Lidocaine distribution

A3. Ahmad, K., and Medzihradsky, F., Distribution of lidocaine in blood and tissues after single doses and steady infusion. Res. Commun. Chem. Pathol. Pharmacol. 2, 813-828 (1971). 

Absorption/Distribution - Lidocaine is ineffective orally it is most commonly administered IV with an immediate onset (within minutes) and brief duration (10 to 20 minutes) of action following a bolus dose. Continuous IV infusion of lidocaine (1 to 4 mg/min) is necessary to maintain antiarrhythmic effects. Following IM administration, therapeutic serum levels are achieved in 5 to 15 minutes and may persist for up to 2 hours. Higher and more rapid serum levels are achieved by injection into the deltoid muscle. Therapeutic serum levels are 1.5 to 6 mcg/mL serum levels greater than 6 to 10 mcg/mL are usually toxic. Lidocaine is approximately 50% protein bound (concentration-dependent). 

The concurrent administration of lidocaine with cimeti-dine but not ranitidine may cause an increase (15%) in the plasma concentration of lidocaine. This effect is a manifestation of cimetidine reducing the clearance and volume of distribution of lidocaine. The myocardial depressant effect of lidocaine is enhanced by phenytoin administration. 

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

Once absorbed, foreign compounds may react with plasma proteins and distribute into various body compartments. In both neonates and elderly human subjects, both total plasma-protein and plasma-albumin levels are decreased. In the neonate, the plasma proteins may also show certain differences, which decrease the binding of foreign compounds, as will the reduced level of protein. For example, the drug lidocaine is only 20% bound to plasma proteins in the newborn compared with 70% in adult humans. The reduced plasma pH seen in neonates will also affect protein binding of some compounds as well as the distribution and excretion. Distribution of compounds into particular compartments may vary with age, resulting in differences in toxicity. For example, morphine is between 3 and 10 times more toxic to newborn rats than adults because of increased permeability of the brain in the newborn. Similarly, this difference in the blood-brain barrier underlies the increased neurotoxicity of lead in newborn rats. 

A 58-year-old man is hospitalized in cardiac intensive care following an acute myocardial infarction. He has had recurrent episodes of ventricular tachycardia that have not responded to lidocaine, and an intravenous infusion of procainamide will now be administered. The patient weighs 80 kg and expected values for his procainamide distribution volume and elimination half-life are 2.0 L/kg and 3 hours, respectively. 

A 70-kg patient is treated with an intravenous infusion of lidocaine at a rate of 2 mg/min. Assume a single-compartment distribution volume of 1.9 L/kg and an elimination half-life of 90 minutes. 

Lidocaine pharmacokinetics tend to follow a single compartment model in neonates, with an increased half-life, and substantially reduced protein binding, leading to a much larger volume of distribution than in adults, but an increased proportion of unbound drug (56). 

Distribution and elimination LIdocane is aitensively biotransformed in the liver to at least two active metabolites monoethylglydnexy-lidide and glycinexylidide. The distribution phase 10 minutes) accounts for the short duration of action follovwng IV bolus administration, and continuous infusion of lidocaine is necessary to... 

Keenaghan, J.B. Boyes, R.N. (1972) The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man. Journal of Pharmacology and Experimental Therapeutics, 180, 454-463. 

Because lidocaine undergoes nearly complete first-pass hepatic metabolism by CyP 3 A4 and 2D6 when administered orally, it is administered only as an intravenous or intramuscular injection. Once in the blood, it is 50% bound to protein, mainly to AAG and albumin. Clearance of lidocaine is very rapid. The distribution half-life is -0.5 hour, and the elimination half-life is 1 to 1.5 hours. Reduced hepatic function impairs clearance and causes prolonged elimination and accumulation of the drug. This is due both to reduced blood flow to the liver (seen in heart failure) and to decreased metabofism of lidocaine. The end effect is lidocaine intoxication if the dose is not adjusted to account for this decreased metabolic rate. 

Congestive heart failure and uremia reduce renal clearance and the volume of distribution and increase the clearance half-life. Tocainide is not highly protein bound, so it does not exhibit die protein-binding phenomenon described for lidocaine after myocardial infarction. Clinically, the dose should be reduced proportionally to glomerular filtration to maintain therapeutic levels. 

Akerman, B., Astrom, A., Ross, S., Tele, A. Studies on the absoption, distribution and metabolism of labeled prilocaine and lidocaine in some animal species. Acta Pharmacol. Toxicol. 1966, 24, 389-403. 

In a patient weighing 70 kg, the volume of distribution of lidocaine is 80 L, and its clearance is 28 L/h. The elimination half-life of lidocaine in this patient approximates... 

Penbutolol has been shown to increase the volume of distribution of lidocaine in normal patients, implying that it may increase the loading dose requirements in some patients. Clinical signs of overdose may include bradycardia, bronchospasm, heart failure, and severe hypotension. 

In the U.S., the drugs most commonly used in spinal anesthesia are lidocaine, tetracaine, and bupivacaine. General guidelines are to use lidocaine for short procedures, bupivacaine for intermediate to long procedures, and tetracaine for long procedures. The distribution of local anesthetics... 

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