Ivermectin Toxicity

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09:24

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Ivermectin Toxicity

Sean Nordt and Stuart Swadron

Ivermectin is an anthelmintic and anti-parasitic agent that has been proposed to have activity against COVID-19.
Although it generally has a wide therapeutic safety profile, two deaths in New Mexico were reported in the popular press as being linked to a veterinary formulation of ivermectin.
The details are unclear and it is uncertain whether these deaths were indeed due to ivermectin.
Nonetheless, these cases raise questions about the safety of large doses of ivermectin, particularly from veterinary products.
Veterinary preparations are very concentrated and available in large amounts (eg, horse paste 1.87 %, Ivomec(R) injectable 10 mg/mL)

The “normal” (eg, antiparasitic) mechanism of action is potentiation of GABA at chloride ion channels in the peripheral nervous system of parasites, resulting in hyperpolarization of cells, paralysis and death.
Humans have GABA in their central nervous system only and ivermectin normally does not penetrate the blood brain barrier (BBB) well.
The proposed mechanism of action in COVID-19 is different and relates to the inhibition of transport of viral material into the nucleus by blocking importin. It does not involve the translocation of viral proteins. Some have suggested this activity may not occur at a “normal” human dose; this may lead people to use ivermectin at much higher doses than can be safely recommended.
The usual human dose for anti-parasitic varies on indication but is generally around 0.15 mg/kg – 0.4 mg/kg once or for several days to a week or longer.
The proposed COVID dose used in some studies is 0.2 mg/kg – 0.3 mg/kg once a day for five days. This is very similar and we would not expect toxicity at these dosages.

Ivermectin is generally well tolerated in humans and animals.
There is limited human data of toxicity but it seems to follow animal toxicity data (ivermectin is used frequently in animals). Much of human data is from the developing world, where ivermectin is commonly used as antiparasitic.
Ivermectin is limited from crossing the blood-brain barrier by the activity of the p glycoprotein pump, however this pump can be overwhelmed, and other factors may predispose patients to toxicity (see below).
Toxicity from ivermectin is uncommon but when it does occur, central nervous system effects predominate. This is expected based on its potentiation of GABA at chloride ion channels.
Factors which may increase risk of toxicity:

Higher concentrations (eg, higher doses)
The presence of p glycoprotein inhibitor medications (eg, verapamil),
Conditions that make the blood-brain barrier more permeable (eg, sepsis), and
CYP3A4 inhibitors (eg, clarithromycin), which will inhibit the metabolism of ivermectin
Individuals with phenotypes with decreased mdr-1 gene, which expresses p glycoprotein pumps

Dizziness, ataxia
Progressive decreasing level of consciousness: obtundation, stupor, encephalopathy, and coma
Seizures (less common)

Can last hours to days
This suggests different or additional effects other than a “benzodiazepine effect” at the chloride ion channel

Treatment is supportive with close observation of the patient’s mental status and neurologic exam
Seizures can be treated with benzodiazepine. There is theoretical concern that sedation with benzodiazepine may potentiate CNS depression; we recommend close monitoring if benzodiazepine is used.
Rapid sequence intubation (RSI) may be required for CNS depression and cardiovascular resuscitation for hypotension or bradycardia.
Generally there is no role for activated charcoal or other GI decontamination because of the risk of CNS depression with ivermectin toxicity.

References

EM:RAP 2021 Special Report October 7th: Ivermectin Toxicity Full episode audio for MD edition 9:24 min - 10 MB - M4A