CLINICAL APPLICATIONS
Lidocaine is very often the drug of first choice for the acute suppression of ventricular arrhythmias.
Although such therapy does not reduce total mortality, it decreases the incidence of primary ventricular fibrillation in patients with documented acute myocardial infarction. Because of lidocaine's complex pharmacokinetics, a monitored environment is desirable to permit evaluation of patient response and detection of toxicity.
Although such therapy does not reduce total mortality, it decreases the incidence of primary ventricular fibrillation in patients with documented acute myocardial infarction. Because of lidocaine's complex pharmacokinetics, a monitored environment is desirable to permit evaluation of patient response and detection of toxicity.
MECHANISM OF ACTION
Lidocaine reduces Vmax and produces shortening or no change in APD and effective refractory period (ERP) of normal Purkinje fibers, unlike quinidine and procainamide, which additionally block potassium channels and lengthen APD. Lidocaine has little effect on the electrophysiology of the normal conduction system; in patients with conduction system abnormalities, it has variable effects.
CLINICAL PHARMACOLOGY
The two desethyl metabolites of lidocaine that are excreted by the kidneys have less antiarrhythmic potency than the parent drug and may contribute to the production of central nervous system (CNS) side effects. Antiarrhythmic activity is correlated with lidocaine's concentration in the central compartment, and the half-life of distribution out of this compartment is rapid (8 min). The time required to reach steady-state conditions is 8 to 10 hours in normal individuals and up to 20 to 24 hours in some patients with heart failure and/or liver disease, whose elimination half-life is much longer than the 1.5 to 2 hours in normal subjects.
DOSAGE AND ADMINISTRATION
Lidocaine's primary use is for acute rapid suppression of ventricular arrhythmias. Single intravenous boluses will achieve only transient therapeutic effects because the drug is rapidly distributed out of the plasma and myocardium. For a stable patient, a total loading dose of lidocaine should be 3 to 4 mg/kg administered as a series of doses over 20 to 30 minutes. For example, after injection of an initial dose of 1 mg/kg over 2 minutes, a series of three loading "boluses" can be administered slowly (50 mg each over 2 minutes) 8 to 10 minutes apart, while the patient is continuously observed for the development of side effects.
At the time of initiation of the loading regimen, a maintenance infusion, designed to replace ongoing losses due to drug elimination, should be started, usually in a range of 20 to 60 mug/kg/min to achieve the desired plasma concentration of about 3 mug/mL. Even in normal individuals, there is great variability in the peak plasma concentration. Therefore, during loading, the patient's electrocardiogram (ECG), blood pressure, and mental status should be monitored; loading should be stopped at the first sign of lidocaine excess, usually transient CNS effects. When symptomatic arrhythmias persist in the presence of documented adequate dosage, defined by side effects or plasma concentration in excess of 5 to 7 mug/mL, another agent should be used. Little therapeutic effect is evident at lidocaine plasma concentrations below 1.5 mug/mL, whereas the risk of toxicity increases above 5 mug/mL. Once steady-state conditions have been achieved, terminating the lidocaine infusion will gradually reduce plasma levels over the next 8 to 10 hours.
Initial loading regimens require no adjustment in patients with renal or liver disease; however, maintenance infusions must be decreased in such patients. With liver disease, there is little change in the volume of distribution but the half-life of elimination is prolonged greatly to as much as 5 hours; steady-state conditions will not be achieved for 20 to 25 hours. During mechanical ventilation, there is low cardiac output and hepatic blood flow, so a decrease in lidocaine dosage is required. Patients with heart failure achieve lidocaine levels that are almost double those in normal individuals given the same dose, and clearance is approximately halved; loading doses and maintenance infusions should be reduced by 50%.
In post-myocardial infarction patients receiving lidocaine infusions for more than 24 hours, the elimination phase half-life can increase up to 50%. An increase in plasma lidocaine occurring at this time often reflects an elevation in plasma levels of alpha-1-acid glycoprotein (AAG), to which lidocaine binds, rather than an increase in active drug. In this situation, the lidocaine dosage should not be reduced, provided the patient is monitored closely for toxicity and has no adverse side effects.
At the time of initiation of the loading regimen, a maintenance infusion, designed to replace ongoing losses due to drug elimination, should be started, usually in a range of 20 to 60 mug/kg/min to achieve the desired plasma concentration of about 3 mug/mL. Even in normal individuals, there is great variability in the peak plasma concentration. Therefore, during loading, the patient's electrocardiogram (ECG), blood pressure, and mental status should be monitored; loading should be stopped at the first sign of lidocaine excess, usually transient CNS effects. When symptomatic arrhythmias persist in the presence of documented adequate dosage, defined by side effects or plasma concentration in excess of 5 to 7 mug/mL, another agent should be used. Little therapeutic effect is evident at lidocaine plasma concentrations below 1.5 mug/mL, whereas the risk of toxicity increases above 5 mug/mL. Once steady-state conditions have been achieved, terminating the lidocaine infusion will gradually reduce plasma levels over the next 8 to 10 hours.
Initial loading regimens require no adjustment in patients with renal or liver disease; however, maintenance infusions must be decreased in such patients. With liver disease, there is little change in the volume of distribution but the half-life of elimination is prolonged greatly to as much as 5 hours; steady-state conditions will not be achieved for 20 to 25 hours. During mechanical ventilation, there is low cardiac output and hepatic blood flow, so a decrease in lidocaine dosage is required. Patients with heart failure achieve lidocaine levels that are almost double those in normal individuals given the same dose, and clearance is approximately halved; loading doses and maintenance infusions should be reduced by 50%.
In post-myocardial infarction patients receiving lidocaine infusions for more than 24 hours, the elimination phase half-life can increase up to 50%. An increase in plasma lidocaine occurring at this time often reflects an elevation in plasma levels of alpha-1-acid glycoprotein (AAG), to which lidocaine binds, rather than an increase in active drug. In this situation, the lidocaine dosage should not be reduced, provided the patient is monitored closely for toxicity and has no adverse side effects.
ADVERSE REACTIONS
CNS symptoms are the most frequent side effects of lidocaine administration. A rapid bolus can induce seizures. With more gradual attainment of excessive levels, drowsiness, dysarthria, dysesthesia, and even coma may occur. Lidocaine can depress cardiac function, leading to decreased lidocaine clearance, and produce an even greater increase in lidocaine concentrations. Sinus node dysfunction can also occur.
DRUG INTERACTIONS
An additive or synergistic depression of myocardial function or conduction may occur during combined therapy with other antiarrhythmic agents, especially during conversion from lidocaine to another agent. A pharmacokinetic drug interaction between propranolol and lidocaine produces higher than expected plasma concentrations of lidocaine. Cimetidine decreases splanchnic, and hence liver, blood flow, decreases lidocaine's volume of distribution, and inhibits the enzymes responsible for lidocaine metabolism.
