Mepivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.
Systemic absorption of mepivacaine produces effects on the cardiovascular system and CNS. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. These cardiovascular changes are more likely to occur after unintended intravascular injection of mepivacaine [see Warnings and Precautions (5.5)].
Following systemic absorption, mepivacaine can produce CNS stimulation, CNS depression, or both. Apparent CNS stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by CNS depression and coma progressing ultimately to respiratory arrest. However, mepivacaine has a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.
The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Mepivacaine will normally provide anesthesia which is adequate for 2 to 2 1/2 hours of surgery.
A clinical study using 15 mL of 2% epidural mepivacaine at the T 9-10 interspace in 62 patients, 20-79 years of age, demonstrated a 40% decrease in the amount of mepivacaine required to block a given number of dermatomes in the elderly (60-79 years, N=13) as compared to young adults 20-39 years).
Another study using 10 mL of 2% lumbar epidural mepivacaine in 161 patients, 19-75 years of age, demonstrated a strong inverse relationship between patient age and the number of dermatomes blocked per cc of mepivacaine injected.
Systemic plasma levels of mepivacaine following administration of CARBOCAINE do not correlate with local efficacy.
Absorption
The rate of systemic absorption of mepivacaine is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution.
A dilute concentration of epinephrine (1:200,000) usually reduces the rate of absorption and plasma concentration of mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with CARBOCAINE.
Distribution
Mepivacaine is approximately 75% bound to plasma proteins.
Mepivacaine appears to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of mepivacaine appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Based on the pharmacokinetic analyses performed in several studies, mepivacaine is rapidly absorbed from the epidural space into the maternal blood stream and readily crosses the placenta as evidenced by detectable mepivacaine blood levels in the fetus as early as 5 minutes after anesthetic block administration. Fetal absorption and distribution of mepivacaine were noted in few cases that demonstrated tissue and organ levels of mepivacaine.
Depending upon the route of administration, mepivacaine is distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
Elimination
The half-life of CARBOCAINE in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours.
Metabolism
Mepivacaine is not detoxified by the circulating plasma esterases. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2′ 6′-pipecoloxylidide).
Excretion
The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It is rapidly metabolized, with only a small percentage of the anesthetic (5 to 10%) being excreted unchanged in the urine. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.
Specific Populations
Patients with Hepatic Impairment
Various pharmacokinetic parameters of the local anesthetics including mepivacaine can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics including mepivacaine [see Use in Specific Populations (8.5, 8.6)].
Patients with Renal Impairment
Various pharmacokinetic parameters of the local anesthetics including mepivacaine can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow [see Use in Specific Populations (8.5, 8.7)].
Mepivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.
Systemic absorption of mepivacaine produces effects on the cardiovascular system and CNS. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. These cardiovascular changes are more likely to occur after unintended intravascular injection of mepivacaine [see Warnings and Precautions (5.5)].
Following systemic absorption, mepivacaine can produce CNS stimulation, CNS depression, or both. Apparent CNS stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by CNS depression and coma progressing ultimately to respiratory arrest. However, mepivacaine has a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.
The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Mepivacaine will normally provide anesthesia which is adequate for 2 to 2 1/2 hours of surgery.
A clinical study using 15 mL of 2% epidural mepivacaine at the T 9-10 interspace in 62 patients, 20-79 years of age, demonstrated a 40% decrease in the amount of mepivacaine required to block a given number of dermatomes in the elderly (60-79 years, N=13) as compared to young adults 20-39 years).
Another study using 10 mL of 2% lumbar epidural mepivacaine in 161 patients, 19-75 years of age, demonstrated a strong inverse relationship between patient age and the number of dermatomes blocked per cc of mepivacaine injected.
Systemic plasma levels of mepivacaine following administration of CARBOCAINE do not correlate with local efficacy.
Absorption
The rate of systemic absorption of mepivacaine is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution.
A dilute concentration of epinephrine (1:200,000) usually reduces the rate of absorption and plasma concentration of mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with CARBOCAINE.
Distribution
Mepivacaine is approximately 75% bound to plasma proteins.
Mepivacaine appears to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of mepivacaine appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Based on the pharmacokinetic analyses performed in several studies, mepivacaine is rapidly absorbed from the epidural space into the maternal blood stream and readily crosses the placenta as evidenced by detectable mepivacaine blood levels in the fetus as early as 5 minutes after anesthetic block administration. Fetal absorption and distribution of mepivacaine were noted in few cases that demonstrated tissue and organ levels of mepivacaine.
Depending upon the route of administration, mepivacaine is distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
Elimination
The half-life of CARBOCAINE in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours.
Metabolism
Mepivacaine is not detoxified by the circulating plasma esterases. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2′ 6′-pipecoloxylidide).
Excretion
The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It is rapidly metabolized, with only a small percentage of the anesthetic (5 to 10%) being excreted unchanged in the urine. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.
Specific Populations
Patients with Hepatic Impairment
Various pharmacokinetic parameters of the local anesthetics including mepivacaine can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics including mepivacaine [see Use in Specific Populations (8.5, 8.6)].
Patients with Renal Impairment
Various pharmacokinetic parameters of the local anesthetics including mepivacaine can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow [see Use in Specific Populations (8.5, 8.7)].
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