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LIDOCAINE

INTRODUCTION
• Lidocaine is a local anesthetic agent that also has
antiarrhythmic effects. It is classified as a type IB
antiarrhythmic agent and is a treatment for
ventricular tachycardia or ventricular fibrillation.
• Lidocaine inhibits transmembrane sodium influx
into the His-Purkinje fiber conduction system
thereby decreasing conduction velocity.2 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.
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THERAPEUTIC AND TOXIC CONCENTRATION

• When given intravenously, the serum lidocaine concentration/time


curve follows a two compartment model. This is especially apparent
when initial loading doses of lidocaine are given as rapid
intravenous injections over 1–5 minutes (maximum rate: 25–50
mg/min) and a distribution phase of 30–40 minutes
• The generally accepted therapeutic range for lidocaine is 1.5–5
μg/Ml
• Upper end of the therapeutic range (>3 μg/mL), some patients will
experience minor side effects including drowsiness, dizziness,
paresthesias, or euphoria.
• serum concentrations above the therapeutic range can cause
muscle twitching, confusion, agitation, dysarthria, psychosis,
seizures, or coma.

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• For dose adjustment purposes, lidocaine serum
concentrations are best measured at steady state
after the patient has received a consistent dosage
regimen for 3–5 drug halflives.
• Lidocaine half-life varies from 1–1.5 hours in
normal adults to 5 hours or more in adult
patients with liver failure
• If lidocaine is given as a continuous intravenous
infusion, it can take a considerable amount of
time (3–5 half-lives or 7.5–25 hours) for patients
to achieve effective concentrations
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• the lidocaine volume of distribution for the
central compartment (Vc in L) would have to be
known to compute the loading dose (LD in mg):
LD = Css ⋅ Vc, where Css is the desired lidocaine
concentration in mg/L.
• The volume of distribution for the central
compartment of the two-compartment model is
used to compute the loading dose because
lidocaine distributes rapidly to the myocardium
and the heart is considered to reside in the
central compartment of the model
• it will still take 3–5 half-lives for the patient to
reach steady-state conditions while receiving a
constant intravenous infusion rate

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• an additional dose (50% of original loading
dose) can be given 20–30 minutes after the
original loading dose or several additional
doses (33–50% of original loading dose) can
be given every 5–10 minutes to a total
maximum of 3 mg/kg

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Clinical Monitoring Parameters
• electrocardiogram (ECG or EKG)
• lidocaine serum concentrations should be obtained in
patients who have a recurrence of ventricular
tachyarrhythmias, are experiencing possible lidocaine
side effects, or are receiving lidocaine doses not
consistent with disease states and conditions known to
alter lidocaine pharmacokinetics
• adverse drug effects: drowsiness, dizziness,
paresthesias, euphoria, muscle twitching, confusion,
agitation, dysarthria, psychosis, seizures, coma,
atrioventricular block, or hypotension.

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Basic Clinical Pharmacokinetic Parameters

• Lidocaine is almost completely eliminated by


hepatic metabolism (>95%).
• Hepatic metabolism is mainly via the CYP3A
enzyme system.
• metabolites are eliminated by the kidney,
patients with renal failure should be monitored
for adverse effects due to metabolite
accumulation even though lidocaine serum
concentrations are within the therapeutic range
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• Liver blood flow will be the predominate factor
influencing the clearance of lidocaine (Cl ≈ LBF,
where Cl is lidocaine clearance and LBF is liver
blood flow, both in L/min), and many disease
states and conditions that alter lidocaine
clearance do so via changes in liver blood flow
• Lidocaine is usually given intravenously but may
also be given intramuscularly.
• Plasma protein binding in normal individuals is
about 70%.

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EFFECTS OF DISEASE STATES AND CONDITIONS ON LIDOCAINE
PHARMACOKINETICS AND DOSING

• Normal adults have an average lidocaine half-


life of 1.5 hours (range: 1–2 hours),
• a central volume of distribution of 0.5 L/kg (Vc
= 0.4–0.6 L/kg)
• the volume of distribution for the entire body
of 1.5 L/kg (Varea = 1–2 L/kg)
• The elimination rate constant (k = 0.693/t1/2,
where t1/2 is the half-life) and clearance (Cl =
kVarea)
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• Patients with liver cirrhosis or acute hepatitis
have reduced lidocaine clearance which results in
a prolonged average lidocaine half-life of 5 hours.
• The Child-Pugh score for a patient with normal
liver function is 5 while the score for a patient
with grossly abnormal serum albumin, total
bilirubin, and prothrombin time values in
addition to severe ascites and hepatic
encephalopathy is 15. A Child-Pugh score greater
than 8 is grounds for a decrease in the initial daily
drug dose for lidocaine (t1/2 = 5 hours)

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• Heart failure causes reduced lidocaine clearance
because of decreased hepatic blood flow secondary
to compromised cardiac output

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Drug Interaction
• Lidocaine has serious drug interactions with β-
adrenergic receptor blockers and cimetidine
that decrease lidocaine clearance 30% or
more
• Lidocaine clearance may be accelerated by
concomitant use of phenobarbital or
phenytoin

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INITIAL DOSAGE DETERMINATION METHODS

1. Pharmacokinetic dosing method


• HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE
• VOLUME OF DISTRIBUTION ESTIMATE
• SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL
AND EQUATIONS
• Css = k0 / Cl or k0 = Css ⋅ Cl
• STEADY-STATE CONCENTRATION SELECTION
The general accepted therapeutic range for lidocaine is 1.5–
5 μg/mL

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2. Literature-Based Recommended Dosing
• lidocaine steady-state serum concentration
expected from the lower end of the dosage range
was 1.5–3 μg/mL and 3–5 μg/mL for the upper
end of the dosage range. Suggested intravenous
lidocaine continuous infusion maintenance doses
are 1–2 mg/min for patients with liver disease or
heart failure and 3–4 mg/min for all other
patients
• lidocaine is given intravenously at the dose of 1–
1.5 mg/kg (not to exceed 25–50 mg/min) for all
patients except those with heart failure

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• The suggested lidocaine intravenous loading
dose for heart failure patients is 0.5–0.75
mg/kg (not to exceed 25–50 mg/min)
• Intravenous loading doses are 1 mg/kg with
up to two additional doses, if needed (total
dose not to exceed 3–5 mg/kg for first hour).
Continuous intravenous infusions doses are
20–50 μg/kg/min.
• For patients with shock, heart failure, or liver
disease patients, initial doses should not
exceed 20 μg/kg/min

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USE OF LIDOCAINE SERUM CONCENTRATIONS
TO ALTER DOSES
1. Linear Pharmacokinetics Method
Dnew / Css,new = Dold / Css,old or Dnew = (Css,new / Css,old)Dold

2. Pharmacokinetic Parameter Method


The pharmacokinetic parameter method requires that
steady state has been achieved and uses only a steady-
state lidocaine concentration (Css in mg/L or μg/mL)

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BAYESIAN PHARMACOKINETIC COMPUTER
PROGRAMS
1. Enter patient’s demographic, drug dosing, and serum
concentration/time data into the computer
program.
2. Compute pharmacokinetic parameters for the
patient using Bayesian pharmacokinetic computer
program
3. Compute dose required to achieve desired lidocaine
serum concentrations.

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