UMEM Educational Pearls - Toxicology

A leading cause of cardiac arrest in patients 40 years and younger is due to drug poisoning.  Adverse cardiovascular events (ACVE) such as myocardial injury (by biomarker or ECG), shock (hypotension or hypoperfusion requiring vasopressors), ventricular dysrhythmias (ventricular tachycardia/fibrillation, torsade de pointes), and cardiac arrest (loss of pulse requiring CPR) are responsible for the largest proportion of morbidity and mortality overdose emergencies. Clinical predictors of adverse cardiovascular events in drug overdose in recent studies include:

  • QTc prolongation on presentation ECG ( > 500 msec )
  • Prior history of either coronary artery disease or congestive heart failure
  • Metabolic acidosis (elevated serum lactate)

 

Bottom line:

Obtain ECG and perform continuous telemetry monitoring in overdose patients with above risk factors. Patients with two or more risk factors have extremely high risk of in-hospital adverse cardiovascular events and intensive care setting should be considered.

 

 

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Category: Toxicology

Title: Toxin-induced nystagmus

Keywords: nystagmus, toxic (PubMed Search)

Posted: 2/22/2018 by Hong Kim, MD, MPH
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Abnormal ocular movement (e.g. nystagmus) can often be observed in select CNS pathology.

Certain drugs/toxin overdose can also induce nystagmus.

  • Anti-epileptics: carbamazepine, lamotrigine, topiramate, phenytoin
  • Ethanol
  • Ketamine, phencyclidine (PCP), dextromethorphan – vertical or rotary nystagmus
  • Serotonergic syndrome/5-HT agonists – opsoclonus
  • Monoamine oxidase inhibitors – ping-pong nystagmus
  • Lithium
  • Scorpion envenomation 

In an "unknown" intoxication, physical exam findings such as nystagmus may help narrow the identity of the suspected ingestion/overdose.



Category: Toxicology

Title: Bupropion Cardiotoxicity

Keywords: Cardiotoxicity, Bupropion, Ventricular dysrhythmia (PubMed Search)

Posted: 2/15/2018 by Kathy Prybys, DO
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Bupropion (Wellbutrin, Zyban) is unique monocyclic antidepressant and smoking cessation agent that is structurally similar to amphetamines.  Bupropion blocks dopamine and norepinephrine reuptake and antagonizes acetylcholine at nicotinic receptors.

  • One of the most common causes of drug-induced seizures.
  • Sinus tachycardia is the most frequently seen cardiac effects with overdose.
  • QTc prolongation and ventricular dysrhythmias can occur in severe overdose. New evidence supports this is not related to cardiac sodium channel block but likely due to blockade of the delayed rectifying (ikr) potassium channel and gap junction inhibition in the myocardium simulating effects class IA effect.

 

Bottom line:

Bupropion is a common cause of drug induced seizures but in severe overdose can also cause prolonged QTc and wide complex ventricular dysrhythmia that may be responsive to sodium bicarbonate. All patients with an overdose of bupropion should have an ECG performed and cardiac monitoring to watch for conduction delays and life-threatening arrhythmias.

 

 

 

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Category: Toxicology

Title: Perils of OTCs

Posted: 2/1/2018 by Kathy Prybys, DO (Emailed: 2/2/2018) (Updated: 2/2/2018)
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Question

47 year old woman presents with cough, headache, weakness, and low grade fever. Her symptoms have been present for several days. Vital signs are temperature 99.9 F, HR 96, RR 16, BP 140/88, Pulse Ox 98%.  Physical exam is nonfocal. She is Influenza negative. She is treated with Ibuprofen and oral fluids.  Upon discharge she mentions she is having difficulty hearing and feels dizzy. Upon further questioning she admits to ringing in her ears. What tests should you order?

