Local Anesthetics: Pharmacology and Toxicity

The development of safe and effective local anesthetic agents has possibly been 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. 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. This introductory article provides a brief update of the clinical pharmacology of local anesthetic agents and formulations used in dentistry at present.

The 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.

Box 1

  • 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

Characteristics of an ideal local anesthetic

This issue of Dental Clinics of North America updates the advancements in local anesthesia therapeutics currently available in dentistry and provides an insight into a wide range of concerns related to the agents used for local anesthesia. This introductory article provides a brief update of the clinical pharmacology of local anesthetic agents and formulations used in dentistry at present. Following this update, a review of the dosing strategies 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 local anesthetic 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.

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

Variations in the clinical characteristics of the local anesthetic agents can be attributed 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. Conversely, only the charged form can dissolve in water and diffuse through extracellular fluid and intracellular cytoplasm. Therefore, an agent’s pKa is the most important factor in determining its diffusion properties and subsequently, the rate of onset. Procaine, with a pKa of 8.9, is 98% ionized at a normal tissue pH of 7.4. After procaine injection, most of the molecules exist in its charged state at normal pH and is therefore unable to cross cell membranes. The onset of anesthesia using procaine and other ester local anesthetics is thus unacceptably prolonged. Amide anesthetics having pKa values in the range of 7.6 to 8.0 have less of the drug in an ionized state, diffuse through tissue more readily, and have acceptably rapid onset times.

The lipid solubility characteristics of a local anesthetic best predict its potency. Procaine is one of the least lipid-soluble and least potent local anesthetics, whereas bupivacaine is highly lipid soluble and most potent. Protein binding characteristics are a primary determinant of the duration of anesthesia. Agents that attach to protein components of nerve membranes are less likely to diffuse from the site of action and enter the systemic circulation. Lidocaine’s short duration and bupivacaine’s long duration of action are due, in part, to their distinctly different protein binding characteristics.

It is clear that lipid solubility, ionization, and protein binding properties contribute to the clinical characteristics of local anesthetics. However, factors such as the site of injection, drug and vasoconstrictor concentration, volume of injection, and inherent vasodilating properties of the anesthetic also influence the clinical performance of a local anesthetic.

Local Anesthetics: Current Practice

Because anesthesia induced using ester anesthetics is less effective than with amides, and because ester anesthetics have a higher incidence of allergic reactions, dental anesthetic formulations containing ester agents are no longer marketed. Lidocaine remains the predominant local anesthetic agent used in the United States. In Canada, formulations of articaine have surpassed lidocaine in popularity, thus becoming the most frequently used dental anesthetic. A survey of US oral surgeons regarding their preferences for local anesthetic agents found bupivacaine, a long-acting local anesthetic, to be commonly administered to manage postoperative pain. Formulations used by less than 2% of the surveyed oral surgery practitioners included mepivacaine with 1:20,000 levonordefrin (Neo-Cobefrin), lidocaine with 1:50,000 epinephrine, 3% mepivacaine plain, and 4% prilocaine plain ( Table 2 ).

Table 2
Local anesthetics administered for third molar extraction
Local Anesthetic Formulation Frequency (%)
2% Lidocaine, 1:100,000 epinephrine 70.4
0.5% Bupivacaine, 1:200,000 epinephrine 11.3
4% Articaine, 1:100,000 epinephrine 7.3
4% Prilocaine, 1:200,000 epinephrine 3.1
2% Mepivacaine, 1:20,000 levonordefrin 1.9
2% Lidocaine, 1:50,000 epinephrine 1.8
3% Mepivacaine 0.7
4% Prilocaine 0.2

Until 1989, a combination of ester anesthetics, procaine and propoxycaine, was available in dental cartridges. This formulation was a combination of 0.4% propoxycaine (Ravocaine) and 2% procaine (Novocain) with 1:20,000 levonordefrin as a vasoconstrictor. As stated earlier, ester anesthetics are generally less effective than amides because they have poor diffusion properties. Procaine is a potent vasodilator and is not effective if used without a vasoconstrictor. The metabolism of esters is through hydrolysis by the plasma and tissue esterases, yielding para-aminobenzoic acid (PABA) and diethylamino alcohol. PABA seems to be the allergen associated with procaine’s significant allergenicity. The concern regarding patient reporting of allergy to local anesthetics is addressed in an accompanying article by Speca and colleagues elsewhere in this issue.

Lidocaine hydrochloride

Lidocaine was introduced into practice in the 1950s and, because of its excellent efficacy and safety, has become the prototypic dental local anesthetic in North America. Besides having excellent anesthetic efficacy, lidocaine has limited allergenicity, with fewer than 20 confirmed cases of serious allergic anaphylactic reactions (ie, anaphylactoid) reported in the last 50 years. Given the frequent use of local anesthesia in dentistry (500,000–1,000,000 injections a day throughout the United States and Canada), the rare incidence of serious life-threatening hypersensitivity reactions associated with lidocaine is an extremely important clinical advantage.

