Inhibition of [3H]Isradipine Binding to L-Type Calcium Channels by the Optical Isomers of Isoflurane Lack of Stereospecificity

Moody, Eric J.; Harris, Bradford D.; Hoehner, Paul J.; Skolnick, Phil

doi:10.1097/00000542-199407000-00018

Cited by 28 publications

(10 citation statements)

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“…Optical isomers of isoflurane exhibited stereoselectivity in their effects, (+)isoflurane being about twofold more effective than the (-)isomer,[25–29] though other studies failed to confirm this. [30–32] Since the safety factor for inhalational anaesthetics is very low, even relatively small degree of stereoselectivity can result in one of the enantiomers offering a significant clinical advantage over the racemic mixture.…”

Section: Basic Conceptsmentioning

confidence: 99%

Chirality and anaesthetic drugs: A review and an update

Mitra¹,

Chopra²

2011

Indian J Anaesth

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Many molecules can exist as right-handed and left-handed forms that are non-superimposable mirror images of each other. They are known as enantiomers or substances of opposite shape. Such compounds are also said to be chiral (Greek chiros meaning ‘hand’). Such chiral molecules are of great relevance to anaesthetic theory and practice. This review summarizes the basic concepts, pharmacokinetic and pharmacodynamic aspects of chirality, and some specific examples of their application in anaesthesia, along with recent advances to elucidate the anaesthetic mechanisms. Chirality is relevant to anaesthesia, simply because more than half of the synthetic agents used in anaesthesia practice are chiral drugs. Almost all these synthetic chiral drugs are administered as racemic mixture, rather than as single pure enantiomers. These mixtures are not drug formulations containing two or more therapeutic substances, but combination of isomeric substances, with the therapeutic activity residing mainly in one of the enantiomer. The other enantiomer can have undesirable properties, have different therapeutic activities or be pharmacologically inert. Specific examples of application of chirality in anaesthetic drugs include inhalational general anaesthetics (e.g. isoflurane), intravenous anaesthetics (e.g. etomidate, thiopentone), neuromuscular blocking agents (e.g. cisatracurium), local anaesthetics (e.g. ropivacaine and levobupivacaine) and other agents (e.g. levosimendan, dexmedetomidine, L-cysteine). In the recent advances, chirality study has not only helped new drug development as mentioned above, but has also contributed in a more profound way to the understanding of the mechanism of anaesthesia and anaesthetic drugs.

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Section: Basic Conceptsmentioning

confidence: 99%

Chirality and anaesthetic drugs: A review and an update

Mitra¹,

Chopra²

2011

Indian J Anaesth

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“…The enantiomers of isoflurane inhibited [ 3 H] isradipine binding to L-type Ca 2 channels in a concentration-dependent fashion, but there was no evidence of stereoselectivity between isomers in either brain or myocardium (Moody et al, 1994a). These findings suggested that the L-type Ca 2 channels in the CNS are unlikely to be related to the anaesthetic actions of isoflurane.…”

Section: The Effect Of Chirality On the Pharmacological Activity Of Fmentioning

confidence: 87%

“…Thus, in view of the very low therapeutic indices of volatile anaesthetic, even a modest increase in anaesthetic potency with no concomitant increase in toxicity could have very significant clinical advantages (Moody et al, 1994a). It must be remembered however, that the effects of the enantiomers of volatile anaesthetics on the surgical patients (being due to many separate intermolecular interactions) are likely to be complex and are unlikely to mimic those found at any particular molecular target.…”

Section: The Effect Of Chirality On the Pharmacological Activity Of Fmentioning

confidence: 99%

The impact of chirality of the fluorinated volatile inhalation anaesthetics on their clinical applications

Aboul‐Enein

Bojarşki

Szymura-Oleksiak

2000

Biomed. Chromatogr.

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This review discusses the various chromatographic enantioseparation methods on an analytical and preparative scale for fluorinated inhalation anaesthetics used clinically, namely halothane, enflurane, desflurane and isoflurane. The differences in the pharmacodynamics and pharmacokinetics between the enantiomers of those anaesthetics are presented. It can be concluded that using a single enantiomer for these fluorinated anaesthetics is advantageous over using the racemic mixture. The racemic switch to a single enantiomer for these fluorinated volatile anaesthetics offers a more effective and safe general anaesthetic.

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“…Am isolierten Herzen führen Ketaminiso-anden gesteuerten GABA-Rezeptoren wiederholt Stereospezifität gezeigt werden, wobei das S(+)-Isomer dem R(-)-Isomer und dem Razemat überlegen ist [20,42], während spannungskontrollierte neuronale und kardiale Ionenkanäle auf molekularer Ebene keinerlei Stereoselektivität für Isofluran aufweisen [43]. Am isolierten Herzen führen Ketaminiso-anden gesteuerten GABA-Rezeptoren wiederholt Stereospezifität gezeigt werden, wobei das S(+)-Isomer dem R(-)-Isomer und dem Razemat überlegen ist [20,42], während spannungskontrollierte neuronale und kardiale Ionenkanäle auf molekularer Ebene keinerlei Stereoselektivität für Isofluran aufweisen [43].…”

Section: Isofluran Wirkt Stereoselektivunclassified

“…Sowohl auf molekularer Ebene [43] als auch auf Organebene [22] war es nicht möglich, kardiale Stereoselektivität von Inhalationsanäs-thetika nachzuweisen (Abb. Hinsichtlich ihrer therapeutischen Breite spielen insbesondere Effekte am kardiovaskulären System eine entscheidende Rolle.…”

Section: Isofluran Wirkt Stereoselektivunclassified

Stereoisomere in der Anästhesie

B¹,

Martin²

1998

Der Anaesthesist

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All optically active molecules have at least one asymmetric atom in common which is attached to four ligands, that can have different three dimensional positions. Therefore it can be concluded that the resulting isomers are chemically identical in all respects except for the direction with which they rotate plane-polarized light. When the isomer and its corresponding enantiomer are present in equal proportions, they are called racemic mixture, a mixture that does not rotate polarized light, since the optical activities of the two isomers cancel each other. Although the isomers are chemically identical other optically active molecules can interact with these isomers in a geometrically specific way termed stereoselectivity. The human body comprises a chiral environment due to optically active proteins; thus it is not surprising that enantiomeric drugs exhibit different pharmacological properties, when used as pure optical isomers. Till today most modern anaesthetics have been optical isomers, which are mainly used as racemic mixture (1:1 mixture). For financial reasons pure isomers were only used for research purposes, but nowadays the wide clinical use of pure isomers is financially feasible due to new production techniques. The terms eutomer and distomer were chosen to indicate the more or less potent form of the drug. The clinical use of pure isomers is only of advisable, if there are significant differences between eutomer and distomer in desired or side effects. Among the modern anaesthetics ketamine, isoflurane, bupivacaine and atracurium exhibit an asymmetric carbon. For most drugs the separation in pure isomers will reduce side effects. For volatile anaesthetics this question is still unanswered, since experimental and clinical results are inconsistent so far.

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Inhibition of [3H]Isradipine Binding to L-Type Calcium Channels by the Optical Isomers of Isoflurane Lack of Stereospecificity

Cited by 28 publications

References 0 publications

Chirality and anaesthetic drugs: A review and an update

Chirality and anaesthetic drugs: A review and an update

The impact of chirality of the fluorinated volatile inhalation anaesthetics on their clinical applications

Stereoisomere in der Anästhesie

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