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Figure 16 Novel hybrid vitamin E/class 1 antiarrhythmics.

6.33.7.1.1.1 Novel hybrid vitamin E/class I antiarrhythmics

Antioxidants such as vitamin E protect against injury due to myocardial ischemia and subsequent reperfusion, although their highly hydrophobic properties reduce their availability to cardiac myocytes. One interesting approach has been to eliminate some of the hydrophobic moieties of vitamin E, and combine the resulting compound with the known class 1 antiarrhythmics such as lidocaine and procainamide to create a bifunctional class of antiarrhythmic antioxidants.23 These compounds inhibit lipid peroxidation with antiarrhythmic effects against ischemia-reperfusion experimentally. Figure 16 shows examples of these new hybrids where procainamide and lidocaine are covalently bound to a-tocopherol with the expectation that the saturated chain will confer selectivity for antiarrhythmic action.

Since the introduction of propranolol in the early 1960s, many other ^-adrenoceptor blockers have been introduced. It is not readily apparent that any have particular advantages over other drugs as antiarrhythmics, although they vary widely in their pharmacological and pharmacokinetic profiles. Differences in their pharmacological profiles are relatively minor, even for cardiac selectivity. There is no unequivocal evidence that such limited ^-adrenoceptor selectivity provides better antiarrhythmic protection, neither does partial agonism. The same is probably true of pharmacokinetic differences, although it is reasonable to suppose that a drug providing the same level of blockade over 24 h would be better.

Apparently there have been few attempts to maximize the ^-adrenoceptor selectivity of ^-adrenoceptor blockers, specifically with respect to antiarrhythmic actions. The structural differences between propranolol and the cardiac selective blockers atenolol and metoprolol are shown in Figure 7.

In view of the above, it is not surprising that little effort has been expended on better class 2 antiarrhythmics. Possibly a markedly selective ^-adrenoceptor blocker with a longer half-life would confer better protection against arrhythmias, but it would be very expensive to test this proposition clinically, since the endpoint for the necessary clinical trials would be mortality.

6.33.7.1.3.1 IKr blockers with faster recovery kinetics from channel binding

Most IKr blockers have undesirable reverse rate dependence that is opposite to what is probably required clinically, since antiarrhythmic actions should be greater at the high rates seen during arrhythmias. Thus, compounds with

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