Lidocaine: A Comprehensive Pharmacological Report

1. Introduction to Lidocaine

1.1. Overview and Historical Context

Lidocaine, also known by its alternative name lignocaine, stands as a cornerstone medication in modern medicine, primarily recognized for its efficacy as an amino amide-type local anesthetic and as a Class Ib antiarrhythmic agent.[1] Its discovery in 1943 by Swedish chemists Nils Löfgren and Bengt Lundqvist, and subsequent introduction to the market around 1948-1949, represented a significant advancement in pharmacology.[2] Compared to its predecessors, such as procaine (Novocain), lidocaine offered a more rapid onset of action, greater potency, and a considerably lower potential for allergic reactions, leading to its swift adoption in clinical practice.[1] The initial brand name for lidocaine was Xylocaine.[5]

The enduring clinical relevance of lidocaine, decades after its introduction, is a testament to its favorable balance of efficacy, safety (when used appropriately), and cost-effectiveness. This is particularly evident when considering its widespread use for fundamental anesthetic needs and specific cardiac arrhythmias, where newer agents have not universally surpassed its utility. This long-standing prominence is further underscored by its consistent inclusion in the World Health Organization's (WHO) List of Essential Medicines, signifying its critical role in basic healthcare systems globally.[1] As an indicator of its continued importance, lidocaine was the 262nd most commonly prescribed medication in the United States in 2022.[2] The early and extensive clinical experience gained under the Xylocaine brand likely established a strong foundation of trust and familiarity among medical practitioners, contributing to its sustained use even after the advent of generic versions.[5] This illustrates how initial market presence and robust branding can significantly influence a drug's long-term therapeutic legacy.

1.2. Drug Identification

Lidocaine is classified as a small molecule drug.[1] Key identifiers include:

• DrugBank ID: DB00281 [1]
• CAS Number (Lidocaine Base): 137-58-6 [10]
• Synonyms: Lignocaine, Xylocaine, 2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide, alpha-diethylamino-2,6-dimethylacetanilide, Lidocaína, Lidocainum.[1]

1.3. Significance

The dual pharmacological actions of lidocaine as both a local anesthetic and an antiarrhythmic agent confer upon it exceptional versatility in clinical settings.[1] It remains a relatively inexpensive generic medication, yet it is prescribed millions of times internationally each year, highlighting its profound impact on medical practice.[1]

2. Chemical and Physicochemical Properties

2.1. Chemical Structure and Nomenclature

Lidocaine is an amino amide derivative. Chemically, it is described as the monocarboxylic acid amide resulting from the formal condensation of N,N-diethylglycine with 2,6-dimethylaniline.[12]

• IUPAC Name: 2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide.[1] (A 2D representation of the chemical structure is typically included in pharmacological profiles).

2.2. Molecular Formula and Weight

• Molecular Formula (Base): C14​H22​N2​O.[1]
• Molecular Weight (Base): Approximately 234.34 g/mol. Specific values reported include 234.3373 g/mol [1] and 234.34 g/mol.[10]

2.3. Physicochemical Properties of Lidocaine Base

The physicochemical characteristics of lidocaine base are crucial for its absorption, distribution, and interaction with biological targets. These properties are summarized in Table 2.1.

Table 2.1: Physicochemical Properties of Lidocaine Base

Property	Value	Source(s)
IUPAC Name	2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide	1
Molecular Formula	C14​H22​N2​O	1
Molecular Weight (g/mol)	~234.34	1
Appearance	White or crystalline colorless solid/powder	10
Melting Point (°C)	66–69	14
Boiling Point (°C)	180-182 (at 4 mmHg); 159-160 (at 2 mmHg)	14
pKa	7.7 - 7.8	3
Solubility in Water	Poorly soluble/Insoluble (base); 4100 mg/L (at 30°C)	14
Solubility in Organic Solvents	Soluble in alcohol, ether, benzene, chloroform, oils	10
LogP (Octanol/Water)	2.1 - 2.84 (experimental/calculated)	9
Hydrogen Bond Acceptors	3	9
Hydrogen Bond Donors	1	9
Rotatable Bonds	6	9
Topological Polar Surface Area	32.34 A˚2	9

