Hello, my name is Rachel Wein, and I'm currently the Emergency Medicine Clinical Pharmacist Specialist at Detroit Receiving Hospital in Detroit, Michigan. And today I'll be talking about some exciting updates for pharmacists in toxicology. The objectives are listed for you here. At the end of this presentation, you should be able to evaluate advances in the recognition and management of patients with toxicological emergencies. Specifically, we'll be focusing on the use of rivastigmine in anticholinergic toxicity and fimepazole in massive acetaminophen ingestions. I have no relevant financial disclosures to report, but we will be talking about two off-label uses of drugs. Our first toxicological update we will be discussing is an alternative to phizostigmine in anticholinergic overdose. Phizostigmine is usually our drug of choice for anticholinergic overdose. It is a carbamate with a tertiary amine structure. It irreversibly inhibits acetylcholinesterase by competitively binding to the enzyme in order to prevent it from degrading acetylcholine, which allows acetylcholine to accumulate in the synaptic cleft and overcome the blockade of muscarinic receptors by the anticholinergic agents. Because phizostigmine is a tertiary amine, it is uncharged, lipophilic, and easily crosses the blood-brain barrier. This action allows phizostigmine to reverse toxic central nervous system effects. However, phizostigmine is on shortage and not expected back until mid-2023. There is another centrally acting reversible acetylcholinesterase inhibitor, which is rivastigmine. Rivastigmine is a common drug used for other indications such as dementia. It has been suggested in recent articles that it can also treat anticholinergic toxicity. It is thought to inhibit the hydrolytic action of cholinesterase, resulting in increased acetylcholine concentration. In addition, rivastigmine has a tertiary amine structure, which means it crosses the blood-brain barrier and can help decrease the toxic CNS effects like phizostigmine. The use of rivastigmine for anticholinergic overdose is detailed in a case report by Hughes and colleagues from 2021. A previously healthy 36-year-old female was brought to the emergency department after being found unresponsive at a bus stop, covered in pink-tinged emesis next to an empty bottle of diphenhydramine. Upon assessment, she was tachycardic up to the 120s and very agitated, with the Richmond agitation sedation score, or RAS score, of positive 3. She was given one milligram of lorazepam intramuscularly and then another one milligram intravenously. At this time, toxicology was consulted, and they recommended administering phizostigmine. However, there was no phizostigmine in the hospital at the time, so the patient was instead administered three milligrams of rivastigmine orally, followed by two additional three milligram oral doses over the course of two hours. On re-evaluation, the patient remained slightly confused, but showed significant improvement in her agitation. Throughout the next 24 hours, the patient did require one additional three milligram dose of rivastigmine orally for a total of 12 milligrams, with complete resolution of her symptoms. In conclusion, as I mentioned, Hughes and colleagues found the patient not only had complete resolution of her symptoms, but she had no adverse effects associated with receiving rivastigmine. Furthermore, the patient did not experience recurrent symptoms of anti-muscarinic toxicity and was able to be discharged shortly after. When comparing phizostigmine and rivastigmine, there are some similarities and differences I would like to highlight. Both phizostigmine and rivastigmine are acetylcholinesterase inhibitors, which work peripherally and centrally. The usual doses are listed for you there. Phizostigmine is only available IV, while rivastigmine is available orally and transdermally. Both drugs are well known to cross the blood-brain barrier. In regards to their pharmacokinetics, rivastigmine has a slower onset of action and a slower duration of action. It lasts 10 hours, while phizostigmine only lasts 45 to 60 minutes. The favorable pharmacokinetics of rivastigmine may actually offer some potential therapeutic advantages in anticholinergic toxicity. Due to its slower rate of CNS penetration, there is a lower potential for initial cholinergic symptoms. Due to its longer duration of action, patients may experience reduced symptoms occurrence and decreased need for redosing. As I mentioned earlier, it comes in multiple formulations and is actually less expensive than phizostigmine. What is the recommended dose of rivastigmine for anticholinergic toxicity? It is suggested to administer 3 to 6 mg orally every 1 hour based on RAF scores until resolution of CNS symptoms. The max dose is 12 mg in 24 hours. So what is rivastigmine's place in therapy? Rivastigmine appears to be a safe and effective alternative to phizostigmine in patients with anticholinergic overdose and may actually offer some therapeutic benefits over phizostigmine. However, more literature is needed to fully evaluate where rivastigmine fits. Next, we will move on to an adjunct of therapy for massive acetaminophen toxicity. Our gold standard for acetaminophen toxicity is N-acetylcysteine, which increases glutathione stores, acts as a glutathione substitute, binds NAPKE, and enhances sulfate conjugation. Unfortunately, despite the use of N-acetylcysteine, hepatotoxicity can still occur, especially in massive overdoses. Femepizole is a known inhibitor of alcohol dehydrogenase in methanol and ethylene glycol poisoning and multiple studies have demonstrated its safety. Due to a couple different mechanisms, which we will discuss in the next slide, femepizole can also be used to treat acetaminophen overdose. The