Clinical Concepts and Commentary on Drug Chirality in Anesthesia

CLINICAL CONCEPTS AND COMMENTARY
Richard B. Weiskopf, M.D., Editor

Anesthesiology 2002; 97:497–502 © 2002 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Drug Chirality in Anesthesia
Carla Nau M.D.,* Gary R. Strichartz, Ph.D.†

MORE than one-third of all synthetic drugs are chiral and bonds connecting their atoms. Although constitutional
are marketed as racemates, 1:1 mixtures of two types of isomers can exhibit similar pharmacologic properties,
molecules bearing identical chemical constitution and they are completely different molecules with different
atomic connections but with a different spatial orienta- physicochemical properties, and often quite different
tion of their constituent atoms. Drug receptors may receptor affinities and specificities. Stereoisomers show
discriminate between stereoisomers in several ways; an identical arrangement of bonds connecting their at-
binding may favor one form over the other, and to a oms, yet the relative orientation of their atoms in space
degree varying with the drug molecule and with the differs. The pharmacologically relevant kind of stereoiso-
state of the receptor, or stereoisomers may have oppo- mers are configurational stereoisomers that cannot be
site effects, one form being an agonist at the same re- made alike by any rotations about single bonds, that are
ceptor where its mirror image is antagonist. Stereoselec- structurally stable, and can be separated from one an-
tivity is interesting from both a scientific and clinical other without interconversion.
point of view. Scientifically, stereoselective responses Enantiomers are pairs of stereoisomers that, in their
give evidence for specific receptor-mediated responses three-dimensional projection, are related to one another
and information about the structure of the binding site. as an object to its mirror image, and thus are not super-
Clinically, the use of single stereoisomers of chiral anes- imposable (fig. 1). A typical example of familiar objects
thetic drugs has received increasing attention recently, related in such a way are the right and left hand. Such
because it might decrease side effects and increase nonsuperimposable objects are said to be chiral. The
drug-safety. most common origin of chirality is the presence of an
In this brief review we define some fundamental terms asymmetric carbon atom, a saturated carbon atom at-
of stereochemistry, introduce the nomenclature for des- tached to four different substituents.
ignating the different stereoisomers (enantiomers), Enantiomers have identical physicochemical proper-
present general principles of stereoselective drug action, ties in an achiral spatially uniform environment, such as
and describe the possible contributions of pharmacoki- an aqueous solution. However, a solution containing
netic and pharmacodynamic mechanisms to stereoselec- only one enantiomer usually causes a measurable rota-
tive advantages. Finally, three examples of chiral anes- tion of the plane of polarized light passing through the
thetic drugs are discussed in the above context. solution, and this rotation has the same degree but op-
posite direction (clockwise or counterclockwise) for
Chemistry corresponding enantiomers. Thus, enantiomers are said
The molecular formula of a drug gives the number of to be optically active.
the different types of atoms forming the drug molecule.
Isomers are compounds with the same molecular for- Terminology
mula, but with different molecular structures. Constitu- The simplest naming system for enantiomers is based
tional isomers differ structurally in the arrangement of on optical activity, using the appropriate sign indicating
whether the rotation of plane polarized light passing
through a solution of the drug is clockwise [dextrorota-
*Postdoctoral Research Fellow, Department of Anesthesia Research Laborato- tory, d( )] or counterclockwise [levorotatory, l( )].
ries, †Professor of Anaesthesia.
These observed signs of rotation, d( ) and l( ), are
Received from the Pain Research Center, Department of Anesthesiology,
Perioperative and Pain Medicine, Brigham & Women’s Hospital, Boston, Massa- often confused with the designations D and L according
chusetts. Submitted for publication June 14, 2001. Accepted for publication to the Fischer Convention that is widely used in carbo-
January 14, 2002. This work was supported by grant No. GM35647 from the
National Institutes of Health, Bethesda, MD, a grant from Chiroscience Ltd., hydrate and protein chemistry and where the configura-
Cambridge, UK (to G.R.S.), and by a stipend of the Deutsche Forschungsgemein- tion about a chiral atom is assigned by comparison to a
schaft, Bonn, Germany (to C.N.).
Address reprint requests to Dr. Strichartz: Pain Research Center, Department
standard, ( )-glyceraldehyde, that is assigned the D con-
of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women’s Hos- figuration. The most rapidly applicable and unambigu-
pital, 75 Francis Street, Boston, Massachusetts 02115. Address electronic mail to: ous convention, however, is the R/S classification of the
gstrichz@zeus.bwh.harvard.edu.
The illustration for this section is prepared by Dimitri Karetnikov, 7 Tennyson
Cahn-Prelog-Ingold convention that specifies the abso-
Drive, Plainsboro, New Jersey 08536. lute configuration in the name of the compound. The