The pKa of lidocaine, approximately 7.7 to 7.8, is a pivotal property influencing its clinical behavior.[3] At physiological pH (around 7.4), a significant fraction (approximately 25%) of lidocaine molecules exists in the un-ionized, lipid-soluble form.[1] This characteristic is fundamental to its rapid onset of action, as the un-ionized form readily penetrates the lipid bilayers of nerve membranes. Once inside the more acidic axoplasm, the molecule re-equilibrates, with a greater proportion becoming ionized to interact with the sodium channel. This pKa value, being relatively close to physiological pH, ensures a sufficient concentration of the membrane-permeable species, distinguishing lidocaine from local anesthetics with pKa values further from 7.4, which may have a slower onset. This pH-dependent ionization also explains the observed reduction in lidocaine's efficacy in inflamed or infected tissues, where local acidosis shifts the equilibrium towards the ionized, less permeable form, thereby hindering its access to the intracellular binding site.[1]

The differential solubility of lidocaine base and its hydrochloride salt is another key physicochemical aspect with direct clinical implications. Lidocaine base exhibits poor solubility in water but is soluble in organic solvents and oils.[10] Conversely, lidocaine hydrochloride is very soluble in water.[10] This disparity dictates the formulation strategies for different routes of administration. Aqueous solutions for injection, such as those used for intravenous, epidural, or infiltration anesthesia, invariably utilize the hydrochloride salt to ensure adequate solubility and stability.[3] Topical formulations, however, may utilize the base form or be specifically designed (e.g., as eutectic mixtures or in specialized patches) to optimize penetration across the stratum corneum or mucous membranes. The pH of the formulation is therefore a critical parameter, influencing not only solubility but also the proportion of the active un-ionized form available at the target site.

Lidocaine's moderate lipophilicity, reflected by LogP values generally ranging from 2.1 to 2.84, strikes a crucial balance between the need to penetrate lipid nerve membranes and the avoidance of excessive tissue sequestration or overly prolonged action, which could heighten the risk of systemic toxicity.[9] This lipophilicity is sufficient for effective interaction with sodium channels but is not so extreme as to lead to a very narrow therapeutic window often associated with highly lipophilic drugs. This balance contributes to its characteristic rapid onset and intermediate duration of action, forming a key part of its favorable pharmacokinetic and safety profile when used as directed.[2]

3. Mechanism of Action

Lidocaine's therapeutic effects stem from its ability to modulate voltage-gated sodium channels, although the specific consequences of this interaction differ between its use as a local anesthetic and as an antiarrhythmic agent.

3.1. As a Local Anesthetic

The primary mechanism of lidocaine as a local anesthetic involves the blockade of voltage-gated sodium channels on the neuronal cell membrane.[1] This action is fundamental to its ability to prevent the generation and conduction of nerve impulses, thereby producing a state of localized numbness.

The process begins with the diffusion of the uncharged, lipophilic form of lidocaine across the neural sheath and the lipid bilayer of the nerve cell membrane into the axoplasm.[1] Within the relatively more acidic environment of the axoplasm, lidocaine molecules re-equilibrate, and a proportion becomes protonated, forming the charged cationic species. It is this charged form that interacts with a specific receptor site located on the intracellular aspect of the sodium channel protein.[1] This binding effectively "locks" the sodium channel, predominantly in its open or inactivated states, thereby preventing the influx of sodium ions that is essential for membrane depolarization.[1]

By inhibiting this sodium influx, lidocaine increases the threshold for electrical excitability in the neuron, slows the rate of depolarization, reduces the amplitude of the action potential, and ultimately prevents its propagation along the nerve fiber.[1] This blockade of nerve impulse transmission effectively prevents pain signals from reaching the central nervous system.

