CLINICAL PHARMACOKINETICS OF LIDOCAINE Dr. Muslim Suardi Faculty of Pharmacy University of Andalas 2013

Lidocaine A local anesthetic agent that also has antiarrhythmic effects Can also be considered for the treatment of polymorphic ventricular tachycardia

THERAPEUTIC & TOXIC CONCENTRATIONS When given iv-ly, the serum lidocaine conc/time curve follows a 2 comp model The generally accepted therapeutic range for lidocaine is 1.5–5 µg/mL. In the upper end of the therapeutic range (>3 µg/mL), some patients will experience minor side effects including drowsiness, dizziness, paresthesias, or euphoria.

Continued Lidocaine Csr above the therapeutic range can cause muscle twitching, confusion, agitation, dysarthria, psychosis, seizures, or coma. Cardiovascular adverse effects such as atrioventricular block, hypotension, & circulatory collapse have been reported at lidocaine conc above 6 µg/mL, but are not strongly correlated with specific serum levels.

BASIC CLINICAL PK PARAMETERS Lidocaine is almost completely eliminated by hepatic metabolism (>95%). After im inj, absorption is rapid & complete with max conc occurring about 1h after administration & 100% BA as long as the patient’s peripheral circulation is not compromised due to hypotension or shock. Plasma protein binding in normal individuals is about 70%.

USE OF LIDO SERUM CONCENTRATION TO ALTER DOSE Linear Pharmacokinetics Method

Problem LK is a 50-year-old, 75-kg (5 ft 10 in) male with ventricular tachycardia who requires therapy with iv LIDO. He has normal liver & cardiac function. The current SS LIDO conc equals 2.2 µg/mL at a dose of 2 mg/min. Compute a LIDO dose that will provide a Css of 4 µg/mL.

1. Compute New Dose to Achieve Desired Csr The patient would be expected to achieve SS conditions after 8h (5 t1/2 =5*1.5 h = 7.5 h) of therapy. Using linear PK, the new dose to attain the desired conc should be proportional to the old dose that produced the measured conc: Dnew = (Css,new / Css,old)Dold = (4 µg/mL / 2.2 µg/mL) 2 mg/min = 3.6 mg/min, rounded to 3.5 mg/min

1.Continued The new suggested dose would be 3.5 mg/min of iv LIDO to be started immediately. A SS LIDO Csr could be measured after SS is attained in 3–5t1/2. Since the patient is expected to have a t1/2 equal to 1.5h, the LIDO Css could be obtained any time after the first 8h of dosing (5 t1/2=5*1.5h = 7.5h)

1.Continued LIDO Csr should also be measured if the patient experiences a return of their ventricular arrhythmia, or if the patient develops potential signs or symptoms of LIDO toxicity.

INITIAL DOSAGE DETERMINATION METHOD Literature Based Recommended Dosing

Problem LK is a 50yo, 75-kg (5 ft 10 in) male with ventricular tachycardia who requires therapy with iv LIDO. He has normal liver & cardiac function. Suggest an initial iv LIDO dosage regimen designed to achieve a SS LIDO concentration equal to 3µg/mL.

1. Choose LIDO Dose Based on Disease States Present in the patient A LIDO LD of 1–1.5 mg/kg & maintenance infusion of 3–4 mg/min is suggested for a patient without heart failure/liver disease

2. Compute Dosage Regimen Because the desired conc is in the lower end of the therapeutic range, a dose in the lower end of the suggested ranges will be used. A LIDO LD of 1 mg/kg will be administered LD = 1 mg/kg*75 kg =75 mg over 1.5–3min.

2. Continued A SS LIDO Csr could be measured after SS is attained in 3–5t1/2. Since the patient is expected to have a t1/2 equal to 1.5h, the LIDO Css could be obtained any time after the first 8h of dosing (5t1/2 = 5*1.5h= 7.5h). LIDO Csr should also be measured if the patient experiences a return of their ventricular arrhythmia, or if the patient develops potential signs of LIDO toxicity.

2. Continued A LIDO maintenance infusion equal to 3 mg/min would be administered after the LD was given. An additional dose equal to 50% of the LD can be given if arrhythmias recur 20–30 min after the initial LD.

USE OF LIDO BOOSTER DOSES TO IMMEDIATELY INCREASE Csr

Problems BN is a 57yo, 50-kg (5 ft 2 in) female with ventricular tachycardia who is receiving therapy with iv LIDO. She has normal liver function & does not have heart failure.

Problems After receiving an initial LD of LIDO (75 mg) & a maintenance infusion of LIDO equal to 2 mg/min for 2h, her arrhythmia reappears & a LIDO conc is measured at 1.2 µg/mL. Compute a booster dose of LIDO to achieve a LIDO conc equal to 4 µg/mL.

1. Estimate Vd According to Disease States Present in the Patient In the case of LIDO, the population average central Vd equals 0.5 L/kg & this will be used to estimate the parameter for the patient. The patient is nonobese, so her ABW will be used in the computation: V = 0.5 L/kg*50 kg = 25 L.

2. Compute booster dose The booster dose is computed using the following eq: BD = (Cdesired – Cactual)Vc = (4 mg/L – 1.2 mg/L)25 L = 70 mg, rounded to 75 mg of LIDO iv-ly over 1.5–3 min. If the MD was increased, it will take an additional 3–5 estimated t1/2 for new SS conditions to be achieved. LIDO Csr could be measured at this time.

2. Continued LIDO Csr should also be measured if the patient experiences a return of their ventricular arrhythmia, or if the patient develops potential signs of LIDO toxicity.