ROPIVACAINE - New Long acting local anaesthetic & Etidocaine

Ropivacaine: NAROPIN - a pharmacological review.

Abstract

Ropivacaine (Naropin, AstraZeneca) a new long-acting amide local anaesthetic agent, is a pure S-enantiomer, with a high pKa and relatively low-lipid solubility. Since its clinical introduction in 1996, it has been the focus of intense interest because of its increased CNS and cardiovascular safety compared with bupivacaine. This article reviews the pharmacology of ropivacaine with particular emphasis placed on toxicological issues. Compared with bupivacaine (the drug of choice for many years), ropivacaine is equally effective for subcutaneous infiltration, epidural, intrathecal and peripheral nerve block surgery, and obstetrics and postoperative analgesia. Ropivacaine is virtually identical to bupivacaine in terms of onset, quality and duration of sensory block, but seems to produce less motor block. The lesser toxicity of ropivacaine compared with bupivacaine has been confirmed in numerous animal experiments as well as human studies, including studies considering the presumed lower potency of ropivacaine. In fact, the reduced cardiovascular toxicity compared with bupivacaine may be a distinct feature of ropivacaine. So far, the increased cost of ropivacaine compared with bupivacaine has limited its wider clinical use -- in spite of the improved safety profile. During the last few years, cost differences between bupivacaine and ropivacaine have been minimized, thus making pharmacoeconomical speculations a much lesser concern when choosing a local anaesthetic drug. In conclusion, ropivacaine appears to be a safer local anaesthetic agent than bupivacaine. It seems particularly indicated for major peripheral nerve blocks and obstetrics. Ropivacaine should be considered when regional blocks are used in neonates and young infants. With the current trend in the cost development, ropivacaine will most likely be used increasingly in the future.

Ropivacaine: A review of its pharmacology and clinical use

Abstract

Ropivacaine is a long-acting amide local anaesthetic agent and first produced as a pure enantiomer. It produces effects similar to other local anaesthetics via reversible inhibition of sodium ion influx in nerve fibres. Ropivacaine is less lipophilic than bupivacaine and is less likely to penetrate large myelinated motor fibres, resulting in a relatively reduced motor blockade. Thus, ropivacaine has a greater degree of motor sensory differentiation, which could be useful when motor blockade is undesirable. The reduced lipophilicity is also associated with decreased potential for central nervous system toxicity and cardiotoxicity. The drug displays linear and dose proportional pharmacokinetics (up to 80 mg administered intravenously). It is metabolised extensively in the liver and excreted in urine. The present article details the clinical applications of ropivacaine and its current place as a local anaesthetic in the group.

Keywords: Anaesthesia, regional anaesthetic, ropivacaine

INTRODUCTION

One of the most important properties of a long-acting local anaesthetic is to reversibly inhibit the nerve impulses, thus causing a prolonged sensory or motor blockade appropriate for anaesthesia in different types of surgeries. The acute pain relief obtained at lower doses in postoperative and labour patients due to sensory blockade is sometimes marred by accompanying motor blockade, which serves no purpose and is quite undesirable.

Bupivacaine is a well-established long-acting regional anaesthetic, which like all amide anaesthetics has been associated with cardiotoxicity when used in high concentration or when accidentally administered intravascularly. Ropivacaine is a long-acting regional anaesthetic that is structurally related to Bupivacaine. It is a pure S(-)enantiomer, unlike Bupivacaine, which is a racemate, developed for the purpose of reducing potential toxicity and improving relative sensory and motor block profiles.

STEREOSPECIFICITY AND STRUCTURE

Enantiomers exist in two different spatial configurations, like right- and left-handed gloves, and are present in equal amounts in a racemic solution. They are optically active and can be differentiated by their effects on the rotation of the plane of a polarised light into dextrorotatory [clockwise rotation (R+)] or levorotatory [counterclockwise rotation (S-)] stereoisomers. The physicochemical properties of the two enantiomeric molecules are identical, but the two enantiomers can have substantially different behaviours in their affinity for either the site of action or the sites involved in the generation of side effects. R(+) and S(-) enantiomers of local anaesthetics have been demonstrated to have different affinity for different ion channels of sodium, potassium, and calcium; this results in a significant reduction in central nervous system (CNS) and cardiac toxicity (cardiotoxicity) of the S(-)enantiomer as compared with the R(+)enantiomer.

The technological advancements have made it possible to develop Ropivacaine as an optically pure S(-) enantiomeric from the parent chiral molecule propivacaine. It belongs to the group of local anaesthetics, the pipecoloxylidides and has a propyl group on the piperidine nitrogen atom compared to bupivacaine, which has a butyl group.

MECHANISM OF ACTION

Ropivacaine causes reversible inhibition of sodium ion influx, and thereby blocks impulse conduction in nerve fibres. This action is potentiated by dose-dependent inhibition of potassium channels. Ropivacaine is less lipophilic than bupivacaine and is less likely to penetrate large myelinated motor fibres; therefore, it has selective action on the pain-transmitting A β and C nerves rather than Aβ fibres, which are involved in motor function.

PHARMACODYNAMICS

CNS and cardiovascular effects

Ropivacaine is less lipophilic than bupivacaine and that, together with its stereoselective properties, contributes to ropivacaine having a significantly higher threshold for cardiotoxicity and CNS toxicity than bupivacaine in animals and healthy volunteers.

