Introduction to Toxicology PDF

Introduction to Toxicology Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours  Practice questions available on Canvas  Required reading:  Chapter 58: Management of the Poisoned Patient, in Basic & Clinical Pharmacology, ed. 15. by...

Introduction to Toxicology Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours  Practice questions available on Canvas  Required reading:  Chapter 58: Management of the Poisoned Patient, in Basic & Clinical Pharmacology, ed. 15. by Trevor Katzung  Available through Canvas, Student Resources, Access Medicine, Books, Library 2 Learning Objectives 1.Discuss the basic principles of toxicology 2.Identify the ways in which toxic agents are classified 3.Explain the approach to managing a poisoned patient 4.Identify common toxins, their associated toxidromes and potential antidotes 3 Principles of Toxicology LO 1 • Toxicology is the study of the adverse effects of chemical or physical agents on living organisms. o Toxin: toxic substances that are produced by biological systems such as plants, animals, fungi, or bacteria. o Toxicant: toxic substances that are produced by or are a by-product of anthropogenic (human-made) activities. • Some chemicals produce death in microgram doses (extremely poisonous) while others may be relatively harmless after doses in excess of several grams. • For a given chemical, multiple different effects can occur in a given pt, each with its own dose-response relationship. 4 Principles of Toxicology LO 1 • Understanding the mechanism of toxicity allows for: o Interpretation of descriptive toxicity data o Estimation of the probability that a chemical will cause harmful effects o Establishing procedures to prevent or antagonize the toxic effects o Designing drugs and industrial chemicals that are less hazardous o Developing pesticides that are more selectively toxic for their target organisms 5 Curtis, Klaassen,. Casarett & Doull's Toxicology: The Basic Science of Poisons, Eighth Edition. Available from: VitalSource Bookshelf, (8th Edition). McGraw-Hill Higher Education (US) CourseSmart ARCHIVE, [Insert Year of Publication]. 6 Classification of Toxic Agents LO 2 • Classification of toxic agents by their: o o o o o o o o o target organs (e.g. liver, kidney) use source (animal and plant toxins) effects (e.g., cancer, mutation, liver injury, etc) Physical state (e.g., gas) chemical stability or reactivity (explosive, flammable, oxidizer) chemical structure (aromatic amine, halogenated hydrocarbon, etc), poisoning potential (extremely toxic, very toxic, slightly toxic, etc) biochemical mechanisms of action (e.g., alkylating agent, cholinesterase inhibitor, endocrine disruptor) 7 LO 3 Management of the Poisoned Patient • Management depends on: • the specific poison(s), • the presenting and predicted severity of illness • elapsed time between exposure and presentation • Treatment includes supportive care, decontamination, antidotal therapy, and enhanced elimination techniques. 8 Initial Management LO 3 (Vital Functions) • Vital Functions (ABCDs) o Establish an open and protected Airway o Ensure effective ventilation and Breathing o Evaluate and support Circulation if needed o Dextrose (if altered mental status) or Decontamination • Identification of poisons – Many intoxicants cause a characteristic syndromes of clinical and laboratory changes – History and physical examination – Electrocardiographic and radiographic studies – Toxicology screens (drug testing) 9 Initial Management LO 3 • History and Physical Examination o History (from pt and/or family members, police etc) o Physical Examination focusing on areas which would give clues to the toxin 1. Vital signs 2. Eyes, mouth, skin, abdomen and nervous system 10 Initial Management (Laboratory Procedures) LO 3 • Blood gases o Hypoventilation results in elevated PCO2 (hypercapnia) and low PO2 (hypoxia) o PO2 may be low in persons with aspiration pneumonia or drug induced pulmonary edema o Poor tissue oxygenation due to hypoxia, hypotension and cyanide poisoning will result in metabolic acidosis 11 Initial Management (Electrolytes) LO 3 Anion Gap • (Na+ + K+) – (Cl- + HCO3-) • Normally 12 – 16 mEq/L • Increases due to: o Diabetic ketoacidosis o Renal failure o Drug induced metabolic acidosis o Drugs: cyanide, ethanol, ethylene glycol, ibuprofen, isoniazid, iron, methanol, salicylates, verapamil 12 Initial Management (Laboratory Procedures) LO 3 • Osmolar Gap o Difference between the measured serum osmolarity and the osmolarity predicted by measured serum conc. of sodium, glucose and BUN o Gap = Osm (measured) – Osm (calculated) o Calculated Serum Osmolality = (2 x [Na]) + [glucose, in mg/dL]/18 + [blood urea nitrogen, in mg/dL]/3 o Calculated value is normally 280 – 290 mOsml/L o Gap normally 