CLINICAL PHARMACOLOGY
Mechanism of Action and Electrophysiology
Studies of the effects of therapeutic concentrations of lidocaine on the electrophysiological properties of mammalian Purkinje fibers have shown that lidocaine attenuates phase 4 diastolic depolarization, decreases automaticity, and causes a decrease or no change in excitability and membrane responsiveness. Action potential duration and effective refractory period of Purkinje fibers are decreased, while the ratio of effective refractory period to action potential is increased. Action potential duration and effective refractory period of ventricular muscle are also decreased. Effective refractory period of the AV node may increase, decrease or remain unchanged, and atrial effective refractory period is unchanged. Lidocaine raises the ventricular fibrillation threshold. No significant interactions between lidocaine and the autonomic nervous system have been described and consequently, lidocaine has little or no effect on autonomic tone.
Clinical electrophysiological studies with lidocaine have demonstrated no change in sinus node recovery time or sinoatrial conduction time. AV nodal conduction time is unchanged or shortened, and His-Purkinje conduction time is unchanged.
Hemodynamics
At therapeutic doses, lidocaine has minimal hemodynamic effects in normal subjects and in patients with heart disease. Lidocaine has been shown to cause no, or minimal, decrease in ventricular contractility, cardiac output, arterial pressure or heart rate.
Pharmacokinetics
Absorption, Distribution, and Excretion
After intravenous injection, lidocaine is quickly distributed in the tissues; the distribution volume (Vd = 1.7 L/kg) is decreased in patients with heart failure (Vd = 1 L/kg). Following intravenous administration of lidocaine the plasma concentration quickly decreases (half-life-α-phase [distribution] 8 min), the elimination half-life (β-phase) is 1.4 to 2.1 hours. In prolonged infusion (>24 h), plasma half-life clearly increases (3.2 h).
Plasma protein binding is about 70%. The plasma protein binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg free base per mL, 60 to 80 percent of lidocaine is protein bound. In addition to lidocaine concentration, the binding is dependent on the plasma concentration of the α-1-acid glycoprotein.
Therapeutic effects of lidocaine are generally associated with plasma levels of 6 to 25 μmole/L (1.5 to 6 mcg free base per mL). The blood to plasma distribution ratio is approximately 0.84. Objective adverse manifestations become increasingly apparent with increasing plasma levels above 6 mcg free base per mL. Lidocaine readily crosses the placental and blood-brain barriers.
Metabolism
Lidocaine is rapidly metabolized by the liver, and less than 10% of a dose is excreted unchanged in the urine. A major pathway of metabolism is through oxidative N-dealkylation to yield the active metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX). The pharmacological/toxicological activites of these metabolites are similar to, but less potent than, lidocaine. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline.
In vitro
studies with human liver microsomes and recombinant human cytochrome P450 (CYP) isoforms showed that both CYP1A2 and CYP3A4 enzymes are the major CYP isoforms involved in lidocaine N-dealkylation.
Drug Interactions
Cimetidine
:
Cimetidine reduces liver blood flow and thus systemic clearance of drugs that are highly extracted by the liver. Clinical Experiments showed that the concomitant administration of cimetidine reduces the systemic clearance of lidocaine and increases lidocaine serum concentration by as much as 50%. Thus, therapeutic serum levels of lidocaine may rise to toxic levels when cimetidine is used concomitantly. Ranitidine has not displayed such an effect.
Propranolol
:
Administration of propranolol during infusion of lidocaine may increase the plasma concentration of lidocaine by about 30%. Patients already receiving propranolol tend to have higher lidocaine levels than controls.
Amiodarone
:
Lidocaine area under the curve (AUC) is increased when amiodarone is administered but that of N-monodesethylated lidocaine is decreased. Moreover, the systemic clearance of lidocaine is decreased, while the elimination half-life (t½) and the distribution volume at steady state of lidocaine remained unchanged. The interaction between amiodarone and lidocaine may be explained by the inhibition of CYP3A4 by amiodarone and/or by its main metabolite N-monodesethylarniodarone (DEA).
Special Populations
Renal Insufficiency
: Renal dysfunction does not affect lidocaine kinetics, buy may increase the accumulation of metabolites. While renal excretion accounts for only a small fraction of the total clearance of lidocaine, approximately 50% of the total elimination of the active metabolite glycinexylidide (GX) is through renal excretion. Patients with significant renal disease may be at risk of accumulating GX after prolonged infusion, which could contribute to the development of CNS toxicity.
Dialysis has negligible effects on the kinetics of lidocaine.
Liver Impairment:
Because of the rapid rate at which lidocaine is metabolized, liver disease and conditions associated with reduced hepatic blood flow (i.e., heart failure, shock, treatment with beta-adrenoceptor blocking drugs) may alter lidocaine kinetics. Considerable prolongation is to be expected in the half-life of lidocaine in patients with liver dysfunction, half-life may be two-fold or greater (5 h).
Geriatrics:
The pharmacokinetics of Xylocaine Injection have not been formally studied in patients 65 years of age. However, published data show that lidocaine has been used in patients 65 years and older. After administration of usual dosages, elderly patients may be more susceptible to lidocaine adverse events because of higher systemic drug exposure. The disposition of lidocaine may be altered in elderly patients with or without concurrent disease. After intravenous or epidural administrations, elderly patients may show reduced plasma clearance, prolonged elimination half-life and increased volume of distribution compared to younger controls. Reductions in plasma clearance may be greater in elderly male patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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