Topical, Local, and Regional Anesthesia and Anesthetics

Mechanism of Action

Local anesthetics block VGSCs, thereby preventing sodium influx into the cell and inhibiting impulse transmission. These agents are also classified as class I antiarrhythmic drugs due to their blockade of cardiac sodium channels, with lidocaine serving as the class IB prototype. They selectively block channels that frequently depolarize, as observed in tachyarrhythmias, thereby slowing transmission.[5]

Local anesthetics function through a sophisticated and complex mechanism primarily involving VGSCs. Recent research has revealed unprecedented details about the molecular-binding sites and conformational changes involved in this process.[6] Anesthetic molecules bind to specific sites within the channel pore, which create a physical and electrochemical blockade that prevents sodium ions from influxing into the neuron.

This blockade occurs in a use-dependent manner, which means that channels that are frequently active (eg, those in rapidly firing neurons or cardiac tissue experiencing tachyarrhythmia) are more susceptible to the blockade. A comprehensive review suggests that this selective targeting helps explain why local anesthetics are effective in treating both pain and cardiac arrhythmias while maintaining a favorable safety profile.[7]

Chemical Classification and Metabolism

Local anesthetics are classified into 2 major chemical families—amino amides and amino esters—each with distinct metabolic pathways. Recent metabolomic studies have shown that amino amides undergo complex hepatic biotransformation involving multiple cytochrome P450 enzymes.[8] Examples of amino amides include bupivacaine, ropivacaine, lidocaine, and mepivacaine. These compounds exhibit remarkable chemical stability in solution, contributing to their longer shelf life and reliability in clinical settings.

A recent study indicates that amino esters undergo rapid hydrolysis by plasma pseudocholinesterases, leading to a faster metabolism, a shorter duration of action, and an increased potential for allergic reactions due to the formation of para-aminobenzoic acid (PABA) metabolites.[9] Recent research has further elucidated the relationship between local anesthetic efficacy and tissue pH.[10] The study demonstrated that local anesthetics exist in both ionized and nonionized forms, but only the nonionized form can penetrate the nerve membrane. Tissue inflammation creates an acidic environment that increases ionization while alkalinizing the solution with sodium bicarbonate can enhance efficacy by increasing the nonionized fraction.

Recent clinical trials have provided new insights into epinephrine's role as a local anesthetic adjuvant to amino amide compounds, suggesting the following benefits:

• It reduces systemic absorption through vasoconstriction.
• It may extend the duration of action of some local anesthetics by up to 50% to 100%.
• It improves surgical field visualization.
• It allows for dose reduction of the primary anesthetic.[11]

However, several important considerations regarding epinephrine must be taken into account, as mentioned below.

• The optimal concentration should not exceed 1:100,000.
• It is contraindicated in certain anatomical locations (eg, nose, ears, digits, and penis).
• It requires careful consideration in patients with cardiovascular disease.
• It may affect tissue perfusion in reconstructive procedures.

Clinical Applications and Safety

Modern imaging techniques have revolutionized the understanding of local anesthetic spread and distribution. A multicenter study demonstrated that ultrasound-guided techniques have significantly improved the safety profile of neuraxial anesthesia by:

• Enabling precise visualization of anatomical structures.
• Allowing real-time monitoring of local anesthetic spread.
• Reducing the required volume of local anesthetics.
• Minimizing the risk of intravascular injection.[12]

Emerging research in this field is focused on novel delivery systems and safety enhancements. A recent in vitro study described the development of pH-responsive local anesthetic formulations that automatically adjust their release based on tissue conditions, potentially revolutionizing their clinical applications if translatable in vivo.[13] This improved understanding of local anesthetic pharmacology continues to enhance patient care and safety in both surgical and pain management settings. The field remains dynamic, with ongoing research aimed at developing more targeted and efficient delivery systems while minimizing potential adverse effects.