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Category: Toxicology

Title: Liver dialysis for poisoning-MARS therapy

Keywords: Liver dialysis, MARS (PubMed Search)

Posted: 1/18/2018 by Kathy Prybys, DO (Emailed: 1/19/2018) (Updated: 1/19/2018)
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Acute liver failure carries a high morbidity without liver transplantation. Liver support systems can act as “bridge” until an organ becomes available for the transplant procedure or until the liver recovers from injury. Artificial liver support systems temporally provide liver detoxification utilizing albumin as scavenger molecule to clear the toxins without providing synthetic functions of the liver (coagulation factors). One of the most widely used devices is the Molecular Adsorbent Recirculating System (MARS).This system has 3 different fluid compartments: blood circuit, albumin with charcoal and anion exchange column, and a dialysate circuit that removes protein bound and water soluble toxins with albumin.

  • Mars has been used in several case reports to treat acetaminophen, Amanita phalloides,Phenytoin, lamotrigine, theophylline, and calcilum channel blockers poisonings.
  • All the extracorporeal liver assist devices are able to remove biological substances (ammonia, urea, creatinine, bilirubin, bile acids, amino acids, cytokines, vasoactive agents) but the real impact on the patient's clinical course has still to be determined.

Bottom Line

MARS therapy could be a potentially promising life saving treatment for patients with acute poisoning from drugs that have high protein-binding capacity and are metabolized by the liver, especially when concomitment liver failure. Consider consultation and transfer of patients to liver center.

 

 

 

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Category: Toxicology

Title: Benefit of activated charcoal in large acetaminophen ( >= 40 gm) overdose.

Keywords: activated charcoal, large acetaminophen overdose, NAC dose (PubMed Search)

Posted: 1/11/2018 by Hong Kim, MD, MPH (Updated: 3/28/2024)
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Acetaminophen (APAP) overdose is the leading cause of liver failure in the U.S. and Europe. Large APAP ingestion can result in hepatotoxicity despite the early initiation of n-acetylcysteine (NAC). 

A recently published study from Austrialia investigated the effect of activate charcoal and increasing the NAC dose for large APAP overdose patients (3rd bag: 100 to 200 mg/kg over 16 hours) during first 21 hours of NAC therapy

acetaminophen ratio (first APAP level taken between 4 to 16 hour post ingestion / APAP level on the Rumack nomogram line at that time point) was determined to compare APAP levels at different time points among study sample

e.g.  

first APAP level at 4 hour post ingestion = 400

APAP level on the Rumack APAP nomogram at 4 hour post ingestion = 150

APAP ratio = 400/150 = 2.67

 

Findings:

  1. Activated charcoal (AC): if given within 4 hours, AC significantly decreased the APAP ratio (OR: 1.4 vs. 2.2)
  2. Increased dose of NAC during the first 21 hour significantly decreased the risk of hepatotoxicity (OR: 0.27; 95% CI: 0.08 - 0.94).

 

Conclusion: 

  1. Administration of AC in patients with history of large APAP overdose (>=40 gm) within 4 hour of ingestion can still be beneficial.
  2. Increasing NAC dosing (3rd bag in first 21 hour thearpy) may decrease the risk of hepatotoxicity. 

Note: Any increase in NAC dosing from the standard 21 hour therapy should be performed after consulting your regional poison center.

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Category: Toxicology

Title: Loperamide Cardiac Toxicity

Keywords: Loperamide, cardiotoxicity, QT prolongation (PubMed Search)

Posted: 12/7/2017 by Kathy Prybys, DO (Emailed: 12/8/2017) (Updated: 12/8/2017)
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Question

Loperamide (Imodium) is a common inexpensive over-the counter antidiarrheal agent. It acts peripherally at the mu opioid receptor to slow gastrointestinal motility and has no CNS effects at therapeutic doses due to it's low bioavailability and limited abillity to cross the blood brain barrier dependent on glycoprotein transport. In the past few years, reports of loperamide abuse causing serious cardio toxicity began to appear in the literature. Abused at daily doses of 25-200 mg to get high or and to treat symptoms of withdrawal. (therapeutic dose: 2-4 mg with a maximun of 8mg for OTC and 16mg for prescription). Loperamide has been called the "poor man's methadone".

