Part 9 — Bruno, the blood-brain-barrier bouncer
Gonna keep this entry short and sweet, and tell you the story of my favorite drug. But first I have to give you some key background on an overlooked part of your body.
The blood brain barrier. It’s one of the wildest things in your body. In part because, to my taste, no one has been able to describe it biologically in a way that allows me to fully envision how the H-E-double-hockey-sticks this works.
But in short, before anything in your blood stream can get into your brain, there is a mesh, a filter, a gate-keeper… Hmm, searching for the right analogy here.
Ah.. maybe it is a night-club bouncer? And this bouncer, let’s call him Bruno, he hangs out behind the velvet rope and literally scopes out every Tom, Dick and Harry who shows up at the club. If they look like the wrong element he blocks their entrance. If they sneak in, he’ll pump them out the door again. And that way he keeps the brain/club pristine with only the right element.
Now chemists working on drugs for depression or other neurological disorders hate this guy: Bruno, the blood-brain-barrier-bouncer. Because they have all these great compounds that totally engage their molecular targets perfectly in a test tube, but when they test them in animal models or the clinic, Bruno keeps them out of the club. While the chemists are increasingly able to figure out who Bruno will let into the club, this still makes the process to finding new neurological drugs more arduous.
However sometimes Bruno can be quite useful in unexpected ways.
To tell the story of my favorite drug we have to go back in time to 3400 BC. That’s when we have historical proof of the first use of the poppy plant for pain relief and other ceremonies. Now, to be clear, opium and it’s modern-day derivatives are complicated and often terrible drugs given the high risk for addiction and abuse. However even early on folks realized that it did have one “side effect” that might have benefits: constipation.
And so, folks used opium tinctures, paregoric, etc to treat acute and chronic diarrhea. Here the opioid compounds slow the peristalsis of your gut and thus the frequency of your visits to the bathroom. But there was one major downside to these therapies — the psychotropic and central nervous system effects.
So a guy named Paul Janssen (yep that one that founded Janssen, which got bought by J&J which created one of our currently authorized vaccines!). Started to play around with versions of opioid compounds that would keep all the gut activity but lose the activity in the brain. Basically, a version of an opioid that Bruno the blood-brain-barrier-bouncer, would reliably throw out of the brain/club. And voila!
Loperamide (or Immodium) was born.
This molecule basically is a great substrate for an enzyme called P-glycoprotein which reliably limits it’s access to the brain, keeping the drug in the rest of the body where it can act on the mu-opioid receptors in the gut to slow peristalsis and control diarrhea.
Now as with all drugs, there is still at Therapeutic Window with loperamide. But due to this clever chemistry, the dose that provides efficacy (2 mg) is 30 fold away from the dose that causes trouble (60 mg). Which is pretty dang impressive in my book.
In case you are curious to know more here are some references!
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017690s005lbl.pdf
https://en.wikipedia.org/wiki/Loperamide
https://www.jnj.com/our-heritage/meet-dr-paul-janssen-a-legend-in-pharmacology
