Chirality and cardiotoxicity of anaesthetic agents
Bernhard M. Graf; MD, Ph.D.
Dept. of Anaesthesiology,
University of Heidelberg
Many anaesthetic agents show at least one asymmetric carbon atom, i.e. an atom surrounded by four different functional groups, called chiral molecules. Three-dimensionally both isomers are characterized by different configurations in space, which can`t be merged into one another by simple rotation. This allows the compounds to exist in at least two forms as mirror images of each other, which are not super-impossible. The both isomers are totally identical regarding physiochemical properties with the exception of the rotation of plane light. Using a pure optically isomer the plane of this light is rotated in a clockwise or counter-clockwise manner. The corresponding enantiomer is causing a rotation of the light in opposed direction, however at the same amount. Normally racemic mixtures, which are 1:1 mixtures of both optical isomers, are clinically mainly used nowadays, half of the molecules rotate the light clockwise half counter-clockwise, so that in summary no deflection takes place. There would be no difference using the more expensive pure optically isomers instead of racemic mixtures, if other chiral compounds wouldn't be able to recognize chiral compounds and to interact differently which each isomer, what is called stereoselective binding.
Local anaesthetics:
The molecular mechanism, by which local anesthetics suppress the transmission of the information "pain" to the CNS, appears quiet clear. These drugs block fast voltage-gated sodium channels as main target side on the molecular site, whereby in addition other ion channels and intracellular systems are also involved. More than 30 years ago, George A. Albright1 could collect more than one case report of sudden cardiac arrests during or after clinical use of local anaesthetics, mainly of the long acting drugs bupivacaine or etidocaine. Local anaesthetics as classical neuronal sodium channel blockers inhibit the electrical conduction as well on the neurones as on the myocardium by preventing depolarisation. The blockade of fast voltage-gated cardiac sodium channels by these drugs is a high specific molecular interaction on segments 6 of domain 1 and domain 4 2, whereby a preferred polar binding of the R(+)-isomers of bupivacaine and ropivacaine is recommended. Therefore already on molecular level the R(+)-isomer of ropivacaine and bupivacaine is more cardiac depressant than the corresponding enantiomer 3.
Direct
myocardial effects demonstrate negative chronotropic, dromotropic and inotropic
effects of long-acting local anaesthetics. For electrical myocardial conduction
stereoselectivity was found. The S(-)-isomers of the used local anaesthetics
were found less delayed compared to racemic mixtures and the R(+)-enantiomers,
while inotropy and chronotropy didn`t show stereoselective effects 4. There for
the use of pure optical S(-)-isomers of bupivacaine (levobupivacaine) and
ropivacaine may help to reduced the rare but catastrophic cardiac intoxication.
Both isomers and also the propyl- and butylderivative of the pipecoloxylidide show nearly identical local anaesthetic potency in
clinical use. This finding of reduced
cardiotoxicity of the S(-)-enantiomers was meanwhile confirmed by
different in-vivo studies and occasional case reports.
S(+)-ketamine is judged to produce more potent anaesthesia than either the racemate or the R(-)-ketamine isomer because of differential activation of specific cerebral receptors, mainly the NMDA-receptors. Other than central nervous system effects, the most important side effects of ketamine occurs in the cardiovascular system. Although ketamine is one of the few sympathomimetic anaesthetic agents –most others are characterized as sympatholytic drugs- higher concentrations of ketamine and its isomers are also cardiac depressant by affecting calcium homeostasis. Using the isolated perfused heart model S(+)-ketamine is less depressant compared to racemic und isomeric R(-)-ketamine. The lesser cardiac depression by the S(+) isomer is attributable to an increased availability of catecholamines, because previous depletion of catecholamine stores and autonomic blockade completely inhibited these differences. The inability of cardiac tissue to reuptake released catecholamines into neuronal or extra-neuronal sites during exposure to ketamine is stereoselective and caused predominantly by the S(+) isomer 5. Cardiac opioid receptors and hypothetical cardiac NMDA-receptors, which show clear stereoselectivity, are apparently not involved in this phenomenon. In summary, narcosis is hemodynamically more stable by using the more potent S(+)-ketamine. In addition, ischemic myocardial preconditioning appears to be advantageous in patients known to be at risk of myocardial ischaemia. The key mechanism of this effect is most likely the opening of the ATP-sensitive potassium channels. Brief ischaemic episodes, followed by periods of reperfusion, increase the resistance to further ischaemic damage by activating KATP-channels. This response is called “ischaemic preconditioning. Next to ischemia drugs like anaesthetics are able to enforce or abolish this effect, whereby racemic ketamine was shown to block KATP-channel and to abolish the protective effect of ischaemic preconditioning. Although so far it is unknown whether this effect on KATP-channel is stereoselective using the R(-) and S(+)-ketamine for ischemic preconditioning in isolated rat hearts recently demonstrated, that at clinically relevant concentrations, only R(-)-ketamine abolishes this cardioprotective effect. S(+)-ketamine doesn’t affect ischemic preconditioning 6, which has to be considered advantageously in patients with high risk of myocardial ischaemia.
References
1. Albright
GA: Cardiac arrest following regional anesthesia with etidocaine and
bupivacaine. Anesthesiology 1979; 51: 285
2. Nau C, Vogel W, Hempelmann G, Brau ME:
Stereoselectivity of bupivacaine in local anesthetic, sensitive ion channels of
peripheral nerve. Anesthesiology 1999; 91: 786- 95
3. Graf BM, Bosnjak ZJ, Martin E, Kampine JP, Kwok
W, M.: Removal of Stereoselectivity of Bupivacaine on Cardiac Sodium Channel
Evidence for a Phosphorylation, dependent Mechanism. Anesthesiology 1996; 85:
A368
4. Graf BM Abraham I, Eberbach N, Kunst G, Stowe
D, E. M: Differences in Cardiotoxicity of Bupivacaine and Ropivacaine are due
to Physicochemical and Stereoselective Properties. Anesthesilogy 2002; accepted
5. Graf BM Vicenzi M, Martin E, Bosnjak Z, Stowe
D: Ketamine Has Stereospecific Effects
On The Isolated Perfused Heart. Anesthesiology 1995; 82: 1426-1437
6. Muellenhaus J, Fraesdorf J, Preckel B, Thaemer
V, Schlack W: Ketamine, but Not S(+)-ketamine, Blocks Ischemic Preconditioning
in Rabbit Hearts In Vivo. Anesthesiology 2001; 94: 630-36