At large doses, loperamide effects the cardiac sodium, potassium and calcium channels which prolongs the QRS complex  and can lead to ventricular arrhythmias, hypotension, and death. Clinical features includes:

  • QT prolongation
  • QRS widening
  • Ventricular arrythmias
  • Hypotension
  • Syncope
  • CNS depression

 

Take Home Point:

Consider loperamide as a possible cause of unexplained cardiac events including QT interval prolongation, QRS widening, Torsades de Pointes, ventricular arrhythmias, syncope, and cardiac arrest. Intravenouse sodium bicarbonate should be utilized to overcome blockade and may temporize cardiotoxic events. Supportive measures necessary may include defibrillation, magnesium, lidocaine, isoproternol, pacing, and extracorporeal life support.

 

 

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Question

 

Different chemical, food or pharmaceutical agent exposure can change the color of the urine.

What could cause this patient's urine to turn green?

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Category: Toxicology

Title: When to hemodialyze in Lithium Toxicity

Keywords: Hemodialysis, lithium (PubMed Search)

Posted: 11/16/2017 by Kathy Prybys, DO (Emailed: 11/17/2017) (Updated: 11/17/2017)
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Lithium salts have been used therapeutically for over a 150 years to sucessfully treat manic depressive symptoms, schizoaffective disorder, and cluster headaches. Lithium has a narrow therapeutic range (0.6-1.5 meq/L) and is 100% eliminated by the kidneys. Multisystem toxicity occurs however CNS toxicity is significant and consist of confusion, lethargy, ataxia,  neuromuscular excitability (tremor, fasciculations, myoclonic jerks, hyperreflexia). Since there is a poor relationship between serum concentration and toxicity in the brain, serum blood levels may not reflect extent of toxicity . The goal of enhanced elimination is to prevent irreversible lithium-effectuated neurotoxcity which causes persistant cerebellar dysfunction with prolonged exposure of the CNS to high lithium levels.

Decision for hemodialysis is determined by clinical judgement after considering factors such as lithium  concentration, clinical status of patient, pattern of lithium toxicity (acute vs. chronic), concurrent interacting drugs, comorbid illnesses, and kidney function. Strongly consider hemodialysis for the following: 

  • Manifestations of severe lithium poisoning
  • Impaired kidney function
  • Decreased level of consciousness, seizures, or life threatening dysrhythmias irrespective of lithium concentration
  • Lithium level greater than 5

 

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Category: Toxicology

Title: Do you have digoxin-like toxins growing in your backyard?

Keywords: cardioactive steroids, cardioactive glycoside (PubMed Search)

Posted: 11/9/2017 by Hong Kim, MD, MPH (Updated: 3/28/2024)
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Many medications are discovered from plants (quinine – cinchona trees) or organisms (penicillin – mold [penicillicum]).

Digoxin was isolated from foxglove (Digitalis lanata), a colorful floral plant often found in many gardens.  There are other sources of cardioactive steroids (aka cardiac glycosides) that have similar effect as digoxin.

  • Oleander (Nerium oleander)
  • Yellow orleaner (Thevetia peruviana) – frequently used for suicide in Southeast Asia
  • Lily of the valley (Convallari majalis) – use in wedding bouquet
  • Dogbane (Apocynum cannabinum)
  • Red squill (Urginea maritima)
  • Bufo toad (Bufo species)  

 

Non-digoxin cardioactive steroid exposure can result in a positive digoxin level due to cross reactivity. This confirms exposure; however, the “digoxin level” does not represent the true extent of the ingested dose or toxicity. 

Non-digoxin cardioactive steroid toxicity

  • Digibind also binds to non-digoxin cardioactive steroids.
  • However, larger doses are often required (initial dose: 10 to 20 vials) than doses required for digoxin toxicity.   


