Isomerism

• Structural isomerism describes molecules with identical chemical formulae but different order of atomic bonds

• Static isomerism can be further classified into:
1. Positional isomerism
2. Chain-branch isomerism


• An example of positional isomerism is isoflurane and enflurane:



• Both have the same chemical formula (C₃H₂ClF₅O), but the different molecular positions confer different subtly different pharmacological properties


• An example of chain-branch isomerism is the molecules dobutamine and dihydrocodeine
• Again, they both have the same chemical formula (C₁₈H₂₃NO₃)
• The different molecular arrangements, however, lead to vastly different pharmacological effects

• Tautomerism is the dynamic interchange between two different forms of a molecular structure depending on the environmental conditions
• The core example is the barbiturate thiopental
• Midazolam, which exhibits pH-dependent ring closure, is also an example of a dynamic structural isomer

• Stereo-isomerism describes molecules with identical chemical formulae and order of atomic bonds, but with a different 3D configuration

• Cis-trans isomers are compounds with two dissimilar groups attached either side of a double-bond (or ring) e.g. alkenes, which form isomers because of the immobility of the double-bond/ring

• The groups can be arranged either diagonally across the bond (trans) or on the same side of the bond (cis), each leading to different chemical properties


• The classic example is the neuromuscular blocking agent mivacurium, which presents as a mixture of its stereoisomers:
• 58% trans-trans isomer
• 36% cis-trans isomer
• 6% cis-cis isomer, which has 10% potency but 10x the half-life of the other stereoisomers

• Optical stereo-isomers arise owing to the presence of a chiral centre, around which other atoms may be placed into two non-superimposable configurations
• A chiral centre is an atom bound to four dissimilar groups (typically a carbon or quaternary nitrogen); it is sometimes also called an asymmetrical carbon
• Molecules which contain a chiral centre are called enantiomers

• Enantiomers were historically differentiated based on their ability to rotate polarised light in different directions
• Molecules were either dextro-rotatory (D) or levo-rotatory (L)
• D-enantiomers rotate polarised light to the right
• L-enantiomers rotate polarised light to the left
• It remains the nomenclature for the orientation of the atomic structure of sugar and amino acid molecules (e.g. dextrose is D-glucose, levobupivacaine is L-bupivacaine)


• A more modern classification is in to rectus (R) or sinister (S) molecules
• The smallest molecular weight group around a chiral centre is arranged as being behind the plane of the page
• The remaining three groups are arranged in the plane of the page
• If the remaining groups' molecular weights decrease in a clockwise fashion it is the R(-) isomer
• If the remaining groups' molecular weights decrease in an anti-clockwise fashion it is the S(+) isomer
• For example S-ketamine, which is more potent and causes less emergence delirium compared to R-ketamine

• Diastereoisomers are molecules with more than one chiral centre; if there are X chiral centres then there are X² possible diastereoisomers
• The classic example is atracurium, which has four chiral centres and ten possible stereoisomers

• A racemic mixture describes a mixture with two enantiomers present in equal proportions, and will not rotate polarised light
• A number of drugs are formulated as racemic mixtures e.g. ketamine, isoflurane, adrenaline, warfarin


• By comparison, an enantiopure solution is a solution where only enantiomer is present
• They are often more expensive to manufacture, but typically benefit from avoiding negative effects associated with a certain enantiomer
• For example:
• Enantiopure S-ketamine is more potent and associated with less emergence delirium than racemic ketamine
• Enantiopure S-bupivacaine (a.k.a levobupivacaine) is thought to be less toxic than racemic bupivacaine
• Adrenaline usually presents as L-adrenaline (15x more potent), with racemic adrenaline (racepinephrine) only being available in North America