Stereochemistry and Anesthetic Pharmacology

No doubt most anesthesiologists have long since deliberately forgotten the nomenclature nightmare of stereochemistry, once learned from the pages of their now dusty organic chemistry textbooks. In this issue of Anesthesia & Analgesia, Nguyen et al. [1] remind us that stereochemistry, and more specifically chirality, are more relevant to anesthesia practice today than ever before and are certainly more pertinent than we ever dreamed they could be when we studied organic chemistry as undergraduate students. In its broadest sense, stereochemistry is the study of how molecules are structured in three dimensions. Chirality is a unique subset of stereochemistry. Taken from the Greek word chier (meaning hand), "chiral" is the term used to designate a molecule that has a center (or centers) of three-dimensional asymmetry. The appropriateness of the term's Greek origin is clear when considering that our hands are perhaps the most common example of chirality. Although they are mirror images of one another, our hands cannot be superimposed. Similarly, chirality in molecular structure results in a set of mirror image molecular twins that cannot be superimposed. This kind of molecular handedness in biologic systems is ubiquitous in nature and is almost always a function of the unique, tetrahedral bonding characteristics of the carbon atom [2,3]. Chirality is thus the structural basis of enantiomerism. Enantiomers are a pair of molecules that exist in two forms that are mirror images of one another but that cannot be superimposed [4]. In every other respect, enantiomers are chemically identical. A pair of enantiomers is distinguished by the direction in which, when dissolved in solution, they rotate polarized light, either dextro (d or +) or levo (l or -) rotatory--hence, the term "optical isomers." When the two enantiomers are present in equal proportions, they are collectively referred to as a "racemic mixture," a mixture that does not rotate polarized light because the optical activity of each enantiomer is canceled by the other. Adding additional confusion to the molecule naming exercise, a second nomenclature system based on absolute configuration uses the designations "sinister" (S) and "rectus" (R), depending on how the molecules are sequenced [5]. Having briefly reviewed the nomenclature nightmare of stereochemistry, the connection between molecular asymmetry and pharmacology remains obscure. Why is chirality an important issue in clinical pharmacology? It is significant because the molecular interactions that are the mechanistic foundation of drug action and disposition occur in three dimensions, and therefore they can be altered by stereochemical asymmetry [6]. The schematic "lock and key" hypothesis of enzyme-substrate interplay implies that biologic systems are inherently chiral in nature. The pharmacologic extension of this notion is that drugs can be expected to interact with other biologic components in a geometrically specific way. Thus, pharmacologically, not all enantiomers are created equal! Drugcellular receptor, drug-metabolic enzyme, and drugprotein binding interactions are virtually always three-dimensionally exacting. The implications of chirality thus span the entire pharmacokinetic-pharmacodynamic spectrum. Enantiomers can exhibit differences in absorption and bioavailability, distribution and clearance, potency and toxicology [7-11]. Enantiomers can even antagonize one another across this pharmacologic spectrum [12]. An additional complexity is that enantiomers can undergo chiral inversion to the other enantiomer, and drug interactions can also be stereoselective [13-15]. When a pharmacologic process discriminates in a relative fashion between enantiomers (e.g., one enantiomer being metabolized more rapidly than the other), it is termed "stereoselective." If the discrimination is absolute (e.g., one enantiomer being completely incapable of producing drug effect), the process is termed "stereospecific." The study by Nguyen et al. is a specific example of this larger issue of chirality and anesthetic pharmacology. The authors set out to determine whether there are clinically important pharmacokinetic differences between enantiomers of thiopental, a drug currently administered as a racemic mixture. To answer the question fully, they not only estimated the clearance and distribution parameters, but also studied protein binding characteristics. They discovered, perhaps as one would predict, that thiopental enantiomer pharmacokinetics are indeed stereoselective (i.e., R-thiopental exhibits more rapid clearance and greater steady state distribution than S-thiopental). However, after accounting for stereoselective binding (i.e., R-thiopental exhibits a 24% larger unbound fraction than S-thiopental), these pharmacokinetic differences between enantiomers were no longer apparent; that is, there were no differences between enantiomers with regard to unbound clearance and unbound steady state distribution volume. Hence, because it is the unbound drug that is pharmacologically active, there do not appear to be any critical pharmacokinetic implications arising from thiopental chirality. Viewed from the context of the earlier thiopental literature, the scientific significance of the study by Nguyen et al. is that the pioneering work of Stanski et al. and others, relating thiopental effect to racemic concentrations, requires less refinement than it might have had significant pharmacokinetic stereoselectivity been demonstrated [16-20]. Since it is a small study, it would of course be unwise to view the conclusions of Nguyen et al. as a definitive resolution of this complex issue. Because the topic is of great interest, corroboration and expansion of the conclusions of Nguyen et al. are emerging from a variety of sources, including Dr. Laurence Mather's laboratory in Australia [21]. Additional study is necessary to confirm these pharmacokinetic conclusions and to further explore the possibility (inevitability?) of clinically important pharmacodynamic differences between thiopental enantiomers. In particular, in view of the well-known biphasic effect of thiopental on the human electroencephalogram, it will be interesting to discover whether there are enantiomeric differences in terms of pharmacodynamic effect and latency to peak effect. The study by Nguyen et al. is a good first crack at addressing the pharmacokinetic component of this complicated issue and reminds us of the scientific importance of chirality with regard to thiopental specifically and to many other drugs in anesthesia as well. While it is not something we think about in everyday practice, the issue of chirality applies to a surprisingly diverse array