The cornerstone treatment of poisoning is removal of the toxin from the patient. This can be accomplished before absorption into the body by decontamination methods (dermal or gastrointestinal) or after absorption by blocking metabolism of parent compound, displacing drugs from receptors, binding toxins with neutralizing agents (chelators, Fab fragments), or enhancing elimination by dialysis. Toxins that are ideal candidates for dialysis include substances that are low molecular weight, have low volume of distribution (stay in the blood stream), or low protein binding. Toxins most commonly treated with dialysis are:

  • Lithium
  • Salicyclates
  • Ethylene glycol
  • Methanol
  • Acetaminophen

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Category: Toxicology

Title: Agatha Christie 2.0 Strychnine

Keywords: strychnine (PubMed Search)

Posted: 10/26/2017 by Hong Kim, MD, MPH (Emailed: 10/27/2017) (Updated: 10/27/2017)
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Her first book “The mysterious affair at Styles,” Agatha Christie introduced her lead detective in her novels, Hercule Poirot - the Belgian detective.  She also described the death of Mrs. Emily Inglethorp by strychnine.

Strychnine is found in a disc-like seed of strychnos nux-vomica, a tree native to tropical Asia and North Australia.

It is currently used as rodenticide (moles and gophers), in Chinese herbal medicine and a traditional remedy in Cambodia.

Strychnine inhibits binding of glycine (a major inhibitory neurotransmitter in spinal cord) to Cl-channel resulting in identical clinical syndrome – seizure-like generalized muscle contraction with normal mental status – as tetanus toxin. Tetanus toxin inhibits the release of presynaptic glycine in the spinal cord. 

 

Management

Goal: decrease muscle hyperactivity

  • 1st line: benzodiazepine
  • 2nd line: barbiturates or propofol
  • 3rd line: paralysis by non-depolarizing agents


Category: Toxicology

Title: Arsenic and Agatha Christie

Keywords: Arsenic poisoning (PubMed Search)

Posted: 10/19/2017 by Hong Kim, MD, MPH
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Agatha Christie is an English crime novelist who frequently used poisons in her books to murder the victims. In her book, Murder is Easy, Ms. Christie uses arsenic/arsenic trioxide to kill several characters.

 

Primary source of arsenic in general population is contaminated food, water and soil. Arsenic exists in several forms: elemental, gaseous (arsine), organic and inorganic (trivalent or pentavalent).

 

Arsenic trioxide has also been used to treat acute promyelocytic leukemia in China; it’s use in other leukemia, lymphoma, and other solid tumors are currently being investigated.

 

Arsenic primarily inhibits the pyruvate dehydrogenase complex and multiple other enzymes involved in the citric cycle/oxidative phosphorylation, resulting in mitochondrial dysfunction.

 

Acute toxicity of arsenic after ingestion

  1. GI symptoms (minutes to several hours) – nausea, vomiting, abdominal pain and cholera like diarrhea.
  2. Cardiovascular: QT prolongation/torsade de pointes, orthostatic hypotension, ventricular dysrhythmias, myocardial dysfunction and shock.
  3. CNS (days): encephalopathy, delirium, coma, and seizure due to cerebral edema and microhemorrhages.
  4. Respiratory: ARDS, respiratory failure,
  5. Others: AKI, leukemoid reaction, hemolytic anemia, and hepatitis.

 

 Management

  1. Chelation: dimercaptrol (BAL) or succimer
  2. Whole bowel irrigation if radiopaque material is present (abdominal XR)
  3. Electrolyte and fluid management
  4. Cardiac monitoring and pressor support in hypotension


Category: Toxicology

Title: Cannabinoid Hyperemesis Syndrome

Keywords: Cannabinoid, cyclic vomiting, Capsaicin (PubMed Search)

Posted: 10/12/2017 by Kathy Prybys, DO
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Cannabinoid hyperemesis is a syndrome (CHS) characterized by severe intractable nausea, cyclical vomiting, and abdominal pain associated with chronic marijuana abuse. It is often a underrecognized cause of cyclic vomiting syndrome. Despite well established anti-emetic properties of marijuana, paradoxical effects on the GI tract exist through cannabinoid receptors which exert their neuromodulatory properties in the central nervous system and the enteric plexus. Multiple theories of mechanism of CHS are in the literature. Diagnosis is based on the following clinical criteria:

  • History of regular cannabis for any duration of time
  • Refractory nausea and vomiting
  • Gastrointestinal evaluations fail to identify other clear causes
  • Compulsive bathing in hot water temporarily alleviates symptoms often done several times a day. A red flag symptom.
  • Resolution of symptoms after cannabis is discontinued

Acute care goals are to treat dehydration and terminate nausea and vomiting. Administration of intravenous fluids, dopamine antagonists, topical capsaicin cream, and avoidance of narcotic medications are recommened treatment measures. Benzodiazepines followed by haloperidol and topical capsaicin are reported to be most effective. Capsaicin  activates the transient receptor potential vanilloid 1 receptors (TRPV1) which impairs substance P signalling in the area postrema and nucleus tract solitarius similar to noxious stimuli, such as heat. 

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Category: Toxicology

Title: Hunan Hand

Keywords: Capsaicin, hunan hand, chili peppers (PubMed Search)

Posted: 10/6/2017 by Kathy Prybys, DO
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Hunan hand syndrome is a painful contact dermatitis that frequently presents in cooks and chili pepper workers after preparing or handling chili peppers. Contact with other body parts gives rise to the terms: "Hunan nose" ''Hunan eye",and "Chili Willie". Capsaicin, found in the fruit of plants from the genus Capsicum such as red chili peppers, jalapeños, and habaneros, is a hydrophobic, colorless, odorless compound that binds with pain receptors causing the sensation of intense heat or burning. The "heat" or pungency of a peppers is measured in Scoville heat units (SHU), the number of times a chili extract must be diluted with water to lose heat. Habanero peppers generate 30,000 SHU. Even at low concentrations capsaicin is a skin irritant. It is the primary ingredient in pepper spray used in law enforcement and in personal defense sprays.   

Treatment consists of decontamination with water irrigation for opthalmic exposure and milk or antacids for dermal or gastrointestinal exposure. Burning can be recurrent and of of long duration depending on tissue penetration. Topical anesthetic especially for the eye and cool compresses for the skin can relieve pain.  Parodoxically capsaicin is used as a topical analgesic medication for local pain relief from muscle pain, itching,  and painful neuropathies (diabetic, postherpetic). Capsaicin initially causes neuronal excitation followed by a long-lasting refractory period due to depletion of substance P, during which neurons are no longer responsive to a large range of stimuli and thus are desensitized.

 

 

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Category: Toxicology

Title: Drug Induced Hyperkalemia

Keywords: Hyperkalemia (PubMed Search)

Posted: 9/22/2017 by Kathy Prybys, DO (Updated: 10/5/2017)
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Hyperkalemia is a potentially life threatening problem which can lead to cardiac dysrhythmias and death.  Drug interactions inducing hyperkalemia are extremely common such as the combination of ACE inhibitors and spironolactone or ACE inhibitors and trimehoprim sulfamethoxazole. Hyperkalemia can also occur with a  single agent and is a relatively common complication of therapy with trimethoprim sulfamethoxazole. The following drugs can cause hyperkalemia:

  • Ace inhibitors
  • Beta blockers
  • Cyclosporine
  • Digitalis
  • Non-steroidal Anti-inflammatory Drugs
  • Pentamidine
  • Potassium supplement
  • Succinylcholine
  • Tacrolimus
  • Trimethoprim sulfamethoxazole 

 

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During the past several years, several new classes of diabetic medications were introduced for clinical use, including SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin).

SGLT2 inhibitors prevent reabsorption of glucose in the proximal convoluted tubules in the kidney and does not alter insulin release.

A recent retrospective study (n=88) of 13 poison center data from January 2013 to December 2016 showed

  1. 91% of the patients were asymptomatic.  
  2. 7% developed minor symptoms (tachycardia, nausea/vomiting, abdominal pain, & confusion)
  3. 2% developed moderate symptoms (metabolic acidosis, hypertension [166/101], & hypokalemia)
  4. Hypoglycemia was not reported.

49 patients were evaluated in a health care facility (HCF) with 18 admissions. Referral to HCF was more common in pediatric patients. This was likely due to unfamiliarity with a new mediation and lack of toxicity data.

Other case reports have shown higher incidence of DKA with the therapeutic use of SGLT2 vs. other classes of DM medications.

