Xenobiotic-induced Toxicity Flashcards
Describe the mechanism by which acetaminophen overdose results in liver toxicity (metabolic-based toxicant)
Acetaminophen metabolized to a reactive intermediate which provokes cellular dysregulation that causes acute liver injury. Glutathione detoxifies this reactive intermediate, so anything that depletes glutathione or increases the formation of the reactive intermediate may lead to liver injury
Tx: N-acetylcysteine administered before liver injury
Describe the primary effects of a heroin overdose (receptor-based toxicant)
Triad of altered mental status, pupillary constriction, and respiratory depression
Tx: Naloxone - antagonist with a higher affinity for the opioid receptor, must be administered repeatedly bc duration of action is shorter than most opioids
Describe the mechanism by which organophosphates produce systemic toxicity (enzyme-based toxicant)
Inhibition of acetylcholinesterase at its esteric site, inactivating the enzyme and reducing breakdown of acetylcholine and increasing its action on the post synaptic neuron or muscle cells
Describe the factors that influence the time course of a response to alcohol (direct CNS depressant)
Food, strength of drink, body weight, body type, gender, rate of consumption, functional tolerance, and presence of other medications affect the speed of absorption of alcohol
alcohol is reaches higher peak concentration with water > glucose solution > light cream
What are the primary targets of acetaminophen toxicity?
ATP depletion, Ca2+ accumulation, and ROS/RNS generation
What impact will an inhibitor of CYP2E1 have on acetaminophen toxicity?
decreased liver damage because of decreased formation of NAPQI
What impact will an agent that depletes GSH have on acetaminophen toxicity?
increased liver damage because of decreased ability to detoxify toxic metabolite
What impact will a depletion of sulfate have on acetaminophen toxicity?
greater liver damage because acetominophen will be shunted more towards the glucoronosyltransferase and CYP pathways
what impact will an inducer of glucoronosyltransferase have on acetaminophen toxicity?
decreased liver damage because acetominophen will be shunted towards that pathway instead of the CYP pathway so form less reactive metabolite
How does acetaminophen cause damage to collateral tissues besides the liver?
Release of DNA and other components results in immune-mediated amplification of cell injury
Describe the 4 stages of acetaminophen overdose
1 - nausea, vomiting, abdominal pain, sweating, discomfort, normal LFTs (intevention with acetylcysteine at this stage)(0-1 days)
2 - liver injury, URQ pain, rise in AST, ALT, bilirubin, INR (1-3 days)
3 - hepatotoxicity peaks, hepatic failure, encephalopathy and hypoglycemia, glucose, lactate, and phosphate abnormalities, coma & death (3-5 days)
4 - recovery for those who survive stage 3 (5-8 days)
Sx of opioid toxicity
hallucination, confusion, fainting, dizziness; eye, face, mouth/tongue/lips/throat swelling; seizures; difficult and slowed breathing; hives/rash; fast or slow heartbeat
What is the mechanism of action of organophosphates inactivating AchE?
The partially electropositive phosphorus is attracted to the partially electronegative serine in the esteric site of the AchE
Sx of organophosphate poisoning
miosis, mental confusion, headache, lacrimation, vomiting, cramps, diarrhea, pulmonary edema, sweating, etc.