Due to a recent episode of ivermectin poisoning in a canine, IEA members reached out to Pete Bill, DVM, Ph.D., Professor of Veterinary Pharmacology at Purdue University.
We thought we would share his answers with you here. The poisoning occurs when a dog ingests the de-wormer either directly or through manure. It is rare, but the consequences are devastating. Our sincere thanks to Dr. Bill for his insight and willingness to share this with the horse community.
There is a lot related to ivermectin and it relates back to distribution of drugs and the P-glycoprotein pump
In a nutshell, ivermectin is a neuro-poison that works on insects by combining with receptors on their neurons that control movement and other motor functions, and keeps these neurons from firing producing paralysis. While mammals do not have this receptor in their peripheral nervous system anywhere (periphery being “outside” of the brain and spinal cord or outside the CNS) mammals DO have a similar receptor to ivermectin located on neurons within their brain. Like in insects, when this receptor is stimulated, it prevents the neuron from firing. In mammals, this is seen as depression, ataxia, progressing to coma, blindness, sometimes seizures (caused by inhibition of inhibitory neurons which allows excitatory neurons to fire more readily and you get seizures).
BUT – because we have a blood brain barrier, that should keep ivermectin from moving from the blood into the brain to reach these receptors.
BUT – ivermectin is very LIPOPHLIC so it DOES penetrate the membranes that form the blood:brain barrier and CAN get into the brain.
BUT – the blood:brain barrier ALSO has the P-glycoprotein pump that grabs certain molecules that enter the brain and throws them back into the blood stream before they can attach to any receptors in the brain and produce an effect.
It is the action of the P-glycoprotein (P-gp) that protects mammals from the toxic effect of ivermectin.
Now, in the case of collie breeds, this breed has a genetic defect in the DNA that codes for P-gp pumps. You’ll see it written as MDR1 (multiple drug resistant 1 gene) or the ABC-B1 gene mutation. Regardless of what it is called, this genetic gene defect codes for P-gp pumps that are less effective than normal so they are not able to keep drugs out of the brain and spinal cord …. the blood brain barrier in these animals would be less effective in keeping drugs out of the brain.
Ivermectin is one of the drugs that P-gp keeps out of the brain. If P-gp is defective, more of the ivermectin can get into the brain than usual and you get toxic effects because the ivermectin can find that receptor on brain neurons and shut those neurons down.
Collies and other related breeds have a high incidence of this genetic defective gene and hence ivermectin has more of a neuro-toxic effect on these breeds. Note that it is not restricted to collies only and this genetic defect has been spread across breeds by cross-breeding. But collies still have the highest incidence.
The classic example of ivermectin toxicosis is a dog’s ingestion of oral equine wormers … that’s the number 1 cause of ivermectin tox because of the high concentration of ivermectin in horse deworming agents. Indeed, even animal with normal genes for P-gp can show toxicosis from ivermectin because the amount of ivermectin coming in across the blood brain barrier (BBB) is too much for the P-gp to keep up with and some of the ivermectin succeeds in stimulating the neurons to shut down producing clinical signs. It’s like trying to keep the water out of a leak boat using a small pump …. if the water is coming in too fast for the pump, you’re going to sink from too much water.
However, it is worse in animals with MDR1 gene defect because their pump works far worse and hence much more of the ivermectin gets to the neurons and you get worse clinical signs. Ivermectin toxicosis can extend for hours to days to weeks depending upon how much of the drug gets into the brain. Treatment for ivermectin toxicosis is simply supportive care until the body is able to get the drug out of the brain (where it likes to hang out … it doesn’t diffuse very readily back into the blood for elimination hence the long toxicity signs).