Chemical and drug toxicity Notes

Chapter 2 Acyanotic Defects NOTES CHEMICAL & DRUG TOXICITY GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Variety of disorders caused by excessive exposure to harmful substances ▪ Adverse effects of exposure ▫ Direct damage to DNA, disruption of metabolic processes, organ dysfunction ▪ Excessive exposure to offending agent ▫ Intentional/unintentional, acute/chronic SIGNS & SYMPTOMS ▪ See individual disorders DIAGNOSIS ▪ See individual disorders TREATMENT MEDICATIONS ▪ Administer available antidote OTHER INTERVENTIONS ▪ Removal of offending agent ▪ Address comorbidities, complications ACUTE RADIATION SYNDROME (ARS) osms.it/acute-radiation-syndrome PATHOLOGY & CAUSES ▪ Group of organ system toxicities caused by excessive exposure to ionizing radiation of whole body/significant part of body ▪ Ionizing radiation ▫ Composed of particles, short electromagnetic waves with potential to damage biological tissues; displaces electrons from orbits → creates unstable atoms → ionization occurs as free electrons collide with other atoms ▫ Causes damage to tissues by direct impact on DNA, proteins, cell membrane lipids, generating free radicals; rapidly dividing cells most vulnerable due to DNA damage; mutagenic, carcinogenic, teratogenic effects Types of ionizing radiation ▪ X-rays, gamma rays ▫ Medical, industrial, military applications (e.g. medical imaging, radiosurgery) ▪ Alpha particles ▫ Unable to penetrate skin, harmful if ingested/inhaled (e.g. plutonium-236, uranium-238) ▪ Beta particles ▫ Penetrate subcutaneous tissues, also harmful if ingested/inhaled (e.g. strontium-90, cesium-137) OSMOSIS.ORG 241

Measurement ▪ Radiation dose: measured in grays (Gy) ▫ Amount of energy deposited into mass of tissue; 1Gy = 1 joule of absorbed energy per kilogram of biological matter ▪ Effective dose: measured in sieverts (Sv) ▫ Type of radiation + variable tissue sensitivity; adjusts relative biologic effect of different radiation types on different tissues (e.g. 1Gy of alpha radiation more dangerous than 1Gy of gamma radiation) ▪ Nuclear medicine procedures: mSv; 1mSv = 1mGy ▪ Typical threshold dose for whole-body/ significant partial-body irradiation ▫ ≥ 1Gy delivered at relatively high dose rate STAGING Four organ-system toxicities ▪ Neurovascular/cerebrovascular ▫ Caused by localized central nervous system (CNS) changes ▪ Gastrointestinal (GI) ▫ Caused by loss of intestinal crypt cells, breakdown of mucosal barrier, loss of epithelium ▪ Hematopoietic ▫ Caused by impairment of mitotically active hematopoietic precursors ▪ Cutaneous ▫ Caused by damage to epidermis, dermis, hair follicles, subcutaneous tissues ▪ Malnutrition, cognitive impairment, hemorrhage, permanent skin/hair loss, malignancies, infertility, congenital malformations, radiation pneumonitis, multiorgan failure, high mortality RISK FACTORS ▪ Occupational exposure (e.g. medical imaging technicians) ▫ Especially with insufficient shielding ▪ Injurious incident (e.g. nuclear power plant, transportation, overtreatment during medical therapy) ▪ Detonation of nuclear bomb/radiological dispersal device (dirty bomb) ▪ ↑ dose, rate of dose; ↓ distance from radiation source, type of radiation ▪ Individuals < 12 years , > 60 more sensitive to radiation 242 OSMOSIS.ORG ▪ Prodromal ▫ 0–2 days post-exposure; fever, tachycardia, nausea, vomiting, headache, fatigue ▪ Latent phase ▫ 2–20 days