In theory, beta-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. The first mechanism has been demonstrated for propranolol and is probably common to all agents lacking intrinsic sympathomimetic activity. The second mechanism is discounted by data showing that propranolol, one of the more highly bound beta-adrenoceptor antagonists, does not alter the free fraction of lignocaine in plasma. In vitro studies support the third mechanism for the more lipid-soluble beta-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

Nadolol and propranolol effects on lidocaine elimination were followed in six healthy men and women. Each received three separate 30-hr infusions of lidocaine (2 mg/min): one alone, one after 3 days pretreatment with nadolol (160 mg daily), and one after 3 days pretreatment with propranolol (80 mg every 8 hr). Liver blood flow was determined by the systemic clearance of indocyanine green. Steady-state plasma lidocaine levels were increased by nadolol (2.1 +/- 0.2 to 2.7 +/- 0.3 micrograms/ml) and by propranolol (2.1 +/- 0.2 to 2.5 +/- 0.3 micrograms/ml). Lidocaine plasma clearance was decreased by nadolol (1030 +/- 81 to 850 +/- 82 ml/min) and by propranolol (1030 +/- 81 to 866 +/- 75 ml/min). Hepatic blood flow was decreased by nadolol (1275 +/- 77 to 902 +/- 102 ml/min) and propranolol (1275 +/- 77 to 957 +/- 119 ml/min). The hepatic extraction ratio for lidocaine was increased by nadolol (0.86 +/- 0.06 to 0.91 +/- 0.05) and by propranolol (0.86 +/- 0.06 to 0.90 +/- 0.06). Lidocaine intrinsic clearance was not changed by nadolol (8.19 +/- 1.87 to 9.52 +/- 2.36 l/min) or propranolol (8.19 +/- 1.87 to 9.50 +/- 3.13 l/min). Our data indicate that both nadolol and propranolol reduce lidocaine clearance by their effects on hepatic blood flow and not by inhibition of lidocaine metabolism

1 Steady state concentrations and clearance of lignocaine were determine in eight healthy volunteers during 360 min continuous lignocaine infusion (2 mg/min). Before the infusion propranolol (0.18 mg/kg i.v.), pindolol (0.023 mg/kg i.v.) or placebo were administered in a random double-blind, cross over design. 2 During the infusion of lignocaine heart rate, cardiac output and arterial blood pressure were measured every 60 min. 3 Propranolol decreased heart rate and cardiac output significantly by 10--20%, while pindolol or lignocaine did not change cardiac output or heart rate significantly. None of the drugs changed the arterial blood pressure. 4 Propranolol pretreatment decreased lignocaine significantly by 14.7% and the steady state concentration was increased by 22.5%. Pindolol produced no significant change in steady state concentration or clearance of lignocaine

The effects of administration of metoprolol and propranolol on lidocaine elimination were studied in six healthy young men who did not smoke. Each received three single intravenous doses of lidocaine (2.5 to 3.0 mg/kg injected over 10 min): one alone, one after 1 day pretreatment with propranolol (40 mg orally every 6 hr), and one after 1 day pretreatment with metoprolol (50 mg orally every 6 hr). Lidocaine clearance was 0.88 +/- 0.28 l X hr-1 X kg-1 before beta blockade, 0.61 +/- 0.20 l X hr-1 X kg-1 during metoprolol dosing, and 0.47 +/- 0.16 l X hr-1 X kg-1 during propranolol dosing. There was no correlation between the change in lidocaine elimination and the steady-state concentrations of metoprolol or propranolol, nor between the change in lidocaine clearance and the change in resting heart rate produced by either beta blocker. Metoprolol and propranolol reduce lidocaine elimination significantly

Propranolol is widely used in clinical practice and is frequently administered along with other drugs. The co-administration of propranolol and other drugs may result in either propranolol-induced changes in the disposition of other drugs or in effects of the other drugs on the pharmacokinetics of propranolol. These changes may be due to alteration in absorption, metabolism or to haemodynamic effects such as altered liver blood flow. Understanding the pharmacokinetics of propranolol is important to the rational interpretation of the effects of other drugs on propranolol´s disposition. The absorption, protein binding and metabolism of propranolol may all be affected by the co-administration of other drugs. Induction of propranolol´s metabolism by halofenate, phenytoin, phenobarbitone, rifampicin and alcohol have all been implicated in altering propranolol clearance, while inhibition of hepatic drug metabolising enzymes by chlorpromazine and cimetidine appear to reduce propranolol clearance. Propranolol may also affect the metabolism of other drugs such as antipyrine, chlorpromazine, theophylline and thyroid hormones. Suggestions that propranolol may alter quinidine´s elimination have not been substantiated. By reducing liver blood flow propranolol may reduce the systemic clearance of other high extraction drugs such as lignocaine

There is evidence, from human and animal studies, that drug-metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific, substrate requirements. Consequently drug interactions may arise when two drugs bind to the same enzyme. The degree of enzyme inhibition will be partly dependent on the relative affinities of the drugs for the enzyme and on their rates of turnover. The decrease in drug clearance produced by enzyme inhibition is dependent on the fraction of the drug normally metabolised by the inhibited pathway(s). Cimetidine, a P-450 enzyme inhibitor, increases the systemic bioavailability of propranolol and labetalol, which undergo extensive metabolism, but does not affect the clearance of atenolol, which is excreted largely unchanged. In this situation, both the extent and type of biotransformation are important. Thus, cimetidine has no effect on the clearance of penbutolol, even though the drug is eliminated almost entirely by biotransformation. The major metabolite is penbutolol glucuronide, and it has been shown recently that cimetidine does not inhibit glucuronylation. Beta-adrenoceptor blockers also act as enzyme inhibitors themselves. For example, antipyrine clearance is decreased by propranolol and to a lesser extent by metoprolol, whereas atenolol has no effect. It has been suggested, therefore, that there is a relationship between the lipid-solubility of beta-adrenoceptor blockers and their ability to inhibit drug metabolism. The clearance of lipophilic beta-adrenoceptor blockers is dependent on hepatic enzyme activity, and is therefore sensitive to enzyme induction. For drugs with high hepatic clearance and subsequent high presystemic elimination, a moderate increase in the extraction ratio will produce a marked decrease in systemic bioavailability. (ABSTRACT TRUNCATED AT 250 WORDS)

Elleve normale frivillige deltog enten eller, eller bÕde og , i et enkeltdosis eller et infusionsstudie af lidocain med eller uden forbehandling med propranolol.Enkeltdosisfors°get viste en folµngelse af eliminationshalveringstiden for lidocain fra 65,0 til 100,7 minutter (p mindre end o.o2) og et fald i clearance fra 18,0 til 10,7 ml/min./kg. under propranololbehandling.Det 36 timer lange infusionsfors°g viste en propranololfremkaldt stigning i lidocains steady-state concentration fra 3,02 til 3,93 microgram per ml og et tilsvarende fald i clearance fra 8,5 til 6,4 ml/min/kg.

To account for a 40% lowering of the systemic clearance of lignocaine by propranolol treatment it has been proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUCpo of lignocaine by 100-140%. This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl X H2O orally with and without propranolol pre-treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpo of lignocaine by 113 +/- 58 s.d.% (P less than 0.005); it increased the peak plasma lignocaine concentration by 79 +/- 50 s.d.% (P less than 0.025) and it prolonged the elimination half-life of lignocaine by 20 +/- 13 s.d.% (P less than 0.05). Propranolol treatment lowered indocyanine green clearance by 11 +/- 15 s.d.%, but this change was not significant statistically. These experimental results are in accord with the theoretical predictions suggesting that propranolol lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow