Ju-Tae Sohn
Loperamide-induced cardiac toxicity and lipid emulsion treatment
Loperamide-induced cardiac toxicity and lipid emulsion treatment

Possible mechanisms underlying lipid emulsion treatment for loperamide-induced cardiac toxicity I read with interest on the case report entitled ‘Loperamide-induced cardiogenic syncope: a case report of a life-threatening presentation of an over-the-counter drug’, recently published in the European Heart Journal – Case Reports. Successful treatment using lipid emulsion as an adjuvant drug with supportive treatments for loperamide-induced cardiotoxicity should be recommended. Loperamide is an antidiarrheal drug that decreases peristalsis and increases transient time. Lipid emulsion, which is mainly used for parenteral nutrition, is the recommended treatment for local anaesthetic systemic toxicity. Furthermore, lipid emulsion can alleviate the intractable cardiac depression caused by a toxic dose of non-local anaesthetic drugs, which are highly lipid soluble cardiac sodium channel blockers. I would like to share a few comments on the lipid emulsion resuscitation of loperamide-induced cardiotoxicity. Similar to highly lipid soluble local anaesthetic bupivacaine (log p: 3.41), a toxic dose of loperamide (log p: 5.13) with high lipid solubility produces QRS widening, QTc prolongation, Torsade de Pointes, and cardiac arrest by inhibiting the cardiac sodium and human ether-à-go-go-related gene (hERG) potassium channels. However, lipid emulsion decreases the transmural dispersion and restores normal sinus rhythm and myocardial contractility from bupivacaine-induced cardiac toxicity. Hegde et al. commented on the ‘static lipid sink’ as the possible mechanism underlying lipid emulsion treatment in loperamide-induced cardiac toxicity. However, these days, the widely accepted mechanism associated with lipid emulsion resuscitation is the ‘dynamic lipid shuttle’, composed of lipid emulsion-induced binding of a lipid-soluble drug and lipid emulsion-mediated increased redistribution of a lipid-soluble drug. The dynamic lipid shuttle is as follows: the lipid phase of a lipid emulsion produced by its intravenous administration absorbs lipid-soluble drugs (for example, bupivacaine) from the heart and brain. Then, the lipid emulsion containing lipid-soluble offending drugs is delivered to the liver, adipose tissue, and muscle for detoxification and storage. In addition, the direct mechanism of lipid emulsion treatment for bupivacaine-induced cardiac toxicity includes positive inotropic effects. Other direct mechanisms associated with lipid emulsion treatment include supply of fatty acids, inhibition of mitochondrial dysfunction, phosphorylation of glycogen synthase kinase-3β, and inhibition of nitric oxide. Moreover, 20% lipid emulsion was able to treat neurologic symptoms caused by loperamide (highly lipid soluble p-glycoprotein substrate) toxicity in a dog with a p-glycoprotein defect due to an adenosine triphosphate-binding cassette transporter gene mutation. Considering previous reports, the putative underlying mechanism of lipid emulsion treatment for highly-lipid soluble loperamide-induced cardiac toxicity is as follows (Figure 1): Lipid emulsion may absorb loperamide from the heart, and lipid emulsion containing loperamide may be delivered to liver, muscle, and adipose tissue, leading to recovery from Torsade de Pointes and myocardial depression through less inhibition of cardiac sodium and hERG potassium channels, and positive inotropic effect.

This case report suggests that lipid emulsion is useful for treating cardiac toxicity caused by highly lipid-soluble loperamide, which is unresponsive to supportive treatments. However, further research is needed to examine the effect of lipid emulsion treatment on cardiotoxicity caused by a toxic dose of loperamide.