Advancements in Local Anesthetics: Dentistry's Pharmacology, Toxicity, and Safety, Tesis de Cirugía Dental

¡Descarga Advancements in Local Anesthetics: Dentistry's Pharmacology, Toxicity, and Safety y más Tesis en PDF de Cirugía Dental solo en Docsity! Local Anesthetics: Pharmacology and ToxicityPaul A. Moore, DMD, PhD, MPHa,b,c,*, Elliot V. Hersh, DMD, MS, PhDd,eKEYWORDS
Local anesthetics
Pharmacology
Toxicity reaction
MRDThe development of safe and effective local anesthetic agents has been possibly the most important advancement in dental science to occur in the last century. The agents currently available in dentistry are extremely safe and fulfill most of the characteristics of an ideal local anesthetic (Box 1). These local anesthetic agents can be administered with minimal tissue irritation and with little likelihood of inducing allergic reactions. A variety of agents are available that provide rapid onset and adequate duration of surgical anesthesia. The agents provide anesthesia that is completely reversible, and systemic toxicity is rarely reported. An ideal local anesthetic agent, one that would induce regional analgesia by selectively inhibiting pain pathways without interrupting transmission of other sensory modalities, has not yet been discovered. This issue ofDental Clinics of North America updates the advancements in local anes- thesia therapeutics currently available in dentistry and provides an insight into a wide rangeofconcerns related to theagentsused for local anesthesia. This introductory article providesabrief updateof theclinicalpharmacologyof local anestheticagents and formu- lations used in dentistry at present. Following this update, a review of the dosing strate- gies needed to prevent local anesthetic toxicity reactions is presented. CLINICAL PHARMACOLOGY OF LOCAL ANESTHETICS For the last 20 years, amides are predominantly used in dentistry as local anesthetic agents. Lidocaine and mepivacaine, 2 of the most commonly used amide locala Department of Dental Anesthesiology, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA 15261, USA b University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA c University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA d Department of Oral Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, 240 South 40th Street, Philadelphia, PA 19104-6030, USA e Office of Regulatory Affairs, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA 19104-6030, USA * Corresponding author. Department of Dental Anesthesiology, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA 15261. E-mail address: pam7@pitt.edu Dent Clin N Am 54 (2010) 587–599 doi:10.1016/j.cden.2010.06.015 dental.theclinics.com 0011-8532/10/$ – see front matter
2010 Elsevier Inc. All rights reserved. Box 1 Characteristics of an ideal local anesthetic 1. Administration of the agent is nonirritating 2. The anesthetic has little or no allergenicity 3. A rapid onset and adequate duration of anesthesia 4. Anesthesia is completely reversible 5. Minimal systemic toxicity 6. Anesthesia is selective to nociception (pain) pathways Moore & Hersh588anesthetic agents in dentistry, have a 50-year history of effectiveness and safety in providing regional anesthesia for dental therapies. Practitioners prefer the amide local anesthetic agents to the ester agents (ie, procaine and propoxycaine) because amides produce profound surgical anesthesia more rapidly and reliably, with fewer sensitizing reactions than ester anesthetics. The availability of various dental formulations of amide agents (Table 1) that provide anesthesia of varying duration has dramatically improved patient care, permitting the development of many of the sophisticated surgical outpatient procedures that are now available in dentistry.1 Variations in the clinical characteristics of the local anesthetic agents can be attrib- uted to differences in chemical properties of their molecular structures. An anesthetic’s dissociation constant (pKa) determines the pH at which the drug’s ionized (charged) and nonionized (uncharged) forms are in equal concentrations. This value is critical for effective anesthesia because the uncharged form of a local anesthetic molecule is essential to permit diffusion across lipid nerve sheaths and cell membranes.Table 1 Local anesthetic formulations Anesthetic Agent Brand Names Formulations Available in Dental Cartridges Duration of Anesthesia Articaine Ultracaine, Septocaine, Articadent, Zorcaine 4% Articaine, 1:100,000 epinephrine Medium 4% Articaine, 1:200,000 epinephrine Medium Bupivacaine Marcaine, Vivacaine 0.5% Bupivacaine, 1:200,000 epinephrine Long Lidocaine