Reversal Agents for Medication Overdoses

During the early days of my nursing career when I was in my residency, I had the opportunity to shadow a member of the rapid response team (RRT). As we were discussing the RRT nurse’s role, we got to talking about emergent situations seen in the clinical setting. From that discussion we arrived at the topic of reversal agents for medication overdoses. Some medications can cause life-threatening conditions such as respiratory depression, bradycardia and even bleeding. And while not all medications have a reversal, some of them do and it’s important to know what they are. In this blog post we’ll talk about some of the most common meds that, if overdone, may require emergent reversal.

Drug: Opioids
Reversal: Naloxone (Narcan)

We’ll start with one you’ve likely already heard of, thanks to the opioid epidemic in the United States. Naloxone reverses the effects of opioids by kicking the opioid off the receptor sites and binding them up for a period of time. The key thing you need to know about naloxone is that its duration of action is typically shorter than that of the opioid, so you need to monitor your patient closely and watch for signs of overdose to reappear. If they do, the patient may need another dose of naloxone.  Naloxone can be given IV, IM, SubQ, in nebulized form or as a nasal spray. It can cause agitation, hypertension and even ventricular tachycardia in high doses.

Drug: Benzodiazepines
Reversal: Flumazenil (Romazicon)

A benzodiazepine overdose depresses the central nervous system causing slurred speech, decreased level of consciousness and ataxia. In severe cases the patient may be comatose and unable to protect their airway or ventilate properly. If the patient is also receiving medications that cause respiratory depression (such as opioids) the degree of respiratory depression can be profound. Flumazenil is given IV, but be aware that it can lower the patient’s seizure threshold significantly and seizure is a very real possibility in patients who are habitual benzodiazepine users. It can also cause confusion, agitation, hypertension, and alterations in heart rate (either too fast or too slow).

Drug: Beta-blockers
Reversal: Glucagon

Patients taking too much of their beta blocker medication (such as lebatalol) can present with serious bradycardia, hypotension, bronchospasm, AV blocks, heart failure and even seizures. High dose glucagon increases heart rate, improves AV conduction and improves myocardial contractility. It is given IV and you’ll need to monitor your patient for hypokalemia, vomiting and, of course, hyperglycemia. Why do you think your patient may become hypokalemic?

Drug: Heparin and enoxaparin (Lovenox)
Reversal: Protamine sulfate

Drug: Warfarin (Coumadin)
Reversal: Prothrombin complex concentrates (PCCs), Vitamin K, fresh frozen plasma (FFP) for coagulation factor replacement

For overdoses of heparin and enoxaparain (which is a low-molecular weight heparin), protamine sulfate will reverse the anticoagulant effects. It acts as a heparin antagonist, but interestingly has a weak anticoagulant effect of its own as well. In fact, a study conducted in 2009 showed that it can actually cause increased bleeding, especially in patients who have undergone cardiothoracic surgery utilizing cardiopulmonary bypass. Protamine is given IV and comes with other serious side effects including hypotension and anaphylaxis reactions. For patient safety, it’s best to only give protamine with resuscitation equipment and treatment for anaphylaxis is within reach.

Patients coming in with severe bleeding due to a warfarin overdose will get treatment based on the severity of the condition. If the patient has major bleeding, the general treatment guidelines as outlined in the Journal of Pathology include vitamin K and PCCs which are aimed at providing complete reversal within 15 minutes. If the patient needs fast, but not immediate, reversal, then FFP is generally used. For reversal that needs to occur within 6 hours, then patients may simply receive IV vitamin K (oral vitamin K works but it’s a lot slower…up to 24 hours).

Drug: Rivaroxaban (Xarelto) or apixaban (Eliquis)
Reversal: Andexanet alfa (AndexXa)

In 2018 the FDA approved a reversal agent for Factor Xa Inhibitors, which up until this time had none. So if patients came in with excessive bleeding due to Xarelto or Eliquis we were really up against the wall. These patients would often require massive blood transfusions or even dialysis. AndexXa binds up and sequesters Factor Xa inhibitors and increases thrombin generation. Because of this, anytime you are abruptly reversal an anticoagulant, the patient will be at high risk for a thrombotic event.

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References

APSF. (2018, August 5). New Factor Xa Inhibitor (Xarelto®) (Eliquis®) Reversal Agent. Retrieved from Anesthesia Patient Safety Foundation website: https://www.apsf.org/news-updates/new-factor-xa-inhibitor-xarelto-eliquis-reversal-agent/

CHEMM. (n.d.). Naloxone. Retrieved September 14, 2019, from https://chemm.nlm.nih.gov/countermeasure_naloxone.htm#admin

Hanley, J. P. (2004). Warfarin reversal. Journal of Clinical Pathology, 57(11), 1132–1139. https://doi.org/10.1136/jcp.2003.008904

Kang, M., & Ghassemzadeh, S. (2019). Benzodiazepine Toxicity. In StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK482238/

Ni Ainle, F., Preston, R. J. S., Jenkins, P. V., Nel, H. J., Johnson, J. A., Smith, O. P., … O’Donnell, J. S. (2009). Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation. Blood, 114(8), 1658–1665. https://doi.org/10.1182/blood-2009-05-222109

Peterson, C. D., Leeder, J. S., & Sterner, S. (1984). Glucagon therapy for beta-blocker overdose. Drug Intelligence & Clinical Pharmacy, 18(5), 394–398. https://doi.org/10.1177/106002808401800507

Rx List. (n.d.). Protamine (Protamines): Side Effects, Interactions, Warning, Dosage & Uses. Retrieved September 14, 2019, from RxList website: https://www.rxlist.com/protamine-drug.htm

UC San Diego Health. (n.d.). LMWH Reversal. Retrieved September 14, 2019, from UC Health—UC San Diego website: https://health.ucsd.edu/specialties/anticoagulation/providers/lmwh/Pages/reversal.aspx