post-exposure; partial functionality ▪ Manifest illness ▫ 21–60 days post-exposure; progression to organ-system syndromes ▪ Recovery/death ▫ Death may occur days after exposure to high amounts of radiation/ weeks, months after low exposure; death inevitable if doses > 10–12Gy COMPLICATIONS SIGNS & SYMPTOMS ▪ Neurovascular/cerebrovascular ▫ Meningeal inflammation, cerebral edema → ↑ intracranial pressure, hemorrhage ▪ GI ▫ Abdominal cramping, pain; loose stools, vomiting → fluid, electrolyte imbalance; bleeding → anemia; bowel ulceration, necrosis, perforation ▪ Hematopoietic ▫ Pancytopenia; bone marrow hypoplasia, aplasia ▪ Cutaneous ▫ Erythema; edema; dry, moist desquamation; ulceration (subcutaneous tissue, muscle, bone); blisters, bullae

Chapter 42 Chemical & Drug Toxicity DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ GI ▫ Segmental inflammation, bowel thickening, fibrosis, bowel obstruction ▪ Neurovascular/cerebrovascular ▫ Cranial edema, swelling LAB RESULTS ▪ Serial complete blood counts (CBCs) ▫ Demonstrate changes in bone marrow function ▪ Peripheral blood sample ▫ Cytogenetic biodosimetry analyzes chromosomal aberrations in lymphocytes; correlation with radiation dose OTHER DIAGNOSTICS ▪ Geiger counter/alpha-radiation detection device ▫ Determines degree of contamination ▪ Medical Treatment Protocols for Radiation Accident Victims (METREPOL) ▫ During first 48 hours TREATMENT MEDICATIONS ▪ Nonradioactive potassium iodide (KI) ▫ Take within first hours of exposure; inhibits corporation of radioactive isotopes of iodine into thyroid gland ▪ External decontamination ▫ Wounds, body orifices ▪ Internal decontamination ▫ Minimize absorption, maximize excretion ▫ Chelating agents: diethylene-triaminepentaacetic acid (DTPA) ▫ Oral ferric hexacyanoferrate (Prussian blue): traps radioactive materials in intestines → prevents reabsorption ▪ Sodium bicarbonate ▫ ↓ risk of renal tubular necrosis ▪ Pain management ▪ Anxiolytics Organ-based management ▪ Hematopoietic: cytokine therapy (e.g. granulocyte colony-stimulating factor); recombinant human erythropoietin, antimicrobials ▪ GI: antiemetics (e.g. selective 5HT3 receptor antagonists), antidiarrheals SURGERY Organ-based management ▪ Hematopoietic: stem cell transplant OTHER INTERVENTIONS ▪ Address injuries (e.g. fractures, burns) ▪ Fluid, electrolyte replacement ▪ Lung lavage, mechanical ventilation Organ-based management ▪ Hematopoietic: blood products ▪ Neurovascular: address increased intracranial pressure; comfort care (outcome likely fatal with neurovascular syndrome) ▪ Cutaneous: debridement, wound care OSMOSIS.ORG 243

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Chapter 42 Chemical & Drug Toxicity ARSENIC POISONING osms.it/arsenic-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure (acute/chronic) to arsenic → disruption of metabolic processes ▫ Naturally-occurring metalloid element, organic/inorganic compounds (organic— relatively low toxicity, inorganic—high toxicity) ▫ Present in soil, groundwater in certain areas; in gaseous state (arsine); tasteless, odorless ▪ Arsenic taken up by red blood cells → distributed to all body tissues, penetrates blood-brain barrier → interacts with intracellular compounds ▫ Interferes with metabolic processes (e.g. binds to sulfhydryl groups → impairs enzymatic reactions, interferes with cellular respiration) ▫ Concentrates in keratin-rich tissues (e.g. skin, hair, nails) ▫ Excreted in urine RISK FACTORS ▪ Ingestion ▫ Contaminated groundwater: natural leaching from soil/agricultural, industrial pollution ▫ Foods (e.g. rice) grown in water containing arsenic ▫ Certain Asian homeopathic compounds ▪ Inhalation ▫ Arsenic-containing gas/dust from melting, refining, coal-fired power plants ▪ Occupational exposure ▫ Glass manufacturing, metallurgy, mining, semiconductor manufacturing (e.g. gallium arsenide), pressure-treated wood products using chromated copper arsenate (CCA) ▪ Potential toxicity when administered therapeutically (e.g. arsenic trioxide for leukemia) COMPLICATIONS ▪ Skin pigmentation, structural changes → squamous cell carcinoma ▪ Fluid, electrolyte imbalance, shock → common cause of death ▪ Blocks cardiac potassium channels → conduction disturbances ▪ Respiratory distress syndrome ▪ Hepatotoxicity ▪ Intravascular hemolysis → renal failure ▪ Peripheral vascular disease, gangrene (“black foot”) ▪ Encephalopathy ▪ Bone marrow depression, pancytopenia ▪ Malignancies ▫ Lung, liver, kidney bladder, colon; basal/ squamous cell carcinoma ▪ Crosses placenta → ↑ risk for spontaneous abortions, stillbirths, preterm births SIGNS & SYMPTOMS ▪ GI ▫ Abdominal cramping, nausea, vomiting, hematemesis, diarrhea ▪ Cardiovascular ▫ Tachycardia, hypotension ▫ Conduction disturbances: QT prolongation, ventricular dysrhythmias (e.g. torsades de pointes) ▪ Neurological ▫ Peripheral neuropathy (“stocking-glove” distribution), diminished vibratory sensation, decreased deep tendon reflexes, delirium, seizures ▪ Skin ▫ Plantar/palmar hyper/hypopigmentation, “raindrop on dusty road” pigmentation, hyperkeratosis, Mees lines on nails (transverse leukonychia) ▪ Breath ▫ Garlic odor OSMOSIS.ORG 245

OTHER DIAGNOSTICS ▪ History of exposure, physical examination ▪ Analysis of hair/fingernails ▫ Degree of chronic exposure ECG ▪ Dysrhythmias TREATMENT MEDICATIONS Figure 42.1 Mee’s lines appear on the nails after an episode of acute arsenic poisoning. DIAGNOSIS LAB RESULTS ▪ 24-hour urinary arsenic excretion ▫ Methylated metabolites of inorganic arsenical compounds ▪ ↑ LFTs, hyperbilirubinemia ▪ CBC: anemia, leukopenia, thrombocytopenia ▪ ↑ blood urea nitrogen (BUN), creatinine ▪ Chelation therapy ▫ Dimercaprol, AKA British anti-Lewisite (BAL); meso-2,3-dimercaptosuccinic acid (DMSA) OTHER INTERVENTIONS ▪ Chronic exposure ▫ Remove source, protective equipment for occupational exposure ▪ Fluid, electrolyte administration, correction of imbalances CYANIDE POISONING osms.it/cyanide-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure to cyanide → arrest of cellular respiration, death ▫ Highly toxic chemical compound ▫ Contains carbon triple-bonded to nitrogen—cyano group (C≡N) ▫ Organic, inorganic, salt, liquid forms ▫ Hydrogen cyanide: distinctive odor of bitter almonds ▫ Cyanogenic compounds found in some fruit seeds (e.g. apricots, peaches) ▫ Seed capsule broken, exposed to 246 OSMOSIS.ORG intestinal beta-glucosidase → cyanide formed ▫ Also produced by certain bacteria, fungi, algae ▫ Sodium nitroprusside: contains five cyanide groups ▪ Rapidly absorbed into body via all routes → 60% bound to protein → metabolized in liver → thiocyanate → eliminated via urine, lungs ▪ Toxic effect ▫ Blocks mitochondrial electron transport → halts aerobic cellular respiration → cellular hypoxia → metabolic switch to

