Ropivacaine is enantiomerically homogeneous and is more than 99% pure S-(-) enantiomer (unlike bupivacaine, which is a racemate). Its lipid solubility lies somwhere between that of lignocaine and bupivacaine (8). It is highly plasma protein binding (94%)(9). The duration of action and onset time (5) are similar to those of bupivacaine. The drug has no affinity for histaminic, serotoninic, alpha- or beta-adrenergic or muscarinic receptors. It is rapidly cleared from plasma and is extensively metabolised by cytochrome P450 to PPX, 3'-OH Ropivacaine and 4'-OH Ropivacaine (10). It has a greater margin of safety (higher therapeutic ratio) than bupivacaine.
Advantages of Ropivacaine over Existing Local Anaesthetic Agents:
Reduced CNS Toxicity:
Local anaesthetics produce their effects by blocking excitable membranes (Chapter 53). Inadvertent intravascular injection or massive systemic absorption will, as the blood level rises progressively, alter these membranes' functions (mainly in the CNS and CVS) (Chapter 36). Convulsions are due to removal of inhibition of central neural structures, probably by alterations to the GABA receptor complex (11). At higher doses, blockage of the sodium channels produces the depressant effects (and the cardiovascular toxicity) (11) (Chapter 95).
Ropivacaine produces less of the mild CNS effects (lightheadedness, tinnitus, tongue numbness) (12) (Table E.2) and is less likely to cause convulsions than bupivacaine. If convulsions occur, they are of shorter duration than those of bupivacaine (Table 36.4) and, provided that treatment starts immediately, resuscitation is almost always effective (Table 36.5). This is not always the case with bupivacaine overdosage (Chapter 12) .
Ropivacaine toxicity from overdosage does not seem to be worsened by pregnancy (unlike bupivacaine) so that the convulsive dose is the same in the pregnant and the non-pregnant female (13, 14).
Reduced CVS Toxicity:
At high dose, ropivacaine is less cardiodepressant than bupivacaine (15). For example, bolus injection of twice the convulsive dose of ropivacaine (16) produces fewer ventricular dysrhythmias and deaths than bupivacaine (Figure 57.1). As is the case for treatment of convulsions, severe systemic toxicity produced by administration of large doses of ropivacaine is easier to treat than that induced by overdosage with bupivacaine.
Malignant ventricular dysrhythmias which are common following bupivacaine intoxication are rare in ropivacaine overdosage. Indeed, the dysrhythmia dose threshold is (approximately) bupivacaine 3.4: ropivacaine 1.7 : lignocaine 1.0 (Chapter 37).
Epidural adrenaline is unnecessary:
Ropivacaine at lower concentrations (unlike bupivacaine) seems to have a mild vasoconstrictive effect. The addition of adrenaline to ropivacaine is not necessary and does not seem to markedly reduce (3, 4) peak plasma levels (Table 113.4).
Effects on the Neonate:
While this is not as yet certain, neonates born to mothers receiving ropivacaine seem to have a higher neurological and adaptive score (NACS) than those having epidural bupivacaine (1, 5, 17, 18) (Table 35.2).
Clinical Use:
Clinical experience in using the drug is reported in Chapter 116.
References:
1. Gatt S. Ropivacaine and other Local Anaesthetics in the 20th Century and Beyond. Proceedings of the Combined ANZCA/ASA Continuing Education Seminars, New Drugs- New Techniques - New Challenges, in press, 1995.
2. Feldman H, Covino B. Comparative Motor-blocking Effects of Bupivacaine and Ropivacaine, a New Amino Amide Local Anesthetic, in the rat and dog. Anesth & Analg 67:1047,1988.
3. Arthur G, Feldman H, Covino B. Comparative Pharmacokinetics of Bupivacaine and Ropivacaine, a New Amide Local Anesthetic. Anesth & Analg 67:1053, 1988.
4. Cederholm I, Evers H, Lofstrom J. Skin Blood Flow after Intradermal Injection of Ropivacaine in Various Concentrations with and without Epinephrine Evaluated by Laser Doppler Flowmetry. Reg Anesth 17:322,1992.