Lidocaine is formulated in cartridges as 2% lidocaine with 1:50,000 epinephrine, 2% lidocaine with 1:100,000 epinephrine, and 2% lidocaine plain. The 2% lidocaine with 1:100,000 epinephrine formulation is considered the gold standard when evaluating the efficacy and safety of newer anesthetics.

Mepivacaine hydrochloride

Mepivacaine has an important role in dental anesthesia because it has minimal vasodilating properties and can therefore provide profound local anesthesia without being formulated with a vasoconstrictor such as epinephrine or levonordefrin (see Table 1 ). The availability of a 3% mepivacaine formulation without a vasoconstrictor is a valuable addition to a dentist’s armamentarium. It is available in dental cartridges as 3% mepivacaine plain or 2% mepivacaine with 1:20,000 levonordefrin.

Mepivacaine plain is often reported to have a shorter duration of soft tissue anesthesia, making it potentially useful in pediatric dentistry in which children are known to chew their lips after dental procedures. However, one investigation suggests that although pulpal durations of mepivacaine plain are shorter than that of 2% lidocaine with epinephrine, duration of soft tissue anesthesia for mepivacaine and lidocaine with epinephrine are nearly identical.

Alternatively, shortening of the duration of soft tissue anesthesia after completion of a dental procedure has been shown using the α-adrenergic receptor antagonist phentolamine. Local anesthesia reversal, a recent advancement in dental anesthesia therapeutics, is addressed in an article by Hersh and Lindemyer elsewhere in this issue.

Prilocaine hydrochloride

Prilocaine, like mepivacaine, is not a potent vasodilator and can provide excellent oral anesthesia with or without a vasoconstrictor. It is available in preparations of 4% prilocaine plain and 4% prilocaine with 1:200,000 epinephrine. The formulation containing epinephrine has anesthetic characteristics similar to 2% lidocaine with 1:100,000 epinephrine. The 4% prilocaine plain formulation provides a slightly shorter duration of surgical anesthesia. Prilocaine plain solution in dental cartridges has a somewhat less acidic pH. Although not confirmed by clinical trials, there is some indication that prilocaine causes less discomfort on injection.

One 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. Consequently, articaine has the shortest metabolic half-life (estimated to be between 27–42 minutes) of the anesthetics available in dentistry. Formulations containing 4% articaine 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. The relative efficacy of lidocaine and articaine formulations 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 infiltration in the mandible. The efficacy of articaine to provide mandibular pulpal anesthesia 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. The molecular structure of bupivacaine (1-butyl-2’,6’-pipecoloxylidide) is identical to mepivacaine 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 structures of mepivacaine provides enhanced lipid solubility and protein binding properties.

Although bupivacaine may provide adequate surgical anesthesia, it is most useful for postoperative pain management. 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 bupivacaine include epinephrine.

A combination strategy for managing postoperative pain using a nonsteroidal antiinflammatory drug before surgery and a long-acting anesthetic may provide maximum patient comfort. The management of postoperative and chronic pain using long-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 hypersensitivity 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 diagnosis and treatment. A critical review of acquired methemoglobinemia is provided in an article by Trapp and Will elsewhere in this issue. Significant cardiovascular stimulation 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 threatening 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 relatively 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. 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). 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. 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 to local anesthetics are most frequently reported in pediatric patients. A typical case report of a local anesthetic toxicity reaction in pediatric dentistry is as follows:

A healthy five-year-old female patient, weighing 36 lb. was scheduled for multiple extractions. The child received N2O/O2 sedation via a nasal mask, followed by maxillary and mandibular injections of five cartridges of 3% mepivacaine (270 mg). Ten minutes later the child experienced “stiffening and shaking” of all extremities that lasted ten seconds. Two more convulsive episodes occurred and cardiopulmonary arrest ensued. Transport to a local hospital and resuscitation measures were unsuccessful. Death occurred four days later.

Table 3
MRDs of injectable local anesthetics
(Brand Name)
Concentration of Local Anesthetic Concentration of epi/levo Maximum Dosing Maximum Number of Cartridges
mg/mL a mg/cartridge b mg/cartridge c Adult MRD (mg) MRD/Ib d (mg/lb) Adults e 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 0.018 e 500 3.3 6.9 2.3 1.1
4% Articaine, 1:200,000 epi 40 72 0.009 e 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
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Oct 29, 2016 | Posted by in General Dentistry | Comments Off on Local Anesthetics: Pharmacology and Toxicity
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