Episode 108 - Antidotes to toxidromes

Episode 105: Antidotes to toxidromes.
Some poisonings share common signs and symptoms and may be treated with antidotes without laboratory confirmation of the offending agent. Dr. Francis discussed with Dr. Arreaza some of those toxidromes and how to treat them.
Written by Aida Francis, MD. Participation by Hector Arreaza, MD.

Definitions:
• Antidotes are substances given as a remedy that inhibit the effects of another drug of abuse or poison. Most are not 100% effective and fatality is still possible after administration.
• Toxidrome is a constellation of signs and symptoms caused by an overdose or exposure to chemicals or drugs that interact with neuroreceptors.

Toxidrome is the combination of the word “toxin” and “syndrome”. Management strategies of toxidromes are determined by the signs and symptoms even when the causative agent has not been identified.

A little bit of Background: The World Health Organization reported that 13% of deaths caused by poisonings are children and young adults. Intentional poisoning attempts are more frequent among adolescent women than men. It is difficult to evaluate poisoned patients because they are too altered to provide history and there is often not enough time to perform a physical exam or obtain serum studies prior to life-saving interventions.
To diagnose a toxidrome clinically, you need three elements: pupil size, temperature, and bowel sounds. For example: Pinpoint pupils with hyperactive bowel sounds point to cholinergic toxidrome, and dilated pupils with high temperature, and hypoactive bowel sounds point to anticholinergic (see details below).
Pinpoint pupils -> Bowel sounds -> Hyperactive: CHOLINERGIC
-> Hypoactive: OPIOIDS
Normal or dilated pupils -> Temperature -> High -> Bowel sounds -> Hyperactive: SYMPATHOMIMETIC
-> Hypoactive: ANTICHOLINERGIC
-> Normal or Low -> Bowel sounds -> Hyperactive: HALLOCUNOGENIC
-> Hypoactive: SEDATIVE-HYPNOTICS
Anticholinergic Toxidrome and the Physostigmine antidote:
• Anticholinergics inhibit the binding of acetylcholine to the muscarinic receptors in the central nervous system and the parasympathetic nervous system. Examples of anticholinergics include atropine and tiotropium.

Other substances that may cause anticholinergic toxidrome include antihistamines (especially first-generation: diphenhydramine), antipsychotics (quetiapine), antidepressants (TCAs, paroxetine), and antiparkinsonian drugs (benztropine).

Symptoms of toxicity include tachycardia, non-reactive mydriasis, anhidrosis, dry mucous membranes, skin flushing, decreased bowel sounds, and urinary retention. Neurological symptoms include delirium, confusion, anxiety, agitation, mumbling, visual hallucination, and strange behavior. Neurological symptoms last longer because of the anticholinergic lipophilic properties which cause them to distribute into fatty organs and tissues like the brain.

“Mad as a hatter, red as a beet, blind as a bat, hot as a hare, dry as a bone” [Spanish: loco como una cabra, rojo como un tomate, ciego como un topo, seco como una piedra, caliente como el infierno]

• The antidote for anticholinergic toxidrome is physostigmine. It is an acetylcholinesterase inhibitor and prevents the metabolism of acetylcholine. This increases the level of acetylcholine in both the central nervous system and peripheral nervous system. Physostigmine can cause seizures and arrhythmia, so close monitoring in the hospital is required during treatment.

Cholinergic toxidrome and its antidotes atropine and pralidoxime:
Acetylcholine is part of the parasympathetic nervous system and cholinergic substances can induce a parasympathetic response. Some of these substances include pesticides, organophosphates, carbamate, and nerve gas.

Chlorpyrifos had been used to control insects in homes and fields since 1965. It has been used in our crops in Bakersfield, and the most recent mass exposure was in May 2017. it was banned on food crops in the US in August 2021. It has been banned for residential use for a longer period. Repeated exposure to chlorpyrifos causes autoimmune disorders and developmental delays in children and fetuses.

The symptoms of cholinergic toxidrome can be summarized with the SLUDGE/ “triple” BBB acronym. This includes salivation, lacrimation, urination, defecation, gastrointestinal cramping, emesis, bradycardia, bronchorrhea, and bronchospasm. There can also be muscle fasciculations and paralysis.

• The antidote is Atropine. Pralidoxime is used for organophosphates only because it cleaves the organophosphate-acetylcholinesterase complex to release the enzyme to degrade acetylcholine. Pralidoxime should be used in combination with atropine, not as monotherapy. It requires hospital admission, and a note for organophosphate, remember that the patient needs external decontamination (shower). Let’s go to part 2 of our discussion, environmental exposure.

