In a world where Ketamine rules all FOAMed, services without access to this “miraKle drug” often get left out of the conversation on safe chemical restraint. So, Ketamine Warriors, I humbly ask that you imagine for a moment that you don’t have your secret sauce, and you must rely upon……BENZOS AND ANTIPSYCHOTICS.

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I will leave the “favorite benzo flavor” out of today’s discussion and instead shoot for a dissection of a fairly popular prehospital/hospital antipsychotic agent, Haldol. 

Before this past May, I never had access to haloperidol. Knew of it and its general characteristics, of course, and heard a couple “B52!!!”s yelled out in the ER but never had an opportunity to use it. This made for an uncomfortable Natalie when I learned 5mg Versed and 5mg Haldol IM was our chemical restraint concoction of choice, so I dove into the research. 

I must be honest here: I didn’t really like what I found. Long onset, sketchy side effects, significant half-life…..not my ideal characteristics for a sedation agent. Then, add on anecdotally how many patients list Haldol as an allergy because they had such adverse reactions-not thrilling news for someone often administering this drug before we are even able to get a name, much less a full medical history, due to excited delirium, tox, or just downright combativeness. So, allow me to make my case for why we should be taking much more care and consideration before grabbing for the haloperidol as a first line drug…

AN OVERVIEW

Indications: Excited delirium, agitation, psychosis, vomiting, chronic hiccups 

Mechanism of Action: Strong antagonist of Dopamine receptors (D2) AKA inhibits dopamine’s effects

Contraindications: Parkinson’s Disease, hypersensitivity. 

Yes, you read that right. Head injury is not a contraindication to Haldol. Go on and take y’all’s mind-blown selves to the research suggesting no harm in intermittent administration to TBI patients, and holler if you need me.

Side Effects: Extrapyramidal symptoms (Parkinson’s-esque), restlessness, worsened agitation, spasms, drooling, dystonia, hypotension, nausea, vomiting, vision changes, irreversible dyskinetic movement syndrome (especially in elderly women)

Really Scary Side Effects: QT Prolongation > Ventricular Arrhythmias >Sudden Cardiac Arrest

Onset: For IM injections, 20 minutes ‘til peak effects in average population, 34 minutes in schizophrenic

Half-life: Almost 21 HOURS 

Mechanism of Metabolism: Lipophilic and hella metabolized by the liver (only ~1% of original drug in the urine)

Drug Interactions: 

  • Lithium: Cause extrapyramidal symptoms, encephalopathy, coma
  • Tricyclic Antidepressants: Decrease metabolism/elimination of TCAs
  • Quinidine, Buspirone, Fluoxetine: Increase Haldol serum levels
  • Carbamazepine, Phenobarbital, Rifampicin: Decrease Haldol serum levels
  • Warfarin: Increase warfarin serum levels
  • Acyclovir: Increase Haldol serum levels
  • Metformin: Decrease efficacy of metformin
  • Insulin: Decrease efficacy of insulin

So, why does haloperidol work?

The best working theory we have for the positive symptoms of schizophrenia is an over-production of dopamine in the mesolimbic system. That’s to say that the hallucinations, delusions, agitation, aggression, disorganization reside……right here 

The part of schizophrenia that we typically want to treat and control in a prehospital emergency setting is acute agitation and aggression; therefore, BOOM we want that pathway to cool its dopamine jets, which Haldol achieves. 

So then, what’s your problem, Nat?

  1. We aren’t always administering this drug to schizophrenic patients. Yes, sometimes, we find the classic clear-cut case or patient we are familiar with who maybe missed their monthly injection. However, most of the time, we are dealing with complex cases in high-stress situations. I so hope we have all joined the school of thought that severe agitation is indeed a medical emergency, and a fragile, dangerous one at that. We must think swiftly about the safest plan for ourselves, our crew, our patients, and any bystanders. I won’t be discussing defusing or other methods of restraint here, just making a point that urgency in stopping the acute problem of agitation is our first priority on these calls. If the patient is hypoxic, we give oxygen. If they’re hypoglycemic, we give sugar. Yet, if they’re combative, they get an antipsychotic? Interesting. 
  1. Haloperidol is not an effective rapid sedative. Like I just said, in order to move forward in the treatment of this patient, we have to bring them from a Level 10 to at least a Level 6. Why wait 20 minutes (or 34!!!!) to get there? Further delaying the ability to fully assess, not to mention treat this patient. Some of y’all’s services don’t have anywhere near those transport times, so, I mean, you’re welcome to the ER staff, but I still have a clinically agitated dude who is further stressed by my bright, moving, terrifying machine with pokey things. That does not make for excellent care. 
  1. It lasts way too long. I mean waytoo long. A half-life of 21 hours is absurd. For comparison, the half-life of midazolam is about 2 hours. If we have an adverse reaction, just hold on to your hats; we have a BIT until this stuff is cleared out. 
  1. Finally, my real beef with the stuff….it’s not ONLY affecting the mesolimbic pathway!

