Effects of beta‐adrenoceptor antagonists on the pharmacokinetics of lignocaine.

Abstract

1 In theory, 3-adrenoceptor antagonists could lower the clearance of free lignocaine in three ways (a) by decreasing hepatic blood flow, (b) by competing for plasma binding sites or (c) by inhibiting the enzymes responsible for metabolising lignocaine. 2 The first mechanism has been demonstrated for propranolol and is probably common to all agents lacking intrinsic sympathomimetic activity.3 The second mechanism is discounted by data showing that propranolol, one of the more highly bound f8-adrenoceptor antagonists, does not alter the free fraction of lignocaine in plasma.4 In vitro studies support the third mechanism for the more lipid-soluble ,8-adrenoceptor antagonists, as does the fact that observed decreases in the clearance of lignocaine in vivo are generally greater than the anticipated maximum lowering of hepatic blood flow.

Penbutolol and propranolol: a comparison of their effects on antipyrine clearance in man.

“…The finding that metoprolol (100 mg twice daily) decreased antipyrine clearance by 18% and that atenolol (100 mg daily) was without effect suggested the hypothesis that inhibition of oxidative drug metabolism by ,B-adrenoceptor antagonists may be related to their lipid solubility. This was supported by in vitro studies showing a strong correlation between inhibition of lignocaine metabolism by rat liver microsomes and the n-octanol/pH 7.4 buffer partition coefficients for a series of 13 0-adrenoceptor antagonists (Deacon et al, 1981;Al-Asady et al, 1982;AlAsady, 1984). Although these in vitro experiments showed penbutolol to be a more potent inhibitor than propranolol the present findings in vivo are not in accord with the lipid solubility hypothesis.…”

“…Again, this contrasts with a 40% inhibition produced by propranolol (Ochs et al, 1980;Conrad et al, 1983). A lack of effect on penbutolol on the intrinsic clearance component of the total clearance of lignocaine (Tucker et al, 1984) is consistent with our findings concerning antipyrine. Furthermore, since penbutolol has intrinsic sympathomimetic activity (Nyberg et al, 1979) it might not be expected to decrease lignocaine clearance by lowering hepatic blood flow.…”

“…Extrapolation of data on the peripheral venous, hepatic portal venous and liver tissue concentrations of propranolol in rats after oral dosing (Schneck & Pritchard, 1981) suggests that liver concentrations of unchanged drug in man during first-pass may be of the order of 20 pLM (AlAsady, 1984). Allowing for a 20-fold dilution of tissue in the preparation of microsomal incubation mixtures, this would be equivalent to an in vitro concentration of 1 ,uM.…”

The impairment of lignocaine clearance by propranolol‐major contribution from enzyme inhibition.

“…Thus, a maximum fall in hepatic blood flow of 20-25% occurs after therapeutic doses of propranolol. However, the extent of this change is insufficient to explain all of the effect of propranolol on lignocaine clearance and in vitro data, from studies with rat and human liver microsomes, indicate an additional inhibitory influence of propranolol on the enzymes which metabolise lignocaine (Deacon et al, 1981;Al-Asady et al, 1982;Bax et al, 1983;Tucker et al, 1984).…”

“…Two mechanisms have been proposed to explain this observation, namely a reduction of liver blood flow and direct inhibition of oxidative drug metabolism by propranolol (Ochs. et al, 1980;Conrad et al, 1983;Tucker et al, 1984). The first of these mechanisms is believed to be the result of a combination of blockade of Plreceptors in the heart, lowering cardiac output, and of P2-receptors in the splanchnic circulation, causing a specific decrease in hepatic portal blood flow (Westaby et al, 1984).…”