Administration

Local anesthetics can be applied topically or subcutaneously to anesthetize local tissues. Topical applications of certain agents, such as viscous lidocaine, include oral ingestion through swishing and spitting, as well as gargling and swallowing for pharyngeal anesthesia. Oral applications can also involve agents, such as benzocaine, which can be applied to the gums or used for treating aphthous stomatitis. These local anesthetics can be administered around peripheral nerves and in the neuraxial space to anesthetize larger nerves or specific dermatomal areas. Additionally, lidocaine can be administered via the IV route to provide surgical anesthesia for an extremity (eg, in a Bier block) or as a cardiac antiarrhythmic.[14][15]

Adverse Effects

Local anesthetics carry a significant risk of systemic toxicity when excessive doses are administered intramuscularly or orally or when typical doses are absorbed more rapidly than expected through intravascular uptake. Once intravascular uptake occurs, redistribution to toxicity-sensitive organs (ie, the brain and heart) leads to the clinical signs of local anesthetic systemic toxicity (LAST). Symptoms typically manifest in the central nervous system, including metallic taste, auditory changes, circumoral numbness, blurred vision, agitation, and seizures. These are often followed by cardiovascular effects such as hypotension, decreased cardiac contractility, dysrhythmias, complete heart block, and cardiovascular collapse.

Bupivacaine is particularly cardiotoxic, with reports of cardiovascular collapse occurring without preceding neurological symptoms. Lipid emulsion therapy is the first-line treatment for LAST (as discussed in more detail below).[16][17] In refractory cases, cardiopulmonary bypass or extracorporeal membrane oxygenation can be effective treatment options.[18][19][20]

Hypersensitivity Reactions

Allergic or hypersensitivity reactions to local anesthetics are rare, with most cases being attributed to the preservative solution rather than the anesthetic itself. Ester-type anesthetics carry a higher risk of allergic reactions compared to amide-based agents. The hypersensitivity response is believed to be caused by PABA—a breakdown product generated by the action of the pseudocholinesterase enzyme. PABA is highly antigenic and can rapidly sensitize lymphocytes, leading to allergic reactions. If a patient experiences a hypersensitivity reaction to an ester-group anesthetic, they are likely to be sensitive to others in the same class. In such cases, an amino-group anesthetic is the preferred alternative.

Reactions attributed to local anesthetics are often caused by apprehension, anxiety, or a fear of needles, which can lead to vasovagal responses, panic attacks, or syncopal episodes. Additionally, reports of tachycardia, flushing, or feelings of impending doom following previous local anesthetic injections may be due to the systemic uptake of epinephrine that is used as an additive rather than the local anesthetic itself. As true allergic reactions to local anesthetics are rare and nonallergic reactions can be multifactorial, obtaining a thorough patient history is essential for accurate risk stratification.

Contraindications

Allergic reactions have been reported for both classes of local anesthetics, although crossover sensitivity is rare. Ester-type local anesthetics are metabolized into a PABA-like compound, and anaphylaxis has been documented in some cases. Amide local anesthetics may contain the preservative methylparaben, which has also been associated with severe allergic reactions.

Knowing the class of local anesthetic that caused the reaction is crucial to avoid that class in the future. Certain pathological conditions, such as decreased cardiac output, renal disease, severe hepatic dysfunction, reduced cholinesterase activity, fetal acidosis, and sepsis, can alter the pharmacodynamics and pharmacokinetics of specific local anesthetics. For instance, patients with impaired hepatic function may experience a prolonged duration of action or an increased risk of toxicity with amide anesthetics, whereas those with cholinesterase deficiency may experience prolonged effects from ester anesthetics.[21]

Extremes of age and low muscle mass are not absolute contraindications for local anesthetic administration, but caution is essential in these settings due to the increased risk of toxicity.[16][22] Muscle serves as a primary (toxicity-neutral) storage depot for excessive intravascular local anesthetics, so muscle wasting becomes an independent risk factor for toxicity. This is because, in the absence of adequate muscle storage, the anesthetic can be redistributed to toxicity-sensitive organs, such as the brain and heart.[22]

Monitoring

Although recommended maximum dosages for local anesthetics are widely available, practitioners should always use the lowest dose necessary to achieve the desired effect due to the significant risk of LAST. All local anesthetics are vasodilators, except for cocaine, which acts as a norepinephrine reuptake inhibitor. This potentiates sympathetic stimulation, leading to hypertension and ventricular irritability. 

Toxicity

Local and topical anesthetics are generally safe when administered appropriately and remain confined to the target site, such as a nerve plexus or infiltrated tissue. However, if large amounts of anesthetic enter the systemic circulation, toxicity can occur due to supratherapeutic drug levels.

Patients suspected of having LAST should be treated immediately with a 20% IV lipid emulsion at a dose of 1.5 mL/kg (based on lean body mass) administered over 1 minute, followed by a continuous infusion of 0.25 mL/kg/min.[17][23] The bolus may be repeated up to 2 times if there is refractory cardiovascular compromise. If epinephrine is required due to complete cardiac collapse, the recommended starting dose is less than or equal to 1 µg/kg. If cardiac function returns but the patient remains hypotensive, the lipid emulsion infusion rate may be increased to 0.5 mL/kg/min. The maximum recommended dosage of lipid emulsion is 12 mL/kg over the first 30 minutes, as outlined in the American Society of Regional Anesthesia and Pain Medicine 2017 Consensus Statement.[16][23]

Enhancing Healthcare Team Outcomes

The safe and effective use of local anesthetics depends on seamless coordination among healthcare professionals, with each team member playing a vital role in achieving optimal patient outcomes. Proper administration demands strict adherence to safety protocols, careful dosing considerations, and comprehensive emergency preparedness across the entire care team.

Roles and Responsibilities of the Interprofessional Healthcare Team

The effective use of local anesthetics requires coordinated efforts among various healthcare professionals. Anesthesiologists and nurse anesthetists are crucial in selecting appropriate agents, determining optimal dosages, and managing potential complications. They provide essential guidance and oversight to ensure safe administration practices across the healthcare team. Emergency medicine physicians and surgeons also need a thorough understanding of local anesthetic pharmacology, as they commonly use these agents in both routine and urgent procedures. Their expertise in anatomical considerations and procedure-specific requirements informs the selection and administration of anesthetics.

Primary care clinicians and advanced practice practitioners often administer local anesthetics in outpatient settings. Their responsibilities include patient screening, risk assessment, and proper monitoring during and after administration. Nursing staff play a vital role in patient monitoring, accurate documentation, and early detection of adverse effects. They facilitate communication between the patient and the healthcare team, often identifying complications first. Pharmacists offer critical expertise on drug interactions, contraindications, and the correct storage and handling of local anesthetics. They ensure the selection of appropriate concentrations and advise on maximum safe doses based on patient-specific factors.

Safety Protocols and Risk Mitigation

The healthcare team must implement several critical safety measures. Resuscitation equipment, including a bag-valve mask, emergency medications, airway management tools, emergency treatment checklists, and monitoring devices, should always be readily available. Lipid emulsion is the first-line treatment for LAST; therefore, it must be immediately accessible alongside standard emergency medications whenever local anesthetics are administered. Standardized local anesthetic dosing protocols should consider patient weight, age (with particular attention to reduced muscle mass), concurrent medications, anatomical location, and procedure duration. Clear communication channels are essential for reporting adverse events, requesting emergency assistance, documenting interventions, and coordinating patient care.

Healthcare Team Performance and Patient Outcomes

Regular team training sessions and simulations are crucial for maintaining emergency preparedness and reinforcing proper protocols. These sessions should involve mock emergency scenarios, equipment familiarization, role-specific responsibility reviews, and communication protocol practice. Detailed records should be maintained for preprocedural assessments, medication administration, patient monitoring, and any adverse events or interventions. This documentation supports continuous quality improvement efforts and helps identify opportunities to enhance safety measures.

Effective management of local anesthetic administration depends on flattening traditional hierarchies to ensure all healthcare team members feel empowered to voice concerns and contribute their expertise. Regular team meetings to review procedures, discuss near misses, and update protocols help maintain high standards of care and patient safety. By fostering an environment of open communication, mutual respect, and shared responsibility, interprofessional healthcare team members can optimize the therapeutic benefits of local anesthetics while minimizing the risk of adverse events. This collaborative approach leads to improved patient outcomes and enhanced safety in healthcare delivery.