Lidocaine is a local anesthetic agent that also has
antiarrhythmic effects. It is a treatment for ventricular tachycardia or ventricular fibrillation.
For patients who are more hemodynamically stable,
sustained monomorphic ventricular tachycardia due to myocardial ischemia or infarction may be successfully treated using lidocaine therapy.
Lidocaine therapy can also be considered for the
treatment of polymorphic ventricular tachycardia due to myocardial ischemia or infarction. Lidocaine inhibits transmembrane sodium influx into the His-Purkinje fiber conduction system thereby decreasing conduction velocity.
It also decreases the duration of the action potential
and as a result decreases the duration of the absolute refractory period in Purkinje fibers and bundle of His. Automaticity is decreased during lidocaine therapy.
The net effect of these cellular changes is that
lidocaine eradicates ventricular reentrant arrhythmias by abolishing unidirectional blocks via increased conduction through diseased fibers. Therapeutic & Toxic Concentrations Lidocaine follows a two compartment model after administered intravenously. This is especially apparent when initial loading doses of lidocaine are given as rapid intravenous injections over 15 minutes (max rate: 2550 mg/min) and a distribution phase of 3040 minutes is observed after drug administration.
Lidocaine moves rapidly from the blood into the
heart, and the onset of action is within a few minutes after completion of the intravenous injection. Because of these, the heart is considered to be located in the central compartment of the two-compartment model for lidocaine. The generally accepted therapeutic range for lidocaine is 1.55 g/mL. In the upper end of the therapeutic range (>3 g/mL), some patients will experience minor side effects including drowsiness, dizziness, paresthesias, or euphoria. Lidocaine serum concentrations above the therapeutic range can cause muscle twitching, confusion, agitation, dysarthria, psychosis, seizures, or coma. Cardiovascular adverse effects such as atrioventricular block, hypotension, and circulatory collapse have been reported at lidocaine concentrations above 6 g/mL, but are not strongly correlated with specific serum levels. Clinical Pharmacokinetic Parameters Lidocaine is almost completely eliminated by hepatic metabolism (>95%). Hepatic metabolism is mainly via the CYP3A enzyme system. Monoethylglycinexylidide (MEGX) is the primary metabolite resulting from lidocaine metabolism. While a portion of MEGX is eliminated renally, most of the metabolite is further converted hepatically to glycinexylidide (GX) and other inactive metabolites. GX is primarily eliminated by the kidney. MEGX and GX have some antiarrhythmic activity (MEGX 80% and GX 10%, relative to lidocaine), but have also been implicated as the cause of some adverse effects attributed to lidocaine therapy. Lidocaine is usually given intravenously but may also intramuscularly. After IM injection, absorption is rapid and complete with maximum concentrations occurring 1 hour after administration and 100% bioavailability as long as the patients peripheral circulation is not compromised.
Oral absorption of lidocaine is nearly 100%.
However, lidocaine is extensively metabolized by the CYP3A enzymes(intestinal wall and liver) resulting in a large first-pass effect. Because roughly 70% of an oral dose is converted to metabolites, MEGX and GX concentrations are high after oral administration of lidocaine resulting in a high incidence of adverse effects. Plasma protein binding in normal individuals is 70%. Of this value, approximately 30% is bounded to albumin while 70% is bounded to 1- acid glycoprotein (AGP). AGP is secreted in large amounts in response to certain stresses and disease states such as trauma, heart failure, and myocardial infarction, resulting in an unbound fraction as low as 10 15%. The continuous increase in protein binding due to AGP secretion causes a continuous decrease in lidocaine clearance in patients with myocardial infarction, and lidocaine concentrations can accumulate to unexpectedly high levels. Disease States and Conditions that Alter Lidocaine Pharmacokinetics Patients with liver cirrhosis or acute hepatitis have reduced lidocaine clearance which results in a prolonged average lidocaine half life of 5 hours.The mechanism for depressed clearance in liver disease patients is destruction of liver parenchyma where hepatic drug metabolizing enzymes are present and reduction of liver blood flow. The central volume of distribution and volume of distribution for the entire body are larger in patients with liver disease because albumin and AGP concentrations are lower in these patients and result in reduced lidocaine plasma protein binding. An index of liver dysfunction can be gained by applying the Child-Pugh clinical classification system to the patient Drug Interactions Lidocaine has serious drug interactions with - adrenergic receptor blockers and cimetidine that decrease lidocaine clearance 30% or more. Propranolol, metoprolol, and nadolol have been reported to reduce lidocaine clearance due to the decrease in cardiac output caused by -blocker agents. Decreased cardiac output results in reduced liver blood flow which explains the decline in lidocaine clearance caused by these drugs. Cimetidine also decreases lidocaine clearance, cimetidine decreases lidocaine clearance by inhibiting hepatic microsomal enzymes. Lidocaine clearance may be accelerated by concomitant use of phenobarbital or phenytoin. Initial Dosage Determination Methods Pharmacokinetic Dosing Method - Half-life and elimination rate costant estimate - Volume of distribution estimate - Selection of appropriate pharmacokinetic model and equations - Steady-state concentration.
Literature-based Recommended Dosing
Doses are based on those that commonly produce steady-state concentrations in the lower end of the therapeutic range, although there is a wide variation in the actual concentrations for a specific patient. USE OF LIDOCAINE BOOSTER DOSES TO IMMEDIATELY INCREASE SERUM CONCENTRATIONS If a patient has a subtherapeutic lidocaine serum concentration and is experiencing ventricular arrhythmias in an acute situation, it is desirable to increase the lidocaine concentration as quickly as possible. In this setting, it would not be acceptable to simply increase the maintenance dose and wait 35 half-lives for therapeutic serum concentrations to be established in the patient. A rational way to increase the serum concentrations rapidly is to administer a booster dose of lidocaine, a process also known as reloading the patient with lidocaine, computed using pharmacokinetic techniques. A modified loading dose equation is used to accomplish computation of the booster dose (BD) which takes into account the current lidocaine concentration present in the patient:
BD = (C desired C actual )Vc,
C desired is the desired lidocaine concentration, C is the actual current lidocaine concentration for the patient, Vc is the central volume of distribution for lidocaine.
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