Droperidol

Droperidol

Systematic (IUPAC) name
1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,5,6-tetrahydropyridin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one
Clinical data
Pregnancy cat.	C (US)
Legal status	?
Routes	Intraveneous, Intramuscular
Pharmacokinetic data
Metabolism	Hepatic
Half-life	2.3 hours
Identifiers
CAS number	548-73-2
ATC code	N01AX01 N05AD08
PubChem	CID 3168
DrugBank	APRD00939
UNII	O9U0F09D5X Y
KEGG	D00308
ChEMBL	CHEMBL1108 Y
Chemical data
Formula	C22H22FN3O2
Mol. mass	379.428 g/mol
SMILES	eMolecules & PubChem

Droperidol /droʊˈpɛrIdɔːl/ (Droleptan, Dridol, Inapsine, Xomolix, Innovar [combination with fentanyl]) is an antidopaminergic drug used as an antiemetic and antipsychotic. Droperidol is also often used for neuroleptanalgesic anesthesia and sedation in intensive-care treatment.

History and use

Discovered at Janssen Pharmaceutica in 1961, droperidol is a butyrophenone, and is a potent D₂ (dopamine receptor) antagonist with some histamine and serotonin antagonist activity.^[1] It has a central antiemetic action and effectively prevents postoperative nausea and vomiting in adults using doses as low as 0.625 mg.^[2] It has also been used as an antipsychotic in doses ranging from 5 to 10 mg given as an intramuscular injection, generally in cases of severe agitation in a psychotic patient who is refusing oral medication. Its use in intramuscular sedation has been replaced by intramuscular preparations of haloperidol, midazolam, clonazepam and olanzapine. Some practitioners recommend the use of 0.5 mg to 1 mg intravenously for the treatment of vertigo in an otherwise healthy elderly patients who have not responded to Epley maneuvers.

Black box warning

In 2001, the FDA changed the labeling requirements for droperidol injection, to include a so-called "Black Box Warning", citing concerns of QT prolongation and torsades de pointes. The evidence for this is disputed, with 9 reported cases of torsades in 30 years and all of those having received doses in excess of 5 mg.^[3] QT prolongation is a dose-related effect,^[4] and it appears that droperidol is not a significant risk in low doses.

Side effects

Dysphoria, sedation, hypotension resulting from peripheral alpha adrenoceptor blockade, prolongation of QT interval which can lead to torsades de pointes, and extrapyramidal side effects such as dystonic reactions/neuroleptic malignant syndrome.^{[citation needed]}

Chemistry

Droperidol is synthesized from 1-benzyl-3-carbethoxypiperidin-4-one, which is reacted with o-phenylendiamine. Evidently, the first derivative that is formed under the reaction conditions, 1,5-benzdiazepine, rearranges into 1-(1-benzyl-1,2,3,6-tetrahydro-4-piridyl)-2-benzymidazolone. Debenzylation of the resulting product with hydrogen over a palladium catalyst, and subsequent alkylation of this using 4-chloro-4'-fluorobutyrophenone yields droperidol.

• C. Janssen, NV Res. Lab., GB 989755  (1962).
• Janssen, P. A. J.; 1963, Belgian Patent BE 626307 .
• F.J. Gardocki, J. Janssen, U.S. Patent 3,141,823 (1964).
• P.A.J. Janssen, U.S. Patent 3,161,645 (1964).

(See pimozide article for proposed mechanism of intramolecular rearrangement.)

References

1. ^ Peroutka SJ, Synder SH (December 1980). "Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency". The American Journal of Psychiatry 137 (12): 1518–22. PMID 6108081. http://ajp.psychiatryonline.org/cgi/reprint/137/12/1518. Retrieved 2009-06-21. 
2. ^ Domino KB, Anderson EA, Polissar NL, Posner KL (June 1999). "Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis". Anesthesia and Analgesia 88 (6): 1370–9. doi:10.1097/00000539-199906000-00032. PMID 10357347. 
3. ^ Kao LW, Kirk MA, Evers SJ, Rosenfeld SH (April 2003). "Droperidol, QT prolongation, and sudden death: what is the evidence?". Annals of Emergency Medicine 41 (4): 546–58. doi:10.1067/mem.2003.110. PMID 12658255. 
4. ^ Lischke V, Behne M, Doelken P, Schledt U, Probst S, Vettermann J (November 1994). "Droperidol causes a dose-dependent prolongation of the QT interval". Anesthesia and Analgesia 79 (5): 983–6. doi:10.1213/00000539-199411000-00028. PMID 7978420. 

Further reading

• Scuderi PE: Droperidol: Many questions, few answers. Anesthesiology 2003; 98: 289-90
• Lischke V, Behne M, Doelken P, Schledt U, Probst S, Vettermann J. Droperidol causes a dose-dependent prolongation of the QT interval. Department of Anesthesiology and Resuscitation, Johann Wolfgang Goethe-University Clinics, Frankfurt am Main, Germany.
• Emergency Medicine Magazine : http://www.emedmag.com/html/pre/tri/1005.asp