Dviii: Describe & give examples of the clinical importance of isomerism

Definitions

  • Isomer = identical formula, different bonding arrangements of atoms, or their orientation in space
  • Structural isomer = same chemical formula, structure is different
  • Stereoisomer = same chemical formula, same atom arrangement, arrangement in space is different (i.e. different 3D configuration)
  • Enantiomer = molecules that are mirror images & cannot be superimposed

Isomer

Structural

Steroisomer

Structural

Chain

Position

Tautomerism

Steroisomer

Optical

Geometric

Cis

Trans

Structural

  • Same chemical formula
  • Different structure
  • May/may not have similar effects
    • ISO/EN (similar)
    • Dihydrocodeine/dobutamine (different)
  • TAUTOMER = ∆ structure depending on pH
Midazolam

Stereoisomerism

  • Same chemical formula
  • Atom arrangement same, but arrangement in space different (i.e. diff 3D config)

Geometric

    • 2 diff groups attached to 2 different atoms
    • Atoms joined by double bonds
    • ∴ rotation of groups restricted
    • Groups same side = cis
    • Groups different side = trans

Cistatracurium = cis-cis isomer of atracurium

  • 50% more potent
  • ↓histamine release

Optical (Enantiomer)

  • Molecules are mirror images therefore cannot be superimposed
  • Contain > 1 chiral centre
  • CHIRAL CENTRE = central atom surrounded 4 different chemical groups so in 3D one extends vertical & others point out
  • Classified by configuration of functional groups attached to chiral centre
    • R (RECTUS) = clockwise (Latin – Right handed)
    • S (SINISTER) = anticlockwise (Latin – Left handed)
  • Enantiomer = 1 chiral centre
  • Diastereoisomer = >1 chiral centres
  • Mainly exist as Racemix (2 isomers 50:50) e. ketamine → S-ketamine = more potent dissociative activity)

Clinical Significance

Ceutics

  • Pure enantiomer is very expensive ∴ most drug are racemic
  • Producing a pure enantiomer allows re-patenting of a drug

PK

    • You can ↓dose
    • Passive absorption = same
    • Active transport may favour one isomer over another
    • 1st pass metabolism may favour one e. L-verapamil has much more OBA cf. s-verapamil
    • PPB → differs ∴ different clearance

PD

  • Enantiomer – receptor interaction i.e. different active/inactive/partially active/antagonist
  • Enantiomer/enantiomic interactions = similar config ∴ compete for same PPB site