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Random Tox Fact of the Week (RTFOW)

Random Tox Fact of the Week (RTFOW; thanks to Ken Spaith for this nugget of knowledge):  Perfluoroalkyl and polyfluoroalkyl (PFAS) are compounds used extensively in non-stick surfaces, stain resistant textiles, as well as water proofing for outdoor gear, such as GoreTex™. One way to think of them is as fluorinated surfactants: Even though fluorine is the most electronegative element, their electron clouds are balanced so that they are super lipophilic and extremely hydrophobic.  Exposure usually occurs through either contamination of drinking water near a manufacturing plant or through chronic consumer-level exposure; such as, scraping of a non-stick surface into food as it is being cooked or through leaching of the PFAS from clothing into the skin. PFAS exposure has  been associated with asthma, hepatotoxicity, renal-toxicity, ulcerative colitis, pre-eclampsia, thyroid dysfunction, testicular CA, hyperlipidemia, and increased serum uric acid levels. The molecules are usually not formally charged, and due to this fact, they are not covalently bound to the surfaces on which they are sprayed; which means, they can relatively easily contaminate the users of products containing PFAS. 

Images are public domain

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RTFOW 7/17: Thienodiazepines

The subject of this week’s Random Tox Fact of the Week (RTFOW) is Thienodiazepines, which are benzodiazepine analogs. Essentially, the benzene ring of the benzodiazepine class has been substituted for a triazolo moiety. Etizolam is the most readily available thienodiazepine. See structures below. A cursory review of the literature indicates that etizolam may have an equipotent pharmacodynamic effect to alprazolam

Many are unscheduled by the DEA and are readily available over the internet. For the curious: here is one place to get tablets. https://www.etizolab.com/product/etilaam/

AND here is one place to get powder: https://www.chemicalfrog.com/product/etizolam/ 

You can get 1 kg of powder for approximately 10,000 $USD. 1 kg has 1,000,000 single mg doses. If pressed and sold “xanny bars” on the street, only 1 kg would have a street value to 2 to 5 million $USD. Just food for thought: perhaps these need to be regulated and schedule in the US, and maybe we should be looking for these substances in seized counterfeit pharmaceuticals.


Etizolam

Diazepam

images are public domain

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Masks with 1-way valves do not protect the public

I have seen many people, including health care professionals, who are utilizing self-purchased PPE. When healthcare professionals use their own PPE, the PPE may not adhere to the standards set up by hospital infection control committees. One such glaring example I have seen in and out of the hospital is the use of N95 respirators with 1-way valves.

Effectively, the wearer breaths filtered air, but when exhaling, the 1-way valve opens allowing for un-filtered and, therefore, easier exhaust of the exhaled breath. This means N95’s with 1-way valves protect the wearer, but do not protect patients or the public. As such, if no other respirator is used, a surgical mask should be placed over the 1-way valve to prevent transmission should the wearer be in the active stages of a COVID-19 infection.

Below are some examples of N95 respirators with 1-way valves:

1-Way Valves for various respirators used during the COVID-19 pandemic, they should not be used unless no other N95 respirator is available. -Wells Brambl, MD 2020

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My Foray into YouTubing, what better time than now.

Background: Wells Brambl, MD is an emergency medicine physician and medical toxicology fellow in New York. In this 16 minute lecture, I summarize the virology of, diagnostic approach and limitations to, and emerging treatments for COVID-19. This lecture consists of my own interpretation of the data and opinions only. It does not reflect the institutions I work for, nor does it constitute medical advice. If you think you have symptoms and need a medical evaluation, see a doctor.

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Ethanol, breathalyzers, and mouth wash

Recently published work by Ernstgård, et al has shown that after 15 minutes, the false positive rate for a breathalyzer approaches zero. In a nut shell, the authors exposed healthy male and female volunteers to both inhaled ethanol (to mimic a workplace exposure) as well as commercially available ethanol containing mouthwash (21.6% EtOH w/w).

Their results show that neither scenario resulted in a significant elevation of blood alcohol concentration (BAC) at 15 minutes.

The study is available in Clinical Toxicology’s June 2019 release: https://www.tandfonline.com/doi/full/10.1080/15563650.2019.1626868

Interestingly, the elimination of mouth wash ethanol and inhaled ethanol appear to follow first order kinetics, which makes sense from a theoretical point of view. First and foremost, these study participants had no exogenous ethanol on board, so the elimination of ethanol from the oral cavity would be a combination of absorption and evaporation, both of which are concentration dependent in small quantities. Whereas, when ethanol is ingested in recreational doses, alcohol dehydrogenase becomes saturated, which results in linear, zero order kinetics.

In New York, it is standard practice for the arresting officer to wait 20 minutes from the time of a traffic stop, a smoked cigarette, observed imbibing of alcohol, chewing gum, or use of ethanol containing mouth wash prior to administration of a roadside breathalyzer test. When combined with the evidence presented in this limited study, this practice appears to nullify the possible legal defense that the client used ethanol containing mouthwash, resulting in a false positive BAC measurement.

This study is far from definitive in the sense that it is not a randomized control trial. The researchers were not blinded. Participants were not blinded. There was no control group (eg alcohol free mouth wash). Therefore, the scientific methodology of this study is too limited to make definitive conclusions. Furthermore, the study only exposed volunteers to 20 mL of Listerine mouthwash for 30s. This is not a very large exposure. Would someone who gargled an entire mouthful of mouthwash have had higher levels for longer amount of time? The study completely fails to address this fact, and as such could not necessarily be used successfully in a court of law to negate the mouthwash defense.

However, that is not how the law works. Criminal law is based upon a preponderance of evidence and proof beyond a reasonable doubt that the client is guilty. So, if we think that principles of the paper are most likely right, then it can stand up in court as the prosecutions counter argument to the mouth-wash argument in DUI defense.

However, there is a critical point that the authors of the paper fail to discuss. The kinetic model of this paper seems to suggest that at 20 minutes residual ethanol from the mouth wash could give a BAC reading of 0.01%. What if a client has a true BAC of 0.07%, but they used mouth wash and are breathalyzed at 20 minutes? At the time of measurement, they may be above the legal limit in terms of breathalyzer measured BAC, however their true serum BAC would be below the legal limit.

Figure
This is the kinetic data from 1 of the subjects for oral exposure to 21.6% containing mouth wash. The main thing to note is that at 19 minutes, the measure breath alcohol concentration is 0.02%.

As a result, the kinetics used in this paper could be used to completely negate beyond a reasonable doubt the prosecution’s assertion that the serum BAC was truly above the legal limit. So, it would seem that law enforcement officers should check the breathalyzer BAC at 20 minutes and then again 20 minutes later to ensure an accurate estimation. A one time reading at 20 minutes could truly be below the legal limit if the client just used mouthwash and had exogenous ethanol in their blood stream. So, this kinetic data could be used as a valid defense for clients with a breathlyzer BAC above, but near the legal limit, and who had used any ethanol containing mouth freshening agent.

It is important to note, that the legal limit in Sweden of 0.02% BAC is much lower than in the United States. In their case, it is even more conceivable that a person could have had 1 drink, metabolized some of that drink and then use a mouth freshening agent upon being pulled over. So, a difference of 0.01% at 20 minutes, could even more easily be the difference between a DUI arrest or not.

Figures reproduced under Creative Commons 4.0 license:

Ernstgård L, Pexaras A, Johanson G. Washout kinetics of ethanol from the airways following inhalation of ethanol vapors and use of mouthwash. Clin Toxicol (Phila). 2020;58(3):171-177.

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Hydrogen Sulfide

Hydrogen Sulfide 

Mechanism of action:

  • Just like cyanide, it inhibits cytochrome 4 of the electron transport chain. It also bind the heme moiety like CO. 
  • Once inhaled, hydrogen sulfide ionize and are metabolized to sulfides and sulfates, interfering with cytochromes and metalloproteins. 

