Drug Interactions between Decadron with Xylocaine and pentobarbital

MONITOR: Barbiturates may decrease the plasma concentrations and systemic effects of both endogenous and exogenous corticosteroids. The mechanism is accelerated corticosteroid metabolism due to induction of the CYP450 3A4 enzymatic pathway by barbiturates.

MANAGEMENT: Patients treated concomitantly with a barbiturate may require higher dosages of corticosteroids or adrenocorticotropic agents. Pharmacologic response to these agents should be monitored more closely whenever a barbiturate is added to or withdrawn from therapy in patients stabilized on their existing corticosteroid or adrenocorticotropic regimen, and the dosage(s) adjusted as necessary.

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Coadministration with inducers of CYP450 1A2 and/or 3A4 may decrease the plasma concentrations of lidocaine, which is primarily metabolized by these isoenzymes. In four healthy volunteers (2 smokers and 2 nonsmokers), administration of a single 400 mg oral dose of lidocaine following pretreatment with the CYP450 inducer phenobarbital (15 mg/day for 4 weeks, followed by 30 mg/day for 4 weeks) decreased lidocaine systemic exposure (AUC) by 37% and increased its oral clearance by 56% compared to administration of lidocaine alone. In another study, the mean bioavailability of a single 750 mg oral dose of lidocaine in six patients receiving chronic antiepileptic drug therapy (consisting of one or more of the following enzyme-inducing anticonvulsants: phenobarbital, primidone, phenytoin, carbamazepine) was approximately 2.5-fold lower than that reported for six healthy control subjects, while intrinsic clearance was nearly threefold higher. By contrast, the interaction was modest for lidocaine administered intravenously, suggesting induction of primarily hepatic first-pass rather than systemic metabolism of lidocaine. When a single 100 mg dose of lidocaine was given intravenously, mean lidocaine AUC was reduced by less than 10% and serum clearance increased by just 17% in the epileptic patients compared to controls. These changes were not statistically significant. Likewise, mean lidocaine AUC decreased by approximately 11% and plasma clearance increased by 15% when a single 50 mg intravenous dose of lidocaine was administered following pretreatment with the potent CYP450 inducer rifampin (600 mg/day for six days) in ten healthy, nonsmoking male volunteers. Another pharmacokinetic study found that cigarette smoke, an inducer of CYP450 1A2, reduced the bioavailability of lidocaine when administered orally, but had only minor effects on lidocaine administered intravenously. When 4 smokers and 5 non-smokers received 2 doses of lidocaine (100 mg IV followed by 100 mg orally after a 2-day washout period), the smoker's systemic exposure (AUC) of oral lidocaine was 68% lower than non-smokers. The AUC of IV lidocaine was only 9% lower in smokers compared with non-smokers. The clinical impact of smoking on lidocaine has not been studied, however, a loss of efficacy may occur.

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Coadministration with barbiturates may decrease the plasma concentrations of lidocaine. The proposed mechanism is induction of lidocaine metabolism via CYP450 3A4. In four healthy volunteers (2 smokers and 2 nonsmokers), administration of a single 400 mg oral dose of lidocaine following pretreatment with phenobarbital (15 mg/day for 4 weeks, followed by 30 mg/day for 4 weeks) decreased lidocaine systemic exposure (AUC) by 37% and increased its oral clearance by 56% compared to administration of lidocaine alone. In another study, the mean bioavailability of a single 750 mg oral dose of lidocaine in six patients receiving chronic antiepileptic drug therapy (consisting of one or more of the following enzyme-inducing anticonvulsants: phenobarbital, primidone, phenytoin, carbamazepine) was approximately 2.5-fold lower than that reported for six healthy control subjects, while intrinsic clearance was nearly threefold higher. By contrast, the interaction was modest for lidocaine administered intravenously, suggesting induction of primarily hepatic first-pass rather than systemic metabolism of lidocaine. When a single 100 mg dose of lidocaine was given intravenously, mean lidocaine AUC was reduced by less than 10% and serum clearance increased by just 17% in the epileptic patients compared to controls. These changes were not statistically significant. Because lidocaine is not available commercially for oral administration, the interaction may be of limited clinical relevance. Both lidocaine and barbiturates are CNS depressants which may lead to additive effects. However, barbiturates may be used together with lidocaine in emergency cases, such as treating convulsions caused by lidocaine overdosage, while considering the depressive effects barbiturates have on respiration and circulation.

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