Chronic phenytoin therapy-induced vecuronium resistance.

This case report highlights a clinically significant pharmacokinetic drug interaction between phenytoin, a widely used anticonvulsant and vecuronium, a non-depolarizing neuromuscular blocker which led to vecuronium resistance.

Introduction

Vecuronium is an aminosteroid non-depolarizing type of muscle relaxant of moderate duration with minimal effect on cardiac muscarinic receptors or autonomic ganglia and does not cause histamine release.[12] It is a commonly used muscle relaxant in laparoscopic operations of moderate duration. Phenytoin is one of the most commonly used anticonvulsant drugs. It induces hepatic microsomal enzymes mainly CYP3A4 and therefore has a high drug interaction potential.

Case Report

A 55-year-old female patient of neurocysticercosis, on phenytoin therapy for 3 years (plasma concentration of drug 10 μg/L), with otherwise normal clinical profile underwent laparoscopic cholecystectomy for cholelithiasis. General anesthesia (GA) was administered following routine pre-anesthetic medications comprising of inj. glycopyrrolate 0.2 mg, inj. ondansetron 4 mg, and inj. fentanyl 100 μg. Induction was done with 2.5% thiopentone sodium 250 mg and intubation with inj. succinylcholine 100 mg. GA was maintained with O2 , N2 O, 0.5% isoflurane and inj. vecuronium 0.1 mg. Vital parameters were monitored including blood pressure, heart rate and SPO2 by pulse oximetry till the end of surgery. The duration of action of vecuronium was markedly reduced to 5--6 min, resulting in recurrent acquisition of lighter plane of anesthesia, bronchospasm with rapid fall in SPO2 from 100% to 85%. Bronchospasm could not be adequately managed with standard bronchiodilators. Vecuronium drip was started at the rate of 2 μg/kg/min but hypoxia still could not be managed. Pneumoperitonium and reverse trendelenberg position of laparoscopic surgery could not be allowed and the procedure had to be converted to an open cholecystectomy. Thereafter, SPO2 was maintained within acceptable limits but resistance to vecuronium continued till the end of surgery.

Discussion

Chronic phenytoin is reported to induce hepatic microsomal and non-microsomal enzymes, thereby leading to various drug interactions. Previously published reports have shown clinically significant drug interaction between phenytoin and various non-depolarizing neuromuscular blockers (NDNMB) mainly vecuronium, pancuronium, pipecuronium, and less commonly with atracurium.[3-8] Long-term therapy with phenytoin or carbamazepine which are potent hepatic microsomal enzyme inducers possibly cause enhanced hepatic metabolism and inactivation of the NDNMB resulting in shortened duration of neuromuscular blockade.[3-7] In addition, some published reports suggest that there might be a pharmacodynamic interaction between phenytoin and vecuronium. Postulations that chronic phenytoin or carbamazepine therapy may induce a “denervation syndrome” which leads to upregulation of acetylcholine receptors leading to an increased requirement of vecuronium and thereby conferring resistance to its neuromuscular blocking action.[5] This case report is an example of an important pharmacokinetic drug interaction between phenytoin and vecuronium which occurred in a case of cholecystectomy. Chronic administration of phenytoin or carbamazepine may lead to vecuronium resistance which might be clinically significant.