Chapter 42 Chemical & Drug Toxicity anaerobic pathway → lactic acidosis RISK FACTORS ▪ Industrial exposure ▫ Metal industries (e.g. extraction, plating), plastics, textiles ▪ Inhalation of smoke from burning synthetic materials ▪ Pediatric risk ▫ Consumption of acetonitrile-containing false fingernail remover ▪ High rate of sodium nitroprusside administration ▪ Rare cases of poisoning from peach, apricot, chokecherry pits COMPLICATIONS ▪ Lactic acidosis, hypoxia → cardiac failure → death SIGNS & SYMPTOMS ▪ Respiratory ▫ Hyperpnea, apnea, pulmonary edema; musty almond odor ▪ Cardiovascular ▫ Hypertension (early), tachycardia, dysrhythmias, asystole ▪ Neurological ▫ Altered level of consciousness, seizures, coma ▪ Mucocutaneous ▫ Flushing (cherry-red), cyanosis ▪ Constitutional ▫ Headache ▪ Exposure to small amounts → weakness, nausea, lacrimation, rhinorrhea DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ Urine cyanide, thiocyanate level ↓ oxygen saturation Arterial blood gas (ABG): lactic acidemia Bright red appearance of blood OTHER DIAGNOSTICS ECG ▪ Dysrhythmias TREATMENT OTHER INTERVENTIONS ▪ Remove source of exposure ▪ Supplemental oxygen ▪ Hydroxocobalamin (vitamin B12a ) ▫ Cyanokit: each hydroxocobalamin molecule binds with one cyanide ion → forms vitamin B12 → excreted in urine ▪ Cyanide antidote kit ▫ Amyl nitrate, sodium nitrate, sodium thiosulfate ▫ Nitrates form methemoglobin ▫ Sodium thiosulfate converts cyanide to thiocyanate → excretion in urine OSMOSIS.ORG 247

ETHYLENE GLYCOL POISONING osms.it/ethylene-glycol-poisoning PATHOLOGY & CAUSES ▪ Ingestion of ethylene glycol → accumulation of toxic metabolites, metabolic acidosis, cellular dysfunction, organ damage ▪ Found in antifreeze, deicing solution, brake fluid, engine coolant, etc. ▪ Metabolism of ethylene glycol → generation of toxic metabolites ▫ Ingestion → absorbed rapidly from GI system → metabolized in liver by alcohol dehydrogenase → converted into glycolaldehyde → aldehyde dehydrogenase converts glycolaldehyde to glycolic acid (later converted into oxalic acid) → metabolic acidosis ▫ Concurrent ingestion of ethanol delays generation of toxic metabolites STAGING Stage I ▪ Neurologic (30 minutes–12 hours postexposure) ▫ Osmolal gap: direct effect of ethylene glycol ▫ Mimics inebriation (e.g. stupor, euphoria, vomiting) ▫ More severe CNS effects as ethylene glycol metabolized (e.g. nystagmus, seizures) Stage II ▪ Cardiopulmonary (12–24 hours postexposure) ▫ Toxic metabolite accumulation → metabolic acidosis, oxalate crystals in heart, lungs, vasculature ▫ Pulmonary edema → dyspnea; Kussmaul respirations (due to metabolic acidosis) ▫ Impaired cardiac function (e.g. heart failure, circulatory collapse) 248 OSMOSIS.ORG ▫ CNS derangements (e.g. cerebral edema) ▫ Death likely Stage III ▪ Renal (24–72 hours post-exposure) ▫ Renal accumulation of calcium oxalate in kidneys + direct effects of toxic metabolites → acute tubular necrosis, renal failure RISK FACTORS ▪ Ingestion of products containing ethylene glycol (unintentional/intentional) COMPLICATIONS ▪ Metabolic acidosis ▪ Hypocalcemia, calcium oxalate crystalluria, renal failure ▪ Hypomagnesemia (cofactor for metabolism of glycolic acid) ▪ Cerebral edema, seizures, coma, death SIGNS & SYMPTOMS ▪ Dizziness, headache, lethargy, slurred speech, nausea/vomiting, tachycardia, tachypnea, hyperpnea DIAGNOSIS LAB RESULTS ▪ Urinalysis: calcium oxalate crystals; hematuria; blood, protein casts ▪ ↑ osmolal gap (soon after ingestion) → marker for ethylene glycol ▪ ↑ anion gap metabolic acidosis (later) → marker for toxic metabolites ▪ Hypocalcemia ▪ ↑ BUN, creatinine ▪ Serum ethylene glycol ▪ CBC: leukocytosis

