Novichok: a fourth-generation class of nerve agents

Salisbury, U.K. April 25, 2018. Decontamination efforts where Sergei and Yulia Skripal were found poisoned. [shutterstock.com]

2.5 out of 5 stars

Novichok: a murderous nerve agent attack in the UK. Vale JA et al. Clin Toxicol 2018 May 14 [Epub ahead of print]

Reference

In an article in yesterday’s New York Times, medical workers who treated Sergei and Yulia Skripal after they were found poisoned and unconscious on March 4 describe how they feared both patients would die and that many more patients might ultimately be affected.

Initially it was thought that the Skripals were suffering from opioid overdose. But after learning that Mr. Skripal had been a spy for Russia, attention turned to some form of organophosphate nerve agent.

British authorities have identified the agent use to poison the Skripals as “Novichok.” This term, which means ‘newbie’ or ‘newcomer’ in Russian, is not all that helpful. It refers to a number of nerve agents that were synthesized after the development of the ‘G’ agents — tabun, soman, sarin — and other agents such as VX. Virtually nothing has been published in the scientific literature about the toxicology of the Novichok agents.

I was hoping that this paper would fill in some of the gaps and expand our knowledge about these “fourth generation” nerve agents. Unfortunately, It does not reveal much that is new or not known from previously available sources. The authors remind us that “more than 100 compounds fall into the Novichok category.” Many of these may be binary agents, meaning that they are formed when two different chemicals — each relatively harmless on its own — are mixed. Some of these may be up to 8 times more toxic than VX. Aside from these tidbits, the article basically reviews organophosphate nerve agents in general. The paper does not contain any lessons learned specifically from the Skripals’ poisoning. Hopefully, that information will follow.

 

 

 

 

Can cannabinoid hyperemesis syndrome be fatal?

shutterstock.com/Stanimir G. Stoev

2.5 out of 5 stars

Cannabinoid Hyperemesis Syndrome: Reports of Fatal Cases. Nourbakhsh M et al. J Forensic Sci 2018 May 15 [Epub ahead of print]

Abstract

This paper reports on 2 fatal cases that the authors argue were attributable to the effects of cannabinoid hyperemesis syndrome (CHS).

CASE #1: A 27-year-old woman is brought to hospital by ambulance after friend found her unresponsive with agonal respirations. On arrival she was apneic with bradycardia and decorticate posturing. Pupils were fixed and dilated. Serum glucose was 34 mg/dL. After presentation she deteriorated and could not be resuscitated.

The patient had an 8-year history of cyclic nausea and vomiting for which no specific cause was found after extensive workup. She also had a long history of smoking marijuana. Two days before this final presentation she had been evaluated for severe nausea and vomiting, and discharged home after symptomatic improvement.

Gross and histologic findings at autopsy did not reveal a specific causes of death. Extensive toxicology testing was positive for Delta-9-THC and Carboxy-THC. Tests of vitreous humor showed hyponatremia, hypochloremia, hypoglycemia, and elevated urea and creatinine. (Strangely, no electrolyte results are reported on pre-mortem blood.) The death was attributed to complications of cannabinoid hyperemesis syndrome.

CASE #2: A 27-year-old man was found dead in a drug rehab center. He had experienced severe vomiting for 5-6 days before death. He had a long history of marijuana use and cyclic vomiting.

At autopsy the body appeared dehydrated. Gross and histologic findings, as well as extensive drug testing, did not reveal a specific cause of death. Vitreous testing showed minimally decreased sodium and chloride levels, as well elevated urea and creatinine. Again, the death was attributed to complications of cannabinoid hyperemesis syndrome.

For sure, significant dehydration can have bad effects, especially when combined with electrolyte abnormalities. Unfortunately, there is not enough clinical or pathological data accompanying these cases to make a convincing argument that CHS alone explains the deaths. However, there are two important take-home lessons:

  1. When patients present with CHS, aside from treating the symptoms, the treating practitioner should evaluate and document hydration status as well as serum glucose and electrolyte levels, and correct any deficiencies.
  2. These patients should not be discharged until they can clearly tolerate oral intake.

Related posts:


Case Series: treating cannabinoid hyperemesis syndrome with capsaicin cream

Review of cannabinoid hyperemesis syndrome

First case of cyclic hyperemesis associated with synthetic cannabinoids

Cannabinoid hyperemesis syndrome: largest case series to date

Review: cannabinoid hyperemesis syndrome

More on cannabinoid hyperemesis syndrome

The anti-munchies: cannabinoid hyperemesis syndrome

 

 

A case of life-threatening loperamide toxicity

3 out of 5 stars

Severe loperamide toxicity associated with the use of cimetidine to potentiate the “high.” Hughes A et al. AM J Emerg Med 2018 May 15 [Epub ahead of print]

Reference

The potential adverse effects of loperamide (Imodium) are often underestimated since, even though it is an opioid, it is available over-the-counter and has been since 1988.

Loperamide is used to treat diarrhea. It acts on the mu-opioid receptors in the gut, decreasing gastric motility. It is rather effective at this. However at therapeutic doses (2-16 mg per day) it does not cause central opioid effects such as euphoria or relief from opioid withdrawal symptoms. There are several reasons for this.

Oral loperamide has limited bioavailability, estimated at less than 1%. It undergoes significant first-pass metabolism  via the hepatic cytochrome P450 (CYP) system. In addition, much of the ingested dose of loperamide does not get absorbed systemically in the first place, since it is actively pumped back into the gut by P-glycoprotein (P-gp).

The P-glycoprotein efflux pump is also active at the blood-brain barrier, ejecting harmful substances before they reach the central nervous system. In a recent column on the topic, I pictured P-gp as a physiological bouncer, a molecular Mr. T.

However, massive amounts of loperamide can overwhelm these defense mechanisms and enter the CNS in significant amounts, achieving central levels sufficient to cause opioid effects and euphoria, and suppress withdrawal symptoms. These effects can be enhanced when loperamide is taken along with another drug that inhibits the hepatic CYP system and/or blocks the P-gp pump. Cimetidine is one such drug.

One other thing. For reasons that have not been fully elucidated, loperamide is cardiotoxic. It can increase the QRS and QTc intervals, sometimes resulting in life-threatening arrhythmias.

This case report illustrates this danger. A 40-year-old female opioid user  was brought to hospital after a syncopal episode. In the emergency department she had recurrent episodes of polymorphic and monomorphic ventricular tachycardia. The EKG showed a QTc of 583. The dysrhythmia was treated with overdrive pacing which had to be continued for 8 days.

Later, the patient admitted abusing massive doses of loperamide as well as cimetidine, but did to give additional details. Interestingly, she had previously presented to another emergency department with a similar episode, which was diagnosed as a presumed seizure.

The key take-home lesson: suspect loperamide toxicity in a patient who presents with new conduction abnormalities, life-threatening dysrhythmias, or an otherwise unexplained history of syncope.

Related posts:

Loperamide abuse and cardiac dysrhythmia

Missing loperamide (Imodium) abuse can be a fatal mistake

Loperamide (Imodium) overdose can cause fatal cardiac toxicity

Cardiac effects of loperamide overdose