Question 20

Created on Wed, 07/12/2017 - 03:16
Last updated on Sat, 09/02/2017 - 20:53
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What are drug enantiomers? (20% of marks). Explain the clinical relevance of enantiomerism (60% of marks). Give a clinically relevant example (20% of marks).

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College Answer

Enantiomers refer to isomeric molecules with centres of asymmetry in 3 dimensions that
are mirror images of each other but not superimposable. Enantiomers may be distinguished 
by the direction in which polarised light is rotated. Interactions involving weak drug-receptor bonds feature a dependence upon recognition of shape, i.e.stereochemical structure is often important. Frequently one enantiomer may bind to a given receptor more avidly than the other, thus pharmacodynamics, pharmacokinetics and toxicity may vary between enantiomers. Many drugs are supplied as racemic mixtures, the components of which have different activity. Clinically relevant examples that candidates could have mentioned, included bupivacaine,ropivacaine, ketamine and carvedilol.

Discussion

In summary, the definition of enantiomerism is as follows:

  • One enantiomer is an optical stereoisomer of another enantiomer
  • The two molecules are mirror images of each other, which are not superimposable (but otherwise they have the same bond structure and 3D shape)
  • Enantiomerism requires one chiral carbon atom (well, it's usually a carbon but that's not essential, as for example cyclophosphamide has a phosphorus atom at the stereocentre)
  • Enantiomers have identical chemical and physical properties. They rotate polarized light  in opposite directions, but otherwise they are identical.
  • Usually,  xray crystallography is required to determine true molecular structure, because polarisation of light is often determined by the properties of the solution. 

Clinical relevance? An article by Williams and Lee (1985) can explain. Essentially, enantiomerism has clinical relevance because the stereoisomers are usually pharmacologically distinct molecules. They are sufficiently distinct in the way they interact with receptors transport proteins and metabolic enzymes to make each molecule a separate "drug", but they are still sufficiently physically and chemically similar to make them difficult to separate in the laboratory.

Enantiomerism and pharmaceutics:

  • The manufacture of enantiopure drugs is more expensive. 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).

Enantiomerism and 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

Enantiomerism and 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

The Wikipedia page about enantiopure drugs has an excellent table of examples; I reproduce it here with no modification:

Racemic mixture Single-enantiomer
Amlodipine (Norvasc) Levamlodipine (EsCordi Cor)
Amphetamine (Benzedrine) Dextroamphetamine (Dexedrine)
Bupivacaine (Marcain) Levobupivacaine (Chirocaine)
Cetirizine (Zyrtec / Reactine) Levocetirizine (Xyzal)
Chlorphenamine (INN)
Chlorpheniramine (USAN) (Chlor-Trimeton)
Dexchlorpheniramine (Polaramine)
Citalopram (Celexa / Cipramil) Escitalopram (Lexapro / Cipralex)
Fenfluramine (Pondimin) Dexfenfluramine (Redux)
Formoterol (Foradil) Arformoterol (Brovana)
Ibuprofen (Advil / Motrin) Dexibuprofen (Seractil)
Ketamine (Ketalar) Esketamine (Ketanest S)
Ketoprofen (Actron) Dexketoprofen (Keral)
Methylphenidate (Ritalin) Dexmethylphenidate (Focalin)
Milnacipran (Ixel / Savella) Levomilnacipran (Fetzima)
Modafinil (Provigil) Armodafinil (Nuvigil)
Ofloxacin (Floxin) Levofloxacin (Levaquin)
Omeprazole (Prilosec) Esomeprazole (Nexium)
Salbutamol (Ventolin) Levalbuterol (Xopenex)
Zopiclone (Imovane / Zimovane) Eszopiclone (Lunesta)

Of the enantiomer pair members which have a significantly different clinical effect, there are several notables:

  • 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

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.