Source: Health Products and Food Branch (CA) Revision Year: 2021
The mode of action of the antiarrhythmic effect of XYLOCARD (lidocaine hydrochloride) appears to be similar to that of procaine, procainamide, and quinidine. Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole. The sinoatrial node is, however, unaffected. In contrast to the latter three drugs, XYLOCARD in therapeutic doses does not produce a significant decrease in arterial pressure or in cardiac contractile force. In larger doses, XYLOCARD may produce circulatory depression, but the magnitude of the change is less than that found with comparable doses of procainamide. Neither drug appreciably affects the duration of the absolute refractory period.
Lidocaine hydrochloride is a well-known anesthetic agent which has been used for many years for regional and topical anesthesia. However, it has been demonstrated to exert an antiarrhythmic effect by increasing the electrical stimulation threshold of the ventricle during diastole.
In decerebrated, vagotomized cats with stellate ganglia destroyed, lidocaine hydrochloride intravenous suppressed cardiac arrhythmias induced by faradic stimulation, barium chloride and epinephrine. The minimal effective dose was 0.5 mg per kg. This was 4 and 5 times less than the minimal doses of procaine and procainamide respectively.
In anesthetized open-chest dogs, lidocaine hydrochloride 5 mg per kg intravenously reduced the duration of methacholine-induced auricular arrhythmias by 55.5%. The effect of quinidine sulphate at the same dose was a reduction 46.5%. Ventricular arrhythmias induced by coronary ligation were controlled by total intravenous doses of 50 mg/kg. Convulsions and vomiting were produced and death occurred in 1 of 6 dogs at 75.5 mg/kg. In the same preparation, interruption of the arrhythmia was obtained by an injection of 15 mg/kg directly into the ventricle. In normothermic or hypothermic dogs the same effect was obtained in ventricular fibrillation induced by mechanical stimulation.
In anesthetized dogs, intravenous infusions of 40-80 mg converted digitalis-induced ventricular arrhythmia to sinus rhythm. Also, acetylstrophanthidin-induced ventricular tachycardia was suppressed at a minimal effective dose of lidocaine hydrochloride of 1 mg/kg intravenously. Digitalis-induced ventricular tachycardia, which failed to respond to electro- shock was converted to normal sinus rhythm by intravenous injection of lidocaine hydrochloride 100 mg and ventricular tachycardia, induced by ouabain was converted to supraventricular tachycardia by intravenous injection of 1-2 mg/kg.
In unanesthetized dogs with ventricular arrhythmia induced by coronary occlusion, intravenous injections of 5-10 mg/kg suppressed the arrhythmia. This effect could be maintained by intravenous infusion with calculated lidocaine hydrochloride blood levels of 1-3 µg/mL.
Other effects in anesthetized intact dogs were depression of myocardial contractile force, heart rate and femoral arterial pressure with lidocaine hydrochloride 0.5 to 6 mg/kg intravenously. At 2.0 mg/kg intra-arterially the same effects were obtained but there was less diminution of contractile force. In both anesthetized and conscious dogs, lidocaine hydrochloride in rapid intravenous injection of 2, 4 and 8 mg/kg caused transient decrease of systolic arterial pressure, venous pressure, cardiac output, mean ejection rate, rate of development of arterial pressure, stroke work and calculated peripheral resistance. Heart rate was slightly increased. Effects were greatest at 8 mg/kg and were more pronounced and of longer duration in anesthetized dogs. There was return to basal levels in 3-5 minutes.
The pharmacokinetics of lidocaine hydrochloride has been studied in normal subjects and in patients.
Following a single intravenous injection, or termination of a continuous intravenous infusion, declining plasma concentration follows a biphasic curve. Plasma half-lives of 8 to 15 minutes have been reported for the initial phase. Various studies have reported the mean half-life at the terminal phase to be in the range 1.2 to 1.9 hours. The minimum effective antiarrhythmic plasma concentration of lidocaine hydrochloride has been reported to be in the range of 1.0 to 1.2 μg/mL; concentrations higher than 5-6 μg/mL are associated with an increased risk of toxicity.
Lidocaine is mainly metabolized in the liver by CYP1A2 and CYP3A4 to its two major metabolites, monoethylglycinexylidine (MEGX) and glycinexylidine (GX), both of which are pharmacologically active. Lidocaine has a high hepatic extraction ratio. Only a small fraction (3%) of lidocaine is excreted unchanged in the urine. The hepatic clearance of lidocaine is expected to depend largely on blood flow.
Absorption: In rats which received 14C-labelled lidocaine hydrochloride by intravenous injection, rapid uptake by all tissues was noted. Tissue distribution studies in monkeys have indicated: high affinity for lung, spleen, kidney, stomach and adipose tissue; moderate affinity for brain and most gastrointestinal organs; and low affinity for musculoskeletal tissue and skin. Similar distribution has been observed in the dog.