Let’s go to the nigrostriatal tract to see what I mean.

Big stuff is going on here…like 80% of the body’s dopamine, NBD. But it’s ok; it’s not like that dopamine is involved in anything important. OH WAIT. MOTOR PLANNING. Without that, well, you kinda...

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Pseudo-Parkinson’s-type extrapyramidal symptoms can occur from the antagonism of the dopamine receptors like dystonia, akathisia, and tardive dyskinesia. Those symptoms can range in severity from tense muscles and restlessness up to difficulty swallowing and breathing. Me no likey. Think about it, though, Parkinson’s patients take Carbidopa to treat their symptoms and increase their dopamine. We are doing the opposite. It can be a bummer. I do wonder if part of the role of the Benadryl in the common B52 cocktail (Benadryl, 5mg Haldol, 2mg Ativan by the way) is to guard against the extrapyramidal symptoms. My literature review was lacking in rationale for it other than generic sedative effects. Anyone care to weigh in?

Now, over to the tuberoinfundibular tract…

Dopamine in the tuberoinfundibular pathway inhibits prolactin release from the pituitary gland. Therefore, inhibiting dopamine increases prolactin. This causes discharge from the breasts and a decrease in estrogen and testosterone which affects fertility, sex drive, and eventually bone density. Also, fairly uncool symptoms for somebody who ended up being a tox patient had we been able to discern that earlier and withhold a dopamine antagonist.

BONUS: Guess what else is really fun! GABA receptors (multipurpose inhibitors in da’ brain) MODULATE Dopamine receptors! So, activating GABA receptors suppresses dopamine receptors. Guess what enhances GABA receptors?! Benzos! So essentially when we 5x5, we are just straight up Hoovering these folks’ dopamine right on out of their mesolimbic systems. Rock on.

SO, NOW WHAT?!

Look, Haldol is a very effective First-Generation Antipsychotic medication for schizophrenia. So far, the literature hasn’t shown increased efficacy of Second Generations (atypical antipsychotics) over First. Haloperidol is the affinity champion on dopamine receptors while Second Generations tend to also antagonize serotonin receptors. The atypicals(i.e. risperidone, olanzapine, clozapine, quetiapine, aripiprazole, ziprasidone), while having a decreased risk of extrapyramidal symptoms, tend to cause more metabolic side effects like weight gain and hyperglycemia. Again, our prehospital purpose is treating time of behavioral crisis, and haloperidol has been proven to be a successful sedative.

On the other hand, I cringe at the thought of Haldol being used as a first line without consideration for its pharmacokinetics. While successful, it is not a simple sedative. It doesn’t really suit the prehospital environment because of its long onset, and it doesn’t suit the average non-dopamine rich patient. If anything, its administration to a non-schizophrenic patient makes me a little worried about airway difficulties from extrapyramidal symptoms, especially when given in conjunction with a respiratory depressant. 

Who knows? Maybe someday I’ll eat these words, but I’m just not too crazy about this stuff being used as a broad sedative (as I’m sure my sass alluded to). I have just one more question…is there still room on the Ketamine train, guys?

SOURCES

https://www.drugbank.ca/drugs/DB00502

http://criticalcare.imedpub.com/haloperidol-use-in-acute-traumatic-brain-injury-a-safety-analysis.php?aid=8802

https://www.liebertpub.com/doi/abs/10.1089/neu.2018.6212

https://www.sciencedirect.com/science/article/pii/S0166432816306817

https://www.news-medical.net/health/GABA-Activation-and-Dopamine-Suppression.aspx

https://www.news-medical.net/health/Haloperidol-Pharmacokinetics.aspx

https://images.app.goo.gl/JNDQSFtsUHxzfbii8

https://psychopharmacologyinstitute.com/publication/the-four-dopamine-pathways-relevant-to-antipsychotics-pharmacology-2096

https://psychopharmacologyinstitute.com/publication/first-vs-second-generation-antipsychotics-2082

 

 

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