Local Anesthetics
Amide local anesthetics

Description: Ropivacaine is a long-acting, amide-type local anesthetic. Its structure and pharmacokinetics are similar to those of bupivacaine; however, ropivacaine appears to be less arrhythmogenic than bupivacaine. Ropivacaine is the S-isomer form, whereas bupivacaine is the R- isomer. In contrast to other local anesthetics, the systemic absorption of ropivacaine is not affected by the addition of epinephrine. Also, the presence of epinephrine does not significantly affect the time to onset or duration of action of ropivacaine. Some studies have shown less motor blocking effects and a shorter duration of action with ropivacaine than with bupivacaine. Ropivacaine was granted final FDA approval October 3, 1996 and was previously approved in 15 other countries.

Mechanism of Action: Ropivacaine works by interfering with sodium entry into nerve cell membranes. Like all local anesthetics, ropivacaine causes a reversible nerve-conduction blockade by decreasing nerve membrane permeability to sodium. This decreases the rate of membrane depolarization, thereby increasing the threshold for electrical excitability. The blockade affects all nerve fibers in the following sequence: autonomic, sensory, and motor, with effects diminishing in reverse order. Loss of nerve function clinically is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone.

Systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance have been reported. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to AV block, ventricular arrhythmia, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilatation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. CNS stimulation is usually manifested as restlessness, tremors, and shivering progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, local anesthetics have a primary depressant effect on the medulla and higher centers. The depressed stage may occur without the prior excitatory stage. Animal studies demonstrated that the cardiac toxicity of ropivacaine is less than bupivacaine, although both agents were more toxic than lidocaine. Ropivacaine caused significantly less depression of cardiac contractility (less QRS widening) than bupivacaine. Both caused evidence of depression of cardiac contractility, but there were no changes in cardiac output. In human studies, similar CNS symptoms were seen with both ropivacaine and bupivacaine.

Pharmacokinetics: Ropivacaine is given parenterally either as an epidural infusion or a regional nerve block. (NOTE: INTRAVENOUS ADMINISTRATION IS TO BE AVOIDED.) The absorption of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patient's hemodynamic/circulatory condition and the vascularity of the administration site. After epidural injection, ropivacaine shows a biphasic absorption, with an initial rapid phase half-life (mean of 14 ± 7 minutes) and a slower phase (4.2 ± 0.9 minutes). After administration of ropivacaine the onset of action occurs at 10—25 minutes for epidural administration, 15—30 minutes for major nerve block and 1—15 minutes for field block, with a duration of 2—4 hours, 5—8 hours and 2—6 hours, respectively. Unlike other local anesthetics, epinephrine has no major effect on either the time of onset or the duration of action of ropivacaine. Therefore, the addition of epinephrine has no effect on limiting systemic absorption of ropivacaine.

Ropivacaine is distributed to all tissues and highly protein bound to alpha-1 acid glycoprotein. Ropivacaine is extensively metabolized by the liver. The CYP450 isoenzymes CYP1A2 and CYP3A4 are involved in the hydroxylation and N-dealkylation of the drug, respectively.[2963] However, CYP3A4 is involved to a lesser extent, and inhibition of this enzyme does not lead to clinically relevant changes in ropivacaine clearance. Ropivacaine is excreted renally with 1% of the dose excreted unchanged. The terminal half life of ropivacaine is 1.8 ± 0.7 hours after intravascular administration and 4.2 ± 1.0 hours after epidural administration. The terminal half-life is longer after epidural administration than after intravenous administration because of this slow absorption. No pharmacokinetic differences are noted between elderly and younger patients. However, in one study the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age.

2963. Arlander E, Ekstrom G, Alm C, et al. Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP 3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol Ther 1998;64:484—91.

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