Xylocaine, Octocaine, Lignospan, Alphacaine 2% Lidocaine, 1:100,000 epinephrine Medium 2% Lidocaine, 1:50,000 epinephrine Medium 2% Lidocaine plain Ultrashort Mepivacaine Carbocaine, Polocaine, Scandonest 3% Mepivacaine plain Short 2% Mepivacaine, 1:20,000 levonordefrin Medium Prilocaine Citanest, Citanest Forte 4% Prilocaine plain Short 4% Prilocaine, 1:200,000 epinephrine Medium Local Anesthetics: Pharmacology and Toxicity 591One of prilocaine’s metabolic products has been associated with the development of methemoglobinemia. Methemoglobinemia has also been reported with overdoses of the topical anesthetic, benzocaine. The significance of this adverse reaction is addressed in an article by Trapp and Will elsewhere in this issue. Articaine hydrochloride Similar to most dental anesthetics available to the dental practitioner, articaine is classified as an amide anesthetic. However, the molecular structure of articaine is somewhat unique, containing a thiophene (sulfur-containing) ring and an ester side chain. As articaine is absorbed from the injection site into the systemic circulation, it is rapidly inactivated via hydrolysis of the ester side chain to articainic acid. Conse- quently, articaine has the shortest metabolic half-life (estimated to be between 27–42 minutes) of the anesthetics available in dentistry.9,10 Formulations containing 4% arti- caine hydrochloride with 1:100,000 epinephrine and 4% articaine with 1:200,000 epinephrine are available in dental cartridges. Studies evaluating mandibular block and maxillary infiltration anesthesia have generally found that onset time, duration, and anesthetic profundity of articaine are comparable to that of 2% lidocaine with 1:100,000 epinephrine.11–16 The relative efficacy of lidocaine and articaine formula- tions is thoroughly reviewed in an article by Paxton and Thome elsewhere in this issue. Articaine does not seem to have a greater allergenicity than other available amide anesthetic agents, probably because the ester metabolite is not the allergen PABA. Reports of toxicity reactions after the use of articaine for dental anesthesia are extremely rare. The rapid inactivation of articaine by plasma esterases may explain the apparent lack of overdose reactions reported after its administration. Articaine and prilocaine have been associated with inferior alveolar and lingual nerve paresthesias. This controversial topic is addressed in an article by Moore and Haas elsewhere in this issue. There is a developing clinical research literature supporting the claim that articaine has superior diffusion properties and that anesthesia can be induced after buccal infil- tration in the mandible. The efficacy of articaine to provide mandibular pulpal anes- thesia after buccal infiltration is critically reviewed in an article by Meechan elsewhere in this issue. Bupivacaine hydrochloride In the last few decades, the long-acting amide local anesthetic bupivacaine has found a place in dentists’ armamentarium. This long-acting agent plays a valuable role in the overall management of surgical postoperative pain associated with dental care.6 The molecular structure of bupivacaine (1-butyl-2’,6’-pipecoloxylidide) is identical to mepi- vacaine except for a butyl (4 carbon) substitution of the methyl (1 carbon) group at the amino terminus of the molecule. The addition of a butyl group to the chemical struc- tures of mepivacaine provides enhanced lipid solubility and protein binding properties.17,18 Although bupivacaine may provide adequate surgical anesthesia, it is most useful for postoperative pain management.19,20 Clinical trials have shown that bupivacaine, having an elevated pKa of 8.1, has a slightly longer onset time than conventional amide anesthetics. Onset times and profundity are optimized when preparations of bupiva- caine include epinephrine.5,21 A combination strategy for managing postoperative pain using a nonsteroidal anti- inflammatory drug before surgery and a long-acting anesthetic may provide maximum patient comfort.22 The management of postoperative and chronic pain using Moore & Hersh592long-acting local anesthetics is the focus of a review article by Gordon and Dionne elsewhere in this issue.TOXICITY REACTIONS ASSOCIATED WITH LOCAL ANESTHESIA A dentist’s ability to safely administer local anesthesia is essential for dental practice. Local anesthetic solutions used in North America for dental anesthesia are formulated with several components: an amide local anesthetic (ester local anesthetic drugs are no longer available in dental cartridges), an adrenergic vasoconstrictor, and a sulfite antioxidant. In susceptible