How to make:

  • As per a Japanese case report: 610HAP[20-25% calcium polysuflides] (a 440 g bottle of a liquid bath essence containing 160-195 g/kg sulfur) and 10 of Sunpole (a 500 mL bottle of a toilet bowl cleaner containing 9.5% HCl)
  • In the US: HCl + “Lime Sulfur Spray”
  • The reaction between calcium sulfate salts and  results in volatilized yellow/green residue on windows maybe visible, smells of rotten eggs

Dose response:

  • 20-100ppm=mild mucous membrane irriation
  • 100-150ppm=olfactory nerve paralysis
  • 150-300ppm=respiratory mucosal irratation and possibly ARDS
  • >500ppm=rapid loss of consciousness
  • >700ppm=cardiopulmonary arrest
  • >1000ppm=cessation of breathing after 1-2 breaths

Intentional uses:

  • Chemical weapon: The main documented deployment of H2S during warfare was by the British during World War 1.
  • “Chemical” suicide: There have been numerous documented cases of completed suicides in vehicles. Often times the victims will place up warning signs so rescue workers are notified of the toxic gas so they can take protective measures.

 

Occupational exposures:

  • Sewer workers in confined spaces. It is produced by bacterial metabolism and is more dense than air so it sinks to the low points of enclosed systems. The classic presentation is that 1 worker enters a low spot and collapses and has immediate respiratory arrest. Once the first worker does not return, another one follows them and suffers the same fate. The term for this is a “knock-down”.
  • Seismic activity: volcanoes, hot springs, etc.
  • Oil and gas workers.

Clinical findings:

  • Acidosis not explained by other cause
  • Pulmonary edema
  • The symptoms will be similar to any mitochondrial toxin, eg cyanide. So expect, shock, circulatory collapse, and altered mental status.
  • including delayed neuropsychiatric effects

Diagnosis:

  • A history of an exposure will be the strongest indicator in combination with the clinical data.
  • Diagnostic testing for H2S includes measurement of blood and urine thiosulfate, but will likely take days to weeks to result because it requires a specialized medical laboratory.
  • Basic labs, including a blood gas and a lactate concentration.

Treatment:

  • Remove  victims from contaminated area
  • Aggressive supportive care
  • 100% NRB vs ?HBO
  • Sodium nitrate (theoretical like cyanide, and may reverse sulfmethemoglobinemia); avoid sodium thiosulfate.

Image references: 

all images public domain license

image 1: https://upload.wikimedia.org/wikipedia/commons/thumb/c/c6/Hydrogen-sulfide-2D-dimensions.svg/2880px-Hydrogen-sulfide-2D-dimensions.svg.png

Image 2: http://hendonpub.com/assets/articles/5110/206a8b6b-1c8f-4546-a48f-17d83b1972fd.jpg

References: 

PMID: 18516944

https://www.riverview.org/downloads/pdfs/rvh-ems-chemical-suicide-presentation.pdf

Goldfrank’s Toxicologic Emergcies, 11e

Visits: 3470
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Palytoxin

This is a 15 minute talk I gave on palytoxin during residency, which I recorded. The YouTube video is embedded. Enjoy this dive into an obscure, yet interesting toxin.

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Infiltration of IV contrast into SQ tissues

I think we all dread this. Just imagine this scenario: you are concerned that your patient has a pulmonary embolus. They are tachycardic, hypoxic on room air, but BP’s are stable (for now). They were a tough stick and 2 nurses tried for 5 minutes, so under real time ultrasound guidance you place what you think is an expert 20g x 48mm angiocath in their right cephalic vein.

You dial the CT tech and ask the radiology technologist to scan the patient next, then you are off to see the next patient on a busy critical shift.

15 minutes later, you get a call: “Ummmm… Doc, patient x…. that line blew. They got the whole load in the right arm. Can you come take a look?”

This happens about 0.24% of patients who receive IV contrast in the upper extremity (or about 1/400 studies).

UNDERSTANDING CONTRAST:

The Omnipaque™ we use for our IV contrast CT studies is Iohexol:

Here is its structure:

1200px-Iohexol.svg_-1.png

The concentration we use is 350 mg/mL, this results in a total osmolality of 844 mOsm/kg water. This is approximately 3 times the osmolality of serum. However, given the fact it is non-ionic, it does not cause a significant osmolar effect. Nonetheless, infiltration will lead to fluid shift of H2O down its gradient into the tissue compartment the infiltrated contrast material occupies, which is typically the interstitial space. This has been shown experimentally in a renal model: after a contrast load, urine output increases because the iohexol is renally excreted.