The lower lipophilicity of ropivacaine versus bupivacaine correlated with the lesser cardiodepressant effects of both ropivacaine isomers than of the bupivacaine isomers in animal studies.

The CNS effects occurred earlier than cardiotoxic symptoms during an intravenous (IV) infusion of local anaesthetic (10 mg/min of ropivacaine or bupivacaine) in human volunteers and the infusion was stopped at this point. Significant changes in cardiac function involving the contractility, conduction time and QRS width occurred and the increase in a QRS width was found to be significantly smaller with ropivacaine than with bupivacaine.

Other effects

Ropivacaine has been shown to inhibit platelet aggregation in plasma at concentrations of 3.75 and 1.88 mg/mL (0.375% and 0.188%), which correspond to those that could occur in the epidural space during infusion. Like other anaesthetics, ropivacaine has antibacterial activity in vitro, inhibiting the growth ofStaphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.

PHARMACOKINETICS

Absorption and distribution

The plasma concentration of ropivacaine depends on the total dose administered and the route of administration, as well as the haemodynamic and circulatory condition of the patient and vascularity of the administration site.

When ropivacaine was administered intravenously in subjects, its pharmacokinetics were linear and dose proportional up to 80 mg. The absorption of ropivacaine 150 mg from the epidural space is complete and biphasic. The mean half-life of the initial phase is approximately 14 minutes, followed by a slower phase with a mean absorption t_1/2 of approximately 4.2 hours.

Ropivacaine is bound to plasma proteins to an extent of 94%, mainly to α1-acid glycoprotein. The total plasma concentration increase during continuous epidural infusion of ropivacaine is caused by an increase in the degree of protein binding and subsequent decrease in clearance of ropivacaine.

Ropivacaine rapidly crosses the placenta during epidural administration for caesarean section, resulting in near complete equilibrium of the free fraction of ropivacaine in the maternal and foetal circulation. However, the total plasma concentration of ropivacaine was lower in the foetal circulation than in the maternal circulation, reflecting the binding of ropivacaine to α1-acid glycoprotein, which is more concentrated in maternal than in foetal plasma.

ETIDOCAINE HYDROCHLORIDE INJECTION

DURANEST

Usual adult and adolescent dose

Etidocaine Hydrochloride and Epinephrine Injection. Doses somewhat smaller than those listed may be required when epinephrine is not used concurrently with the local anesthetic.

Usual adult prescribing limits

4 mg per kg of body weight or 300 mg per injection.

Usual pediatric dose

Dosage has not been established.

Strength(s) usually available

U.S.—
Without preservative      1% (10 mg per mL) (Rx) [Duranest-MPF]

Packaging and storage:

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
May be autoclaved.

Unused portions of solutions must be discarded because they contain no preservative.

ETIDOCAINE HYDROCHLORIDE AND EPINEPHRINE INJECTION

Usual adult and adolescent dose

Caudal anesthesia        50 to 150 mg (10 to 30 mL) of etidocaine hydrochloride as a 0.5% solution; or 100 to 300 mg (10 to 30 mL) of etidocaine hydrochloride as a 1% solution. Additional incremental doses may be administered at two- to three-hour intervals as needed.

Lumbar peridural anesthesia or Cesarean section or Intra-abdominal or pelvic surgery or Lower-limb surgery: 100 to 300 mg (10 to 30 mL) of etidocaine hydrochloride as a 1% solution; or 150 to 300 mg (10 to 20 mL) of etidocaine hydrochloride as a 1.5% solution. Additional incremental doses may be administered at two- to three-hour intervals as needed.

Gynecological procedures: 50 to 150 mg (10 to 30 mL) of etidocaine hydrochloride as a 0.5% solution; or 50 to 200 mg (5 to 20 mL) of etidocaine hydrochloride as a 1% solution. Additional incremental doses may be administered at two- to three-hour intervals as needed.

Dental infiltration or nerve block 15 to 75 mg (1 to 5 mL) as a 1.5% solution.

Percutaneous infiltration 5 to 400 mg (1 to 80 mL) of etidocaine hydrochloride as a 0.5% solution.

Peripheral nerve block  25 to 400 mg (5 to 80 mL) of etidocaine hydrochloride as a 0.5% solution; or 50 to 400 mg (5 to 40 mL) of etidocaine hydrochloride as a 1% solution. Additional incremental doses may be administered at two- to three-hour intervals as needed.

Usual adult prescribing limits

5.5 mg per kg of body weight or 400 mg per injection of etidocaine hydrochloride with epinephrine 1:200,000.

Usual pediatric dose

Dosage has not been established.

Strength(s) usually available

U.S.—
Without preservative      1% (10 mg per mL), with epinephrine 1:200,000 (Rx) [Duranest-MPF (sodium metabisulfite 0.5 mg per mL)]

1.5% (15 mg per mL), with epinephrine 1:200,000 (Rx) [Duranest-MPF (sodium metabisulfite 0.5 mg per mL)]
For dental use

1.5% (15 mg per mL; 27 mg per 1.8-mL dental cartridge), with epinephrine 1:200,000 (Rx) [Duranest (sodium metabisulfite 0.5 mg per mL)]

Packaging and storage:

Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. Protect from light.

Stability:
Do not autoclave.

Do not use if solution is discolored.

Unused portions of solutions not containing a preservative must be discarded.