THE REDUCTION OF LIDOCAINE CLEARANCE BY dl-PROPRANOLOL: AN EXAMPLE OF HEMODYNAMIC DRUG INTERACTION

¹ Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee

A Pharmacokinetic drug interaction between propranolol and lidocaine has been found in the anesthetized dog. The administration of dl-propranolol prolonged the half-life of lidocaine from 91.0 ± 8.0 to 134.6 ± 18.1 minutes whereas saline was without effect. The mechanism of this interaction was investigated by adnministering d-or dl-propranolol (0.25 mg/kg i.v. followed by 3 µg/kg/min) during a steady-state infusion of lidocaine (20 mg/kg i.v. followed by 0.14 mg/kg/min). dl-Propranolol increased arterial lidocaine concentration from 3.92 ± 0.34 to 5.31 ± 0.61 µg/ml and decreased lidocaine clearance from 433 ± 48 to 332 ± 40 ml/min. Hepatic extraction was measured directly and was unchanged from 78.6 ± 4.8 to 78.2 ± 4.6%. Cardiac output was reduce by dl-propranol from 1.22 ± 0.08 to 0.63 ± 0.09 liters/mim. Liver blood flow calculated by the Fick principle with lidocaine as an indicator was reduced from 532 ± 83 to 427 ± 66 ml/min. There were no hemodynamic changes or alterations lidocaine disposition with d-propranolol. This drug interaction occurs by a previously undescribed mechanism in which beta adrenergic blockade due to dl-propranolol decreases cardiac output and liver blood flow with a resultant reduction in the rate of delivery of lidocaine to its major site of elinmination in the liver.

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