Anesthesiology, V 97, No 2, Aug 2002 497

498 C. NAU AND G. R. STRICHARTZ

Fig. 1. Potential sources of chiral contri-
butions to anesthetic drug actions in vivo.
Differences caused by pharmacokinetic
as well as pharmacodynamic interactions
may influence the disposition of drugs
throughout the body and their actions at
their target tissues or receptors. Absent
from this diagram is that the main action
of a drug may influence its own disposi-
tion; for example, an agent that acts pe-
ripherally on the sympathetic nervous
system may alter local blood flow and
thus modify its own vascular removal.

four substituents around the chiral center are assigned a way that is complementary to corresponding groups of
priorities depending on atomic number and atomic a static binding site (fig. 1). In a more dynamic model,
mass. The R configuration is assigned if, looking down taking into account the possible conformational changes
the bond from the chiral center to the substituent with of both receptor and drug that occur during a binding
the lowest priority, the other substituents are ordered process, a three point-attachment to a specific receptor
from higher to lower priority in a clockwise direction, can be imagined as selectively induced by one of the
and the S configuration is assigned if these substituents enantiomers. In other words, the corresponding groups
are so ordered in a counterclockwise direction. This is are preferentially aligned in their optimal orientation by
the preferred International Union of Pure and Applied one of the enantiomers in reciprocal, mutually comple-
Chemistry (IUPAC)-endorsed method of naming and mentary interactions during the binding process, one
identifying stereoisomers, and is the one used in this example of the phenomenon of “induced fit” that ac-
review. companies many protein-ligand binding events.
The “stereoselectivity ratio” indicates the relative affin-
General Principles ity or potency between the two enantiomers of a chiral
Most pharmacologic responses are mediated through molecule. This ratio can range over three to four orders
receptors. The critical element determining the specific- of magnitude, from 104 to less than 10. Inasmuch as
ity of the response is the recognition of the drug mole- stereoselectivity is often a reflection of specificity for a
cule by the receptor molecule. From this concept, ste- receptor, large stereoselectivity ratios for the actions of
reoselective responses to drugs have been taken as a chiral drug are usually interpreted as evidence for tight
strong evidence for specific receptor-mediated re- binding to a structurally well-defined site, usually as-
sponses. In general, drugs that bind to their target re- sumed to be a protein. One must be cautious, however,
ceptor with higher affinity, a feature that is usually ac- in construing weak stereoselective responses as support
companied by greater specificity, are also drugs that for the existence of protein receptors. Phospholipids
show the largest stereoselectivity. and cholesterol both contain chiral carbon atoms and
There are minimal structural requirements for a mole- could themselves mediate stereoselective effects, as ex-
cule to express stereoselectivity in a drug-receptor bind- amples of weakly stereoselective drug interactions with
ing process. In 1933, Easson and Stedman suggested lipid bilayers have shown.2 Conversely, lack of stereose-
“three of the groups linked to the asymmetric carbon lectivity does not necessarily imply nonreceptor-associ-
atom in an optically active (chiral) drug are concerned in ated responses, as the chiral center could be located in a
its attachment to its specific receptor in the tissue.”1 region of the drug molecule that is irrelevant for inter-
According to this oversimplified model, the substituents action with the receptor (silent chirality).
of the active or more potent enantiomer are oriented in It is important to recognize that the clinical actions of

