# Pharmacology of Local Anesthetics

## Introduction

Local anesthetics are the most frequently used drugs in oral and maxillofacial surgery. A thorough understanding of their pharmacology, mechanism of action, clinical properties, and potential toxicity is essential for safe and effective practice. The OMFS surgeon must be able to select the appropriate agent, calculate maximum dosages, and recognize and manage adverse reactions.

## Mechanism of Action

Local anesthetics produce reversible blockade of neural impulse conduction by inhibiting sodium ion influx through voltage-gated sodium channels. They bind to the intracellular portion of the sodium channel in its inactivated state, blocking the propagation of action potentials along nerve fibers. Small, myelinated fibers (pain and temperature -- A-delta and C fibers) are blocked before large, myelinated fibers (motor -- A-alpha and A-beta), producing the characteristic differential nerve blockade in which pain is blocked before touch, and touch before motor function.

## Chemical Structure

### Two Classes

Ester local anesthetics include procaine, chloroprocaine, tetracaine, and benzocaine. They contain an ester linkage between the aromatic ring and the intermediate chain and are metabolized by plasma pseudocholinesterase through rapid hydrolysis. They carry a higher incidence of allergic reactions due to the PABA metabolite. Amide local anesthetics include lidocaine, mepivacaine, bupivacaine, articaine, prilocaine, and ropivacaine. They contain an amide linkage and are metabolized by hepatic microsomal enzymes. True allergic reactions to amides are extremely rare.

### Structure-Activity Relationships

Three key relationships govern clinical behavior. Lipid solubility determines potency, with higher lipid solubility producing greater potency. Protein binding determines duration of action, with higher protein binding producing longer duration. The pKa determines onset of action, with a pKa closer to physiologic pH producing faster onset.

## Commonly Used Local Anesthetics in OMFS

| Agent | Class | Onset | Duration (with epi) | Max Dose (mg/kg) | Absolute Max | pKa | Key Feature |
|---|---|---|---|---|---|---|---|
| Lidocaine 2% | Amide | 2-3 min | 60-90 min | 4.4 (with epi) | 500 mg (with epi) | 7.7 | Most widely used |
| Articaine 4% | Amide | 1-2 min | 60-75 min | 7.0 | — | 7.8 | Superior mandibular infiltration |
| Mepivacaine 3% (plain) | Amide | 2-3 min | 20-40 min (infilt) | 4.4 | 300 mg | 7.6 | No vasoconstrictor needed |
| Mepivacaine 2% (w/ levo) | Amide | 2-3 min | 60-90 min | 4.4 | 300 mg | 7.6 | Alternative vasoconstrictor |
| Bupivacaine 0.5% | Amide | 5-8 min | 4-12 hr (block) | 1.3 | 90 mg | 8.1 | Prolonged postop analgesia; cardiotoxic |

### Lidocaine (Xylocaine)

Lidocaine is an amide with rapid onset (2-3 minutes) and a duration of 60 to 90 minutes with epinephrine or 30 to 60 minutes without. The maximum dose is 4.4 mg/kg with epinephrine, with an absolute maximum of 300 mg without epinephrine and 500 mg with epinephrine. Its pKa is 7.7. It is the most widely used local anesthetic in dentistry.

### Articaine (Septocaine)

Articaine is an amide with a unique thiophene ring that also contains an ester linkage, allowing dual metabolism. It has a very rapid onset (1-2 minutes) and a duration of 60 to 75 minutes with epinephrine. The maximum dose is 7.0 mg/kg. It demonstrates superior buccal infiltration efficacy in the mandible due to enhanced tissue diffusion. Concerns about increased risk of paresthesia with inferior alveolar nerve blocks have been raised but remain debated.

### Mepivacaine (Carbocaine)

Mepivacaine is an amide with rapid onset (2-3 minutes). The 3% plain formulation provides 20 to 40 minutes of infiltration anesthesia and 40 to 60 minutes of block anesthesia, while the 2% formulation with levonordefrin lasts 60 to 90 minutes. The maximum dose is 4.4 mg/kg with an absolute maximum of 300 mg. The 3% plain formulation is useful when a vasoconstrictor is contraindicated.