 

Bottom line:

Limit data is available regarding the toxicologic profile of SGLT2 inhibitors.

Based upon this small retrospective study, hypoglycemia may not occur and majority of the patient experience minimal symptoms.

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Category: Toxicology

Title: X-rays in poisoning diagnosis?

Keywords: Radiographs, poisoning (PubMed Search)

Posted: 9/7/2017 by Kathy Prybys, DO (Emailed: 9/8/2017) (Updated: 9/8/2017)
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Question

Radiographs studies can be valuable in poisoning diagnosis, management, and prognosis.  Radiographic imaging should be utilized for the following toxins:

Heavy metals 
  • Iron (gastrointestinal)
  • Mercury (gastrointestinal, intravenous or subcutaneous)
  • Lead (bullets intraarticular, gastrointestinal foreign bodies, lead lines)
  • Zinc phosphide (gastrointestinal)

Container toxins - Body packers

  • Drug packets and vials

Sustained Released preparations

  • Potassium Chloride
Button Batteries and Coins

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There have been reports of “intoxication” or adverse effects among first responders and law enforcement due to exposure to a “powder” suspected to be fentanyl or its analog.

 

This has led to a significant concern among first responders and law enforcement when investigating or handling “powder” at the scene of overdose or drug enforcement related raids. (http://www.foxnews.com/health/2017/08/15/police-department-gets-hazmat-like-protective-gear-for-overdose-calls.html)

 

American College of Medical Toxicology and American Association of Clinical Toxicology recently published a position statement to help clarify the potential health risk associated with exposure to fentanyl and its analogs.

 

  1. Opioid toxicity is unlikely from incidental dermal exposure.
  2. Nitrile gloves provide sufficient protection against dermal exposure.
  3. N95 respirator provide sufficient protection against aerosolize fentanyl/opioids.
  4. Naloxone should be administered for patients with objective signs of opioid toxicity - hypoventilation and CNS depression – not for vague or subjective symptoms.


Category: Toxicology

Title: Deadly in a drop!

Keywords: Botulinum, Dimethylmercury, VX, Tetrodotoxin (PubMed Search)

Posted: 8/17/2017 by Kathy Prybys, DO (Emailed: 8/31/2017) (Updated: 8/31/2017)
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Botulinum
  • Most poisonous substance known to man
  • LD50 oral dose 1 mcg/kg
  • Heat labile single polypeptide chain undergoes proteolytic clevage irreverisibly binds  and blocks cholinergic transmission causing a deadly neuroparalytic syndrome
  • Rx: Botulin antitoxin (equine derived against Clostriduim botulinum A,B,E)
Dimethylmercury (CH3)2 Hg
  • Highly toxic, restricted availability is rapidly absorbed and metabolized to methylmercury crosses CNS
  • LD50 of 50 mcg/kg means a dose as little as 0.1ml can result in severe poisoning
  • Death of Darmouth inorganic chemist Karen Wetterhahn who spilled a few drops on back of her latex gloved hand, quickly permeated, and absorbed causing severe neurotoxocity and death 10 months later
  • Rx: Chelation

VX ("venomous agent X") 

  • Organophosphate nerve agent has been used as chemical weapon
  • Colorless, odorless, low volatility, and high lipophilicity
  • LD50 of 0.04mg/kg (10 mg). Death can occur within 15 minutes after absorption
  • Blocks acetylcholinesterase enzyme causing excess accumulation of acetylcholine at the neurojunction and cholinergic poisoning
  • Rx: Decontamination, Atropine, 2-PAM
Tetrodotoxin
  • 100 fresh and salt water varieties (pufferlike fish/blue ringed octopus, frogs)
  • Heat stable, water soluble found in fish skin, liver, ovaries,intestine, and muscle
  • 25 mg (0.000881 oz) expected to be lethal to a 75 kg person
  • Neurotoxicity by inhibition of Na-K pump and blockade neuromuscular transmission
  • Rx: Supportive measures

LD50 expresses the dose at which 50% of exposed population will die as a result of exposure.

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