Chapter 42 Chemical & Drug Toxicity OTHER DIAGNOSTICS ▪ History of exposure, physical examination ECG ▪ Dysrhythmias secondary to hypocalcemia TREATMENT MEDICATIONS ▪ Fomepizole: inhibits alcohol dehydrogenase ▪ Ethanol: competitive inhibitor of alcohol dehydrogenase Address acute complications ▪ Fluids, sodium bicarbonate: metabolic acidosis ▪ Benzodiazepines: seizures ▪ Calcium gluconate: hypocalcemia ▪ Magnesium sulfate: hypomagnesemia OTHER INTERVENTIONS ▪ Gastric aspiration ▫ Within 60 minutes of ingestion ▪ IV isotonic fluids → facilitate urinary excretion of metabolites ▪ Respiratory support ▪ Hemodialysis ▫ Significant metabolic acidosis, renal failure, hemodynamic instability FETAL ALCOHOL SYNDROME (FAS) osms.it/fetal-alcohol-syndrome PATHOLOGY & CAUSES ▪ Prenatal exposure to alcohol → dysmorphic craniofacial features, growth deficits, neurobehavioral impairment, CNS dysfunction ▪ Embryo, early fetus have underdeveloped hepatic enzymes needed for ethanol metabolism → ↓ ethanol metabolism → ↑ ethanol concentration → teratogenic effects ▪ Degree of alcohol-related teratogenesis influenced by stage of development, dosage, duration of exposure ▫ Vulnerability continues throughout all three trimesters, all organ systems at risk RISK FACTORS ▪ Maternal alcohol consumption ▫ No safe amount of alcohol consumption during pregnancy ▪ Low socioeconomic status ▪ Poor psychological indicators ▪ Sibling diagnosed with FAS COMPLICATIONS ▪ Cardiac ▫ Atrial/ventricular septal defect ▪ Musculoskeletal ▫ Flexion contractures, scoliosis ▪ Auditory ▫ Conductive/neurosensory hearing loss ▪ Ophthalmologic ▫ Optic nerve hypoplasia, strabismus ▪ Renal ▫ Aplastic/dysplastic/hypoplastic kidneys, horseshoe kidney ▪ Mental health disorders ▫ Attention-deficit/hyperactivity disorder, mood impairment ▪ Neurological ▫ Seizure disorder ▪ Intellectual, cognitive deficits ▪ Developmental delay OSMOSIS.ORG 249

SIGNS & SYMPTOMS ▪ Sentinel dysmorphic features ▪ Growth restriction (intrauterine/postnatal) ▪ Functional, behavioral issues ▫ Poor impulse control, poor judgment, attention problems, hyperactivity; deficits in learning, speech, memory TREATMENT OTHER INTERVENTIONS ▪ Early intervention ▫ Occupational, speech, behavioral therapy; specialized education; parenting training DIAGNOSIS OTHER DIAGNOSTICS ▪ Documentation of maternal alcohol consumption Four features required ▪ Two of three sentinel craniofacial anomalies ▫ Short palpebral fissures ▫ Smooth philtrum ▫ Thin vermilion border of upper lip ▪ Pre/postnatal growth deficiencies ▫ Height/weight ≤ 10th percentile (racially/ ethnically-appropriate standard growth curve) ▪ Deficient brain growth, abnormal morphogenesis, abnormal neurophysiology, including ≥ one ▫ Head circumference ≤ 10th percentile ▫ Structural brain anomalies visualized through imaging ▫ Recurrent nonfebrile seizures (other causes of seizures ruled out) ▪ Neurobehavioral impairment ▫ Children ≥ three years old: cognitive/ behavioral impairment ▫ Children < three years old: developmental delay 250 OSMOSIS.ORG Figure 42.2 The face of a baby diagnosed with fetal alcohol syndrome. There is a smooth philtrum, a thin upper lip and small eye openings.

Chapter 42 Chemical & Drug Toxicity FETAL HYDANTOIN SYNDROME osms.it/fetal-hydantoin-syndrome PATHOLOGY & CAUSES ▪ Prenatal exposure to phenytoin/metabolites → spectrum of congenital anomalies, growth deficiencies ▪ Teratogenic mechanism unclear; may be related to phenytoin-associated impairment of folate absorption RISK FACTORS ▪ Prenatal exposure to phenytoin/ metabolites; no safe amount of phenytoin during pregnancy ▪ ▪ ▪ ▪ (bowed upper lip; broad alveolar ridge; cleft lip, palate) Limbs ▫ Stiff, tapered fingers; digit, nail hypoplasia; hip dislocation Mild/moderate growth deficiencies ▫ Prenatal onset, continues through postnatal life Mild/moderate mental deficiencies Short neck, umbilical/inguinal hernia, pilonidal sinus, low-set hairline DIAGNOSIS OTHER DIAGNOSTICS COMPLICATIONS ▪ Microcephaly, congenital heart defects, growth deficiency, systemic abnormalities (e.g. nervous, renal, GI systems) SIGNS & SYMPTOMS ▪ Craniofacial anomalies ▫ Wide anterior fontanel; ocular hypertelorism, epicanthal folds; nasal (short; flat, broad nasal bridge); mouth ▪ History of maternal ingestion of phenytoin during pregnancy, physical examination TREATMENT OTHER INTERVENTIONS ▪ Early intervention ▫ Occupational, speech, behavioral therapy; specialized education MERCURY POISONING osms.it/mercury-poisoning PATHOLOGY & CAUSES ▪ Excessive exposure to mercury → neurotoxicity, widespread interruption of cellular processes, teratogenesis ▪ Naturally occurring metal found in various forms in environment ▫ Organic, inorganic, methylmercury (MeHg) Sources ▪ Medical preservative (thiomersal) ▪ Thermometers (phased out) ▪ Dental amalgam ▪ Dietary: inorganic mercury from industrial waste → transformed to methylmercury by soil, marine organisms → bio-amplified in tissues of predatory fish (e.g. tuna) ▪ Household items (e.g. fluorescent bulbs, OSMOSIS.ORG 251

batteries, paint) ▪ Fungicides, pesticides ▪ Some homeopathic folk remedies Properties ▪ Lipid soluble; easily crosses cellular membranes ▫ Disrupts cellular physiology by binding to functional groups (e.g. sulfhydryl, carboxyl, phosphoryl) ▫ Crosses blood-brain barrier → neurotoxic effects (impairs synthesis of proteins, nucleic acids; disrupts neurotransmitter synthesis, uptake) ▫ Crosses placenta → concentrates in fetus → teratogenic effects ▪ High affinity for sulfhydryl groups in red blood cells (RBCs) → distributed throughout body ▪ Other organ toxicities ▫ Concentrates in kidneys → oxidative damage; pulmonary, GI ▪ Eliminated in feces, urine RISK FACTORS ▪ Occupational (e.g. dentists, hygienists, miners, ceramic workers, taxidermy) COMPLICATIONS ▪ Minamata disease ▫ Neurotoxicity caused by severe methylmercury poisoning ▪ Renal, respiratory failure; hemorrhagic colitis; fetal anomalies, death SIGNS & SYMPTOMS ▪ Acute exposure ▫ Cough, dyspnea, circulatory collapse, vomiting, bloody diarrhea ▪ Chronic inhalation exposure (classic triad) ▫ Tremor (e.g. intentional tremor, tetanus mercurialis) 252 OSMOSIS.ORG ▫ Neuropsychiatric problems (e.g. fatigue, memory loss, mental instability) ▫ Gingivostomatitis ▪ Chronic ingestion exposure ▫ Nervous system: tremor, headache, dysarthria, paresthesia, irritability, psychosis ▫ Cardiovascular: hypo/hypertension ▫ Hematologic: cytopenias ▫ Ocular: conjunctivitis; corneal opacities, ulcers DIAGNOSIS LAB RESULTS ▪ Mercury, anemia in urine/blood; leukocytosis ▪ Renal tubular damage ▫ N-acetyl-beta-D-glucosaminidase (NAG), albuminuria, epithelial cell casts, oliguria TREATMENT MEDICATIONS ▪ Chelation therapy: oral DMSA, intravenous (IV) dimercaprol (contraindicated with methylmercury, may shift mercury to brain) OTHER INTERVENTIONS ▪ Remove source of exposure; IV fluids, electrolytes; respiratory support

Chapter 42 Chemical & Drug Toxicity PARACETAMOL TOXICITY osms.it/paracetamol-toxicity PATHOLOGY & CAUSES ▪ Excessive ingestion of paracetamol (acetaminophen) → fulminant hepatic failure, coma, death ▪ Acetaminophen metabolization in liver ▫ 90% conjugated via glucuronic acid → nontoxic compounds → excreted in urine ▫ 2% excreted unchanged in urine ▫ Remainder metabolized by cytochrome P450 system → toxic intermediary N-acetyl-p-benzoquinone imine (NAPQI) conjugated by hepatic glutathione → further metabolized → excreted in urine ▫ Glutathione rapidly depleted in acute overdose → accumulation NAPQI → binds to cellular proteins → hepatic necrosis STAGING Stage I ▪ 0–24 hours post-ingestion; nonspecific indications of toxicity Stage II ▪ 24–72 hours post-ingestion; onset of hepatotoxicity, deterioration of renal function Stage III ▪ 72–96 hours post-ingestion; fulminant hepatic failure Stage IV ▪ hepatic recovery; regeneration of liver if individual survives Stage III RISK FACTORS ▪ Acute overdose of acetaminophen (intentional/unintentional) ▪ Chronic ingestion of supratherapeutic doses ▪ ▪ ▪ ▪ ▫ Multiple acetaminophen-containing products, acetaminophen Concomitant ingestion of certain drugs ▫ Hepatic enzyme inducers (e.g. CYP2E1 inducers isoniazid, rifampin, phenobarbital), drugs that deplete glutathione (e.g. zidovudine, trimethoprim-sulfamethoxazole) Decreased hepatic glucuronidation capacity (e.g. chronic alcohol use) Existing hepatic disease (e.g. alcoholic liver disease, hepatitis) Genetic ▫ Gilbert syndrome (inherited deficiency in glucuronidation), cytochrome P450 polymorphisms COMPLICATIONS ▪ Liver failure; death related to liver, multiorgan failure SIGNS & SYMPTOMS ▪ May be asymptomatic/demonstrate nonspecific findings (e.g. nausea, vomiting, malaise) ▪ Progressive liver damage ▫ Right upper quadrant (RUQ) pain, jaundice, hypoglycemia, coagulopathy, hepatic encephalopathy, impaired renal function, metabolic acidosis DIAGNOSIS LAB RESULTS ▪ Urinalysis: renal damage ▪ Serial blood draws for serum acetaminophen concentration ▫ Plot on the Rumack–Matthew nomogram if time of ingestion known ▪ LFTs ▫ ↑ transaminases: AST, ALT OSMOSIS.ORG 253