proposed benefit of femepizole in acetaminophen toxicity occurs by two mechanisms. The first is CYP2E1 inhibition. Several studies have demonstrated femepizole's inhibition of CYP2E1. In vitro data from human liver microsomal protein studies suggest that the concentration of femepizole at which CYP2E1 is maximally inhibited occurs at 100 micromoles. The serum concentration achieved in humans following a loading dose of 15 milligrams per kilogram of femepizole over 30 minutes is well above this. Due to femepizole's potent CYP2E1 inhibition, the conversion of acetaminophen to NAPKE is prevented via this mechanism. The second mechanism of action is through the inhibition of the JNK enzyme, or the sejun N-terminal kinase. NAPKE-induced mitochondrial dysfunction leads to formation of reactive oxygen species. This oxidative stress leads to activation of the JNK enzyme. This enzyme translocates to the mitochondria, amplifying oxidant stress, and ultimately results in the cessation of ATP production. The JNK enzyme can lead to the rupture of the outer mitochondrial membrane, causing release of intermembrane proteins, which can potentially lead to DNA fragmentation. When femepizole inhibits JNK, this prevents any further toxicity during the metabolic phase. The first use of femepizole for acetaminophen toxicity was described by Zell Cantor and colleagues in 2013. A 59-year-old female was found down at home with an unknown ingestion at an unknown time. Her initial acetaminophen level was 1,147 milligrams per liter, and the level peaked two hours after presentation at 1,193 milligrams per liter. She was treated with activated charcoal, sodium bicarbonate, and acetylcysteine. And then femepizole was also started, given her anion gap acidosis. Toxic alcohol ingestion was suspected. The patient received 15 milligrams per kilogram of femepizole one time, and IV and acetylcysteine was continued for 48 hours. She started to recover, and her transaminases decreased on day three and normalized by day four. Zell Cantor and colleagues reported that this was the largest acetaminophen ingestion that was treated solely with IV and acetylcysteine. It wasn't until 2016 where Yip and Hurd, given the promising in vitro and animal data, suggested that femepizole may have actually played a role in improving the clinical outcomes that were reported in this case. In fact, this case report is the first that may suggest the existing animal data may be clinically relevant in humans, and supplemental femepizole treatment following severe acetaminophen poisoning may be of benefit. More case reports followed after 2013. In these particular instances, both case reports, both patients ingested massive amounts of acetaminophen, which required both IV and acetylcysteine, femepizole, and even hemodialysis in one of them. There was concern for hepatic failure. However, these patients did see decreases in their acetaminophen levels and were able to be discharged safely home. I would also like to discuss this case series by linking colleagues from 2022. This is a case series of 14 patients treated with standard IV and acetylcysteine and femepizole as an adjunct. In particular, I have case 13's time course posted on the screen. This was a 16-year-old woman with no significant medical history who presented to the emergency department after experiencing abdominal pain and vomiting after stating that she took 15 acetaminophen tablets one day prior. Her initial acetaminophen level, approximately 24 hours after ingestion, was 24 micrograms per ml. Her presenting transaminases were an ALT of 2,314 units per liter and an AST of 4,062 units per liter. She started on IV and acetylcysteine. Two hours after acetylcysteine was started, her transaminases rose again. She was transferred to a tertiary medical center, and at 32 hours post-ingestion, she was administered a loading dose of femepizole, 15 milligrams per kilogram, over 30 minutes. Transaminases were improving four hours post-femepizole. The patient ended up making a full recovery and transaminases significantly improved after treatment. In all of these 14 cases, it was concluded that no significant liver injury occurred despite persistently elevated acetaminophen levels. So the authors found that femepizole as an adjunct either completely prevented any hepatotoxicity, mitigated the effects, or reversed significant hepatocellular damage. The recommended dosing of femepizole is 15 milligrams per kilogram, followed by 10 milligrams per kilogram every 12 hours. In this case, usually only one to two doses are needed. Where is femepizole's place in therapy? Well N-acetylcysteine is still the treatment of choice, but femepizole does seem to be a reasonable option to consider in select poison patients. Femepizole should be considered when there are signs of hepatotoxicity or massive ingestion. Although femepizole may be a costly drug, it is less expensive than the continued ICU or transplant care a patient may receive after entering fulminant hepatic failure. In conclusion, here are some key takeaways from this presentation. Rivastigmine dose based on RAS scores appears to be safe and effective in treating anticholinergic overdose. Rivastigmine may have potential benefits over physostigmine due to its favorable kinetics. Finally, femepizole is a safe adjunctive agent in massive acetaminophen overdoses and can actually reduce hepatocellular injury and should be considered in select poison patients. Thank you for listening to this presentation about updates in toxicology for the year. If you have any questions, my contact info is listed on this slide. And I just want to thank again the Society of Critical Care Medicine.

rivastigmine

anticholinergic overdose

femepizole

acetaminophen toxicity

toxicological emergencies