Clinical Toxicology, Ingestions & Antidotes Master Table

Rapid differentiation of the six classic emergency toxidromes relies on pairing autonomic vital signs with pupil diameter, skin moisture (sweat glands are sympathetic M₃ cholinergic), bowel sounds, and neuromuscular tone. Both sympathomimetic toxicity (cocaine, amphetamines, cathinones, ephedrine) and anticholinergic toxicity (diphenhydramine, atropine, jimsonweed, tricyclics) present with tachycardia, hypertension, hyperthermia, agitated delirium, and marked mydriasis; the decisive bedside discriminator is skin moisture and bowel sounds—sympathomimetic patients have profuse diaphoresis and active bowel sounds, whereas anticholinergic patients have bone-dry axillae/mucous membranes, absent bowel sounds, and urinary retention. Conversely, both opioid toxicity (fentanyl, heroin, oxycodone) and cholinergic toxicity (organophosphates, carbamates, nerve agents, Inocybe/Clitocybe muscarine mushrooms) present with pinpoint miosis and CNS/respiratory depression; however, opioid overdose causes quiet bradypnea (<8–10 breaths/min), bradycardia, hypothermia, and hypoactive bowel sounds, whereas cholinergic toxicity produces fulminant bronchorrhea, sialorrhea, lacrimation, diarrhea, and nicotinic muscle fasciculations.

Gastrointestinal decontamination and enhanced elimination protocols have specific chemical indications and strict contraindications. Single-dose activated charcoal (1 g/kg) adsorbs nonpolar, organic xenobiotics within the gastrointestinal lumen when administered within 1 to 2 hours of ingestion (requires an intact or endotracheally protected airway), but fails to bind polar/inorganic substances recalled via "PHAILS": Pesticides/Petroleum hydrocarbons/Potassium, Heavy metals (lead, mercury, arsenic), Acids/Alkalis/Alcohols (ethanol, methanol, ethylene glycol), Iron, Lithium, and Solvents. Whole-bowel irrigation with isotonic polyethylene glycol electrolyte solution is reserved for substances not bound by charcoal (iron tablets, lithium), sustained-release/enteric-coated calcium channel blocker or beta-blocker overdoses, and illicit drug "body packers." Finally, urinary alkalinization with intravenous sodium bicarbonate (targeting urine pH 7.5–8.0) exploits the Henderson-Hasselbalch equation (pH − pK_a = log([A⁻]/[HA])) to convert filtered weak acids—specifically salicylates (aspirin), phenobarbital, and methotrexate—into charged, membrane-impermeable anions (A⁻) that are trapped in the renal tubular lumen and rapidly excreted (always correcting hypokalemia first so distal tubules do not reabsorb K⁺ in exchange for H⁺, which would paradoxically acidify the urine).

For the vast majority of therapeutic drugs, hepatic/renal elimination follows first-order kinetics: metabolizing enzymes remain unsaturated ([C] ≪ K_m on Michaelis-Menten kinetics), so a constant fraction (percentage) of the drug is cleared per unit time, plasma concentration decays exponentially, and the elimination half-life (t_1/2 = (0.693 × V_d) / CL) remains constant regardless of dose. In contrast, three classic drugs—Phenytoin, Ethanol, and Aspirin (at toxic salicylate doses) ["PEA"]—saturate their hepatic metabolic enzymes ([C] ≫ K_m), shifting to capacity-limited zero-order (Michaelis-Menten) kinetics. Under zero-order kinetics, a constant amount (milligrams) of drug is eliminated per hour, plasma concentration declines linearly over time, small dose increases produce disproportionate, non-linear spikes in serum concentration, and t_1/2 progressively lengthens as plasma concentration rises. In ethanol metabolism, cytosolic alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde and mitochondrial acetaldehyde dehydrogenase (ALDH2) oxidizes acetaldehyde to acetate, both reducing NAD⁺ to NADH. The resulting high NADH/NAD⁺ ratio shunts pyruvate to lactate (lactic acidosis), oxaloacetate to malate (halting gluconeogenesis and causing fasting hypoglycemia), and dihydroxyacetone phosphate to glycerol-3-phosphate while inhibiting mitochondrial β-oxidation (causing hepatic steatosis and ketoacidosis).

Phase I hepatic biotransformation (oxidation, reduction, hydrolysis via smooth endoplasmic reticulum Cytochrome P450 hemoproteins, especially CYP3A4, CYP2D6, CYP2C9, and CYP2C19) yields slightly polar metabolites, whereas Phase II conjugation (glucuronidation, acetylation, sulfation, glutathione conjugation, methylation) appends bulky water-soluble groups for renal or biliary excretion (geriatric patients lose Phase I oxidation capacity early, making "LOT" benzodiazepines—Lorazepam, Oxazepam, Temazepam—which undergo direct Phase II glucuronidation without active metabolites, safer in older adults and cirrhosis). Potent CYP450 inducers increase nuclear receptor (PXR/CAR)-driven transcription of CYP enzymes over 7–14 days, accelerating the clearance of co-administered substrates and causing therapeutic failure (e.g., subtherapeutic INR on warfarin, breakthrough seizures, acute allograft rejection on tacrolimus/cyclosporine, or unintended pregnancy on oral contraceptives): Rifampin, Carbamazepine, Phenytoin, Phenobarbital, St. John's Wort, Chronic Ethanol, and Griseofulvin. Conversely, potent CYP450 inhibitors acutely block enzyme activity within hours, precipitating severe toxicity of narrow-therapeutic-index drugs (warfarin bleeding, phenytoin ataxia/nystagmus, theophylline seizures, statin rhabdomyolysis): Ritonavir/Cobicistat, Ketoconazole/Itraconazole/Voriconazole, Clarithromycin/Erythromycin (not azithromycin), Ciprofloxacin, TMP-SMX, Metronidazole, Amiodarone, Cimetidine (not famotidine), Grapefruit juice (intestinal CYP3A4), and Acute Ethanol binge.

Three analgesics and psychotropics account for the highest-yield emergency toxicology vignettes on licensing exams. In acetaminophen (APAP) overdose (>7.5–10 g or >150 mg/kg in adults), normal Phase II glucuronidation and sulfation pathways saturate, shunting APAP into hepatic CYP2E1 to generate the hepatotoxic electrophile N-acetyl-p-benzoquinone imine (NAPQI). Once hepatic glutathione stores fall below 30%, unquenched NAPQI covalently binds centrilobular (Zone III) hepatocyte proteins, causing fulminant hepatic necrosis at 24–72 hours after a deceptive 0–24 hour stage of mild nausea/diaphoresis. A serum APAP level plotted on the Rumack-Matthew nomogram starting at 4 hours post-ingestion guides administration of N-acetylcysteine (NAC), which replenishes cysteine for glutathione synthesis. In salicylate (aspirin) toxicity, patients develop tinnitus, hyperthermia (from mitochondrial oxidative phosphorylation uncoupling), and a pathognomonic mixed respiratory alkalosis (direct medullary respiratory center stimulation within 15–30 minutes) plus high-anion-gap metabolic acidosis (uncoupled lactic/ketoacidosis + salicylic acid), treated with IV sodium bicarbonate (urinary alkalinization) and hemodialysis if serum levels exceed 100 mg/dL or pulmonary/cerebral edema develops. In tricyclic antidepressant (amitriptyline, imipramine) overdose, patients exhibit the "3 Cs" (Coma, Convulsions, Cardiotoxicity): fast Na⁺ channel blockade widens the QRS complex (>100 ms) with a terminal R wave in aVR, necessitating immediate IV sodium bicarbonate boluses (which simultaneously provides a high extracellular Na⁺ load to overcome competitive channel blockade and alkalinizes serum pH to 7.45–7.55 to increase protein binding and favor the non-ionized unblocked drug state).

Ingestions of methanol (windshield washer fluid, moonshine) or ethylene glycol (automobile antifreeze) initially produce an elevated osmolar gap (>10 mOsm/kg) from the unmetabolized parent alcohol; as hepatic alcohol dehydrogenase (ADH) and aldehyde dehydrogenase oxidize the parent alcohol, the osmolar gap narrows while a severe high-anion-gap metabolic acidosis emerges. Methanol is metabolized to formic acid, which poisons retinal mitochondrial cytochrome oxidase to cause optic disc hyperemia, visual "snowstorm" scotomas, and permanent blindness; ethylene glycol is metabolized to glycolic and oxalic acid, which precipitates as envelope-shaped (dihydrate) or needle-shaped (monohydrate) calcium oxalate crystals in renal tubules, causing acute tubular necrosis and hypocalcemia. Both toxic alcohols are treated immediately with fomepizole (a direct competitive ADH inhibitor; ethanol is second-line), plus folinic acid/folate for methanol (enhancing formic acid clearance) or thiamine + pyridoxine for ethylene glycol, and emergent hemodialysis if end-organ damage or severe acidosis is present. In severe β-blocker overdose (bradycardia, hypotension, AV block, hypoglycemia), first-line antidotal therapy is high-dose IV glucagon (which binds cardiac G_s-coupled glucagon receptors to increase cAMP and contractility completely independent of blocked β₁ receptors). In severe calcium channel blocker overdose (bradycardia, hypotension, hyperglycemia from blocked pancreatic β-cell L-type Ca²⁺-dependent insulin exocytosis), therapy combines IV calcium, norepinephrine, and high-dose insulin euglycemia therapy (HIET). Finally, bupivacaine cardiotoxicity is rescued with 20% intravenous lipid emulsion ("lipid sink").

Heavy metal chelation therapy uses polydentate organic ligands containing sulfhydryl (-SH), carboxyl, or amine groups to form stable, water-soluble ring complexes (chelates) that can be excreted renally or biliarily. In pediatric lead (Pb²⁺) poisoning (from pre-1978 peeling lead-based paint chips, contaminated soil, or lead pipes, inhibiting δ-aminolevulinic acid [ALA] dehydratase and ferrochelatase to cause microcytic anemia with coarse basophilic stippling, elevated erythrocyte protoporphyrin, Burton gingival lead lines, metaphyseal radiographic "lead lines," and neurodevelopmental regression), management is strictly stratified by venous blood lead level (BLL): for BLL <45 μg/dL, chelation is NOT indicated—management consists of environmental lead abatement, nutritional iron/calcium/vitamin C optimization, and serial venous BLL monitoring; for BLL 45–69 μg/dL in an asymptomatic child, oral succimer (DMSA) is first-line; and for BLL ≥70 μg/dL or any signs of lead encephalopathy (ataxia, vomiting, papilledema, seizures), inpatient parenteral combination therapy with dimercaprol (BAL, formulated in peanut oil for deep IM injection—contraindicated in peanut allergy!) plus Calcium Disodium EDTA (initiated 4 hours after the first BAL dose so EDTA does not mobilize skeletal lead into the brain) is mandatory. Acute iron (Fe²⁺) overdose is chelated with IV deferoxamine (producing classic vin rosé pink-orange urine); arsenic and inorganic mercury are chelated with dimercaprol (BAL) or succimer; and copper (Wilson disease) is chelated with penicillamine or trientine plus oral zinc.

Marine neurotoxins and foodborne biotoxins target voltage-gated sodium channels or histamine pathways with rapid postprandial onset. Tetrodotoxin (pufferfish/fugu ovaries and liver) and saxitoxin (paralytic shellfish poisoning from dinoflagellate "red tides" concentrated in mussels, clams, and oysters) bind the extracellular pore opening of voltage-gated Na⁺ channels, blocking inward Na⁺ current and causing perioral paresthesias within 30 minutes that progress rapidly to ascending flaccid paralysis and diaphragmatic respiratory arrest. Conversely, ciguatoxin (concentrated in large tropical reef fish such as barracuda, grouper, and snapper) binds voltage-gated Na⁺ channels in the open state, causing persistent depolarization presenting with GI distress, bradycardia/hypotension, and pathognomonic cold allodynia / temperature reversal dysesthesia (cold objects feel burning hot). Scombroid poisoning occurs after consuming improperly refrigerated dark-meat fish (tuna, mahi-mahi, mackerel) in which surface bacteria decarboxylate histidine into heat-stable histamine, causing immediate peppery oral burning, facial flushing, urticaria, bronchospasm, and tachycardia within 15–30 minutes that responds rapidly to H₁/H₂ antihistamines and epinephrine. Among mushroom poisonings, Amanita phalloides (Death Cap) contains amatoxins that potently inhibit eukaryotic RNA polymerase II (synthesis of mRNA), causing delayed (6–24 hour) cholera-like diarrhea followed at 48–72 hours by fulminant hepatic and renal necrosis (treated with IV silibinin, high-dose penicillin G, and N-acetylcysteine).

Lead (Pb²⁺) poisoning occurs in children living in pre-1978 housing (peeling lead paint, contaminated water pipes) and adults working in battery manufacturing, radiator repair, or indoor firing ranges. Lead covalently inhibits two sulfhydryl-dependent enzymes in the heme synthesis pathway: cytosolic δ-aminolevulinic acid (ALA) dehydratase and mitochondrial ferrochelatase. Accumulation of ALA causes neuropsychiatric toxicity and colicky abdominal pain, while ferrochelatase blockade prevents Fe²⁺ incorporation into protoporphyrin IX (elevating erythrocyte zinc protoporphyrin). Lead also inhibits pyrimidine 5'-nucleotidase, preventing ribosomal RNA degradation in maturing erythrocytes and producing classic coarse basophilic stippling on peripheral blood smear alongside microcytic, hypochromic sideroblastic anemia. Radiographs in children reveal radio-opaque "lead lines" at the metaphyseal growth plates of long bones and Burton lines along the gingiva. Management depends on blood lead level (BLL): <45 μg/dL requires environmental abatement; 45–69 μg/dL is treated with oral succimer (DMSA); and ≥70 μg/dL or lead encephalopathy requires parenteral dimercaprol (BAL) + calcium disodium EDTA.

Arsenic poisoning (contaminated well water, wood preservatives, smelters, pesticides) presents acutely with cholera-like "rice-water" hemorrhagic gastroenteritis, garlic-scented breath, QT prolongation/Torsades de Pointes, and shock. Trivalent arsenite binds lipoic acid sulfhydryl groups to inhibit the pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase, while pentavalent arsenate uncouples glycolysis. Chronic arsenic exposure causes stocking-glove peripheral neuropathy, palmoplantar hyperkeratosis, transverse white fingernail striae (Mees lines), and squamous cell carcinomas of the skin/lung plus hepatic angiosarcoma; chelate acutely with dimercaprol (BAL) or succimer. Mercury poisoning (elemental vapor from thermometers/fluorescent bulbs, inorganic salts, or organic methylmercury in predatory fish) causes tremor, neuropsychiatric erethism ("Mad Hatter syndrome"), gingivostomatitis, and membranous nephropathy.

Carbon Monoxide (CO) binds hemoglobin with ~240 times the affinity of oxygen to form carboxyhemoglobin (COHb), both reducing total O₂-carrying capacity and shifting the oxygen-hemoglobin dissociation curve sharply to the LEFT (inhibiting O₂ unloading to tissues). Patients present in winter after using indoor space heaters, generators, or charcoal grills with throbbing headache, dizziness, confusion, normal PaO₂ on arterial blood gas, falsely normal standard pulse oximetry, and bilateral globus pallidus necrosis on brain MRI. Treat with 100% normobaric oxygen (shortening COHb half-life from 300 minutes to 90 minutes) or hyperbaric oxygen (half-life <30 minutes; indicated for COHb >25%, pregnancy >15%, syncope, coma, or myocardial ischemia).

Cyanide (CN⁻) (house fire combustion of polyurethane/plastics, nitroprusside infusion, amygdalin/apricot pits) binds ferric iron (Fe³⁺) in cytochrome c oxidase (Complex IV) of the mitochondrial electron transport chain, halting aerobic ATP synthesis even in the presence of abundant oxygen. Cells switch entirely to anaerobic glycolysis, producing profound high-anion-gap lactic acidosis (>10 mmol/L), bitter almond odor, flushed skin, and elevated mixed venous O₂ saturation (tissues cannot extract oxygen). First-line antidote is IV hydroxocobalamin (Vitamin B_12a precursor that directly binds cyanide to form non-toxic cyanocobalamin [B₁₂] excreted in urine), followed by sodium thiosulfate (provides sulfur donor for hepatic rhodanese to convert cyanide into harmless thiocyanate). Avoid nitrite induction of methemoglobinemia in smoke-inhalation victims because concomitant carboxyhemoglobinemia + methemoglobinemia causes lethal hypoxia.

Methemoglobinemia occurs when oxidizing drugs (dapsone, topical benzocaine/lidocaine, inhaled nitric oxide, amyl/sodium nitrites, well-water nitrates in infants) oxidize hemoglobin ferrous iron (Fe²⁺) to ferric iron (Fe³⁺), which cannot bind O₂ and shifts the remaining heme subunits' dissociation curve to the LEFT. Classic triad: central cyanosis unresponsive to 100% O₂, "chocolate-brown" arterial blood, and a pulse oximetry SpO₂ fixed at ~85% despite normal arterial PaO₂. Administer IV methylene blue (which serves as an artificial electron acceptor reduced by NADPH-methemoglobin reductase to leukomethylene blue, which then reduces Fe³⁺ back to Fe²⁺); if the patient has G6PD deficiency, methylene blue is ineffective and triggers severe Heinz-body hemolysis—use high-dose ascorbic acid (Vitamin C) or exchange transfusion instead.

Five core pharmacokinetic equations govern clinical dosing across every specialty. First, the apparent Volume of Distribution (V_d) relates the total amount of drug in the body (D, or D × F if given orally) to the initial plasma concentration (C₀): V_d = (Amount of Drug in Body) / C₀. Hydrophilic, large, or heavily albumin-bound drugs (e.g., heparin, warfarin, aminoglycosides) remain confined to the vascular/extracellular space (V_d ≈ 3–14 L), whereas lipophilic basic drugs that sequester inside peripheral tissues and adipocytes (e.g., amiodarone, chloroquine, tricyclic antidepressants, digoxin) exhibit massive apparent V_d values (>200–1,000 L—explaining why hemodialysis cannot effectively remove TCAs, digoxin, or amiodarone in overdose). Second, the Loading Dose (LD) rapidly achieves a target plasma concentration (C_p) and depends exclusively on V_d and bioavailability (F): LD = (V_d × C_p) / F. Crucially, renal or hepatic failure does NOT change the Loading Dose (unless edema/ascites alters V_d). Third, the Maintenance Dose (MD) replaces drug cleared over each dosing interval (τ) at steady state and depends strictly on Clearance (CL): MD = (CL × C_ss × τ) / F. Thus, renal or hepatic impairment mandates reducing the Maintenance Dose (or extending the dosing interval τ). Fourth, Elimination Half-Life (t_1/2) is directly proportional to V_d and inversely proportional to CL: t_1/2 = (0.693 × V_d) / CL. Reaching steady-state plasma concentration during a constant infusion always requires 4 to 5 half-lives (1 t_1/2 = 50%, 2 t_1/2 = 75%, 3 t_1/2 = 87.5%, 3.3 t_1/2 = 90%, 4 t_1/2 = 93.75%, 5 t_1/2 = 96.875%), and changing the infusion rate alters the final C_ss height but never changes the time required to reach steady state.

Drugs with a narrow therapeutic index (TI = TD₅₀ / ED₅₀ in animal studies, or TC₅₀ / EC₅₀ in human clinical practice) require serial therapeutic drug monitoring (TDM) of serum trough or peak concentrations: lithium, digoxin, phenytoin, valproate, carbamazepine, vancomycin (AUC/MIC or trough), aminoglycosides, tacrolimus, cyclosporine, sirolimus, and theophylline. For highly albumin-bound drugs like phenytoin (~90% albumin-bound) and warfarin (~99% albumin-bound), only the unbound (free) fraction is pharmacologically active and cleared by the liver. In patients with hypoalbuminemia (nephrotic syndrome, cirrhosis, malnutrition) or uremia (which displaces phenytoin from albumin), total serum phenytoin appears falsely low while the biologically active free phenytoin concentration may be normal or toxic—mandating calculation of the Sheiner-Tozer albumin-corrected phenytoin or direct measurement of a free phenytoin level. Finally, mandatory pre-prescription pharmacogenomic screening prevents fatal idiosyncratic reactions: HLA-B*5701 screening before abacavir (prevents fatal multiorgan hypersensitivity; never rechallenge), HLA-B*1502 in Asian ancestry before carbamazepine/phenytoin and HLA-B*5801 before allopurinol (prevents Stevens-Johnson syndrome/TEN), TPMT (thiopurine methyltransferase) and NUDT15 before azathioprine/6-mercaptopurine (prevents life-threatening myelosuppression), G6PD before rasburicase, primaquine, and dapsone, and UGT1A1*28 for irinotecan neutropenia/diarrhea.