The most danger for infiltration occurs with high flow rates achieved during CT angiography studies. The auto injector typically used has a flow rate 4-5 mL/s achieved with a pressure gradient anywhere from 50-100 psi. If the IV has poor flow due high intracatheter or intravenous resistance, then the pressure can increase to upward of 400 PSI to achieve flow. When this high pressure occurs, the IV can become dislodged. Remember Newtonian mechanics: Pressure exerts a force, and for each force there is an equal and opposite reaction.

MANAGEMENT OF IV INFILTRATION OF A CONTRAST LOAD:

####first and foremost, you need to inform the patient what happened. Explain why this happened. Apologize for the complication. Address any pain issues. Tell them how you and the team will care for their likely painful upper extremity. Finally, you can reassure them for the reasons below.

*Gradually, the infiltrated contrast will diffuse out of the tissue compartment and back into the serum. This diffusion can be enhanced with gentle warm compresses.

**Plastic surgery recommendations for this complication are elevation of the extremity, local massage, and frequent neuromuscular checks.

***In a study of 102 cases of IV contrast extravasation in the upper extermity, surgical intervention was required in 0. The surgeons behind this study recommend surgical consultation if there obvious signs of skin compromise or compartment syndrome.

****compartment syndrome has been reported in the case literature, so please, please, please, watch for that. The incidence is on case report level, so it is likely very, very low.

SOME TIPS PREVENTION OF IV INFILTRATION OF US GUIDED PIV’s:

*Always use the 48 mm angiocath

**The more of the catheter that is in the lumen of the vein, the less likely it is to become dislodged. So a good rule of thumb is at least 1 cm of the catheter within the lumen of the vein. So any target >2cm deep to the skin will be difficult to properly position using a 45 degree angle of approach.

One fun final fact: non-ionic iodinate contrast materials are procoagulants and as per the FDA they should be avoided at all cost patients with homocystinuria.

Best regards,

Wells

References:

note: image of iohexol is public domain

https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018956s095,020608s031lbl.pdf

https://www.sigmaaldrich.com/catalog/substance/iohexol821146610895011?lang=en®ion=US

Jonas Pologe’s US PIV POD

Belzunegui T, Louis CJ, Torrededia L, Oteiza J. Extravasation of radiographic contrast material and compartment syndrome in the hand: a case report. Scand J Trauma Resusc Emerg Med. 2011;19:9.

Sbitany H, Koltz PF, Mays C, Girotto JA, Langstein HN. CT contrast extravasation in the upper extremity: strategies for management. Int J Surg. 2010;8(5):384-6.

Solomon R. Contrast media: are there differences in nephrotoxicity among contrast media?. Biomed Res Int. 2014;2014:934947

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Theoretical Mechanism for Vaping Associated Lung Injury

Recently, there has been a significant amount of news media coverage on Vaping Associated Lung Injury (VALI) lately. We certainly are starting to see more cases. However, it is unclear if something has changed with the formulation of vaping liquids or if this disease has existed as long as vaping, but diagnosis availability limited the number of diagnoses made. Regardless, medical professionals and the media have taken a huge interest in VALI.

Typical features include: recent heavy vape use, cough, respiratory symptoms, hypoxia at rest or on exertion, GI upset, tachycardia, fever, leukocytosis, patches of bilateral ground glass opacities on chest CT. Often times patients will be diagnosed with a viral syndrome or community acquired pneumonia and be discharged from ED only to bounce back a few days later with more serious symptoms. It is also possible many diagnoses of VALI are mistakenly diagnosed as multifocal pneumonia with sepsis. The technical diagnostic criteria for VALI are a patient with respiratory symptoms, a history of vaping, ground glass opacities on CT, a negative infectious workup, and no other likely etiology for their presentation.

