Isomerism

Describe isomerism and provide examples

Isomerism describes groups of compounds which have the same chemical formula but different chemical structures. Isomerism is relevant because different isomers may have different enzymatic and receptor affinities, altering their pharmacokinetic and pharmacodynamic properties.

Types of Isomerism

Isomers can be divided into:

• Structural Isomers
  Identical chemical formula but different arrangement of atoms. Structural isomerism is subdivided into:
  • Static
    Further subdivided into:
    • Chain isomer
      The carbon skeleton varies, but position of functional groups is static.
    • Position isomer
      The carbon skeleton is static, but the position of functional groups varies.
      • e.g. Isoflurane vs. enflurane
  • Dynamic (also known as tautomer)
    The molecule exists in a different molecular structures depending on the environment.
    • e.g. Midazolam has pH dependent imidazole ring opening. When the pH is less than 4 the ring remains open, maintaining water solubility. Midazolam is supplied at pH of 3.5, and so is water soluble on injection but (due to its pKa of 6.5) becomes 89% unionised at physiological pH therefore able to cross lipid membranes.

• Stereoisomers
  Atoms are connected in the same order in each isomer, but different orientation of functional groups. Stereoisomers are not super-imposable, meaning the different isomers can't be rotated so that they look the same. Stereoisomers are divided into:
  • Geometric Isomers
    Have a chemical structure (e.g. a carbon-carbon double-bond) prevents free rotation of groups, so different locations of chemical groups will create an isomer. Geometric isomers are known as cis- or trans- depending on whether the subgroups are on the same or opposite sides (respectively) of the chemical structure.
    • e.g. Atracurium
  • Optical Isomers
    Optical isomers are chiral. This means they have no plane of symmetry. Optical isomers:
    • Were initially named based on how they rotated under polarised light:
      (Note this is different from D- and L- molecules, where the D-isomer refers to the molecule synthesised from (+)glyceraldehyde).
      • Dextrorotatory
        (d- or (+) isomers) molecules rotate clockwise under polarised light.
      • Levorotatory
        (l- or (-) isomers) molecules rotate counter-clockwise under polarised light.
    • Unfortunately, different molecules were found to rotate in different directions depending on the temperature. Therefore, a different classification scheme (R/S) is also used:
      • Based on chemical structure
      • "Priority" is assigned to each atom in the structure
      • Highest priority is usually those with the highest molecular weight, but other rules exist for ambiguous or very large molecules
      • The molecule is arranged in space such that the lowest priority atom is facing "away"
      • An arrow is then drawn from the highest priority to the lower priority atoms:
        • If this arrow travels clockwise it is the R (Rectus) isomer
        • If this arrow travels counter-clockwise it is the S (Sinister) isomer
    • Optical isomers are divided into:
      • Enantiomers
        Possess one chiral centre.
        • e.g. levobupivacaine is less cardiotoxic than racemic bupivacaine.
      • Diastereoisomers
        Possess multiple chiral centres, and may have multiple stereoisomers. Since not all are mirror images, these are not enantiomers.
        • For a molecule with n chiral centres up to n² isomers are possible, though some of these may be duplicates.

Preparations

Drugs can be provided as:

• Racemic solutions
  A racemic solution is one which where the different enantiomers are present in equal proportions.

• Enantiopure preparations
  A drug produced with a single isomer, which may be more efficacious or less toxic (and definitely more expensive) than the racemic preparation.

References

1. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
2. CICM. The Mock Exam.
3. ChemGuide. Geometric isomerism
4. ChEBI. Misoprostol. European Molecular Biology Laboratory.
5. ANZCA July/August 2000
6. Day J, Thomson A, McAllister T. Get Through Primary FRCA: MTFs. 2014. Taylor & Francis Ltd.