Sure, it’s all hunky dory with medications. We love to talk about our mortality benefits and decreased symptoms and improved patient quality of life. Until something goes wrong. And then we see the dark side of pharmacy. (Image)

Steph’s Note: After many (MANY) requests over the years, we are proud to present…drum roll, please…the tl;dr of toxicology! While this is only scratching the very surface of the “when good drugs go bad” angle of pharmacy, we have included 5 of the most commonly encountered toxidromes in this post. Not too shabby for a tl;dr approach.

Making yet another of our tl;dr dreams come true (along with past posts on vasopressors, DKA, electrolytes, bleeds, SIADH, and burns, as well as several handy pocket guides) is Josef Nissan, our critical care guru. We continue to live in awe of how much knowledge Dr. Nissan is able to efficiently and effectively pump out to y’all, and this post is no exception. Alright, tell us about the the Mr. Hyde side of these drugs!

Let’s be real. Somewhere in your pharmacy career you’ve been (or will be) asked these two questions:

What is the phone number for the US Poison Control Center Hotline?
Patient X is experiencing classic symptoms of which of the following toxidromes?

Spoiler alert, the answer to the first question is easy: 1-800-222-1222. Log it away, just memorize it. Now, the second question might be a little bit more challenging. But fear not! After you’ve finished this post, I expect you to be a master of toxicology. Anyway, let’s dive right in.

Physiology of the Autonomic Nervous System

To better understand this topic (rather than purely memorizing it), it’s important that we review the basic physiology of the autonomic nervous system. Let’s take a trip down memory lane to Physiology 101.

Our autonomic nervous system is composed of the parasympathetic and sympathetic systems. The parasympathetic nervous system releases a neurotransmitter called acetylcholine that binds to muscarinic receptors, leading to “rest and digest” effects. On the other hand, the sympathetic nervous system releases endogenous catecholamines (epinephrine, norepinephrine, & dopamine) leading to “fight or flight” effects.

Take a look at the table below to get a summarized understanding of the physiological differences between the parasympathetic and sympathetic nervous systems:

Now that we’ve refreshed our memories with the autonomic nervous system, let’s put the pieces of the puzzle together to see how certain toxidromes can have differing effects on our body. The most commonly encountered toxidromes are anticholinergic, cholinergic, sympathomimetic, opioid, and sedative-hypnotic.

Buckle up, let’s do this!

The Anticholinergic Toxidrome

Anticholinergic agents exhibit their effects by antagonizing muscarinic receptors, thus preventing acetylcholine from binding. As a result, what symptoms would you expect to see? Well, the exact opposite of the parasympathetic nervous system, of course.

A common mnemonic I like to use to remember the anticholinergic toxidrome is this:

“Red as a beet” – secondary to vasodilation
“Dry as a bone” – secondary to inhibition of sweat and salivary glands
“Hot as a hare” – secondary to lack of sweating and increased hyperthermic effects
“Blind as a bat” – secondary to pupil dilation
“Mad as a hatter” – secondary to increased agitation, delirium, hallucinations, and psychosis
“Full as a flask” – secondary to urinary retention

Common anticholinergic drugs known to induce these effects include atropine, benztropine, glycopyrrolate, scopolamine, antihistamines (e.g., diphenhydramine), and tricyclic antidepressants. Now let’s dig into the fun part.

How can we treat a patient presenting with anticholinergic toxicity? Primarily supportive care to help reverse some of the symptoms a patient might be exhibiting. However, if symptoms are severe enough, we can always administer a cholinergic agent to help reverse ongoing symptoms.

More specifically:

Supportive care: IV fluids, cooling, sedation, and intubation if necessary
If active seizures: administer benzodiazepines
If patient is agitated/delirious: administer IV/IM physostigmine 0.5 to 2 mg; may repeat every 10-30 minutes until response occurs

Physostigmine is a cholinergic agent, meaning it potentiates the effects of acetylcholine. It does this by inhibiting acetylcholinesterase, the enzyme that normally breaks down acetylcholine. So the end effect is increased central and peripheral concentration of acetylcholine, which works against the anticholinergic toxicities. Physostigmine begins to work within 3 to 8 minutes and lasts 45 to 60 minutes.