Anesthesiology, V 97, No 2, Aug 2002

DRUG CHIRALITY IN ANESTHESIA 499

drugs, rarely at equilibrium between their external The most important molecular targets for local anes-
source and the target receptors, are strongly influenced thetics are voltage-gated Na channels of excitable mem-
by pharmacokinetic processes that themselves are often branes, which control the permeability of Na ions.4 By
stereoselective. Receptor interactions are only one as- binding to Na channels, local anesthetics prevent their
pect of the overall effect. normal function and consequently block the propaga-
tion of action potentials. Binding is dependent on the
Clinical Aspects of Chirality membrane potential and on the pattern of depolariza-
More than one-third of all synthetic drugs are chiral.3 tions, indicating that it is modulated by the “state” or
Most of them, however, are available as 1:1 mixtures of conformation of Na channels. Open and especially in-
enantiomers, so-called racemic mixtures or racemates. activated Na channels show a higher affinity for local
Examples of chiral drugs used in anesthesia are ket- anesthetics than resting channels.
amine, thiopentone, isoflurane, enflurane, desflurane, A variety of Na channel isoforms, including neuronal
atracurium, mepivacaine, bupivacaine, tramadol, atro- and cardiac types, has been investigated for bupivacaine
pine, isoproterenol, and dobutamine. stereoselectivity. From these studies it appears to be a
Whether the clinical use of single stereoisomers (ho- common feature of Na channels to display only weak
mochiral drugs) provides significant advantages depends or moderate stereoselectivity toward bupivacaine enan-
on both pharmacokinetic and pharmacodynamic prop- tiomers. Stereoselectivity also seems to be influenced by
erties of the enantiomers (fig. 1). Unfortunately, detailed the channel state. For inactivated states, R-bupivacaine
pharmacokinetic profiles of the enantiomers of racemic exhibits about a 1.5-fold higher potency compared to
drugs are often unknown. Generally, several processes S-bupivacaine. Resting and open states show no signifi-
of drug disposition together determine the overall phar- cant stereoselectivity.5 The weak bupivacaine stereose-
macokinetic profile. Each of these processes may have lectivity is mirrored in all in vitro and in vivo studies
different stereoselective preferences. Enzymic metabo- investigating stereoselective differences by bupivacaine
lism and protein binding, for example, are potentially
enantiomers in neuronal blockade.
highly stereoselective, while passive processes like dif-
Ropivacaine (a pure S-enantiomer) is less potent than
fusion or absorption are less likely to show stereoselec-
S-bupivacaine or racemic bupivacaine to block Na
tivity. As a result, even though the separate pharmaco-
channels.6 No studies of stereoselectivity for ropiva-
kinetic processes of enantiomers can be quite
caine-related enantiomers have been reported.
stereoselective, the overall stereoselectivity may be mod-
Recent clinical studies comparing the action of S-bu-
est. Using a single enantiomer at least makes pharmaco-
pivacaine to racemic bupivacaine have demonstrated
kinetics less complex.
that the anesthetic and analgesic effects of S-bupivacaine
In the pharmacodynamic evaluation, stereoselectivity
of one or several therapeutic actions, or stereoselectivity are largely similar to those of racemic bupivacaine. For
of undesirable side effects resulting from interactions extradural anesthesia, sensory block tended to be longer
with other than the therapeutic target, or both, have to with S-bupivacaine compared with racemic bupiva-
be taken into account. Theoretically, elimination from a caine.7 A study comparing ropivacaine with racemic
racemic drug of an enantiomer that contributes less to bupivacaine for femoral nerve block found that both
the therapeutic action will increase the therapeutic in- drugs produced equally effective sensory and motor
dex. If the side effect is stereoselective and arises from a block in equal concentrations.8 Extradural ropivacaine,
less or equally potent enantiomer, its elimination will however, produced significantly less motor block than
favorably reduce the side effect. Further advantages of racemic bupivacaine.9,10 In studies investigating mini-
using enantiomers include less complex and more selec- mum local anesthetic concentrations of epidural ropiva-
tive pharmacologic profiles, and less complex, and im- caine and racemic bupivacaine for pain relief in obstetric
portantly, more predictable concentration-response patients, ropivacaine was significantly less potent than
relationships. bupivacaine, with a potency ratio of 0.6.11
Animal toxicity studies have reported a 50% higher
Three Examples of Chirality in Anesthetic Drugs systemic toxicity for R- over S-bupivacaine, attributable
Local Anesthetics: S-(levo)bupivacaine and Ropi- to cardiotoxicity (direct effects on the myocardium or
vacaine. Bupivacaine is widely used clinically as a po- indirect, centrally mediated effects, or both) and CNS
tent, long-acting local anesthetic. Its known potential for toxicity.12 When cardiovascular collapse was induced by
central nervous system, and especially cardiovascular intravenously delivered local anesthetics in dogs, rescici-
system toxicity, however, stimulated a search for new tation was more likely for S-bupivacaine than racemic
and safer agents, resulting in the introduction of ropiva- bupivacaine, but most favorable for ropivacaine.13
caine (the S-enantiomer of a bupivacaine homolog, car- Lower binding to plasma protein of S-bupivacaine com-
rying a propyl-chain instead of a butyl-chain at the ter- pared with R-bupivacaine14 balances their differential
tiary amine) and levobupivacaine (S-bupivacaine). dosing for cardiovascular collapse; at this toxic end-point



