Lecture 13 Biochemical Toxicology PDF

Biochemical Toxicology 1. Toxicology The study of the adverse effects of chemicals on the body Approximately 24 common drugs or toxins account for 80% ER visits Each laboratory has its own drug-testing menu Importance of drug testing: Workplace Competitive sports Pregnancy...

Biochemical Toxicology 1. Toxicology The study of the adverse effects of chemicals on the body Approximately 24 common drugs or toxins account for 80% ER visits Each laboratory has its own drug-testing menu Importance of drug testing: Workplace Competitive sports Pregnancy Toxicity diagnosis 2. Diagnosis of Poisoning Made more often based on clinical findings than lab findings Guide test selection and interpretation Important data: Date/time exposure Physical condition/symptoms (which drug/toxin?) Each specific substance produces a specific toxic syndrome (toxidrome) when there is larger amount of drug in the body Symptoms may overlap Difficult identification Biochemical tests requested in most suspected poisoning: Serum urea, electrolytes LFTs Blood glucose Blood gases 3. Routes of Exposure Chemical’s physical state and route of exposure influence toxicity Commonly toxic effects occur at the site of absorption Toxins enter the body through: Skin Gastrointestinal tract Concentration, distribution, metabolism Lungs Fastest route for toxins to enter systemic circulation Concentration of gas is important, solubility in blood Other routes Injections Eyes 4. Tests for Confirmation of Poisoning Signs and symptoms in poisoning E.g., anticholinergic drugs and ethanol effects Measures of drug levels Qualitative Simply presence or absence of drug E.g., Nonaccidental poisoning, confirmation of brain death Quantitative Knowledge of plasma concentration may alter treatment E.g., Acetaminophen, salicylate, carbon monoxide Indication of severity of the poisoning Serial measures can be useful 5. Dose-Response Relationship Any chemical can be toxic Most drugs and toxins exhibit a dose-response curve Each curve is different for each drug/toxin Threshold Chemicals with no well-defined safe levels Poisons 6. Acute and Chronic Toxicity Toxic dose (TD) Lethal dose (LD) Acute toxicity occurs in a short amount of time Single or multiple exposures in a short period of time Expressed as LD50 Chronic toxicity occurs over longer periods of time Repeated or continuous exposure Metal Poisoning 7. Metal Poisoning Essential Vs. Toxic metals One of the oldest forms of toxicity known to man Most cases due to environmental contamination or administration of drugs, cosmetics Effects: renal tubular damage, gastrointestinal erosions, and neurological damage Many workers have been chronically exposed to metals that cause tissue injuries Toxic metals Lead Mercury Aluminum Arsenic Cadmium 7.1 Metal Poisoning - Lead Heavy metal Environmental toxin in lead-based paint made before 1978 and soil Exposure routes: Consequences: Ingestion ▪ Disruption of heme production Traditional medicines, lead-based paints ▪ CNS RBC, bones, CNS Neurotransmitters Inhalation Neuronal function Industrial pollution ❖ Impacts neuronal connection= Cardiovascular and respiratory effects activity dependent Absorption (skin) Childhood mental development Less likely to cause systemic effects Levels above 3.5 µg/dL - concern 7.2 Metal Poisoning - Mercury Dense liquid that vaporizes at room temperature Used in dental amalgams, thermometer and sphygmomanometers (in past) Most toxic with methanol = methylmercury Exposure routes Consequences: Inhaled (most harmful form) Absorbed through skin Ions of mercury react with proteins Ingested (fish and shellfish) Proteins become immunogenic – tissue damage Bile is the main route of mercury Mercury concentrates in the kidneys before excretion excretion Long-term exposure = CNS toxicity 7.3 Metal Poisoning - Arsenic It may be found in insecticides, paints, weed killers, etc. Acute ingestion (symptoms after 1 hour) Violent gastrointestinal pain, vomiting, hypovolemic shock, circulatory failure Urine analysis Chronic ingestion Chronic arsenic poisoning is difficult to diagnose Diarrhea, dermatitis, renal symptoms and polyneuropathy It was used in treatment of colitis Hair analysis (> 0.5 µg/g hair; significant exposure) 7.4 Metal Poisoning – Diagnosis and Treatment What do clinicians rely on? Biochemical measures: Plasma/serum/blood levels Urine Hair Common treatments Removal of the source Chelating agents E.g., Dimercaprol Excretion Alcohol Poisoning 8. Alcohols - Methanol Methyl alcohol or wood alcohol Antifreeze, paints, illegal