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Isomerism

Created: 2/8/2006
Updated: 13/11/2009

 

IsomerismThe property of isomerism occurs when two or more compounds have the same atomic formulae, but a different structural arrangement, which often results in different properties.

There are two broad categories of isomerism:

  • Structural isomerism
  • Stereoisomerism

Structural isomerism

Structural isomers are molecules that have identical chemical formulae, but a different order of atomic bonds. This may result in the compounds having similar actions, like the anaesthetic volatile agents isoflurane and enflurane, or different actions, such as dihydrocodeine and dobutamine.

Tautomerism

Tautomerism is a special case of structural isomerism. Tautomers are organic compounds that are interchangeable by a chemical reaction precipitated by a change in the physical environment. This reaction often results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. A common example of this is keto-enol tautomerism, as seen with barbiturates. Their solubility depends on the transformation from the keto to the enol form, which occurs readily in alkaline solutions. 

Another example is midazolam, which is ionised in solution at pH4, but changes structure at physiological pH 7.4 to form a seven-membered unionised ring which is lipid-soluble and able to cross the blood-brain barrier.

Stereoisomerism

Stereoisomerism describes those compounds which have the same molecular formula and chemical structure, but a different three-dimensional configuration.

Stereoisomers may be:

  • Geometric
  • Optical

Geometric isomers

Geometric isomerism or cis-trans isomerism describes the orientation of functional groups within the molecule. Such isomers typically contain double bonds which cannot rotate, but they can also arise from ring structures, where the rotation of bonds is greatly restricted. If the groups are on the same side the conformation, it is called cis- and if on opposite sides, trans-. Cis isomers and trans isomers often have different physical properties. Differences between isomers generally arise from the differences in the shape of the molecule or the overall dipole moment. The benzylisoquinolinium muscle relaxants, such as atracurium, have two identical heterocyclic groups linked through an ester-containing carbon chain. Each of the heterocyclic groups contains a planar ring with groups that may be arranged in either the trans- or cis- conformation. Atracurium is formulated as a mixture of 10 stereoisomers, resulting from the presence of four chiral centres. Cis-atracurium is one of the 10 stereoisomers present in atracurium. Mivacurium contains three such geometric isomers, trans-trans (58%), cis-trans (36%) and cis-cis (6%).

Optical isomers

Optical isomers are the same in every way, except being non-superimposable mirror images of each other. This is brought about by one or more chiral centres, such a quaternary nitrogen or carbon atom surrounded by four different chemical groups. Imagine a three-dimensional tetrahedron in front of a mirror.

The chiral centre 

The four different groups around the carbon or quaternary nitrogen can now be used to distinguish isomers.
They are also called optical isomers because they rotate the plane of polarised light either to the right, referred to as +, dextro, d or D isomer, or to the left, referred to as -, laevo (levo), l or L isomer. More recently, this classification has been replaced by the R or S notation, which describes the arrangement of the molecules around the chiral centre (R is for rectus, the Latin for right, and S for sinister, left). The atom of the lowest atomic number is imagined to lie behind the plane of the page. The other three atoms now lie in the plane of the page, and if their atomic numbers descend in a clockwise manner, then this is the R enantiomer; if anticlockwise, it is the S form. As with other isomers, they can have different properties. The R and S structures are mirror images of each other and are referred to as enantiomers. The R and S structures may be laevo or dextro-rotary to polarised light, demonstrating that there is no relationship between these classifications.

Clinical examples of different isomers.

A racemic mixture is one in which the different enantiomers are present in equal proportions.
Examples:

  • Bupivacaine
  • Atropine
  • Inhalational anaesthetic agents (except sevoflurane)

In sheep experiments in which racemic bupivacaine was administered in toxic quantities, it was found that the concentration of the dextro isomer was higher in the myocardium and brain than the concentration of the laevo isomer. The laevo isomer was used in rats and its effect was compared with the dextro isomer. It was found that with doses of 2 mg/kg, all the animals of the dextro group developed apnoea, bradycardia and hypotension, and finally died. By contrast, no animal in the laevobupivacaine group had apnoea and only 30% had a slight bradycardia.

The pharmaceutical industry has now developed single enantiomers with the most desirable characteristics.
Examples of such enantiopure preparations include:

  • S(-)ropivacaine
  • S(-)bupivacaine (Laevobupivacaine)
  • S(+)ketamine

Laevobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. Electrophysiological studies have been carried out which demonstrate that blockade of the inactive Na+ channels is stereoselective, with the D isomer being more potent and faster than the L isomer. As this includes the cardiac fibres, it explains the higher cardiotoxicity associated with the D isomer.

The single S(+) enantiomer of ketamine is two to three times as potent as the R(-) enantiomer and produces less cardiac depression. The S(+) enantiomer does not block myocardial ischaemic preconditioning and causes less intense hallucinations.

Video 1: A short video which summarises the isomers of hexane and explains how small structural changes can result in different compounds.


ArticleDate:20060802
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