Current Topics in Medicinal Chemistry - Volume 1, Issue 3, 2001

In 1850, about three centuries after the conquest of Peru by Pizzaro, the Austrian von Scherzer brought a sufficient quantum of coca leaves to Europe to permit the isolation of cocaine. As suggested by his friend Sigmund Freud, descriptions of the properties of the coca prompted the Austrian Koller to perform in 1884 the first clinical operation under local anesthesia, by administration of cocaine on the eye. The use of cocaine for local and regional anesthesia rapidly spread throughout Europe and America. The toxic effects of cocaine were soon identified resulting in many deaths among both patients and addicted medical staff. Local anesthesia was in a profound crisis until the development of modern organic chemistry which led to the synthesis of pure cocaine in 1891. New amino ester local anesthetics were synthesized between 1891 and 1930, such as tropocaine, eucaine, holocaine, orthoform, benzocaine, and tetracaine. In addition, amino amide local anesthetics were prepared between 1898 and 1972 including nirvaquine, procaine, chloroprocaine, cinchocaine, lidocaine, mepivacaine, prilocaine, efocaine, bupivacaine, etidocaine, and articaine. All of these drugs were ostensibly less toxic than cocaine, but they had differing amounts of central nervous system (CNS) and cardiovascular (CV) toxicity. Bupivacaine is of special interest because of its long duration of action and history of clinical application. Synthesized in 1957, the introduction of bupivacaine on the market in 1965 paralleled the progressive and cumulative reports of CNS and CV toxicity, leading to the restriction of its use and the identification of a special therapy-resistant CV toxicity. Numerous experimental studies were conducted to identify the fine cellular mechanism of this toxicity, which refines our understanding of the action of local anesthetics. The identification of optically active isomers of the mepivacaine family led to the selection of ropivacaine, a pure S-(-) enantiomer, whose toxicology was selectively and extensively studied before its introduction on the market in 1996. During the rapid and extensive use of ropivacaine in the clinic, unwanted side effects have been found to be very limited

Increasing insight into the mechanisms of perioperative physiologic responses and the resultant effects on patient outcome suggests that some responses may be detrimental to long-term recovery. Thus, initial belief in the adaptive wisdom of the body [1] has been supplanted by the concept that a stress-free perioperative period may minimize detrimental physiologic responses and resultant morbidity [2]. The perioperative use of neuraxial- or regional anesthesia and analgesia have profound inhibitory effects on the bodys response to surgery compared to the same operation performed during general anesthesia alone. Increasing evidence has emerged suggesting that such afferent nociceptive blockade may improve a variety of postoperative morbidity parameters and improve surgical outcome. We review the clinical evidence from studies examining the effects of regional anesthesia and analgesia on postoperative morbidity in specific physiologic systems.

alpha2-Adrenergic receptor agonists are analgesic agents, and the alpha2-adrenergic agonist clonidine has been used in clinical studies for regional analgesia after intrathecal administration. We review here recent developments concerning the structure activity relationships of a new class of potent alpha2-adrenergic agonists and their use as analgesic agents. The effect of structure upon cardiovascular side effects is also monitored, such as the prolongation of the QT portion of the cardiac action potential.

Neural damage is a possible consequence of general anesthesia, central nervous system blockade, and regional anesthesia. Damage may be caused by ischaemic and mechanical or chemical factors, which may occur either alone or in combination. Neural damage may be secondary to prolonged and severe arterial hypotension compromising blood supply to the cord, a spinal haematoma whose main etiological factor is a coagulation abnormality, an intraneural injection, and peripheral neuropathy related to perioperative positioning. Mechanical trauma by the needle bevel is an important factor contributing to neuropathy. Neurological complications may also result from a direct neurotoxic effect of local anesthetic agents, which is concentration and dose-dependent. A better understanding of these mechanisms will provide a reliable basis for the development of improved pharmaceutical therapy.

The use of single stereoisomers are gaining popularity in the world of anesthesiology. The reduced costs of production have made these compounds available for clinical application. The majority of drugs used in anesthesiology such as ketamine, isoflurane, etomidate, atracurium, bupivacaine and ropivacaine have an asymmetric carbon, and are still used primarily as racemic mixtures (1:1 mixture of R and S enantiomers). Among local anesthetics, the S enantiomers often have favorable biological properties. This insight has led to the development of ropivacaine. Ropivacaine is the first local anesthetic marketed as pure S-(-) enantiomer. Its pharmacodynamic and pharmacokinetic profile is similar to that of bupivacaine, but in vitro and in vivo studies have shown that ropivacaine is less cardiotoxic. Clinical data suggests that ropivacaine has a greater margin of safety than bupivacaine, which is necessary for further expanding the application of regional anesthesia. The time has come for the use of single enantiomers in regional and general anesthesia