5. Gatt S, Crooke D, Anderson A, Lockley S. Pain Relief and Sensory and Motor Block in Mothers receiving Epidural Ropivacaine 0.25% and Bupivacaine 0.25% for Analgesia in Labour - a Double Blind, Parallel, Randomised Comparison of Efficacy. Acta Anaesth Scand, in press, 1995.
6. Kopacz D, Emanuelsson B, Thompson G, Carpenter R, Stephenson C. Pharmacokinetics of Ropivacaine and Bupivacaine for Bilateral Intercostal Blockade in Healthy Male Volunteers. Anesthesiology 81:1139, 1994.
7. Zaric D, Axelson K, Philipson L, Nydahl P, Larsson P, Jansson J, Leissner P. Blockade of the Abdominal Muscles Measured by EMG during Lumbar Epidural Analgesia with Ropivacaine - a Double Blind Study. Acta Anaesth Scand 37,1993.
8. Rosenberg P, Kytta J, Alila A. Absorption of Bupivacaine, Etidocaine, Lignocaine and Ropivacaine into n-Heptane, Rat Sciatic Nerve and Human Extradural and Subdural Fat. BJA 58:310, 1986.
9. Lee A, Fagan D, Lamont M, Tucker G, Halldin M, Scott D. Disposition Kinetics of Ropivacaine in Humans. Anesth & Analg 69:736, 1989.
10. Oda Y, Furuichi K, Tanaka K, Hiroi T, Imaoka S, Asada A, Fujimori M, Funae Y. Metabolism of a New Local Anesthetic, Ropivacaine, by Human Hepatic Cytochrome P450. Anesthesiology 82:214, 1995.
11. McCaughey W. Adverse Effects of Local Anaesthetics. Drug Safety 7:178, 1992.
12. Scott D, Lee A, Fagan D, Bowler G, Bloomfield P, Lundh R. Acute Toxiclty of Ropivacaine Compared with that of Bupivacaine. Anesth & Analg 69:563, 1989.
13. Morishima H, Pedersen H, Finster M, Hiraoka H, Tsuji A, Feldman H, Arthur R, Covino B. Bupivacaine Toxicity in Pregnant and Non-pregnant Ewes. Anesthesiology 63:134, 1985.
14. Santos A, Pedersen H, Moroshima H, Finster M, Arthur G. Pharmacokinetics of Ropivacaine in Nonpregnant and Pregnant Ewes. Anesthesiology 69:A432, 1988.
19. Santos AC; Arthur GR; Pedersen H; Morishima HO; Finster M; Covino BG Systemic toxicity of ropivacaine during ovine pregnancy. Anesthesiology 1991 Jul;75(1):137-41
15. Kerkkamp H, Gielen M. Cardiovascular Effects of Epidural Local Anaesthetics. Comparison of 0.75% bupivacaine and 0.75% ropivacaine, both with adrenaline. Anaesthesia 46:361-5, 1991.
16. Rutten A, Nancarrow C, Mather L, Illsley A, Runciman W, Upton R. Hemodynamic and Central Nervous System Effects of Intravenous Bolus Doses of Lidocaine, Bupivacaine and Ropivacaine in Sheep. Anesth & Analg 69:291,1989.
17. Gatt S, Crooke D, Lockley S, Anderson A, Armstrong P, Alley L. A Double Blind, Randomised, Parallel Investigation into the Neurobehavioural Status and Outcome of Infants Born Vaginally to Mothers Receiving Epidural Ropivacaine 0.25% and Bupivacaine 0.25% for Analgesia in Labour. Anaes Int Care, in press, 1995.
18. Stienstra R, Jonker T, Bourdrez P, Kuijpers J, vanKleef J, Lundberg U. Ropivacaine 0.25% versus Bupivacaine 0.25% for Continuous Epidural Analgesia in Labor: a Double Blind Comparison. Anesth & Analg 80:285, 1995.