Ok, one toxidrome down, more to go.

The Cholinergic Toxidrome

Now, let’s flip the script 180 degrees. Cholinergic agents exhibit their effects by agonizing muscarinic receptors. So, what symptoms would you expect to see from excess acetylcholine?

Parasympathetic nervous system overload, of course. Basically, this is “rest and digest” cranked up to the max.

Mmm, this isn’t quite the “rest and digest” associated with the cholinergic toxidrome… (Image)

A common mnemonic I like to use to remember the cholinergic toxidrome is DUMBBELLS:

Diarrhea
Urination
Miosis (pupil constriction)
Bradycardia
Bronchospasm
Emesis
Lacrimation
Lethargy
Salivation

Common cholinergic drugs known to induce these effects include pesticides (organophosphates), physostigmine (oh hey, this drug again!), neostigmine, pyridostigmine, rivastigmine, donepezil, galantamine, and carbamates.

So how do we treat cholinergic toxicity? I’m glad you asked!

Much like the other toxidrome treatments, supportive care is the mainstay of therapy. Give IV fluids if a patient is dehydrated and intubate if necessary. If a patient is seizing, benzodiazepines remain the treatment of choice. If symptoms persist and/or are severe, anticholinergic agents can be used.

Most commonly, the anticholinergic agent of choice here is atropine. IV atropine blocks acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS. For mild to moderate symptoms, give a 1 to 2 mg bolus. If the previous dose does not induce a response, double the dose every 3 to 5 minutes.

For severe symptoms, start with a 3 to 5 mg bolus and repeat by doubling the dose every 3 to 5 minutes if needed. After the desired response is achieved with IV boluses, administer 10-20% of the total cumulative IV bolus dose as an IV continuous infusion per hour. Adjust the infusion rate as needed to maintain adequate response without causing atropine toxicity.

So for example, if a patient required 20 mg of IV atropine boluses to induce the desired response, start an IV atropine infusion of 2 mg/hour, and then adjust as necessary to maintain response and avoid toxicity.

Another possible medication for management of the cholinergic toxidrome is pralidoxime. It reactivates cholinesterase that had been inactivated by phosphorylation due to exposure to organophosphate pesticides and cholinesterase-inhibiting nerve agents by displacing the enzyme from its receptor sites. Dosing is dependent on the agent causing the toxidrome as well as the severity of symptoms. Check out this summary:

Dosing of pralidoxime
- For acetylcholinesterase overdose (e.g., neostigmine, pyridostigmine): 1000 to 2000 mg IV followed by increments of 250 mg every 5 minutes as needed
- For organophosphate poisoning, doses may be given either IV or IM as follows:
  - Intravenous Dosing (IV):
    - Loading Dose: 30 mg/kg (maximum 2000 mg)
    - Maintenance Dosing:
      - Continuous Infusion (preferred): 8-10 mg/kg/hour (maximum: 650 mg/hr)
      - Intermittent Infusion: may repeat loading dose after 1 to 2 hours if muscle weakness has not been relieved, followed by repeated dosing every 4 to 6 hours as needed
  - Intramuscular Dosing (IM):
    - Mild Symptoms: 600 mg; repeat as needed for persistent mild symptoms every 15 minutes to a maximum total dose of 1800 mg
    - Severe Symptoms: 600 mg; repeat twice in rapid succession to deliver a total dose of 1800 mg

Two toxidromes down, let’s forge on!

The Sympathomimetic Toxidrome

This penguin’s ready to rummmmbllllleeee!!!! (Image)

Here’s another toxidrome that we can fully understand simply by remembering the autonomic nervous system. As the name suggests, sympathomimetic agents will mimic our sympathetic nervous system. So, what symptoms would you expect to see here?

