Episode 92- Naloxone for ACE-I overdose

Episode Summary:

Learn how naloxone can be used in the setting of an ACE-I overdose. Who would have thought?

Show Notes:

Key Points:

“Naloxone for ACE-I overdose”:
– Ace-Inhibitors work by blocking angiotensin-converting enzyme from converting angiotensin I to angiotensin II—leading to a decrease in sympathetic outflow in the brain and less vasoconstriction which leads to a reduction in the BP
– In an overdose, patients can have severe and refractory hypotension and even bradycardia. Bradycardia is due to reduction of central sympathetic outflow (unlike other vasodilators, ACE-I do not cause reflex tachycardia- more on that below)
– Endogenous opioids (beta-endorphins) inhibit central sympathetic effects in the brain- leading to a reduction in the BP and blunting of reflex tachycardia. ACE-I block enkaphalinase, the enzyme that degrades beta-endorphins in the brain. This leads to an increase in the amount of beta-endorphins in the brain, leading to a more pronounced reduction in sympathetic outflow which ultimately leads to hypotension and bradycardia
Patients are treated with supportive care, fluids, and vasopressors- but naloxone is also an option. Naloxone, being an antagonist for both exogenous and endogenous opioids, works by blocking beta-endorphin’s central effects– increasing the BP and the heart rate
– Only a handful of case reports describe using naloxone in this setting. Most patients had pronounced and sustained BP and HR response to boluses (0.2-2 mg IV) or continuous infusions of naloxone
ER-Rx Episode 92


Hello and welcome to Episode 92 of ER-Rx- a podcast tailored to your clinical needs. I’m your host, Adis Keric. This is a huge episode for me because it’s the third anniversary of starting the podcast- so this is officially Episode 1 of Season 4. This year I’ll be introducing a brand-new logo and some new Podcast art- so let me know what you think about those. I released a little teaser logo with the cupcake and the “anniversary”text last week—now we’re back to how it’s going to look from here on out. A big shout-out to my cousin Arnel who designed the logo and podcast art- if you need anything done, please reach out to him on his website, which I’ll post to the Show Notes.

I also have some very exciting things to announce in the coming months- so stay tuned for that. To all of the people listening- thank you so much for tuning in, leaving comments, and answering all of my polls on Instagram. Whether you’ve been around since 2020 or are just tuning in- please feel free to reach out to me if you have any ideas for a future episode, if you’d like to come on the show and share your knowledge, or if you’ve seen something interesting that you want the rest of our community to know about. I’m truly honored to be a small part of your lives and your practice and I’ll keep working super hard to bring you a podcast that’s concise, accurate, and useful.

With that, we’ll get right into this Mini Grand Rounds episode. I’m gonna talk about a very cool and rare use of naloxone. I’ve personally never seen this done and have just recently learned about it: using it to reverse ACE-Inhibitor overdoses- which seems like it makes no sense at all, but just wait until we get into it in this episode.

ATII, as discussed in last week’s episode, works by increasing sympathetic outflow in the brain and constricting blood vessels- both of which increase the BP. Ace-Inhibitors work by stopping angiotensin-converting enzyme from converting angiotensin I to angiotensin II—indirectly leading to the opposite effect; a decrease in sympathetic outflow in the brain and less vasoconstriction which leads to a reduction in the BP.

It’s no surprise then that ACE-Inhibitor overdoses, although pretty uncommon, can cause severe and refractory hypotension. Sometimes they can even cause bradycardia- by mechanisms we think involve the reduction of central sympathetic outflow (as a side note, unlike most other vasodilators, ACE-Inhibitors don’t cause reflex tachycardia, and tachycardia isn’t a feature of ACE-Inhibitor overdoses as one would think it should be).

Anyways, textbooks will treat these overdoses with supportive care, fluids, and vasopressors- but what is rarely mentioned is that naloxone can be an option here (that’s right- naloxone).

To fully understand why naloxone works in this setting, we have to talk about endogenous opioids called beta-endorphins. Beta-endorphins inhibit central sympathetic effects in the brain- leading to a reduction in the BP and blunting of reflex tachycardia. Besides their known effect on angiotensin converting enzyme, ACE-Inhibitors also block something called enkaphalinase, the enzyme that degrades beta-endorphins in the brain. This means that ACE-Inhibitors indirectly increase the amount of beta-endorphins in our brain- leading to a more pronounced reduction in sympathetic outflow which ultimately leads to hypotension and possibly bradycardia.

