What are drug enantiomers? (20% of marks). Explain the clinical relevance of enantiomerism (60% of marks). Give a clinically relevant example (20% of marks).
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.
In summary, the definition of enantiomerism is as follows:
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:
Enantiomerism and pharmacokinetics:
Enantiomerism and pharmacodynamics:
The Wikipedia page about enantiopure drugs has an excellent table of examples; 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:
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.