▫ ↑ bilirubin, lipase ▪ Metabolic panel ▫ ↑ BUN, creatinine, ammonia; ↓ glucose ▪ Coagulation ▫ ↓ prothrombin time, INR ▪ ABG ▫ ↓ pH; anion gap OTHER DIAGNOSTICS SURGERY ▪ Liver transplant OTHER INTERVENTIONS ▪ Activated charcoal: adjunctive treatment for GI decontamination ▪ Address complications ▫ Hemodialysis: renal failure ▫ Fresh frozen plasma: coagulopathy ▪ History of acetaminophen use, physical examination (liver toxicity) TREATMENT MEDICATIONS ▪ Acetylcysteine: most effective if administered within eight hours of ingestion; replenishes glutathione, detoxifies NAPQI SEROTONIN SYNDROME osms.it/serotonin-syndrome PATHOLOGY & CAUSES ▪ Potentially life-threatening disorder ▫ Excessive presence of serotonin (5-hydroxytryptamine/5-HT), overactivation of central serotonin receptors → clinical manifestations related to mental status, neuromuscular excitation, autonomic excitation ▪ May be caused by therapeutic use of single serotonergic drug, overdose, drug interactions between ≥ two drugs 5HT increase ▪ ↑ serotonin synthesis ▫ Phentermine, L-tryptophan ▪ ↑ serotonin release ▫ Amphetamines/amphetamine derivatives; dopamine agonists ▪ ↑ activation of serotonergic receptors ▫ Certain antidepressants (buspirone); triptans; prokinetic agents (e.g. 254 OSMOSIS.ORG metoclopramide); ergot alkaloid derivatives; lithium ▪ ↓ serotonin reuptake ▫ Selective serotonin reuptake inhibitors (SSRIs); serotonin noradrenergic reuptake inhibitors (SNRIs); tricyclic antidepressants (TCAs); 5HT3, receptor antagonists; certain opiates (e.g. methadone, tramadol), drug abuse (e.g. ecstasy); Saint John’s wort ▪ ↓ serotonin metabolism ▫ Monoamine oxidase inhibitors (MAOIs); triptans ▪ ↓ activity of certain CYP450 enzymes ▫ Dextromethorphan RISK FACTORS ▪ Therapeutic use of serotonergic drug ▪ Polypharmacy (increases likelihood of drug interaction)

Chapter 42 Chemical & Drug Toxicity COMPLICATIONS ▪ Ventricular dysrhythmias ▪ Rhabdomyolysis, myoglobinuria (due to hyperthermia) → renal failure ▪ Metabolic acidosis ▪ Acute respiratory distress syndrome SIGNS & SYMPTOMS ▪ Neuromuscular excitation ▫ Hyperreflexia, tremors, clonus, muscle rigidity, bilateral Babinski sign ▪ Autonomic nervous system hyperactivity ▫ Vomiting, diarrhea, hypertension, tachycardia, dysrhythmias, tachypnea diaphoresis, hyperthermia, mydriasis ▪ Altered mental status ▫ Anxiety, agitation, confusion TREATMENT MEDICATIONS ▪ Antidote (if supportive measures insufficient) ▫ Cyproheptadine (H1, 5-HT2 antagonist effects) ▪ Benzodiazepines, short-acting antihypertensives ▫ Address symptomatology OTHER INTERVENTIONS ▪ Discontinue serotonergic drug ▪ Cooling measures, IV fluids, supplemental oxygen ▫ Address symptomatology DIAGNOSIS LAB RESULTS ▪ ↑ white blood cell count, creatine phosphokinase; ↓ serum bicarbonate OTHER DIAGNOSTICS Hunter Serotonin Toxicity Criteria ▪ History of taking serotonergic agent + any one of following clinical features ▫ Spontaneous clonus ▫ Inducible clonus + agitation/diaphoresis ▫ Ocular clonus + agitation/diaphoresis ▫ Tremor + hyperreflexia ▫ Hypertonia + temperature > 38°C/100°F + ocular/inducible clonus OSMOSIS.ORG 255