patients, any of these components may induce systemic, dose-dependent, adverse reactions. Although extremely rare, allergic and hypersen- sitivity reactions to local anesthetics and sulfites may occasionally occur (see the article by Speca and colleagues elsewhere in this issue for further exploration of this topic). Signs and symptoms of the various adverse reactions associated with local anesthetics, such as methemoglobinemia, are quite distinctive, permitting rapid diag- nosis and treatment. A critical review of acquired methemoglobinemia is provided in an article by Trapp and Will elsewhere in this issue. Significant cardiovascular stimu- lation can occur after rapid administration of agents containing an adrenergic vasoconstrictor. Serious reactions are extremely infrequent and when treated properly, they are unlikely to result in significant morbidity or mortality. The most serious and life threat- ening of adverse reactions are toxicities caused by relative excessive dosing of the local anesthetic or vasoconstrictor. These reactions are preventable with proper patient assessment and dosage calculations. When the anesthetic agent contained in a dental cartridge diffuses away from the site of injection, it is absorbed into the systemic circulation where it is metabolized and eliminated. The doses needed for local anesthesia in dentistry are usually minimal, and systemic effects after absorption of the drug are quite uncommon. However, if an inadvertent vascular injection occurs, if repeated injections are administered, or if rela- tively excessive volumes are used in pediatric dentistry, then blood levels of a local anesthetic may become significantly elevated. The addition of epinephrine to local anesthetic formulations can significantly reduce the absorption of the anesthetics. Toxicity Reactions to Excessive Local Anesthetic Dose Initially, excitatory reactions to local anesthetic overdose are seen, such as tremors, muscle twitching, shivering, and clonic-tonic convulsions.23–25 These initial excitatory reactions are thought to be disinhibition phenomena resulting from selective blockade of small inhibitory neurons within the limbic system of the central nervous system (CNS).2 Whether this initial excitatory reaction is apparent or not, a generalized CNS depression with symptoms of sedation, drowsiness, lethargy, and life-threatening respiratory depression follows if blood concentrations of the local anesthetic agent continue to increase. With extremely high toxic doses, myocardial excitability and conductivity may also be depressed, particularly with the highly lipid-soluble long- acting local anesthetic bupivacaine.26 Cardiac toxicity to local anesthetic overdose is most often manifested as ectopic cardiac rhythms and bradycardia. With an extreme local anesthetic overdose, cardiac contractility is depressed and peripheral vasodilation occurs, leading to significant hypotension. Compliance with local anesthetic dosing guidelines is the first and most important strategy for preventing this adverse event. Dosing calculations used to avoid systemic reactions to local anesthetics are dependent on the agent administered and the patient’s body weight (Table 3). True dose-dependent toxicity reactions Table 3 MRDs of injectable local anesthetics Agents (Brand Name) Concentration of Local Anesthetic Concentration of epi/levo Maximum Dosing Maximum Number of Cartridges mg/mLa mg/cartridgeb mg/Cartridgec Adult MRD (mg) MRD/Ibd (mg/lb) Adultse 50 lb Child 25 lb Child 2% Lidocaine, 1:100,000 epi 20 36 0.018 500 3.3 13.8 4.6 2.3 2% Lidocaine, 1:50,000 epi 20 36 0.036 500 3.3 13.8 4.6 2.3 2% Lidocaine plain 20 36 — 300 2.0 8.3 2.8 1.4 4% Articaine, 1:100,000 epi 40 72 0.018e 500 3.3 6.9 2.3 1.1 4% Articaine, 1:200,000 epi 40 72 0.009e 500 3.3 6.9 2.3 1.1 3% Mepivacaine 30 54 — 400 2.6 7.4 2.5 1.2 2% Mepivacaine,1:20,000 levo 20 36 0.09 400 2.6 11.1 3.7 1.8 4% Prilocaine 40 72 — 600 4.0 8.3 2.8 1.4 4% Prilocaine, 1:200,000 epi 40 72 0.009 600 4.0 8.3 2.8 1.4 0.5% Bupivacaine,1:200,000 epi 5 9 0.009 90 0.6 10 NR NR All cartridges are assumed to contain approximately 1.8 mL. Abbreviations: epi, epinephrine; levo, levonordefrin; MRD, maximum recommended dose; NR, not recommended. a Calculation for drug concentration. For example, 2% lidocaine solution 5 2 g/100 mL 5 2000 mg/100 ml 5 20 mg/mL. b Calculation of mg/cartridge. For example, 2% lidocaine: 20 mg/mL  1.8 mL/cartridge 5 36 mg/cartridge. c Calculation of mg/cartridge of epinephrine: for example, 1:100,000 5 1 g:100,000 mL 5 1000 mg:100,000 mL 5 0.01 mg/mL. A 1.8-mL cartridge contains 0.018 mg of epi. d Calculation of weight-based