Enantiomerism

Created on Sat, 09/02/2017 - 00:01
Last updated on Mon, 09/25/2017 - 21:19

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This chapter answers parts from Section A(ii) of the 2017 CICM Primary Syllabus"Describe the pharmaceutics and formulation of drugs including ...isomerism". At the time of writing, this chapter represents the only pharmaceutics question ever asked in the Primary written paper, this being Question 20 from the second paper of 2012.  "Explain the clinical relevance of enantiomerism"and "give a clinically relevant example" seems to be the entire expectations from the college regarding this topic. 

Back to high school chemistry:

  • Isomer molecules  have the same formula but different molecular structure
  • Structural isomers  have atoms and functional groups joined in different ways
  • Stereoisomer molecules  have the same bond structure but different 3D shape
  • Enantiomers have the same bond structure and 3D shape, but are mirror images of each other
  • Racemic mixture is a 50/50 mix of two enantiomers, wheras an enantiopure mixture only contains one enantiomer
  • Stereoselectivity is the phenomenon whereby biologic macromolecules (eg. enzymes) show strong binding preference for one enantiomer over another

Definitions

One enantiomer is an optical stereoisomer of another enantiomer. The two molecules are mirror images of each other, which are not superimposable - much like your left and and right hand. This trick requires at least one chiral carbon atom, or some similar structure (it does not have to be carbon- for example, in cyclophosphamide there is a chiral phosphorus atom). This is in contrast to diastereoisomers, which are stereoisomers of each other but which are not mirror-images and which usually have two chiral carbon stereocenters.

Enantiomers have identical chemical and physical properties. They rotate polarized light  in opposite directions, but otherwise they are identical. This optical activity is also dependent on things other than enantiomerism, for instance on sample concentration, pH, temperature and light wavelength. One can take some dextro-ibuprofen and change the pH of the solution until polarised light is rotated into the opposite direction, thereby apparently producing levo-ibuprofen. But the drug of course does not undergo any structural change. In other word, optical activity has nothing to do with the absolute configuration of the molecule. Absolute configuration is generally determined by Xray crystallography, and represents the "true" alignment of atoms in the molecule.

Typical nomenclature of enantiomers is to prefix the chemical name with dextro (+) or levo (-), according to optical activity - or R and S for those drugs in which the absolute configuration is known, or D and L for aminoacids. It is of interest to note that though all naturally occurring amino acids are L-enantiomers by optical activity, not all of them turned out to be R-enantiomers upon interrogation by Xray crystallography. 

enantiomerism of amphetamine

Here, the "handedness" of L-amphetamine and R-amphetamine is illustrated using childish hand drawings. Both molecules have some CNS effect, but dextroamphetamine has the greatest activity, being ten times more potent as a centrally acting indirect sympathomimetic (inhibitor of noradrenaline reuptake). The original benzedrine of the 1930s was a racemic mixture, and was marketed as an inhaler to combat nasal congestion. These days most amphetamine preparations are predominanty based on dextroamphetamine, with some levoamphetamine admixture. Enantiopure amphetamine preparations are expensive to prepare.

In general, industrial-scale methods for separating enantiomers add at least a single magnitude factor to the cost of manufacture. For instance, one may wait for the enantiomers to form crystals (which will be macroscopically different to the naked eye), then manually separating the crystals. Or, one may convert the enantiomers into diastereoisomers by getting them to form a salt with a chiral acid or base; the diastereoisomers formed in this manner will hopefully have very different physicochemical qualities and will be easily separated. Alternatively, one may make use of natural processes which are enantioselective: for example, most naturally available enzymes are enatioselective, and will only metabolise one enantiomer in a solution, leaving the other one behind - but this represents a loss of 50% of the finished product. Lastly, one may take advantage of the fact that enantiomers will have different reaction kinetics with different chiral catalysts or reagents; because the reaction takes place faster for one anantiomer and not the other, one may be able to separate them out of a solution (one enantiomer undergoes a reaction which for example renders it insoluble, while the other remains in solution).

Clinical relevance of enantiomerism

An excellent, albeit dated, article by Williams and Lee (1985) holds forth extensively on this topic, and can serve as the sole reference for the remainder of this chapter (thankfully, because the curriculum textbooks are near-useless in this area).

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

Examples of clinically important enantiomers

McConathy and Owens (2003) produce a list of racemic drugs in psychiatric practice, and the list of drugs in the Wikipedia page about enantiopure drugs is also an excellent starting point. 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.

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.