There have been numerous articles that show that vapor clouds contain significant amount of free radicals. Presumably this is due to direct exposure to thermal electromagnetic radiation on the heating coil. Many formulations now use tocopheryll acetate, which is then converted in vivo into tocopherol, or Vitamin E. Tocopherol is a free radical scavenger and is involved biochemical redox pathways that eventually deplete glutathione (see figure below). Some data show the higher level “mod” vaporizers produce as much free radicals as conventional cigarettes. However, the frequency and quantity of use amongst users, especially if perceived to be safe, may increased when compared to smokers of tobacco cigarettes.

Furthermore, given the clinical findings of lipid laden macrophages and their red stain with “oil red o” on bronchial alveolar lavage (BAL), it is also conceivable a mechanism of action is the deposition of diluents, leading to a multifocal lipoid pneumonia. Others have also suggested that nanometal particles from the heating coil may be inhaled, leading to lung injury.

Finally, steroids have been the mainstay of treatment. Normoxia should be maintained, but hyperoxia avoided to prevent the accumulation of free radicals. Typically antibiotics are given until infection is ruled out. Thus, if a contributory mechanism of injury is chronic depletion of glutathione, an treatment could be IV NAC in combination with aerosolized NAC (Mucomyst). NAC is well tolerated and unlikely to cause harm if administered correctly. However, a prospective trial that assesses the role of NAC for this indication needs to be performed.

Biochemical pathways for antioxidants in the lung demonstrating theoretical role for NAC in treatment of vaping associated lung injury (VALI). Please note the diluents of the vaping liquid are depositing on the air-lipid surface.

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Toxic Plants and Animals Flashcard Set

Flashcards aid in memory repetition of difficult to memorize plants that may show up on boards and in-service exam. This list will grow as I distill my readings and notes into only the highest yield memorization points.

note: all images used are public domain, unless otherwise cited within the flashcard

2nd note: you can zoom in on all images for a better picture, resolution is preserved

Latrodectus spp.

Latrodectus spp.: describe their general characteristics, habitats, pathophysiology, symptoms, and treatment modalities.

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  • *Lactrodectus mactans and geometricus are the black widow and brown widow, respectively.
  • *Widows are found all over the United States (except Alaska), but seem to be more predominant in the south. The are also found abundantly across the globe in non-arctic regions.
  • *Envenomation from the bite infiltrates a variety of insect/crustacean specific toxins and alpha-latrotoxin, which is a pore forming toxin at the presynaptic terminal. Ca2+ influxes as a result, leading to an exocytosis of neurotransmitters (eg, NE, dopamine, seratonin, GABA, glutamine, etc).
  • *Pain can be local, regional, or systemic. Systemic manifestations involved generalized myalgia, headache, diaphoresis, and abnormal vital signs. Myopathy can also occur, which may progress to rhabdomyolysis and acute renal failure.
  • *Indications for antivenom include high risk populations with severe symptoms, such as pregnant patients.
  • *Treatment should predominantly involve benzodiazepines and opioid analgesics for moderate to severe symptoms. Minor symptoms can be treated with NSAIDs and cold packs.
  • ***Bonus: females practice sexual cannibalism and eat the males after copulation.

L. Geometricus 

Mfield, Matthew Field, http://www.photography.mattfield.com [GFDL 1.2 (http://www.gnu.org/licenses/old-licenses/fdl-1.2.html)]

L. Mactans

Shenrich91 [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]

Latrodectus spp.
Centuroides spp

Describe important clinical features of Centuroides Exilicauda and Sculpuratus and  (common name, features, pathophysiology, and treatment).

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  • Common name: bark scorpion
  • Distributed in the Southwest US and Mexico
  • Fluoresces with a black light
  • Neurotoxin 1-4 cause membrane depolarization of neurons; the venom also contains hyaluronidase, phospholipase, and acetylcholinesterase
  • Grading scale for envenomation
    • 1: Paresthesias at bite site, positive “tap” test
    • 2: Paresthesias at sites remote from the bite
    • 3: Cranial nerve symptoms OR peripheral neuromuscular junction (NMJ) dysfunction (eg shaking).
    • 4: Both cranial nerve symptoms AND peripheral NMJ symptoms
  • Patients with 3 or 4 should get antivenom, as should high risk patients such as pregnant patients to prevent preterm labor

Charles & Clint [CC BY 2.0 (https://creativecommons.org/licenses/by/2.0)]

Centuroides spp
Loxosceles

What are Loxosceles spp. Common name? Distribution? Venom mechanism?Clinical effects?  Severe toxicity? Treatment?

