Chch2mhchch3i

Table 4.5 Pharmacological activity of the stereoisomers of labetalol.

Table 4.5 Pharmacological activity of the stereoisomers of labetalol.

Activity (pA2 values)

R1

R2

R3

R4

a1

P1 P2

R, R -

HO

H

H

CH3

5.87

8.26 8.52

S, S -

H

OH

CH3

H

5.98

6.43 <6.0

R, S -

HO

H

CH3

H

5.5

6.97 6.33

S, R -

H

OH

H

CH3

7.2

6.37 <6.0

show increased toxicity is at present unknown. Labetalol/dilevalol represents an interesting example indicating that removal of unrequired stereoisomers from a mixture may not be a trivial matter.

4.6.3 Anticoagulants

The 4-hydroxycoumarin anticoagulants act by competitive inhibition of the vitamin K dependent step in clotting factor synthesis. Warfarin (4.77), and the related compounds phenprocoumon (4.111) and acenocoumarol (4.112) are used as racemic mixtures and in the case of these agents it is difficult to differentiate their pharmacodynamic effects from their pharmacokinetic properties. For example (R)-acenocoumarol is reported to be several times more potent than the S-enantiomer. However, pharmacokinetic studies have indicated that the clearance of (S)-acenocoumarol is ten times that of its antipode and at therapeutic doses of the racemate the plasma concentrations of the S-enantiomer are at the limits of detection. The pharmacological activity observed resulting from administration of the racemate is therefore almost entirely due to the R-enantiomer. Animal studies however have demonstrated that (S)-acenocoumarol is intrinsically more potent than the Renantiomer, a result that would be expected as the S-enantiomers of both warfarin and phenprocoumon are between two to six times more active than their antipodes depending on the test species used.

At normal therapeutic dose levels warfarin is a relatively safe drug and cases of excessive dosage may be managed by the administration of vitamin K. The major problems associated with the use of warfarin arise as a result of drug interactions and warfarin is probably the most extensively investigated drug with respect to stereoselectivity and drug interactions. Some agents selectively interact with (S)-warfarin, e.g. phenylbutazone, sulfinpyrazone, whereas others are selective for (R)-warfarin, e.g. cimetidine, enoxacin, and other agents, e.g. amiodarone show no stereoselectivity. The majority of the interactions

appear to have a pharmacokinetic rather than a pharmacodynamic basis, the underlying mechanism of which may be fairly complex. For example coadministration of phenylbutazone with racemic warfarin results in an enhanced anticoagulant effect with no significant change in the plasma half-life or clearance of the "total" drug. Examination of the effect of phenylbutazone on the protein binding and clearance of the individual enantiomers of the drug indicated a greater displacement of (R)-compared to (S)-warfarin from protein binding sites and a marked reduction of the unbound clearance of the S-enantiomer compared to a much smaller inhibition of (R)-warfarin. The resultant effect of these differential interactions is a marked reduction in the total clearance of the more active S-enantiomer and an increase in the clearance of (R)-warfarin. Thus, the increased pharmacodynamic effect results from a combination of stereoselectivity in both displacement of the enantiomers of warfarin from plasma protein binding sites and inhibition of metabolism. The complexity of the situation is emphasized as the total warfarin clearance, i.e. the value obtained using "total" plasma concentrations, does not change.

4.6.4 Antihistamines

The Hrblocking activity of the dimethylaminopropyl series of antihistamines, e.g. pheniramine (4.113), chlorpheniramine (4.114) and brompheniramine (4.115), resides in the enantiomers of the S-absolute configuration. The eudismic ratios being approximately 30, 200 and 150 respectively. In the case of chlorpheniramine the therapeutic index for the two enantiomers are 3380 and 25 for S and R respectively, determined in guineapigs. Both chlorpheniramine and brompheniramine have been marketed as the single

0 0

Post a comment