MRD: for example, 500 mg for a 150-lb adult 5 500 mg/150 lb 5 3.3 mg/lb. e Calculation of maximum number of cartridges: for example, for lidocaine/epi, the adult MRD for lidocaine/epi is 500 mg; 500 mg/36 mg per cartridge 5 13.8 cartridges. Lo ca l A n e sth e tics: P h a rm a co lo g y a n d To xicity 5 9 3 Table 4 Safe dose for local anesthetics: the Rule of 25a Body Weight in lbs (kg) Number of Anesthetic Cartridges 25 (11.25) 1 50 (22.5) 2 75 (33.75) 3 100 (45) 4 125 (56.25) 5 150 (67.5) 6 a An easily remembered rule for determining a safe dose of dental local anesthetics in children is to use the “Rule of 25”: 1 cartridge of any anesthetic formulation can be administered safely for every 25 lb of the child’s body weight. Moore & Hersh596adequacy), protect the patient from injury, place the patient in supine position, and maintain the airway. If the patient is unconscious and in respiratory arrest, positive pressure oxygen ventilation is essential. Because local anesthesia–induced convul- sions are usually transient, administration of an anticonvulsant, such as intravenous diazepam, 5 to 10 mg, is rarely required. Toxicity Reactions to Excessive Vasoconstrictors Dose Epinephrine and levonordefrin are the 2 catecholamine vasoconstrictors formulated with local anesthetic agents in dental cartridges. As shown in Fig. 1, the use of a vaso- constrictor can improve the safety of the formulation by slowing the systemic absorp- tion of the local anesthetic and decreasing the peak blood levels of the anesthetic. There is minimal stimulation of the cardiovascular system after submucosal injection of 1 or 2 cartridges of anesthetic containing epinephrine or levonordefrin. However, when excessive amounts of these adrenergic vasoconstrictors are administered, or when the agents are inadvertently administered intravascularly, cardiovascular stimu- lation, with clinically significant increases in blood pressure and heart rate, can occur. For example, the administration of 7 cartridges of 4% articaine with 1:100,000 epinephrine has been found to increase the heart rate on an average by 9 beats per minute (bpm) (from 69 to 78 bpm) and to increase systolic blood pressure by 6 mm Hg (from 125 to 131 mm Hg).10 The small amount of epinephrine in a dental cartridge was once thought to be inca- pable of significantly increasing epinephrine blood levels after local anesthetic admin- istration. Most of the cardiovascular stimulation reported after local anesthesia administration was thought to be due to patient fear and anxiety or the pain of injec- tion. However, studies have found that the epinephrine in as little as 2 cartridges of 1:100,000 formulations can significantly increase circulating epinephrine levels. Lipp and colleagues33 administered 2 mL of 4% articaine containing tritium-labeled epinephrine (1:100,000) to determine the extent to which the increase in total epineph- rine plasma levels was due to the administered tritium-labeled epinephrine. With submucosal injections (16 subjects), the total epinephrine levels increased from a baseline level of 200 pg/mL to a peak level of 631 pg/mL at 7 minutes (Fig. 2).The increase in total epinephrine levels was mostly due to the injected tritium-labeled epinephrine. Because of the apparent inadvertent intravascular local anesthetic injec- tions in 4 subjects, a rapid increase in epinephrine levels to a mean peak level of 2645 pg/mL was seen within a minute of their injections. Although this increase was Time (Minutes) 5 10 15 20 25 30 35 40 45 2800 2400 2000 1600 1400 1000 800 400 Tritium labeled epinephrine Total epinephrine Intravascular epinephrine 2,645 pg/ml at 30 seconds 631 pg/ml at 7.0 minutes E pi ne ph ri ne P la sm a C on ce nt ra tio ns ( pg /m l ) Epinephrine Plasma Concentrations Fig. 2. Plasma concentrations of epinephrine after the administration of 2 mL of 4% arti- caine containing tritiated epinephrine (1:100,000). Epinephrine levels measured in the 4 patients who inadvertently received intravascular injections are shown (dotted line). Triti- ated epinephrine levels (dashed line) and total epinephrine concentrations (solid line) rep- resenting subjects receiving submucosal injections are also shown. (From Lipp M, Dick W, Daubländer M, et al. Exogenous and endogenous plasma levels of epinephrine during dental treatment under local anesthesia. Reg Anesth 1993;18(1):6–12; with permission.) Local Anesthetics: Pharmacology and Toxicity 597short lived, some of these patients were found to have significant cardiovascular stim- ulation indicated by tachycardia and extrasystoles. It is clear that very large volumes or inadvertent