Carbon Monoxide Toxidrome and the antidote oxygen:
Carbon monoxide intoxication is usually due to smoke inhalation injury. Carbon monoxide is a silent gas produced by carbon-containing fuel or charcoal. Carboxyhemoglobin (COHb) forms in red blood cells when hemoglobin combines with carbon monoxide, reducing the binding and availability of oxygen at the tissue level.

It’s like CO falls in love with hemoglobin and hemoglobin cheats on Oxygen by binding to CO instead, and neglects oxygen delivery to tissues. Carbon monoxide also causes direct cellular toxicity. The symptoms and signs of poisoning include headache, altered mental status, nausea, vomiting, visual disturbance, Cherry-red lips, coma, and seizure. You can also see lactic acidosis and pulmonary edema. Neurological symptoms can be chronic, so it’s important to follow up.

The blood COHb level must be used to confirm the diagnosis because standard pulse oximetry (SpO2) and arterial partial oxygen pressure (PaO2) cannot differentiate COHb from normal oxygenated hemoglobin. You must obtain a serum COHb level.

• The antidote is 100% oxygen or hyperbaric oxygen therapy and close follow-up. Consider intubating if there is edema of the airways due to inhalation injury.

Cyanide Toxidrome which include sodium nitrite, sodium thiosulfate, and hydroxocobalamin

In combination with Carbon Monoxide poisoning Cyanide poisoning can simultaneously be caused by inhalation of smoke or colorless hydrogen cyanide or ingestion of cyanide salts or prolonged use of sodium nitroprusside (ICU for hypertensive emergency).

Symptoms are very similar to carbon monoxide poisoning. There may be long-term neurologic deficits and Parkinsonism. Diagnosis is clinical and waiting for serum cyanide levels can cause treatment delay. However, serum lactate levels over 10 mmol/L suggest cyanide poisoning.

• Since cyanide poisoning resembles carbon monoxide poisoning and both toxidromes typically present simultaneously in the pathognomonic fire victim, treat simultaneously with sodium nitrite, sodium thiosulfate, and hydroxocobalamin as well as oxygen as mentioned with carbon monoxide poisoning.

Hypnotic and sedative substances (antidote: flumazenil)
Examples of hypnotic or sedative substances are alcohol, benzodiazepines, or zolpidem. Signs and symptoms of toxicity include slurred speech, ataxia, incoordination, disorientation, stupor, and coma with mild and rare hypoventilation and bradycardia.

• The antidote is flumazenil which is a competitive antagonist at the benzodiazepine receptor. After treatment monitor patients for seizures in case of TCA poisoning, arrhythmia, or epilepsy.

Opioid toxidrome (antidote: naloxone)
Examples of opioid intoxication in children would be heroine in adolescents or accidental ingestion of pain medication in young children. Signs and symptoms are similar to the sedative toxidrome except for the pathognomonic finding of miosis or “pinpoint pupils” on physical exam. There will also be respiratory depression, hyporeflexia, bradycardia, muscle rigidity, and absent bowel sounds or constipation. Hypoventilation is severe and can cause death.

• The antidote is naloxone which is a synthetic opioid receptor antagonist that can diagnose and treat opioid poisoning. It is indicated if the respiratory rate is less than 12. It has a short half-life and is repeatedly administered every 3-5 minutes until the respiratory drive is restored in order to avoid rebound respiratory depression and intubation. It has a rapid onset so the patient must be observed for 24 hours for opioid withdrawal symptoms.

Summary: It is important to be able to recognize a toxidrome and antidote early. Once the antidote is administered, you should observe the patient 24 hours for symptoms of rebound toxicity or withdrawal. Consider repeat administration of the antidote if rebound symptoms occur and treat withdrawal symptoms as needed. Don’t forget to consider multidrug poisoning if symptoms are non-specific. Thank you for having me on your podcast to review this topic.
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Conclusion: Now we conclude our episode number 108, “Antidotes to Toxidromes.” Remember you can start treatment of a patient with typical signs and symptoms of specific toxidromes, especially in patients who are unstable. We hope you enjoyed this episode. We thank Hector Arreaza, Aida Francis, and Arianna Lundquist. Audio Edition by Adrianne Silva.
Even without trying you go to bed being a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. If you have any feedback, contact us by email at [email protected], or visit our website riobravofmrp.org/qweek. See you next week!
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References:
1) Jaelkoury, CC BY-SA 3.0 , via Wikimedia Commons.

2) Hon KL, Hui WF, Leung AK. Antidotes for childhood toxidromes. Drugs Context. 2021;10:2020
11-4. Published 2021 Jun 2. doi:10.7573/dic.2020-11-4, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177957/.

3) Royalty-free music used for this episode: Space Orbit by Scott Holmes, downloaded on July 20, 2022 from https://freemusicarchive.org/music/Scott_Holmes/.