Naloxone, being an antagonist for both exogenous and endogenous opioids, works by blocking beta-endorphin’s central effects– increasing the BP and even increasing the heart rate. And it’s effects are very pronounced and sustained.

Only a handful of case reports describe using naloxone in this setting. I’ll post them all to my Read by QxMD collection which you can find in the show notes, on the website, or in the podcast description wherever you happen to be listening to this. I’ll describe a few of them now.

One case report talks about a patient taking extra doses of lisinopril to treat his high BP (estimated 300 mg total over 48 hours). This lead to syncope and arrival to the ED. He presented with BPs in the 70s and HR in the 90s. Despite 2L of fluids, he remained hypotensive. He then got 0.4 mg IV naloxone with a plan to start a continuous infusion if repeat doses were needed. One minute after naloxone, his BP went up to the 90s and stayed there without any further intervention- he didn’t need vasopressors or any more naloxone doses. He even discharged the next day. I know what you’re thinking; maybe this patient just overdosed on some opioids, but that was ruled out- he was not on any opioids per his report, pharmacy fill histories, and clinically his mental and respiratory status just did not fit with that picture. (Haluska, et al.).

Another second case report describes a patient who overdosed on perindopril and then developed severe bradycardia and hypotension. After getting some atropine and a little bit of epinephrine with some response, he was given 2 mg IV naloxone which immediately reversed his bradycardia and improved his BP. He was started on a naloxone infusion (0.04 mg/kg/h) with great response, and when the naloxone was accidentally stopped during a shift change, he fell back into severe bradycardia which again completely reversed once naloxone was restarted. He needed the infusion for 24 hours, at which point his hemodynamics were normal, allowing him to be discharged 6 days later (Robert, et al).

The last case report describes a captopril overdose (500g mg total taken). After gastric lavage and activated charcoal, the patient became lethargic and dropped pressures to the 70s. They gave her 1.6 mg of IV naloxone thinking the patient may have overdosed on narcotics—and they were surprised to see immediate reversal of hypotension. Within 5 minutes, her BP was 140. In 10 minutes, she got hypotensive again, and once again immediately responded to 2 more mg of IV naloxone and didn’t need any more after that. Just like in the first case- she was not on any opioids, which was confirmed by a negative tox screen. (Varon, et al.).

To wrap up- keep in mind that ACE-Inhibitors work not only by reducing the amount of ATII and leading to vasodilation, but they also have some central effects on the brain. Endogenous opioids also work in the brain and they typically lead to a reduction of sympathetic drive. ACE-Inhibitors block an enzyme that degrades these beta-endorphins- making their actions more pronounced and explaining why patients who take ACE-Inhibitors, or overdose on them- don’t develop reflex tachycardia as we would expect. To treat an ACE-Inhibitor overdose, along with fluids and supportive care- try giving some naloxone. I don’t really care what dose you give; try 0.2-2 mg IV boluses repeating if needed. Most patients do well with just one or two doses, but you may have to start a low-rate continuous infusion at around 0.4-2 mg/hr for a some short amount of time. This means you can completely avoid giving vasopressors.

Some questions remain: one is why does naloxone have such a prolonged effect in this setting- with most patients only needing 1-2 doses- but it doesn’t have such a long effect when treating opioid overdoses? One thought is that there are some major pharmacodynamic differences when reversing exogenous opioids vs endogenous ones. The second question is: will this work for ARBS? I don’t think so. I could not find anything in the literature to support this, which makes sense because I don’t think they inhibit enkaphalinase or increase the amount of beta-endorphins like ACE-Inhibitors do—but I am happy to be corrected on this if I’m mistaken.

And just as a point of clarity before we wrap up, in this setting it’s also not unreasonable to try Giapreza, our synthetic ATII – with some case reports showing this could be an option for patients who don’t respond to pressors or naloxone.

Before we go, I just wanted to send a huge shout out and thank you to Travis for his massive donation on BuyMeACoffee.com. Travis is one of our fantastic Nurse Practitioners in the MICU and he also has the coolest mohawk in town- thank you again. Donations like his help keep this podcast running without ads and free for everyone.

As always, thank you so much for your time, and thank you for wanting to learn more about pharmacotherapy. If you have any comments or anything you’d like to add to this episode, please give me a shout out on the @errxpodcast Instagram page, or reach out to me personally on errxpodcast.com- I’d love to respond to all comments and criticisms.


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