Chemical and drug toxicity Notes


Osmosis High-Yield Notes

This Osmosis High-Yield Note provides an overview of Chemical and drug toxicity essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Chemical and drug toxicity:

Acute radiation syndrome

Fetal hydantoin syndrome

Mercury poisoning

Paracetamol toxicity

Serotonin syndrome

Arsenic poisoning

Cyanide poisoning

Ethylene glycol poisoning

Fetal alcohol syndrome

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) 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
Chapter 42 Chemical & Drug Toxicity 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 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 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) 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 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 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 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 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

Osmosis High-Yield Notes

This Osmosis High-Yield Note provides an overview of Chemical and drug toxicity essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Chemical and drug toxicity by visiting the associated Learn Page.