the free plasma concentrations of the two enantiomers come, also appear to derive from binding to the NMDA
are equal.13 receptor.
S-bupivacaine and ropivacaine are examples of single Ketamine is an example of a drug that exhibits stereo-
enantiomer drugs that suggest a clinical advantage over selective actions in both the main-effect and the most
traditionally used racemic bupivacaine, supposedly important side effects, and thus may present additional
caused by a significant decrease in side effects. However, advantages for the stereoselective use of this drug. Fur-
two issues will require further evaluation before a sound thermore, the most unwanted side effect originates from
judgment about their true advantage in clinical anesthe- the less potent enantiomer for the main-effect, exempli-
sia is established: First, clinical data directly comparing fying the most desirable balance of stereoselective ef-
the potency of S-bupivacaine and ropivacaine are need- fects for the actions of anesthetic drugs. S-ketamine
ed; if it turns out that potency ropivacaine has a lower promises to be clinically advantageous over racemic ket-
potency than S-bupivacaine, the therapeutic index argu- amine in avoiding an unnecessary drug-load and improv-
ment may favor S-bupivacaine. Second, accumulated ing postoperative recovery.
clinical experience is required to confirm the safety Volatile Anesthetics: Isoflurane. Enantiomers of
advantage of S-bupivacaine and ropivacaine over race- volatile anesthetics have been of minor clinical interest
mic bupivacaine. but have been used to address two long-standing ques-
Ketamine. Ketamine, a phencyclidine derivative, is an tions about the mechanisms of action of these drugs:
intravenous anesthetic producing dissociative anesthesia First, is disruption of the normal function of ion channels
characterized by catalepsy, amnesia and analgesia, nor- by volatile anesthetics a primary result of binding to
mal or slightly enhanced laryngeal reflexes and skeletal these proteins or a secondary result following nonspe-
muscle tone, and respiratory stimulation. Ketamine’s cific pertubation of lipid membranes? Second, which
central nervous system-derived sympathetic stimulation specific sites are the relevant targets for reaching the
usually overrides its direct myocardial depressant effects. different end-points of general anesthesia?
Stereoselective actions of isoflurane isomers were first
Postanesthetic excitatory and emergence phenomena,
demonstrated on some ion channels of molluscan CNS
also of central origin, limit the usefulness of ketamine for
neurons.20 At the same time, isoflurane isomers were
single-drug anesthesia.
equally effective in directly modifying the physical prop-
Clinically, the S- and R-enantiomers differ in their phar-
erties of lipid bilayers and partitioned equally between
macodynamic and pharmacokinetic effects. S-ketamine
lipid bilayers of phosphatidylcholine and phosphatidic
is about three times more potent than R-ketamine as an
acid. The observations of stereoselectivity support the
anesthetic and analgesic agent,15 whereas postanesthetic
hypothesis that the functional effects of volatile anes-
excitatory and emergence reactions are similar for the
thetics involve their binding to protein targets, indeed,
racemic mixture and the enantiomers. S-ketamine is the to ion channels, rather than to bulk membrane lipids, as
primary contributor to cardiovascular stimulation, one implied by theories of membrane perturbation.
mechanism being a more pronounced inhibition of re- The value of data about stereoselective actions of vol-
uptake of released catecholamines. The plasma clear- atile anesthetics in vitro is that they provide a basis for
ance of S-ketamine is significantly greater than that of discrimination among relevant loci of anesthesia in vivo.
R-ketamine,15 most probably based on a enantiomeric If stereoselectivity found in vivo is not manifested at a
selectivity in hepatic metabolism by microsomal putative target in vitro, then that site is less likely to be
enzymes.16 involved in the anesthetic process than a locus that does
Ketamine binds stereoselectively to the phencyclidine exhibit this stereoselectivity.
(PCP) binding site of the N-methyl-D-aspartate (NMDA) However, there are contradictory reports about
type of glutamate-gated ion channels and thereby non- whether the enantiomers of isoflurane have different
competitively inhibits the action of this excitatory amino anesthetic potencies. Recently, Dickinson et al.21 re-
acid neurotransmitter.17 Other molecular mechanisms ported that intravenously administered S-isoflurane was
involve opioid receptors, nicotinic and muscarinic ace- about 40% more potent than R-isoflurane at producing a
tylcholine receptors, and monoaminergic signaling path- loss of righting reflex in rats. In addition, S-isoflurane
ways. Although there is good correlation between ket- induced about 50% longer sleep times than R-isoflurane.
amine’s actions on NMDA receptors and its clinical This observation is consistent with the demonstrated
actions, the clinical relevance of effects on other poten- stereoselectivity of isoflurane anesthesia based on sleep
tial targets is not apparent. Studies of the enantiomers of time after intraperitoneal injection of isoflurane enanti-
ketamine, however, could indicate which of these other omers in mice. Further, studies determining the mini-
receptors might be important for the various behavioral mum alveolar concentration (MAC) for isoflurane-iso-
end-points of anesthesia in vivo. Two other clinical mers administered by the conventional inhalational
actions of ketamine, preconditioning18 and neuroprotec- route in rats either found S-isoflurane to be about 50%
tion,19 that may be important for postoperative out- more potent than R-isoflurane22 or found the enanti-


DRUG CHIRALITY IN ANESTHESIA 501

omers to differ only minimally in their anesthetic reoselective actions of isoflurane are primarily of scien-
potencies.23 tific interest.
Three issues complicate the interpretation of these
findings: First, the small number of animals that can be
tested, and thus the power of most studies, is limited by Conclusions
the small quantities of enantiomers that are available. The clinical use of chiral anesthetic drugs as 1:1 mix-
Second, the different modes of administration of isoflu- tures of their enantiomers has been the accepted prac-
rane might allow for different, stereoselective, pharma- tice for most of the history of anesthesia. This has been
kokinetic contributions. Third, different molecular tar- partly caused by an early general ignorance about the
gets might underly the different anesthesia-defining end- role of chirality in pharmacology, and later by the ex-
points that were chosen in the studies. The second pense required to separate the stereoisomers on a large
problem could be resolved by direct measurements of scale. With increasing knowledge about stereoselective
anesthetic concentrations in blood, if not in brain and advantages better methods have been developed to sim-
spinal cord, at the time of behavioral end-points, al- plify the separation and preparation of stereoisomers. In
though this is a challenging requirement for tissue from response to growing concerns about the medical and
small animals. legal ramifications of drug toxicity, future chiral anes-
Stereoselective actions may provide clues to determin- thetic drugs will most likely be primarily developed and
ing the relevant targets involved in the anesthetic pro- administered as the single more potent or less toxic
cess. Among ion channels the most sensitive to anesthet- enantiomer. However, the clinical advantages of single
ics appear to be the fast, neurotransmitter-gated ion enantiomers must be balanced against the additional
channels located at synapses, especially the -aminobu- costs from using these markedly more expensive drugs.
tyric acid receptor type A (GABAA), glycine, 5-HT3, and Although there are few scientific arguments for continu-
neuronal nicotinic ACh receptors. Much work has fo- ing to administer drugs as chiral mixtures when single,
cused on the GABAA receptor. GABA is the most impor- pure, and specific stereoisomers are both safer and more
tant inhibitory neurotransmitter in the brain. Volatile and potent, economic factors must also be considered in the
other general anesthetics like barbiturates, benzodiaz- choice of anesthetic agent. Such decisions should ac-
epines, propofol, and anesthetic steroids all potentiate count for differences in the longer-term postoperative
inhibitory postsynaptic currents evoked by low concen- outcomes, as well as the immediate perioperative safety
trations of GABA in vitro. The degree to which these in of the drugs used in our practice.
vitro effects lead to an enhancement of inhibitory syn-
aptic transmission in vivo, and thus, to the phenomena
of general anesthesia, remains to be shown. However, References
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