Distributions: Studies on plasma binding in monkey and man have indicated approximately 60% plasma binding within the plasma concentration range usually seen in clinical use. However, plasma binding was markedly reduced at concentrations of lidocaine hydrochloride exceeding 10 μg/mL, presumably due to saturation of the binding sites.
Metabolism: Studies in rabbit and rat have demonstrated that the liver is the principal site of metabolism. In man, hepatic clearance studies have shown that approximately 70% of the lidocaine hydrochloride passing through the liver was extracted. Microsomal enzyme systems are primarily responsible for hepatic metabolism. The major degradative pathway appears to be by conversion to monoethylglycinexylidide, followed by hydrolysis to 2,6,-xylidine; further conversion to 4-hydroxy-2,6-xylidine appears to occur in man.
Excretion: Up to 10% of administered lidocaine hydrochloride may be excreted in the urine as unchanged drug. Although biliary secretion and intestinal absorption of lidocaine hydrochloride metabolites have been reported in rats, there is no evidence of biliary secretion in man.
| SPECIES | SEX | ROUTE | LD50 (mg/kg) |
|---|---|---|---|
| mice | F | i.v. | 17.9 |
| mice | F | i.p. | 164 |
| mice | F | i.m. | 200 |
| mice | M | i.m. | 154 |
| rat | F | i.v. | 19.7 |
| rat | M | i.v. | 21.4 |
| dog | M & F | i.m. | 100 |
| guinea pig | F | i.m. | 73 |
| guinea pig | M | i.m. | 67 |
| rabbit | M | i.m. | 450 |
Acute intravenous studies were performed in rabbits which received six serial injections of 1, 2, 3, 4 or 5 mg/kg at 15 minute intervals. At the 2 mg/kg dose level, slight depression was seen, beginning with the third injection. At 3 mg/kg there was depression and rigid extension of limbs after the last 5 injections. At 5 mg/kg there was severe depression and rigid limb extension after each injection; loss of righting reflex and convulsions began with the second injection and there was gasping for breath after each of the last injections.
Dogs were given intravenous incremental doses at 30 minute intervals until death occurred. Doses of 0.1 to 3.0 mg/kg were tolerated with minimal CNS or cardiovascular effects. Convulsions, mydriasis, salivation, urination and defecation were observed after 10 mg/kg.
Respiratory arrest and death occurred in one dog after 30 mg/kg; cardiovascular collapse, respiratory arrest and death occurred in remaining animals after 100 mg/kg. Mean arterial blood pressure and heart rate increased briefly, beginning at 3.0 mg/kg, and decreased after 100 mg/kg. Myocardial conduction time was not significantly changed prior to 100 mg/kg administration.
Acute local responses were studied in rats and rabbits following single intramuscular injections of 2%, 4%, 6%, 8% and 10% solutions of lidocaine hydrochloride. Microscopic examination revealed inflammatory changes with all solutions. In general, reactions produced by 2% solutions were least, although lesions seen with all other concentrations were of similar degree. In rabbits sacrificed seven days after intramuscular administration, there was evidence of marked muscle fiber regeneration; after 30 days there was virtually complete resolution of inflammatory changes at the site of injection.
In one study, dogs received daily intravenous injections according to the following schedule:
0.1 mg/kg for 7 days, 0.3 mg/kg for 7 days, 1 mg/kg for 7 days and 3 mg/kg for 21 days. Mild transient convulsions were seen in one dog at the high dose level. No other signs of toxicity were observed. Gross and microscopic examination at autopsy did not reveal any drug related effects.
In a second study, dogs received daily intravenous injections of 2.5, 5 or 10 mg/kg for 28 days. No overt symptoms were observed at the low dose level. At the 5 mg/kg level there was transient sedation, ataxia, head tremor, prostration and emesis. At the 10 mg/kg level there were severe tremors, muscular weakness, ataxia, prostration and convulsions, although animals recovered within 5-10 minutes. No ECG or hemochemistry changes were seen. No evidence of drug-related pathology was seen at autopsy. Injection sites showed inflammatory changes in drug and saline-treated animals.
In rats which received daily intravenous doses of 1.5, 4.5 or 15.0 mg/kg for 14 days, overt effects were observed only at the 15.0 mg/kg level, at which convulsions and death occurred. Increased blood glucose levels were seen in male rats at all dose levels. At autopsy, no changes were attributed to drug treatment. Mild inflammatory changes were seen at injection sites.
Studies of lidocaine in animals to evaluate the carcinogenic and mutagenic potential have not been conducted.
Studies of lidocaine in animals to evaluate the effect on fertility have not been conducted.
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