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

Abstract

1 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. 2 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 AUCP0 of lignocaine by 100-140%.3 This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl.H20 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 < 0.005); it increased the peak plasma lignocaine concentration by 79 ± 50 s.d.% (P < 0.025) and it prolonged the elimination half-life of lignocaine by 20 + 13 s.d.% (P < 0.05). 4 Propranolol treatment lowered indocyanine green clearance by 11 + 15 s.d.%, but this change was not significant statistically. 5 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.

Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

“…1997), which suggests that CYP3A4 is not very significant in the metabolism of lignocaine, or that lignocaine has alternative elimination routes. This finding is supported by previous studies with the P-adrenoceptor antagonist, propranolol, which reduces lignocaine clearance (Ochs et al 1981) and increases the AUC of oral lignocaine over 100'X~ (Bax et al 1985). These changes are due to a reduction of the intrinsic clearance of lignocaine as well as hepatic blood flow (Tucker et al 1984).…”

Clinical Pharmacokinetics of Epidural and Spinal Anaesthesia

“…Drugs that reduce the hepatic clearance of local anaesthetics mainly by enzyme inhibition, such as propranolol (Bax et al 1985;Bowdle et al 1987;Tucker et al 1984), may be expected to result in more extensive systemic accumulation of local anaesthetics; however, controlled studies to confirm this expectation are lacking.…”

A triptan too far?

“…There is an increase in the C max of zolmitriptan (10 mg) of 37% with propranolol coadministration (160 mg/day)42 accompanied by a reduction in the N-desmethyl metabolite of 24%44 which again again does not limit use of the 5 mg dose. It is not clear whether this effectis due to inhibition of P -450 enzymes45 or due to reduced hepatic blood flow 46. Based on a meta-analysis of the phase II/III placebo controlled studies zolmitriptan has, at two hours, a headache response of 64% (95% CI 59–69%) with a therapeutic gain of 34% (95% CI 27–41%) for 2.5 mg, and a headache response of 66% (95% CI 62–70%) with a corresponding therapeutic gain of 37% (30–44%) for the 5 mg dose 49.…”