### Bupivacaine (Marcaine)

Bupivacaine is an amide with slower onset (5-8 minutes) and a prolonged duration of 4 to 12 hours with epinephrine for nerve blocks. The maximum dose is 1.3 mg/kg with an absolute maximum of 90 mg. It is ideal for prolonged postoperative analgesia following procedures such as third molar surgery and orthognathic surgery. It carries higher cardiotoxicity potential than other amides.

![Chemical structures of lidocaine and articaine illustrating the amide linkage and the thiophene ring unique to articaine](/images/residency/omfs/local-anesthetic-structures.jpg)

## Vasoconstrictors

Epinephrine is the most commonly used vasoconstrictor in dental local anesthetics. Its benefits include prolonging duration, reducing bleeding at the surgical site, slowing systemic absorption (reducing toxicity risk), and providing a more profound block. Common concentrations are 1:100,000 (most common), 1:200,000, and 1:50,000. The maximum dose of epinephrine is 0.2 mg for healthy patients and 0.04 mg for patients with significant cardiovascular disease per AAOMS guidelines. Levonordefrin is used with mepivacaine at a 1:20,000 concentration and has approximately 15% the potency of epinephrine.

## Maximum Dose Calculations

Maximum dose is calculated based on lean body weight in mg/kg, accounting for all local anesthetic administered (infiltration plus blocks). For example, in a 70 kg patient receiving lidocaine 2% with epinephrine, the maximum dose is 7.0 mg/kg multiplied by 70 kg, yielding 490 mg (or 500 mg absolute maximum). Each 1.7 mL cartridge contains 34 mg of lidocaine 2%, so the maximum number of cartridges is approximately 14.

## Local Anesthetic Systemic Toxicity (LAST)

### Signs and Symptoms (Progressive)

Early CNS excitation manifests as circumoral numbness, metallic taste, tinnitus, visual disturbances, dizziness, restlessness, tremors, and seizures. Late CNS depression produces drowsiness, respiratory depression, and coma. Cardiovascular toxicity causes hypotension, bradycardia, arrhythmias, and cardiac arrest. Bupivacaine has a narrow margin between CNS and cardiovascular toxicity, making it more cardiotoxic than other amides.

### Management of LAST

The injection is stopped immediately. The airway is maintained and 100% oxygen administered. Seizures are treated with benzodiazepines (midazolam) or small doses of propofol. The cornerstone of LAST treatment is Intralipid 20% (lipid emulsion therapy) given as a 1.5 mL/kg IV bolus followed by a 0.25 mL/kg/min infusion. ACLS protocols are followed for cardiovascular collapse, but vasopressin, calcium channel blockers, and beta-blockers are avoided. Prolonged CPR may be required, as lipid rescue may take time.

![Flowchart for recognition and management of local anesthetic systemic toxicity including lipid emulsion rescue protocol](/images/residency/omfs/last-management-algorithm.jpg)

## Allergic Reactions

True allergy to amide local anesthetics is exceedingly rare. Most reported "allergies" are vasovagal episodes, anxiety reactions, or responses to epinephrine. Ester local anesthetics (via the PABA metabolite) have higher allergic potential. Methylparaben preservative in multidose vials may also cause allergic reactions. When true allergy is suspected, referral to an allergist for skin testing is appropriate.

![Table summarizing the clinical properties of commonly used local anesthetics including onset, duration, maximum dose, and pKa](/images/residency/omfs/local-anesthetics-comparison-table.jpg)

## Clinical Pearls

The maximum allowable dose should always be calculated before administering local anesthetic, especially in smaller patients and children. Articaine provides superior buccal infiltration in the posterior mandible, potentially reducing the need for inferior alveolar nerve blocks. Bupivacaine offers prolonged postoperative analgesia and is valuable for managing post-surgical pain. Intralipid 20% must be immediately available in any setting where large volumes of local anesthetic are administered. Most reported local anesthetic "allergies" are not true allergies, and thorough history taking is essential.

## References

1. Becker DE, Reed KL. Local anesthetics: review of pharmacological considerations. *Anesth Prog*. 2012;59(2):90-101.
2. Neal JM, Barrington MJ, Fettiplace MR, et al. The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity. *Reg Anesth Pain Med*. 2018;43(2):113-123.
3. Malamed SF. *Handbook of Local Anesthesia*. 7th ed. Elsevier; 2020.
4. Yapp KE, Hopcraft MS, Parashos P. Articaine: a review of the literature. *Br Dent J*. 2011;210(7):323-329.