29 Scoring Systems

Rumack-Matthew Nomogram

Plots serum acetaminophen concentration versus time after a single, acute ingestion. The treatment line begins at 150 mcg/mL at 4 hours, 75 mcg/mL at 8 hours, 37.5 mcg/mL at 12 hours, and 4.7 mcg/mL at 24 hours (log-linear decline). Levels above the line indicate potential toxicity and warrant NAC therapy. The nomogram is valid only for: known single acute ingestion, level drawn between 4–24 hours post-ingestion, and non-extended-release formulations. It is NOT valid for chronic ingestions, staggered ingestions, unknown ingestion time, or repeated supratherapeutic ingestions (RSI) — for these, use clinical judgment, ALT/AST trends, and APAP concentration.

CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol, Revised)

COWS (Clinical Opiate Withdrawal Scale)

Poisoning Severity Score (PSS)

The PSS is applied to each organ system independently (GI, respiratory, nervous, cardiovascular, metabolic, hepatic, renal, hematologic, muscular, dermal, eyes, ears) and the overall grade is the highest grade in any system. Used primarily in clinical research, poison center data reporting, and for standardized comparison of poisoning outcomes across studies. The PSS should be scored at the time of worst clinical severity during the acute episode. It is validated for acute exposures and is endorsed by the EAPCCT and the International Programme on Chemical Safety (IPCS).

Poison Control Resources

King's College Criteria (Non-Acetaminophen ALF)

For reference, the non-acetaminophen criteria differ from acetaminophen-specific criteria (Section 6): INR > 6.5 (PT > 100 seconds) regardless of encephalopathy grade, OR any three of: age < 10 or > 40 years, non-A/non-B hepatitis or drug-induced etiology, jaundice > 7 days before encephalopathy onset, INR > 3.5, bilirubin > 17.5 mg/dL. These criteria help identify patients who should be urgently referred for liver transplant evaluation.

Glasgow Coma Scale (GCS) in Poisoning

While the GCS was developed for trauma, it is frequently used in toxicology to track mental status. A GCS ≤8 generally indicates the need for airway protection (intubation). However, GCS has limitations in poisoning: some substances cause dissociative states that confound scoring, and rapidly reversible causes (opioids with naloxone) may not require intubation despite low GCS.

Prescott Criteria for NAC Efficacy

Historically used to assess NAC treatment outcomes in APAP toxicity: AST/ALT peak values, time to peak transaminases, development of coagulopathy (INR > 1.3), and clinical encephalopathy. Patients treated with NAC within 8 hours of ingestion have < 5% risk of hepatotoxicity (AST > 1000 IU/L) and essentially 0% mortality from hepatic failure. Patients treated 16–24 hours post-ingestion still benefit from NAC, with reduced mortality and improved transplant-free survival compared to no treatment.

Severity Assessment in Common Poisonings

30 Abbreviations Master List