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  • Brown recluse
  • Loxosceles venom is a heterogenous medely of proteins including: sphingomyelinases, phospholipases, astacin-like metalloproteases, and the inhibitor cystine knot (ICK) peptides, serine proteases, serpins, hyaluronidases.
  • Typically Loxoscelism is limited to local tissue necrosis, often patients will mistake an abscess for a bite of this spider.
  • Mild systemic signs include: fever, flu-like symptoms, nausea/vomiting, disseminated rash
  • Severe toxicity: intravascular hemolysis, hemoglubinuria or hematuria, DIC, hypotension, pulmonary edema
  • Supportive care, wound care, steroids are controversial.

PMID:31248109

Loxosceles
Gyrometra spp

 

  • Arłukowicz-grabowska, et al PMID=31014949
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  • Gyrometra Esculenta is a false morel.
  • Contains hydrazine which depletes vitamin B6, a cofactor which is necessary for GABA synthesis by GAD. This can result in seizure.
  • Treat with pyridoxine, similar to INH.
  • Phenobarbital would be preferential because Benzodiazepines require the some endogenous GABA.
Gyrometra spp
Aconitum spp
  • Image above:
  • Common names? Toxin? Mechanism? Symptoms?
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  • Monkshood, Friar’s cap, Wolfbane
  • Aconitine: an alkaloid
  • Sodium channel opener
  • GI upset -> parasthesias -> confusion -> hypotension / ventricular arrhythmia
  • Tx=supportive, lidocaine for dysrhythmia
Aconitum spp
Heracleum spp
  • Image above:
  • Common name? Toxin? Effects? Treatment?
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  • Cow Parsnip, notable Heracleum Maximum in North America
  • Furanocumarins: Angelicin (upper) and Psoralen (lower); note there are other isomers not shown
  • Phototoxic vesicicular rash that form after exposed to sunlight. They intercalate with DNA leading to decreased robustness of DNA damage repair from UV sunlight.
  • Treatment: supportive, wound care.
Heracleum spp
Lophophora williamsii
  • Image above:
  • Common name? Main active xenobiotic? Effects? Toxicity?
  • .
  • https://www.pinterest.com.mx/pin/383368987016954066/
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  • Peyote contains mescaline, a phenethylamine. Effects include sympathomimesis, hallucinations and is an etheogen used in some religious ceremonies in North America.
  • Can cause severe nausea, vomiting, drug induced psychosis, however there have not been any deaths associated with consumption of the plant.
  • Lophophora williamsii
    Cicuta spp
    • The plant above:
    • Common name? Mechanism? Demographic of victims?

     

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    Cicuta sp., particularly Cicuta Maculata,  commonly known as water hemlock contain cicutoxin which directly antagonizes GABA-A receptors, resulting status epilepticus as soon as 15 min after ingestion.

    Usually victims are adult foragers who mistake the plant for wild carrots or ginseng.

    If soon enough after ingestion, can consider lavage. Benzos for seizures.

     

    Cicuta spp
    Nicotine agonist containing plants

    What are some plants with nicotine agonism paired with the presumed active xenobiotic?

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    • Nicotiana sp. = nicotine
    • Cystisus scoparius = sparteine
    • Caulophylum thalictroides = methylcystisine
    • Cystisus Laburnum = cystisine
    • Conium maculatum = gamma-coniceine and its plant metabolite coniine
    Nicotine agonist containing plants
    Conium spp
    • The above plant:
    • Common name? Effect of toxin?  Primary cause of death? Treatment? Historical significance?
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    • Poison Hemlock
    • Nicotinic agonist: Coniine
    • Respiratory muscle paralysis, seizure
    • Tx= Atropine, mechanical ventilation
    • Socrates ingested this at the order of the state for his subversive ideas
    Conium spp
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