0. A significant gap is produced by high serum concentrations of intoxicants of low MW such as ethanol, methanol, ethylene glycol 13 Initial Management (Laboratory Procedures) LO 3 • Serum Potassium changes may be harmful o Myocardial function depends on serum potassium o Drugs which cause hyperkalemia: beta blockers, digitalis (overdose), fluoride, lithium, potassium sparing diuretics o Drugs which cause hypokalemia: beta agonists, methylxanthines, most diuretics 14 Initial Management (Imaging Procedures) LO 3 • Electrocardiogram o Widening QRS complex duration is typical of overdose with TCA and other drugs that block the sodium channel in cardiac conducting tissue o Prolongation of the QT interval by antidepressants, antipyschotics, methadone, lithium • Imaging Findings o Plain film of the abdomen may be useful because some tablets (e.g. Fe and K) may be radiopaque o Chest radiographs may reveal aspiration pneumonia, hydrocarbon pneumonia or pulmonary edema o CT scan if head trauma 15 Decontamination LO 3 • Decontamination procedures o Removal of toxin from skin or GI tract o should be undertaken simultaneously with initial stabilization of the pt, diagnostic assessment and lab evaluation. • Skin o Remove contaminated clothing o Wash skin with soap and water o For ocular exposure: Flush eyes with saline or tepid water to a neutral pH 16 Decontamination LO 3 • GI Tract Decontamination o Ideally therapy should be initiated within 1 hour of ingestion • Gastric lavage – May be performed using orogastric or nasogastric tube if pt is awake or airway is protected with and endotracheal tube – Lavage solutions: usually 0.9% saline at body temperature – DO NOT use in patients who have ingested a corrosive because of the risk of esophageal damage. – Gastric lavage can be used in a comatose patient if the airway has been protected with a cuffed endotracheal tube. 17 Decontamination LO 3 • Activated Charcoal o Large surface area; can adsorb many drugs and poisons o 10:1 of charcoal to estimated dose of toxin by weight o Does not bind iron, lithium, potassium. Poorly to alcohols and cyanide o Not useful if corrosive mineral acids and alkali ingested • Cathartics (laxatives) o Whole bowel irrigation with polyethylene glycol-electrolyte solution 18 Elimination Enhancement (Dialysis Procedures) LO 3 • Peritoneal dialysis is inefficient in removing most drugs • Hemodialysis o Assists in the correction of fluid, electrolyte imbalance and acid-base status o Efficient if toxin has low protein binding, low Vd, small MW and water soluble o E.g. of substances easily removed: methanol, ethylene glycol, salicylates, theophylline, phenobarbital, lithium • Forced diuresis (not recommended) and urinary pH manipulation (e.g. urinary alkalinization for salicylates) 19 POISONS AND SPECIFIC ANTIDOTES 20 LO 4 General mechanisms of action of antidotes Mechanism Examples Removal of circulating poison from plasma • Chelating agents for heavy metal poisoning e.g. deferoxamine for iron poisoning • Chemical binding or precipitation, e.g. calcium gluconate for fluoride poisoning, binding to specific antibody e.g. digoxin-specific antibody fragments in cardiac glycoside poisoning Receptor agonism • Direct agonism e.g. isoprenaline in beta adrenoceptor antagonism poisoning • Indirect antagonism e.g. glucagon in beta adrenoceptor poisoning Receptor antagonism • Direct antagonism e.g. atropine in organophosphate poisoning 21 LO 4 General mechanisms of action of antidotes Mechanism Examples Replenish depleted natural protective compound • Replenish protective species e.g. N-acetylcysteine in APAP poisoning • Bypass block in metabolism e.g. folinic acid in methotrexate poisoning, vitamin K in warfarin poisoning Prevent conversion to toxic metabolite • Ethanol in methanol poisoning Protective action on target enzyme • Pralidoxime competitively reactivates cholinesterase 22 23 LO 4 Common toxins, their associated toxidromes and antidotes Acetaminophen • Produces toxicity when normal metabolic pathways are saturated • Hepatotoxic metabolite produced: N-acetyl-p-benzoquinone imine, NAPQI • After therapeutic doses, the liver generates glutathione which detoxifies NAPQI. In overdose, glutathione is depleted. • The antidote, N-acetylcysteine (NAC), is a glutathione precursor and substitute and assists with sulfation • NAC is most effective when given within 8 to 10 hours of ingestion 24 LO 4 Whalen, Karen. Lippincott Illustrated Reviews: Pharmacology. Available from: VitalSource Bookshelf, (8th Edition). Wolters Kluwer Health, 2022. 