of anesthetic drugs. In addition to thiopental, the sedative hypnotics methohexital and ketamine are also administered as racemates. Etomidate, an exception to the rule, is given as a single enantiomer. The inhaled drugs halothane, enflurane, isoflurane, and desflurane also have a center of molecular asymmetry, as do the local anesthetic agents mepivacaine, prilocaine, and bupivacaine. The analgesics ibuprofen, ketorolac, and methadone are also cases in point. For some of these chiral anesthetic drugs in widespread clinical use, there are important implications arising from their chirality. For example, the S(+) enantiomer of ketamine is known to be more potent than the R(-) form and is also less likely to produce psychotic emergence reactions [22-24]. Similarly, in addition to pharmacokinetic differences, the cardiac toxicity of bupivacaine is thought to be predominantly due to the d-bupivacaine enantiomer [25-27]. In view of this enantiomeric duality, it is perhaps not surprising to discover that many of the drugs recently released into clinical anesthesia have chiral centers but have been developed as a pure enantiomer. Ropivacaine, a close relative of bupivacaine, does not appear to have a propensity for the cardiac toxicity associated with bupivacaine, at least in part because it was developed as a single enantiomer that is theoretically less prone to be toxic to the heart [28]. Cisatracurium, another example of fine-tuning chirality to pharmacologic advantage, is the R-R' optical isomer of atracurium in the cis-cis configuration (more nomenclature nightmares) that does not release histamine and therefore is not associated with the cardiovascular side effects of atracurium [29]. Remifentanil, a new esterase-metabolized opioid in the final stages of development, exists in a single form because it does not have a center of molecular asymmetry; the pharmacologic complexities associated with chirality therefore do not apply [30]. Interestingly, nature's own anesthetic pharmacopoeia is also mindful of chirality. Perhaps without being cognizant of it, anesthetists have been administering pure enantiomeric forms of chiral drugs from the earliest days of our specialty. Morphine sulfate (actually l-morphine) and d-tubocurarine are notable examples. Because these drugs are synthesized by nature's stereospecific enzymatic machinery, they exist in a single form before they are extracted and purified. Undoubtedly, the emphasis on chirality in clinical pharmacology is here to stay. We have witnessed an explosion of enantiomer-specific investigation in the last decade. While about a third of drugs currently in use are chiral drugs and are administered as a racemate, this percentage is likely to decline in future years [31]. Regulatory agencies and pharmaceutical companies have become acutely aware of chirality's importance and are likely to shy away from the scientific ambiguities associated with the development of racemic drugs [32-34]. There is now even a scientific journal, Chirality, specially devoted to the pharmacological, biological, and chemical consequences of molecular asymmetry [35]. Why was chirality not as important to our practice 25 years ago? While we understood the theoretical implications of chirality at that time, the technology necessary to demonstrate the pharmacologic differences of enantiomers was not widely available. Advances by chemists in stereospecific separation and assay were required before the widely suspected theoretical importance of chirality could be confirmed [36-38]. Equally important, the technology enabling the synthesis of industrial quantities of pure enantiomer was necessary to make the clinical administration of such drugs a practical reality [39,40]. Having for the most part achieved these advances in stereospecific separation, assay, and synthesis, the focus on the importance of chirality in pharmacology over the last decade has prompted some experts to suggest that experiments performed with racemic mixtures are of little or no value. Viewing a racemic mixture as a drug that is 50% impure, such experts have disparagingly referred to the less active or inactive enantiomer as "stereochemical ballast" [7]. In what has become a widely cited and classic editorial addressing the pharmacology of chirality, Ariens [41] suggested that experiments performed using racemic mixtures are little more than "sophisticated scientific nonsense." It is quite possible to make a cogent theoretical argument that studies on racemic mixtures may be fatally flawed if the enantiomers have different pharmacodynamic activity or if their concentrations decline at different rates. Does this mean that the volumes of carefully performed scientific work describing the clinical pharmacology of anesthetics administered as racemic mixtures, such as thiopental, are clinically useless? Of course not! Lamenting the fact that some of the clinical pharmacology database upon which we base our practice was completed at a time when stereospecific synthesis and assay were not widely practical gets us nowhere, especially when these drugs continue to be administered successfully as racemic mixtures. Instead, as a specialty we now recognize that advances in stereochemistry have enabled us to refine our anesthetic pharmacology knowledge base. The manuscript by Nguyen et al. is an example of how the stereospecific study of racemic mixtures can elucidate the clinical implications of chirality that were formerly suspected but unproven. Nguyen et al.'s study also provides some evidence that the characterization of thiopental pharmacology based on study of the racemate was not too far afield from the more recent information based on study of the individual enantiomers (at least where pharmacokinetics are concerned). We can expect to see a great deal more of this kind of enantiomer-specific study in the future. It is conceivable that such work may change the way we use some of our racemic anesthetics. We may yet see, for example, the development of bupivacaine as a single, less toxic enantiomer (l-bupivacaine) [42]. It is astonishing that the advance of science has brought the clinical relevance of chirality in our specialty into clear focus in just a few decades. Not long ago, we suspected the importance of chirality but did not have the tools to confirm it; now, we not only know of its significance but have also begun to exploit it to our pharmacologic advantage. Having joined hands with the medicinal chemists, we have moved the pharmacology of chirality from the drawing board into the clinic. As its Greek etymology suggests, chirality is in our hands now [43]. The helpful comments and suggestions of Dr. Laurence Mather in reviewing the editorial are gratefully acknowledged.