Metabolism lignocaine

Animal experiments have shown (A3) that equilibration of lignocaine between blood and brain occurs relatively slowly. This may explain why plasma levels of lignocaine that can readily be tolerated, without cerebral side effects, after intravenous bolus injection nevertheless are associated with serious toxic symptoms when produced by constant intravenous infusion or when resulting from impaired metabolic degradation. 

Metabolism of drug during the first-pass through the liver may be reduced if its extraction depends on blood flow as hepatic blood flow is characteristically low in heart failure. This mechanism leads to a higher Cp of drugs in this group (e.g., lignocaine, an example discussed earlier in the chapter). 

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

Figure 2.5 An outline of the known metabolic pathways of the local anaesthetic lignocaine...

Sotaniemi EA, Lumme P, Arvela P, et al. Age and CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in man. Therapie 1996 51 363-366. 

Hepatic blood flow may be reduced by as much as 30% which prolongs the t/ of the lipid-soluble members whose metabolism is dependent on hepatic flow (i.e. whose first-pass metabolism is extensive and actually dependent on the rate of delivery of blood to the liver), including propranolol itself also lignocaine (lidocaine), which is liable to be used concomitantly for cardiac arrhythmias. 

Pharmacokinetic. Agents metabolised in the liver provide higher plasma concentrations when another drug that inhibits hepatic metabolism, e.g. cimetidine, is added. Enzyme inducers enhance the metabolism of this class of P-blockers. P-adrenoceptor blockers themselves reduce hepatic blood flow (fall in cardiac output) and reduce the metabolism of p-blockers and other drugs whose metabolic elimination is dependent on the rate of delivery to the liver, e.g. lignocaine (lidocaine), chlorpromazine. 

Fig. 1.8 The metabolic fate of Lidocaine (lignocaine). (Reproduced with permission from Keenaghan Boyes (1972).)...

The same experimental conditions were used by Beckett et al. for further studies of nicotine metabolism in man. However, phendimetrazine was used as the internal standard for nicotine, and lignocaine for cotinine. 

As with neonates, drug-metabolizing capacity in elderly subjects is also reduced in comparison with young adults for some compounds, such as benoxaprofen, propranolol and lignocaine. Other drugs such as isonazid and warfarin show a similar plasma half-life in elderly as in young adults. It seems that phase 1 metabolism is more likely to be affected in the elderly than phase 2 reactions. However, it... 

Perucca E, Richens A, Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients, BrJ Clin Pharmacol 91 8, 21-31,... 

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