Viva A(iii)

This viva refers to  Section A(ii) of the 2017 CICM Primary Syllabus, which asks the trainees to  "describe the pharmaceutics and formulation of drugs including ...isomerism".  

What is an isomer?
  • Isomer molecules  have the same formula but different molecular structure
  • Structural isomers  have atoms and functional groups joined in different ways
What is a "stereoisomer"?
  • Stereoisomer molecules  have the same bond structure but different 3D shape
What is an enantiomer?
  • Enantiomer molecules have the same bond structure and 3D shape, but are mirror images of each other (i.e. their shapes cannot be superimposed).
What is meant by "racemic" when referring to a mixture of substances?
  • Racemic mixture is a 50/50 mix of two enantiomers, heras an enantiopure mixture only contains one enantiomer.
What is the phenomenon of stereoselectivity?
  • Stereoselectivity is the phenomenon whereby biologic macromolecules (eg. enzymes) show strong binding preference for one enantiomer over another
What are the chemical properties of enantiomers?
  • Enantiomers rotate polarized light  in opposite directions, but otherwise they have identical chemical and physical properties. 
  • They appear distinct under Xray crystallography
  • They may have different reaction kinetics with chiral catalysts
  • They are metabolised differently by stereoselective enzymes
  • Crystals of enantiomers are macroscopically different
What are the implications of enantiomerism for drug manufacture and pharmaceutics?
  • The manufacture of enantiopure drugs is more expensive.  Industrial-scale methods for separating enantiomers add at least a single magnitude factor to the cost of manufacture. Approximately 1 in every 4 drugs currently on the market is a racemic mixture, often because of this factor.  
  • Production of enantiopure drugs allows re-patenting if the racemic drug is off-patent (i.e. you can re-brand the drug and continue to charge people a premium rate).
What are the implications of enantiomerism for pharmacokinetics?
  • Dose decrease is possible. For instance, one only needs to take 1mg of eszopiclone, whereas before one would have had to take a whole 2mg of racemic zopiclone. 
  • Passive absorption is unchanged. There is no difference between the lipid or aqueous solubilities of enantiomers, so passive absorption is the 
  • Active transport mechanisms may favour one drug over another, eg. L-dopa is absorbed more rapidly than D-dopa. A more extreme example is methotrexate: the D-enantiomer has 2.5% bioavailability as compared to the L-enantiomer, because the L-enantiomer enjoys active transport and the D-enantiomer relies on sluggish passive absorption
  • Stereoselectivity of first pass enzymes may result in different rates of presystemic extraction; one might end up selecting out one of the enantiomers - for example, this happens to verapimil, where systemic availability of the more active L-verapimil was 2 to 3 times smaller than for D-verapimil
  • Stereoselectivity of clearance mechanisms: S-ibuprofen should be 160 times more potent than R-ibuprofen, but in vivo activity is only 1.4:1 because of an in-vivo racemisation
  • Stereoselectivity of protein binding may result in different rates of renal clearance and dialytic removal (but there is no convenient example of this in routine use). An inconvenient foregattable example is L-tryptophan, which binds albumin 100 times more avidly than D-tryptophan
What are the implications of enantiomerism for pharmacodynamics?
  • Enantiomer-receptor interactions: obviously, some drugs will be active, and others may only be partially active, inactive or antagonistic. 
  • Enantiomer-enantiomer interactions: in most scenarios, enantiomers are sufficiently similar that they will compete for the same protein binding sites (i.e. the inactive enantiomer will displace the active drug, making it more available)- this is seen in propoxyphene
What are some examples of enantiomer pairs in clinical use, which have significantly different effects?
  •   Thalidomide (only one of the enantiomers is teratogenic, but the non-teratogenic one ends up being converted into the other enantiomer in-vivo, making the overall drug effect racemic)
  • Ethambutal, of which only the S,S-enantiomer is effective against tuberculosis (whereas the R,R-enantiomer is effective against your eyesight)
  • Propanolol, both enantiomers of which have some local anaesthetic effect but only one (L-propanolol) is an effective β-blocker
  • Carvedilol, of which only the S-enantiomer is highly effective as a β-blocker (but both enantiomers block α-receptors)
  • Methamphetamine, of which the dextroenantiomer has CNS activity whereas the levoenantiomer is a totally benign peripherally active vasoconstricttor, used as a nasal decongestant
  • Ketamine, of which the S-ketamine enantiomer has a more potent dissociative activity

References

References

Williams, Kenneth, and Edmund Lee. "Importance of drug enantiomers in clinical pharmacology." Drugs 30.4 (1985): 333-354.

Hutt, A. J., and S. C. Tan. "Drug chirality and its clinical significance." Drugs 52.5 (1996): 1-12.

McConathy, Jonathan, and Michael J. Owens. "Stereochemistry in drug action.Primary care companion to the Journal of clinical psychiatry 5.2 (2003): 70.

Ariens, E. J. "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology." European journal of clinical pharmacology 26.6 (1984): 663-668.

Cladrowa-Runge, Sabine, et al. "Enantiomeric separation of amphetamine related drugs by capillary zone electrophoresis using native and derivatized β-cyclodextrin as chiral additives." Journal of Chromatography A 710.2 (1995): 339-345.