“Fight or flight” on steroids. Specifically:

Hyperthermia
Tachycardia
Hypertension
Agitation/Psychosis
Seizures
Mydriasis (dilated pupils)
Diaphoresis

Not of the Bath and Body Works variety... (Image)

Common sympathomimetic drugs known to exhibit these effects include ketamine, synthetic cannabinoids, bath salts, cocaine, amphetamines, and ecstasy. Treatment generally includes supportive care and benzodiazepines for hypertension, hyperthermia, and agitation.

Not too hard to remember, right?

The Opioid Toxidrome

If I had to guess, this toxidrome is likely the one you’re most comfortable with. But just in case you’re not, let’s review the pathophysiology. Opioid agonists bind to mu, kappa, and sigma receptors, leading to central nervous system depression and analgesia. Opioid toxicity generally presents with:

Bradypnea
Bradycardia
Hypotension
CNS depression/coma
Miosis (pinpoint pupils)
Seizures (in the setting of tramadol overdose)
QT prolongation (in the setting of methadone overdose)
Constipation/bowel obstruction

Commonly abused agents include both natural and synthetic opioids. If you’re like me and have a hard time remembering which is which, take a peek below:

Natural opiate derivatives: codeine, heroin, hydrocodone, morphine, oxycodone
Synthetic opioids: buprenorphine, dextromethorphan, fentanyl, methadone, meperidine

In regard to treatment, naloxone remains the mainstay of treatment. Naloxone works by competitively inhibiting opioid receptors, resulting in the displacement of the opioid from the receptor site. Naloxone dosing is dependent on the formulation and severity of opioid toxicity.

Naloxone IV (preferred): 0.04 mg to 2 mg; may repeat with escalating doses every 2-3 minutes as needed
Naloxone IM, SubQ: 0.04 mg to 2 mg; may repeat with escalating doses every 2-3 minutes as needed
Naloxone Inhalation: 2 mg; may repeat as needed. Transition to IV or IM administration when possible
Naloxone Intranasal: 1 spray as a single dose in one nostril; may repeat with a new nasal spray every 2-3 minutes in alternating nostrils if patient does not respond to initial dose
Naloxone Endotracheal: 0.8 to 5 mg as a single dose. Transition to IV or IM administration when possible

Phew, we’re getting there. I promise!

The Sedative-Hypnotic Toxidrome

As you probably already know, GABA is the main central inhibitory neurotransmitter leading to CNS depression. With regards to pathophysiology, the majority of sedative-hypnotic agents work by increasing GABA neurotransmission. As a result, sedative-hypnotic toxicity generally presents with the following:

Hypothermia
Bradypnea
Bradycardia
Hypotension
CNS depression/lethargy/coma

Common sedative-hypnotic agents known to exhibit these effects include barbiturates, benzodiazepines, ethanol, ethylene glycol, isopropyl alcohol, methanol, general anesthetics, and muscle relaxants.

Regarding treatment, supportive therapy is the mainstay of treatment. Particularly, if a patient is overly sedated to the point they cannot protect their airway, then intubation is imminent. Now of course there are certain antidotes that inhibit GABA receptors such as flumazenil. However, use is strongly discouraged in patients taking chronic GABAergic agents given flumazenil use has been associated with an increased risk of seizures. If flumazenil is clinically appropriate, the dosing regimen is as follows:

Flumazenil (IV): 0.2 mg over 2 minutes; if the desired level of consciousness is not obtained 30 seconds after the dose, 0.3 mg can be administered over 3 minutes; if the desired level of consciousness is still not obtained, 0.5 mg can be administered over 5 minutes and repeated at 1-minute intervals; maximum cumulative dose: 3 mg

The tl;dr of Toxidrome Poisoning

Phew. That was a lot to cover. But if you’re a visual learner like me, here is a table I made that summarizes literally everything we went over.

You’re welcome :)

A Pharmacist-Friendly Introduction to Toxicology