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Introduction

  • Antipsychotic medications are used for numerous acute states in the emergency department,

    • especially agitation.

  • IV access is often not available for patients with agitation and alternative routes must be

    • considered; the drug of choice may change depending on the route of administration.

  • This handout will focus on the pharmacotherapy of the most utilized antipsychotics in the

    • emergency department for acute agitation.

Clinical Detail

PharmacologyHaloperidol (Haldol®)Droperidol (Inapsine®)Olanzapine (Zyprexa®)Ziprasidone (Geodon®)
DosePO: 0.5-5 mg
IM/IV: 2-5 mg		IM: 5-10 mg
IV: 2.5-5 mg		PO: 5-10 mg
IM: 5-10 mg		PO: 20-40 mg
IM: 10-20 mg
OnsetPO: 30-60 min
IM: 20-40 min		IV/IM: 5-15 minPO (ODT): 15-20 min
IM: 5-10 min		PO: 45-60 min
IM: 15-60 min
Elimination Half-life10-37 hours2-4 hours30-37 hours2-5 hours
Parenteral Concentrations available5 mg/1 mL2.5 mg/1 mLPowder for Solution: mix with 2.1 mL sterile water to make 5 mg/1 mL solutionPowder for Solution: Mix with 1.2 mL sterile water for injection 20 mg/1 mL
QTc Prolongation (Dose used in study)4.7-14.7 mSec (10-15 mg)+16 mSec women
+22 mSec men (4.5 mg)		+6.4 mSec (20 mg)+15.9 mSec (30 mg)
CommentsGive lower dosage range in elderlyRisk of QTc prolongationBBW for QTc prolongation
Frequently on drug shortage		Warning to separate from benzodiazepines administration by 1 hour
Caution for QTc prolongation

Evidence

Author, yearDesign / sample sizeIntervention & ComparisonOutcome
Klein, 2018Observational
n=737		IM haloperidol 5 mg
IM ziprasidone 20 mg
IM olanzapine 10 mg
IM midazolam 5 mg
IM haloperidol 10 mg		At 15 minutes, midazolam resulted in more patients adequately sedated compared with ziprasidone 20 mg, haloperidol 5 mg, haloperidol 10 mg, and olanzapine. At 15 minutes, olanzapine resulted in more patients adequately sedated compared with haloperidol 5 and 10 mg.
Taylor, 2017RCT
n=349		IV midazolam 5 mg + droperidol 5 mg
IV olanzapine 10 mg
IV droperidol 10 mg		Ten minutes after the first dose, significantly more patients in the midazolam-droperidol group were adequately sedated compared with the droperidol and olanzapine groups. Patients in the midazolam-droperidol group required fewer additional doses or alternative drugs to achieve adequate sedation.
Hsu, 2010RCT
n=42		IM haloperidol 7.5 mg
IM olanzapine 10 mg
ODT olanzapine 10 mg
PO risperidone 3 mg		IM olanzapine or orally disintegrating olanzapine tablets showed significantly greater improvement in PANSS-EC scores than did patients who received IM haloperidol at points 15, 30, 45, 60, 75, and 90 minutes after injection. There was no significant difference in effectiveness among intramuscular olanzapine, ODT olanzapine, and oral risperidone solution.
Martel, 2005RCT
n=144		IM droperidol 5 mg
IM ziprasidone 20 mg
IM midazolam 5 mg		There were more patients who remained agitated in the ziprasidone group at 15 minutes than in the droperidol and midazolam group. At 45 minutes, there were more agitated patients in the midazolam group than in the droperidol and ziprasidone groups. No cardiac dysrhythmias were identified.
Nobay, 2004RCT
n=111		IM midazolam 5 mg
IM lorazepam 2 mg
IM haloperidol 5 mg		The mean time to sedation was 18.3 minutes for midazolam, 28.3 minutes for haloperidol, and 32.2 minutes for lorazepam. (P< 0.05) Time to arousal was 81.9 minutes for patients receiving midazolam, 126.5 minutes for haloperidol, and 217.2 minutes for lorazepam. (P<0.05)
Wright, 2001RCT
n=311		IM haloperidol 5 mg
IM olanzapine 10 mg
IM Placebo		Significant differences between olanzapine and haloperidol were observed at 15, 30, and 45 minutes after the first injection in scores on Agitated Behavior Scale, and Agitation Calmness Evaluation Scale. Significant differences between haloperidol and placebo were observed from 30 minutes onward on agitation scores. At 24 hours, changes in QTc intervals with active treatments were not significantly different from those with placebo.
Thomas, 1992RCT
n=21		IM/IV haloperidol 5 mg
IM/IV droperidol 5 mg		Droperidol decreased combativeness significantly more than IM haloperidol at 10 and 30 minutes. There was no significant difference between the two drugs when given by the IV route.

Conclusions

  • Several antipsychotics are commonly used for acute agitation in the emergency department, including haloperidol, droperidol, olanzapine, and ziprasidone, with the drug of choice influenced by the available route of administration.
  • These agents differ in onset, elimination half-life, and available parenteral concentrations; in the comparative trials reviewed, olanzapine and droperidol generally achieved adequate sedation faster than haloperidol.
  • QTc prolongation is a shared concern across these antipsychotics (olanzapine carries a boxed warning, droperidol and ziprasidone carry QTc cautions), so dosing and monitoring should account for cardiac risk and patient-specific factors such as age.

References

Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Accessed 2020, September 15.

http://www.micromedexsolutions.com/

Zun LS. J Emerg Med. 2018;54(3):364-374.

Mattson A, et al. Am J Health Syst Pharm. 2020

Miceli JJ, et al. Clin Ther. 2010;32(3):472-491

Yimcharoen P, et al. Gastrointest Endosc. 2006;63(7):979-985.

Haddad PM, Anderson IM. Drugs. 2002;62(11):1649-1671

Klein LR, et al. Ann Emerg Med. 2018;72(4):374-385.

Martel M, et al. Acad Emerg Med. 2006 Feb;13(2):233.

Wright P, et al. Am J Psychiatry. 2001;158(7):1149-1151.

Taylor DM, et al. Ann Emerg Med. 2017;69(3):318-326.e1

Hsu W, et al. J Clin Psychopharmacol. 2010;30(3):230-234.

Thomas H, et al. Ann Emerg Med. 1992;21(4):407-413.

Nobay Fet al,. Acad Emerg Med. 2004;11(7):744-749.

Tags:antipsychotics acute agitation haloperidol olanzapine

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Antipsychotics for Acute Agitation. Pharmacy Friday Pearls. 09-18-2020.pdf