intravascular injections can produce clinically significant cardiovascular responses. Using anesthetic formulations containing no or limited concentrations of vasoconstrictors, using a slow injection technique, and aspirating carefully and repeatedly are the common recommendations to prevent rapid systemic absorption of epinephrine and levonordefrin. A patient’s medical health history that indicates significant cardiovascular impair- ment may indicate limiting the use of vasoconstrictors. Although vasoconstrictors are rarely contraindicated, the potential stimulation of the cardiovascular system after intravascular injections should guide the dental practitioners to avoid vasoconstrictor- containing formulations if possible. A common recommendation, when a vasocon- strictor is required for a dental treatment and when there is a medical history that suggests a need for caution, is to limit the dose of epinephrine to 0.04 mg.34 This dose reduction can be achieved by limiting the total anesthetics used to one of the following:
One cartridge of an anesthetic containing 1:50,000 epinephrine
Two cartridges of an anesthetic containing 1:100,000 epinephrine
Four cartridges of an anesthetic containing 1:200,000 epinephrine. In addition, practitioners must be alert to drug interactions when using local anes- thetics containing the vasoconstrictors epinephrine and levonordefrin. Earlier reports suggest that vasoconstrictors should be used with caution in patients taking nonse- lective b-adrenoreceptor blockers, tricyclic antidepressants, cocaine, and a-adren- ergic blockers.35 Patients taking nonselective b-adrenergic antagonists such as Moore & Hersh598propranolol may experience exaggerated systemic vasoconstrictive responses to epinephrine or levonordefrin.17 This drug interaction is critically reviewed in article by Hersh and Giannakopoulos elsewhere in this issue. Local anesthetic administration using agents containing vasoconstrictors may also be a concern among patients who are pregnant. A review of this potential risk and treatment recommendations for this special population is presented in another article by Fayans and colleagues elsewhere in this issue.SUMMARY The amide local anesthetic agents currently available in dentistry are extremely safe and effective. The availability of various formulations of lidocaine, mepivacaine, prilo- caine, articaine, and bupivacaine permits a practitioner to select agents that can meet treatment requirements. Many advances in local anesthesia therapeutics and arma- mentarium have become available to the dental practitioner in recent years. Through careful selection of agents and proper adjustment of dosing, most serious adverse reactions associated with dental local anesthetic agents can be prevented.REFERENCES 1. Yagiela J. Injectable and topical local anesthetics. In: ADA/PDR guide to dental therapeutics. 5th edition. Chicago: American Dental Association Publishing Co; 2009. p. 11–3. 2. Covino BG, Vassallo HG. Local anesthetics: mechanisms of action and clinical use. New York: Grune & Stratton; 1976. 3. Moore PA. Manual of local anesthesia in dentistry. 4th edition. Rochester (NY): Eastman-Kodak Co; 1996. 4. Haas DA. An update on local anesthetics in dentistry. J Can Dent Assoc 2002;68 (9):546–51. 5. Moore PA. Bupivaciane: a long-lasting local anesthetic for dentistry. Oral Surg 1984;58:369–74. 6. Moore PA, Nahouraii HS, Zovko J, et al. Dental therapeutic practice patterns in the U.S. I: anesthesia and sedation. Gen Dent 2006;54(2):92–8. 7. Hersh EV, Hermann DG, Lamp CL, et al. Temporal assessment of soft tissue anesthesia following mandibular block injection. J Am Dent Assoc 1995;126: 1531–5. 8. Wahl MJ, Overton D, Howell J, et al. Pain on injection of prilocaine plain vs. lido- caine with epinephrine: a prospective double-blind study. J Am Dent Assoc 2001; 132:1396–401. 9. Oertel R, Rahn R, Kirch W. Clinical pharmacokinetics of articaine. Clin Pharmaco- kin 1997;33(6):417–25. 10. Hersh EV, Giannakopoulos H, Levin LM, et al. The pharmacokinetics and cardio- vascular effects of high-dose articaine with 1:100,000 and 1:200,000 epineph- rine. J Am Dent Assoc 2006;137(11):1562–71. 11. Malamed SF, Gagnon S, Leblanc D. Efficacy of articaine: a new amide local anes- thetic. J Am Dent Assoc 2000;131(5):635–42. 12. Donaldson D, James-Perdok L, Craig BJ, et al. A comparison of Ultracaine DS (articaine HCl) and Citanest forte (prilocaine HCl) in maxillary infiltration and mandibular nerve block. J Can Dent Assoc 1987;53(1):38–42. 13. Lemay H, Albert G, Helie P, et al. Ultracaine in conventional operative dentistry. J Can Dent Assoc 1984;50(9):703–8.