25 LO 4 Common toxins, their associated toxidromes and antidotes Aspirin • Poisoning causes uncoupling of oxidative phosphorylation and disruption of normal cellular metabolism. • First sign of salicylate toxicity is hyperventilation and respiratory alkalosis due to medullary stimulation. This is followed by metabolic acidosis and an increase in the anion gap due to accumulation of lactate as well as excretion of bicarbonate by the kidney to compensate. • Hyperthermia due to uncoupling of oxidative phosphorylation. • Vomiting and hypercapnia may also occur. • With severe cases: profound metabolic acidosis, seizures, coma, pulmonary edema, cardiovascular collapse. 26 LO 4 Common toxins, their associated toxidromes and antidotes Aspirin • If massive ingestion – aggressive gut decontamination including gastric lavage, repeated doses of activated charcoal and consideration for whole bowel irrigation. • IV fluids to replace fluid losses caused by tachypnea, vomiting and fever • IV sodium bicarbonate to alkalinize the urine and promote salicylate excretion (ion trapping) • For severe poisoning, emergency hemodialysis to remove the salicylate quickly and restore acid base balance and fluid status. 27 LO 4 Pharmacology Of Chelators • Chelating agents are drugs used to prevent or reverse the toxic effects of a heavy metal on an enzyme or other cellular target, or to accelerate the elimination of the metal from the body. • Chelating agents contain one or more coordinating atoms, usually oxygen, sulfur, or nitrogen, which donate a pair of electrons to a cationic metal ion to form one or more coordinate-covalent bonds. 28 Pharmacology Of Chelators Metal Chelator Lead, mercury Succimer (Dimercaptosuccinic acid, DMSA): Lead Edetate Calcium Disodium Ethylenediaminetetraacetic acid, EDTA) LO 4 *mainly for lead but may be useful for zinc, manganese and certain heavy radionuclides Copper Penicillamine – copper (previously used for lead and mercury but now succimer used) Iron Deferoxamine, deferasirox 29 POISONING BY CHEMICALS 30 LO 4 31 Carbon Monoxide LO 4 • CO is a tasteless, colorless, odorless gas released on incomplete combustion of most hydrocarbon compounds. CO poisoning can be fatal and is a very common cause of death in fire victims. • The classic causes of CO poisoning include leaving the door of a gas oven open (mistakenly or by trying to warm the house), sleeping in a running car, and being exposed to smoke during a house fire. • Common sources of CO include smoke or vapor from domestic fires; faulty, improperly installed, or poorly maintained heating systems; gas wood stoves and ovens; fireplaces, furnaces, and grills; and car exhaust. 32 Carbon Monoxide LO 4 Management • Administer oxygen through a tight-fitting mask • Use of hyperbaric oxygen is advocated when: – the blood carboxyhemoglobin concentration exceeds 40% – there is unconsciousness – neurological defect – ischemic changes on ECG – pregnancy or – the clinical condition does not improve after 4 hours of normobaric therapy 33 Cyanide LO 4 • Cyanide can occur as the gas hydrogen cyanide (HCN) and in liquid and solid forms as cyanide salt compounds. HCN gas is released on combustion of many plastics and rubber. • Sources of ingested CN most commonly include inhalation of HCN during house fires, of the products of combustion of plastics and rubber, and of fumes given off by cigarette smoke or vehicle exhaust. • An iatrogenic source is seen after intravenous (IV) administration of the vasopressor medication sodium nitroprusside. 34 Cyanide LO 4 • Much less commonly, CN poisoning can occur after excessive oral ingestion of foods, such as apricot seeds, lima beans, and almonds. • After entering the circulation, these foods can be metabolized to CN. Finally, children may inadvertently ingest metal polishes, insecticides, or cleaners that contain CN. Management • Hydroxocobalamin is the drug of choice. It binds to CN, forming cyanocobalamin, which is then excreted in the urine. • See table on slide 31 35 Methanol • Widely available as a solvent and in paints and antifreezes. • Metabolites are highly toxic. Methanol like ethanol is metabolized by zero order metabolism. LO 4 Management • • • Correct the metabolic acidosis Inhibiting methanol metabolism with ethanol which occupies the dehydrogenase enzymes in preference to methanol, competitively prevents metabolism of methanol to its toxic products. Hemodialysis 36 Ethylene Glycol LO 4 • Constituent of antifreezes for car radiators. • Metabolism to glycolate and oxalate causes acidosis and renal damage. Management • IV sodium bicarbonate corrects the acidosis • calcium gluconate to correct the hypocalcemia • Ethanol or fomepizole competitively inhibits the metabolism • Hemodialysis eliminates the poison 37 Learning Objectives 1.Discuss the basic principles of toxicology 2.Identify the ways in which toxic agents are classified 3.Explain the approach to managing a poisoned patient 4.Identify common toxins, their associated toxidromes and potential antidotes 38