Central and regional block procedures have a well-defined role as safe and effective methods in modern anesthesia and analgesia with long-acting local anesthetics. Recent studies have shown that the incidence of intoxication by these drugs is a rare but catastrophic event. As classic neuronal sodium channel inhibitors, local anesthetics block peripheral fast voltage-gated sodium channels on neuronal axons, and these drugs have a particularly high level of activity in the CNS and the cardiovascular system. CNS-toxicity follows a two-stage process, whereby at lower concentrations inhibitory neurons are blocked first resulting in generalized convulsions, and at higher concentrations a global CNS depression can be seen. Although seizures are an impressive clinical syndrome, they can often be treated safely without permanent damage. More important is the cardiotoxicity of these drugs, which can be divided into indirect cerebrally mediated and a direct myocardial component. Like CNS-toxicity in general, indirect cardiotoxicity demonstrates an initial stimulating effect, followed by a depressive component at higher concentrations. Direct myocardial actions are comprised of negative chronotropic, dromotropic and inotropic effects. For dromotropy, stereoselectivity was found. The S-(-)-isomers of the long-acting local anesthetics were less delayed compared to racemic mixtures and the R-(+)-enantiomers. For inotropy, no stereospecific depression of this parameter was noted between isomers of ropivacaine or bupivacaine, but bupivacaine produced a significantly greater depression of LV pressure than ropivacaine, mepivacaine, or lidocaine. Pharmacokinetic differences in lipophilicity of local anesthetics correlate well with the depression of mitochondrial ATP-synthesis in fast metabolizing cells. Intracellular ATP-level may be involved in contractility and resuscitation of cardiomyocytes, as be proven by in-vitro and in-vivo data. Therefore the use of pure optical S-(-)-isomers of local anesthetics may help to reduce these rare but catastrophic events. Presently, ropivacaine appears to be the safest long-acting local anesthetic.

Ropivacaine is a new long-acting local anesthetic which is a pure (S)-(-)-enantiomer, with an efficacy profile similar to that of bupivacaine. Compared in equal doses, ropivacaine shows more separation between sensory and motor blockade than bupivacaine. Moreover, ropivacaine has a lower systemic toxicity than bupivacaine.In obstetrics, ropivacaine and bupivacaine have been compared for Cesarean section and for epidural pain relief during labor and delivery. For Cesarean section, both drugs provide similar analgesia when given in equal doses, but motor block is less pronounced with ropivacaine. Neonatal outcome as determined by Apgar scores and Neurological Adaptive Capacity Scores (NACS) is also similar. For epidural pain relief during labor and delivery, both drugs are equally effective, either when given alone or in combination with opioids; a meta-analysis of six studies showed that compared to bupivacaine, the use of ropivacaine is associated with significantly less motor block and instrumental deliveries. This clinical profile of ropivacaine presently makes it the local anesthetic of first choice in obstetrics.

Ropivacaine, the S-(-)-enantiomer of N-(2,6-dimethylphenyl)-1-propyl-2-piperidinecarboxamide is a new long-acting local anesthetic. This review demonstrates that it is effective in brachial plexus anesthesia. It is at least as efficient as bupivacaine in terms of quality, duration of analgesia, anesthesia, and motor block. It could have some advantages over bupivacaine in terms of onset time of sensory and motor block, but this remains controversial. In single-shot brachial plexus block, it is equipotent to bupivacaine and has a similar pharmacokinetic profile. Its minimal effective concentration is 0.5percent, and the benefit of increasing its concentration to 0.75 or 1percent remains debatable. Its use during continuous brachial plexus block has been much less studied, and conflicting results involving efficacy during continuous interscalene block and inefficacy during continuous axillary block have been obtained. Further investigations are required to assess its efficacy during such block.Because of lower CNS and cardiac toxicity, ropivacaine is safer than bupivacaine. It would be thus the preferred local anesthetic for brachial plexus blockade when long-lasting anesthesia and analgesia is required.

Ropivacaine is a new amide local anaesthetic, which is the first commercially available in its category as a pure S-(-) enantiomer. In most recent studies [40], ropivacaine exhibited a very close pharmacodynamic profile to equipotent doses of bupivacaine. Concentrations of 0.5percent, 0.75percent and 1percent (5, 7.5 and 10 mg / mL, respectively) ropivacaine are used for intraoperative anaesthesia, while the concentration of 0.2percent (2 mg / mL) is preferred for postoperative analgesia, either alone or in combination with opioids and / or clonidine. Ropivacaine is responsible for excellent postoperative analgesia following epidural and peripheral perineural injections, using single-shot injections and continuous infusions. Differential sensory / motor block is only apparent at low concentrations (0.2percent and less). A significant amount of recent literature focuses on its use for peripheral blocks of the lower limbs, i.e. sciatic and femoral nerve blocks. The primary benefit of ropivacaine is its lower toxicity, mainly lower cardiotoxicity, following accidental intravascular injection. This higher therapeutic index leads to an improved safety profile as compared with potent local anaesthetics such as racemic bupivacaine. For that reason, ropivacaine is a good choice for both intraoperative and postoperative regional anaesthesia and analgesia.