moonshine, etc. Main exposure routes Ingestion/inhalation/skin absorption Once methanol is ingested: Metabolized in liver– formaldehyde – formic acid Lab considerations: (slow) – CO2 and water Metabolic acidosis (with increased anion gap), respiratory failure, blindness - Anion Gap Mechanisms of actions: - Serum osmolality 1-CNS depressant - Serum methanol levels 2-Converted in the liver to formaldehyde and formic acid 8. Alcohols - Ethanol Most common overdose seen in emergency situations Ethanol Mechanism of action in cells/organs? All trauma patients have ethanol measured! Legal limit for driving in Ontario 0.08% - 80 mg/dL 8. Alcohols - Ethanol Acute ethanol poisoning Effects Directly related to the blood ethanol concentration More difficult to determine in cases of coma, other drugs, head injury Diagnosis Blood ethanol measure When not available: Plasma osmolality Osmol gap How rapid is the acute ethanol poisoning recovery? Health renal and hepatic functions 8. Alcohols - Ethanol Chronic ethanol poisoning Effects of chronic ethanol abuse Toxicity of acetaldehyde Failure of homeostatic and synthetic mechanisms in liver e.g., ROS Early sign: hepatomegaly Sequelae of chronic intake Impaired glucose tolerance Diabetes mellitus Hypertriglyceridemia Cirrhosis Coagulation defects Cardiomyopathy 8. Alcohols - Ethanol Diagnosis of chronic ethanol ingestion Patient’s history Blood markers – no objective marker Gamma-glutamyl peptidase (GGT) Serum triglyceride MCV (poor diet) Hyperuricemia 9. Alcohols - Isopropanol Common solvent and disinfectant Mouthwashes, skin lotions, hand sanitizers, etc. Exposure route: ingestion/inhalation Metabolism Liver- isopropanol to acetone (slowly eliminated) Consequences CNS (2x ethanol effect) Death (rare) Diagnosis Plasma isopropanol level Urine acetone level 10. Alcohols– Ethylene Glycol Widely used in antifreeze Sweet taste! Exposure routes Ingestion (absorbed by GI tract) Nontoxic itself Metabolites: glycolic acid (most important), oxalic acid, etc. Mechanism of action Ethylene glycol to glycolic acid (high anion gap; metabolic acidosis) and oxalic acid (precipitates in urine as calcium oxalate crystals) Glycolic acid correlates directly with mortality rates CNS (can be confused with ethanol intoxication) Nausea, vomiting, depressed reflexes, coma  11. Anion Gap and Osmol Gap Usefulness in Toxicology The anion gap test is useful for investigating the (Na+ + K+) – (Cl- + HCO3-) = Anion Gap cause of toxidrome 8 to 16 mmol/L Increased anion gap – increase in unmeasured anions in specimen E.g., methanol, ethylene glycol, salicylates, etc. Osmol gap Serum osmolality = (2 x [Na + ]) + Increased osmol gap – presence of other compounds (BUN/2.8) +(glucose/ 18) (toxins) Osmotically active substance not accounted E.g., Methanol, ethanol, isopropanol, ethylene glycol, acetone, etc Osmol GAP (measured – calculated) = less than 10 mOsm/Kg 12. Toxicity of Common Medications Drugs have: Therapeutic effects Side effects A drug may become toxic Common causes of poisoning include: Salicylate Pixabay.com Acetaminophen (Paracetamol) 12. Toxicity of Common Medications ❖Salicylate poisoning Acetylsalicylic acid (Aspirin) Rheumatoid arthritis Rapidly absorbed, hydrolyzed to salicylate (salicylic acid) Severe metabolic acidosis Stimulation of respiratory centre in brain (respiratory alkalosis) Hyperventilation Treatment: forced Contribute to the anion gap alkaline diuresis Symptoms/signs Tinnitus and acid-base abnormalities 12.Toxicity of Common Medications ❖Acetaminophen (paracetamol) poisoning Not toxic but toxic metabolites (saturated liver enzymes) Serious hepatocellular damage Antidote? N-acetylcysteine Before 12 hours of ingestion Prevents all hepatotoxic and nephrotoxic effects Triphasic clinical course First 24 hours (nausea, vomiting, diaphoresis, anorexia) 24 to 48 hours Apparent improvement Hepatic necrosis Increased bilirubin, ALT and AST, prolonged prothrombin time 3 to 5 days postingestion (liver failure) Laboratory consideration Bilirubin, ALT and AST, prothrombin time 12. Toxicity of Common Medications Chronic Poisoning Gradual buildup in drug concentration over a period of time Ingestion of usual medications Plasma drug concentration can be helpful Withdrawn of drug in use Dose decrease What about synergistic effects? E.g., Ethanol and benzodiazepines 13. Role of the Laboratory in Poisoning Confirm diagnosis Provide information for patient management Further investigation Antidotes Hemodialysis (water soluble chemicals) Plan resumption of usual therapy Aid in diagnosis of brain death Forensic uses