November 29, 2022

A look at the toxicology of two OTC drugs: aspirin (salicylates) and acetaminophen. Based on information from the Bishop Clinical Chemistry Textbook and “PharmGKB summary: Pathways of acetaminophen metabolism at the therapeutic versus toxic doses” found here:

Hi everyone this is dr ed with a clean camera review video we’re going to look at the toxicology of acetaminophen and salicylates all right let’s start with a salicylate so um that is aspirin also known as estrogenic acid it is a common analgesic antipyretic and anti-inflammatory drug you can buy pretty much in any pharmacy uh its function is to decrease

Thromboxane and prostaglandin formation through the inhibition of the saccharo cyclooxygenase enzyme and so therefore it lowers inflammation and the prostaglandins and all that which cause pain cause fever and cause inflammation uh the toxic effects are seen when ingested at high doses so you can see a metabolic acidosis it can possibly lead to death um you

Can see hyperventilation also if the patient has hyperventilation they can then can develop respiratory alkalosis and other acid-base disturbances you get inhibition of the krebs cycle which results in excess conversion of pyruvate to lactate so then that’s lactic acidosis and that’s the metabolic acidosis and you can also see excess ketone body formation also

Again trying to produce energy and stuff like that using ketosis so um with salicylate poisoning you could get a respiratory alkalosis or you can get a metabolic acidosis or you can get one and then the other and so these can be quite complex acid-base disturbances the next one is acetaminophen so uh it is also known as nstop amino phenol a abbreviated apap or

Paracetamol which is para if you travel in europe and all that you will see it as paracetamol it is a commonly used analgesic drug we actually don’t know exactly how it works overdose is associated with severe hepatotoxicity in overdose the accumulation of reactive intermediates including free radicals and in cells result in a toxic effect and which is necrosis of

The liver so it kills all the hepatitis and liver cells um the consumption of a single dose greater than seven grams an adult and more than a dose of or more than 150 milligrams per kilogram in a child is considered potentially toxic to the liver in the kidneys due to the highly active metabolite which is an acetyl p benzoquinone uh i’m amine i mean so it’s napqr

So napqr is what causes trouble in acetaminophen overdoses so uh acetaminophen overdose is one of the most common drug related toxicities that is reported to poison centers it is the main cause of acute liver failure in the united states the onset of the hepatocyte damage though is long it takes three to five days after ingestion before you really start seeing

The damage to the liver and the initial symptoms of toxicity are vague they’re not specific and not predictive of the hepatic damage that is starting to happen to quantitate it um there’s a lot of immunoassays that is the most common available in pretty much any clinical lab but you can also do high performance liquid chromatography but that would be a reference

Lab test so um a little bit here um with the dosage so collection time is important so if you know when a patient has taken the acetaminophen then um usually you want to get at least a four hour level and maybe a 12 hour level and if at four hours um the levels are let’s say above about a hundred um microgram per ml of plasma then you can have this pro probable

Hepatic toxicity uh if it is below that they should be able to clear it just fine and then after 12 hours it’s more like 50 if i remember right so above 50 you can see hepatic toxicity but below 50 no hepatic toxicities so again knowing when the patient took the medicine is really important so a little bit on how acetaminophen is metabolized so you can understand

Why it’s toxic after a therapeutic dose uh cinnamon is mostly converted to the pharmacologically inactive glucuronide and sulfate conjugates so that’s the bulk of it goes to either glucoronidal sulfation and um there’s a minor fraction that will be oxidized to a reactive metabolite which is the napqi and that should be with a normal dose should be only five to

Ten percent of the dose ends up as napqi so again nabqi is highly reactive and is primarily responsible for all the hepatotoxicity of acetaminophen detoxification of napqr occurs through is binding with the sulfhydryl group of glutathione which is a master antioxidant and it uh forms a um tylenol glutathione clunk complex or pseudometric complex which then is

Ultimately excreted in the urine as cysteine and mercuteric acid conjugates but at supratherapeutic doses so doses above what is recommended for acetaminophen so anything more than four grams per day uh the sulfation pathways become saturated while uh the glucoronidation and oxidation increases a smaller amount is excreted unchanged after a highly toxic dose of

Acetaminophen the glucuronidation gets saturated as well and you get higher proportions of the drug that are eliminated unchanged and a higher proportion gets oxidized to the napqi so this time is more than 15 becoming napql which is what causes all the damage so uh the problem with apqs is that it eventually depletes the glutathione stores and then starts to

Form protein protein adducts through the binding to cysteine groups on cellular proteins and that’s where it starts causing all the damage any pqr primarily targets mitochondrial proteins and ion channels leading to the loss of energy production ion misbalance and cell death and this is all indeed hepatocytes so therefore an acid steal cysteine rnac was shown to

Be an effective antidote for a cinnamon overdoses in humans because it can replenish glutathione stores so any acetylcysteine is a precursor to glutathione and it’s actually hard to give glutathione and it be properly absorbed so it’s better to give it all the building blocks which is in in acetal cysteine and then let the body convert that to glutathione so

Then uh as the glutathione is replenished scavengers uh it scavenges the reactive oxygen species in the mitochondria and enhances the full sulfation metabolic pathway so it helps clear that toxic napq if uh inacetyl cysteine is administered within eight to ten hours after an acute overdose it reduces the risk of hepatotoxicity to less than five percent so that

Is just like first line of defense that’s what they do um overall in acetal cysteine prevents liver damage renal failure and death and it’s treatment of choice for tylenol overdose or for acetaminophen overdose and that is it

Transcribed from video
Toxicology of Acetaminophen and Salicylates By Dr. A’s Clinical Lab Videos