Drug lnteraction and "Knockout Drops" - ACS Publications

The scene involves the unwitting consumption by an individual of the classic. "knockout drop" mixture or "Mickey Finn" which sup- posedly induces a de...
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Dominick A. Labianca Brooklyn College of CUNY Brooklyn, 11201

Drug lnteraction and "Knockout Drops"

The incident is familiar. Many of us have either read about it in literary works or have seen it portrayed on the motion picture and television screens. The scene involves the unwitting consumption by an individual of the classic "knockout drop" mixture or "Mickey Finn" which supposedly induces a deep sleep and sets the stage for the commission of a destructive act. The mixture ingested by the victim contains chloral hydrate and ethanol, both of which are central nervous system (CNS) depressants (1, 2). Although the reputed "knockout d r o ~ "effect of such a mixture has never been scientifically substantiated, concurrent intake of the two drum is known to ~ r o d u c ea CNS denression meater than tha; caused by either drug when used separately (I). Moreover, dilation of blood vessels, facial flushing, restlessness, rapid heart rate, and reduced hlood pressure or hypotension are other effects which have been reported (1).

Of considerable significance is that chloral hydrate-ethan01 mixtures can be particularly dangerous, if not fatal, when the quantity of chloral hydrate used exceeds the dosage usually associated with its therapeutic use as a sedative and h v ~ n o t i caeent (3). Enuallv imnortant is that all e t h a n o i - ~ N Sdepressant m i x k r e s are potentially dangerous (3). and therefore a discussion of the enhanced or syn&gistic effect associated with the familiar "knockout drops" would he informative.

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Synergism Through Alteration of Biotransformation There are several mechanisms whereby one drug can act synergistically with another (4), and one of the most common as well as the one concerned with the present analysis involves alteration of the biotransformation of a drug to its inactive metabolites. Through such a mechanism, the expected termination of action of a drug is prevented from occurring within a certain time period, and thus an enhancement of the drug's activity is effected. Perhaps such synergism may he desirable for its therapeutic value in certain circumstances, but in other instances the individual involved absorbs, in effect, an increased dosage of a drug which can he toxic if its concentration is high enough. Chloral Hydrate-Ethanol Interaction The initial step in the biotransformation of ethanol is oxidation to acetaldehyde, and after a series of other oxidative metabolic transformations, carbon dioxide and water are formed (3, ii). For chloral hydrate, the primary stage of metabolism involves rapid reduction to trichlormthanol, the agent responsible for maintaining the hypnotic effect associated with chloral hydrate ingestion (fi). The well-established deactivation pathways of chloral hydrate involve its oxidation to the hv~noticallv inactive tri-. chloroacetic acid and the conversion of trichloroethanol to hv~noticallvinactive urochloralic acid. the trichloroethanbi derivative of glucose oxidation product glucuronic acid

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The synergistic effect assorinted with chloral hydrareethanol rornhinntions can be linked to the primary step in the hiotransformation of each drue. The oxidation of ethanol to acetaldehyde occurs througYh the action of the zinc-

containine enzvrne alcohol dehvdroeenase (ADH) counled with nicotinaiide adenine din;cle&de ( N h ) (5, 6a: a), one of the Dhvsioloaicalh - . active forms of vitamin B complex constituent nicotinic acid (9).In this stage, coenzyme NAD serves as a hydrogen acceptor and is reduced to NADH. The reduction of chloral hvdrate to trichloroethanol, on the other hand, requires an ADH-NADH complex (fia, S ) , and this reaction regenerates NAD by oxidation of coenzyme NADH. The deactivation pathways of chloral hydrate are also NAD-de~endent, as is the oxidation of acetaldehyde (fia). Clearly, therefore, when both chloral hydrate and ethanol have been ingested, there is competition by each drug for the same enzyme, namely ADH, with NAD and NADH servine as the resoective coenzvmes in the nrimarv hiotransforma%on steps. TWO significant effects of'this interaction are that the rate of oxidation of ethanol to acetaldehyde is decreased and that an ethanol-induced increase in the concentration of ADH-NADH complex via the ethanol-ADH-NAD svstem accelerates chloral hvdrate reduction to trichloroethanol (6a). Moreover, since NAD is required for the initial chloral bydrate-ethanol transformations and for acetaldehyde oxidation, less NAD will be available for the NAD-dependent deactivation pathways of chloral hydrate (fia). The overall results of these competitive interactions are that hlood ethanol and trichloroethanol concentrations and CNS depression are greater than when either ethanol or chloral hydrate is taken alone (fia, 10).

Conclusion Although investigations of the chloral hydrate-ethanol interaction in man have produced no evidence for the existence of a "knockout drop" effect (10, II), perhaps the relative concentration of each component in a chloral hydrate-ethanol mixture ultimately determines whether such an effect is produced (11). The essential fact, however, is that concurrent consumption of chloral hydrate and ethanol can be dangerous (2, 3, 101, and very serious consequences can result from the administration of a mixture of the two drugs as a practical joke, or as part of some other illicit action, or an inadvertent occurrence involving an individual undergoing chloral hydrate therapy. Indeed, there have been many cases of poisoning resulting from the illicit addition of chloral hydrate to alcoholic beverages (7). Literature Cited

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I I I '-~ualuationoof Imractionr."~ m e r i c a n~harmaceutical~ s w c i a t i a n ,wash^ ingt0n.D.C..1973. pp. 15-16. Baker. C. E.. IPubiishsr), "Physician's DenL Referenre." 26th Ed.. Medics1 Ecu. numics. Ink. Subsidiary of Lifton Publication%. Inc., Division of Liuon Indusfries. Inc..Oradell. N. J.. 1972. p. 1344. (31 Parkar. W. J.J. A m e r Phorm. Asaoc. NSIO. 664 (L970). I41 Fin& E., and Woodbury. D. M., in "The Phsrmaeological Baris d Therapeutics," IEdirors: Gmdmen, L. S.,and Gilman, A ) . 6th Ed.. The Macmillan Co.. New York. 1970.p. 24. I51 Rifchio, J. M.. in Ref. 14). p. 141. I61 Is1 Sellors. E. M.. Len& M., Koch-Weser. J.. LeBlsnc. F.. and Kslsnt. H., Clin. Pharmocol. The,.. 13.37 (19721.ibl References cited in (a). 171 Maynert. E. W.. i n "DrilVs Pharmacology in Medicine.'' [Editor: DiPalma. d. R.I. 4thEd.. MeGraw-HUBookCo., New York, 1971. p.229. I81 Cabana. H. L..andGessner,P.K.. J. Phormarol. Erp. Thsi.. l74.2Ml19701. I91 Gmongard. P. i n Rel. (4% pp, iS2-1654. 1101 S d o r s , E. M.. C u r , G.. Rcrnstein. .J. G.. Sellers, S., and Koch-Werr. J.. Clvl. Phormocoi. Then. 13, j0 (1972). 1111 Kaplan, H. L., Forney, R. B.,Hughes, F. W., Jain, N. C.. J. Forensic Sri.. 12, 295

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Volume 52,Number 2, February 1975

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