This chapter answers parts from Section A(ii) of the 2017 CICM Primary Syllabus; "Describe the pharmaceutics and formulation of drugs including ...isomerism". It probably also answers Section D(ix), which expects the exam candidates to "Describe and give examples of the clinical importance of isomerism" in a duplication of syllabus curriculum material which can only be attributed to the work of multiple isolated authors. 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
- a 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
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 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 words, 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 amino acids. 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.
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 predominantly 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 enantioselective, 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 enantiomer 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).
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:
Enantiomerism and pharmacokinetics:
Enantiomerism and pharmacodynamics:
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:
|Amlodipine (Norvasc)||Levamlodipine (EsCordi Cor)|
|Amphetamine (Benzedrine)||Dextroamphetamine (Dexedrine)|
|Bupivacaine (Marcain)||Levobupivacaine (Chirocaine)|
|Cetirizine (Zyrtec / Reactine)||Levocetirizine (Xyzal)|
Chlorpheniramine (USAN) (Chlor-Trimeton)
|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: