of distribution and a lack of vasodilation, which reduces prilocaine’s toxicity. However, it does have the propensity to cause methemoglobinemia, secondary to metabolism of the aromatic ring to O-toluidine. Methemoglobinemia is a condition in which excessive methemoglobin levels reduce the amount of hemoglobin available for oxygen transport to the tissue, resulting in reduced blood oxygenation. The clinical symptoms include dark blood and greyness or cyanosis of the Etidocaine Etidocaine is a long-acting amide local anesthetic originally introduced in 1972 (Agasti, 2011) by Astra. Its pharmacokinetic properties are characterized by an onset of action similar to that of lidocaine (2 to 4 minutes) and a duration of action (up to 470 minutes) comparable to that of bupivacaine, which will be discussed in the next section. Etidocaine is more lipophilic than lidocaine, which contributes to its higher potency, rapid onset of Bupivacaine Introduced in 1963 (Gadsden, n.d.), bupivacaine has been one of the most commonly used amide local anesthetics (Moore, Nahouraii, Zovko, & Wisniewski, 2006). Bupivacaine is a long- acting agent capable of producing sustained anesthesia and analgesia that can be prolonged even further by the addition of epinephrine. The molecular structure of bupivacaine is identical to mepivacaine except for a four-carbon substitution of the one carbon group at the amino moiety of the molecule. The addition of this butyl group to mepivacaine increases the lipophilic nature and protein binding properties of the drug, such that the effective concentration of bupivacaine for most dental procedures is just 0.5%. Although bupivacaine provides effective local anesthesia, its long duration of action makes it most useful for postoperative pain management. Clinical trials have shown that bupivacaine, having a high pKa of 8.1, and therefore a slightly longer onset time of 5 to 8 minutes, combined with a shorter intraoperative local anesthetic such as lidocaine, results in sustained local anesthesia in patients, when injected close to the end of the dental appointment. Onset time Articaine Articaine is the newest local anesthetic in North America, first introduced in Canada in 1982 but not in the United States until 2000. It has gained much of the market share in North America, while the use of other agents has remained fairly constant (Snoeck, 2012; Malamed, 2021). Articaine’s popularity results in part from its ability to diffuse into bone better than other local anesthetics. This makes it an ideal agent for cases when there is difficulty achieving profound anesthesia with mandibular blocks. Articaine has an onset and duration of action similar to lidocaine but, given its unique chemical structure that includes carboxyl group ester linkage, articaine is metabolized very quickly (Figure 2). Articaine is metabolized rapidly into articainic acid by plasma carboxylesterases with a plasma half-life of 20 minutes (Oertel, Rahn, & Kirch, 1997). Because less than 10% of articaine is metabolized by cytochrome P450 isoenzymes, it is relatively resistant to pharmacokinetic drug interactions (U.S. Food and Drug Administration, 1998). The drug is available as a 4% solution with either 1:100,000 or 1:200,000 epinephrine for vasoconstriction. It has been suggested that this higher drug concentration of articaine is responsible for an increased number of patients with prolonged paresthesias compared to other local anesthetics. However, scientifically sound research and data fail to support this claim (Toma et al., 2015; Hopman, Baart & Brand, 2017). Additionally, a clear causal relationship between anesthetic agent and neurological complications like paresthesia Liposomal bupivacaine More recently there has been an increased interest in a new product utilizing liposomal bupivacaine (Exparel ® ) as a possible therapy to offer very long-acting local anesthesia (up to 96 hours, while helping to reduce reliance on prescribing opioids for post-
lips, mucous membranes, and nail beds. The development of methemoglobinemia is usually seen only when exceeding the maximum recommended dose of prilocaine (8 mg/kg or more), and it does not typically cause significant sequelae in healthy patients. The IV administration of methylene blue (1 to 2 mg/ kg) is the usual treatment. Prilocaine is available as a 4% plain solution or with 1:200,000 epinephrine for vasoconstriction. The drug has an elimination half-life of about 96 minutes. action, and a prolonged duration of local anesthesia. Etidocaine is primarily used as a 1.5% solution with 1:200,000 epinephrine for vasoconstriction. Etidocaine products were removed from the United States market in 2001, not for reasons of safety or effectiveness (Kux, 2012), but because the small market share made the product unprofitable for the manufacturer. and local anesthetic profundity are additionally optimized when preparations of bupivacaine include epinephrine, such that the duration of action can last for up to 440 minutes, beyond the completion of the dental procedure (Laskin, Wallace, & DeLeo, 1977; Trieger & Gillen, 1979; Moore & Dunsky, 1983; Becker & Reed, 2012). With its high lipid solubility, bupivacaine is substantially more cardiotoxic than lidocaine. The cardiotoxicity of bupivacaine is cumulative and considerably greater than would be expected from its local anesthetic potency alone. Part of the cardiotoxicity of bupivacaine can be mediated centrally, as studies have shown that direct injection of bupivacaine into the medulla produces malignant ventricular arrhythmias. Because of its toxicity profile, cumulative doses of bupivacaine beyond 90 mg should be avoided. Bupivacaine is employed most commonly as a 0.5% solution with 1:200,000 epinephrine for vasoconstriction. The drug has an elimination half-life of about 210 minutes. cannot be confirmed from the literature (Yapp, Hopcraft, & Parashos, 2011; Hopman, Baart & Brand, 2017). Based on the clinical research to date, procedural trauma appears to be a valid alternative explanation for these reported neurological complications. The act of administering local anesthetics via nerve blocks can cause damage to the nerves in the region, regardless of which solution is used. Figure 2: Articaine Structure
operative pain management (Lexicomp, 2021). Unfortunately, there are some significant patient safety issues associated with the liposomal formulation of bupivacaine beyond the exorbitant cost (over $200 per injection), compared to commercially
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