Pharmacology chiral drugs

Caldwell, J., (1995) Regulation of Chiral Drugs, Pharmaceutical News, 2, 22-23. Caldwell, J. (1995) Chiral Pharmacology and the Regulation of New Drugs, Chem. and Industry, 5, 176-179. 

There are also known cases of drug enantiomers that possess completely different therapeutic properties. The (+)-2/ ,35 -stereoisomer of propoxyphene (dextropropoxyphene) is marketed as an analgesic agent, whereas its enantiomer ( )-(25, 3/ )-propoxyphene (levopropoxyphene) is available as an effective anti-tussive agent [3]. The enantiomers of some chiral drugs are known to possess essentially identical qualitative and quantitative pharmacological activities, for example, the antihistamine promethazine, which is marketed as a racemate [5]. 

Thus the (R) form cannot correctly be described as inert. Statements such as the (R) form is inert and the (S) form is pharmacologically active and is therefore also responsible for adverse side effects must be examined carefully and tested by experiments which are capable of measuring stereospecific differences. In the monitoring of drug levels and metabolites in body fluids, methods which do not distinguish between the (R) and (S) forms of chiral drugs and their metabolites are likely to yield pharmacokinetic nonsense. 

The majority of the new drugs approved and the most often prescribed drugs in the United States have at least one asymmetric center [169]. Approximately half of these chiral drugs are of a racemic composition. Many of the optically pure drug substances are of natural origin, while the majority of the synthetically derived products are in racemic form [172]. Enantiomers can differ in their pharmacological activity or one may be inactive or... 

Similar to many other cases of biologically active compounds, stereochemistry influences the pharmacological effect of a chiral drug. This can be explained by the fact that there is only one energeticaUy favorable (specific) interaction of an active molecule with its receptor, both being chiral structures. Qualitative and quantitative differences are caused by different receptor affinities as demonstrated in Fig, 1 (1). The metabolism (biotransformation) of drugs is mainly caused by enzymes, which are chiral macromolecules and discriminate between substrate molecules of different stereochemistry, This may result in metabolites of different activity and in different pharmacokinetics, resorption, and excretion. Therefore, racemic drugs should be looked on as a 1 1 mixture of two different compounds. 

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