DROPERIDOL

History

General anesthesia with inhaled anesthetics and barbiturates depresses the entire CNS in a nonspecific manner. Laborit and Huguenard^{[706] [707]} in the 1950s sought an anesthetic technique that would produce "artificial hibernation" devoid of circulatory and respiratory depression. Their concept was to use drugs that would produce neurovegetative blockade (multifocal inhibition) of the cellular, autonomic, and endocrine mechanisms normally activated in response to stress.^[708] The first attempt at developing this concept was the lytic cocktail, which contained an analgesic (meperidine), two tranquilizers (chlorpromazine and promethazine), and atropine. Although this combination of drugs did enjoy widespread use for conscious sedation, it produced respiratory depression and was not used for general anesthesia. Janssen ^[709] synthesized haloperidol, the first member of the butyrophenones, and it became the primary neuroleptic component in neuroleptanesthesia (NLAN). DeCastro and Mundeleer^[710] in 1959 combined haloperidol with phenoperidine (a meperidine derivative also synthesized by Janssen) in a forerunner to the practice of NLAN. Droperidol, a derivative of haloperidol, and fentanyl, a phenoperidine congener, both synthesized by Janssen, were used by DeCastro and Mundeleer^[710] in a combination that they reported to be superior to haloperidol and phenoperidine. This NLAN combination produced more rapid onset of analgesia, less respiratory depression, and fewer extrapyramidal side effects. The fixed combination of droperidol and fentanyl, marketed as Innovar in the United States, was the drug primarily used for NLAN. The use of NLAN has largely disappeared in modern anesthetic practice. The primary use of droperidol in anesthesia has been as an antiemetic and to a lesser extent as a sedative and antipruritic. The present package insert for droperidol in the United States carries a black box warning regarding the potential for fatal arrhythmias and recommendations that it be administered only with continuous electrocardiographic monitoring. However, with the withdrawal of droperidol in certain countries and more stringent labeling regarding potentially lethal dysrhythmias in others, the use of droperidol has decreased tremendously. The validity of the risk of low-dose droperidol causing QT prolongation, dysrhythmias, and death has been challenged by numerous editorials, articles, and letters reviewing the cases that prompted this action.^{[711] [712] [713] [714] [715] [716]}

Droperidol is a butyrophenone, a fluorinated derivative of the phenothiazines ( Fig. 10-27 ). ^[708] Butyrophenones produce CNS depression characterized by marked apparent tranquility and cataleptic immobility. They are potent antiemetics. Droperidol is a potent butyrophenone, and like the others, it produces its action centrally at sites where dopamine, norepinephrine, and serotonin act. It has been postulated that butyrophenones may occupy GABA receptors on the postsynaptic membrane, thereby reducing synaptic transmission and resulting in a build-up of dopamine in the intersynaptic cleft.^{[708] [709]} In particular, droperidol results in submaximal inhibition of the α₁ -, β₁ -, and γ₂ -subunits of GABA_A and full inhibition of α₂ - acetylcholine receptors. This submaximal inhibition of GABA receptors by droperidol may explain the anxiety, dysphoria, and restlessness that can occur with its administration.^[717] An imbalance in dopamine and acetylcholine is thought to occur and result in an alteration in normal transmission of signals in the CNS. The chemoreceptor trigger zone is the emetic center, and "red" astrocytes transport neurolept molecules from the capillary to dopaminergic synapses in the chemoreceptor trigger zone, where they occupy GABA receptors ( Fig. 10-28 ). This is thought to be

Figure 10-27 Structure of droperidol, a butyrophenone derivative.

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Figure 10-28 Site of action of droperidol. The mode of action of neuroleptanesthetics is at the chemoreceptor trigger zone (CTZ). GABA, γ-aminobutyric acid. (Redrawn with modification from Janssen PAJ: Pharmacological aspects. In Bente D, Bradley P [eds]: Neuropsychopharmacology. Amsterdam, Elsevier, 1965, p 151.)