Selectivity

The pharmacologist who produces a new drug and the doctor who gives it to a patient share the desire that it should possess a selective action so that additional and unwanted (adverse) effects do not complicate the management of the patient. Approaches to obtaining selectivity of drug action include the following.

Modification of drug structure

Many drugs are designed to have a structural similarity to some natural constituent of the body, e.g. a neurotransmitter, a hormone, a substrate for an enzyme; replacing or competing with that natural constituent achieves selectivity of action. Enormous scientific effort and expertise go into the synthesis and testing of analogues of natural substances in order to create drugs capable of obtaining a specified effect and that alone (see Therapeutic Index p. 94). The approach is the basis of modern drug design and it has led to the production of adrenoceptor antagonists, histamine-receptor antagonists and many other important medicines. But there are biological constraints to selectivity. Anticancer drugs that act against rapidly dividing cells lack selectivity because they also damage other tissues with a high cell replication rate, such as bone marrow and gut epithelium.

Selective delivery (drug targeting)

The objective of target tissue selectivity can sometimes be achieved by simple topical application, e.g. skin and eye, and by special drug delivery systems, as by intrabronchial administration of P2-adrenoceptor agonists or corticosteroids (inhaled pressurised metered aerosol for asthma). Selective targeting of drugs to less accessible sites of disease offers considerable scope for therapy as technology develops, e.g. attaching drugs to antibodies selective for cancer cells.

Stereoselectivity

Drug molecules are three-dimensional and many drugs contain one or more asymmetric or chiraP centres in their structures, i.e. a single drug can be, in effect, a mixture of two nonidentical mirror images (like a mixture of left- and right-hand gloves). The two forms, which are known as enantiomorphs, can exhibit very different pharmacodynamic, pharmacokinetic and toxicological properties. For example, (1) the S form of warfarin is four times more active than the R form,4 (2) the peak plasma concentration of S fenoprofen is four times that of R fenoprofen after oral administration of RS fenoprofen, and (3) the S, but not the R enantiomorph of thalidomide is metabolised to primary toxins. Many other drugs are available as mixtures of enantiomorphs (racemates). Pharmaceutical development of drugs as single enantiomers rather than as racemic mixtures offers the prospect of greater selectivity of action and lessens risk of toxicity.

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