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Section IBasic principleslying behind the plane of the page. The other three atoms now lie in this plane and
their atomic numbers are identified; if their atomic numbers descend in a clockwise
fashion then this is the R (rectus) form, if anticlockwise it is the S (sinister) form.
The R and S structures are mirror images of each other and they are referred to as
enantiomers.There is no link between the R and S classification and the laevo and
dextro classification, and an S structure may be laevo or dextro-rotatory to plane
polarized light.
Ingeneral, the three-dimensional conformation of a drug determines its pharma-
codynamic actions at a molecular level. If the drug acts via a receptor, then confor-
mation is of importance and there may be a marked difference in activity between
enantiomers. However, if drug activity depends upon a physicochemical property
then enantiomers would be expected to show similar activity.Diastereoisomers
When more than one chiral centre is present there are multiple possible stereoiso-
mers. These are not all mirror images of each other, so they cannot be called enan-
tiomers, instead the term diastereoisomers is used.
Morethan one chiral centre.Ifamolecule contains more than one chiral atom,
then with n such chiral centres n^2 stereoisomers are possible. Although the maxi-
mum number of possible isomers is n^2 ,ifthe molecule exhibits internal symmetry
some of the possible configurations are duplicates. For example, atracurium has four
chiral centres (two carbon atoms, two quaternary nitrogen atoms) with 16 theoret-
ically possible isomers, but it is a symmetric molecule, so only ten distinct three-
dimensional structures actually exist.
Some anaesthetic drugs are presented as a mixture of isomers (e.g. halothane,
isoflurane) others have no chiral centre (e.g. sevoflurane, propofol). One recent
development in the pharmaceutical industry is to identify the most active or least
toxic isomer and produce the drug as a single isomer (e.g. ropivacaine). Such prepa-
rations, where just a single enantiomer is present, are called enantiopure (see
below). In nature, molecules with chiral centres normally exist as single isomers (e.g.
D-glucose) as enzymes selectively produce just one conformation. If natural agents
are used for medicinal purposes, the purification process often results in rac-
emization so both isomers will be present in the pharmaceutical preparation (e.g.
atropine).Racemic mixtures
These are mixtures of different enantiomers in equal proportions. Examples include
the volatile agents (except sevoflurane), racemic bupivacaine and atropine. While
the mixture may contain equal amounts of the two isomers, the contribution to
activity, both pharmacodynamic and pharmacokinetic, may be very different and,
indeed, one may be responsible for undesirable toxicity or side effects.