Lidocaine exhibits a phenomenon known as use-dependent or frequency-dependent blockade.[26] This means that its blocking effect is more pronounced in neurons that are firing rapidly. This occurs because lidocaine has a higher affinity for sodium channels in their open or inactivated states, which are more frequently occupied during high-frequency neuronal activity. While the precise three-dimensional structure of the lidocaine binding site is complex, studies involving mutagenesis and electrophysiology suggest it is located within the inner pore of the sodium channel, with significant contributions from amino acid residues in the S6 transmembrane segments of domains III and IV of the channel's alpha subunit.[27] Lidocaine's interaction with the channel also appears to involve allosteric coupling to the voltage-sensing domains (S4 segments) in domains III and IV, affecting their movement.[27]

Beyond its primary action on sodium channels, lidocaine has also been noted to possess N-methyl-D-aspartate (NMDA) receptor antagonist properties.[3] This secondary mechanism may contribute to its analgesic effects in certain pain states, particularly those involving neuropathic pain or central sensitization.

3.2. As a Class Ib Antiarrhythmic Agent

Lidocaine's classification as a Class Ib antiarrhythmic agent also stems from its interaction with voltage-gated sodium channels, specifically within cardiac myocytes (e.g., the Nav1.5 isoform).[1]

The electrophysiological consequences of this interaction in the heart include:

1. Effect on Phase 0 Depolarization: Lidocaine reduces the maximal rate of rise (Vmax) of phase 0 of the cardiac action potential. This effect is more pronounced in cardiac cells that are partially depolarized (e.g., in ischemic tissue) or firing at a rapid rate, due to its preference for open or inactivated channels.[3]
2. Action Potential Duration (APD): It characteristically shortens the APD in normal ventricular myocardial cells and Purkinje fibers.[28]
3. Effective Refractory Period (ERP): Lidocaine typically shortens the ERP to a lesser extent than it shortens the APD, or it may prolong the ERP relative to the APD.[22] This differential effect on APD and ERP helps to prevent the re-entry phenomena that can sustain certain arrhythmias. Some sources explicitly state it increases the refractory period.[28]
4. Automaticity: Lidocaine suppresses abnormal automaticity, particularly in ectopic pacemaker sites, by decreasing the slope of phase 4 diastolic depolarization.[28]

Lidocaine exhibits rapid association and dissociation kinetics with cardiac sodium channels, binding preferentially to channels in the inactivated state and, to a lesser extent, the open state.[28] This "fast-in, fast-out" characteristic is particularly relevant in ischemic myocardium, where cells tend to have a more depolarized resting membrane potential and prolonged action potentials, resulting in a greater proportion of sodium channels residing in the inactivated state. This state-dependent binding allows lidocaine to selectively target arrhythmic tissue while exerting less effect on normally functioning cardiac tissue at therapeutic concentrations, contributing to a relatively favorable therapeutic window for its antiarrhythmic actions.

Overall, these electrophysiological modifications enable lidocaine to suppress ventricular tachyarrhythmias, especially those associated with myocardial infarction or cardiac surgery, by interrupting re-entrant circuits and diminishing ectopic pacemaker activity.[1] It also acts to increase the ventricular fibrillation threshold.[28] The fundamental action of blocking sodium channels thus underlies both its local anesthetic and antiarrhythmic effects, with the differing outcomes arising from the specific tissue targeted and the distinct electrophysiological roles of these channels in neurons versus cardiomyocytes. This shared mechanism also means that systemic absorption of lidocaine administered for local anesthesia can lead to cardiac and CNS effects, which forms the basis for concerns about systemic toxicity.

4. Pharmacokinetics

The pharmacokinetic profile of lidocaine, encompassing its absorption, distribution, metabolism, and excretion (ADME), is critical to understanding its clinical use, efficacy, and potential for toxicity.

4.1. Absorption

Lidocaine's absorption is highly dependent on the route of administration, the specific formulation, the vascularity of the application or injection site, and the presence of vasoconstrictors like epinephrine, which can decrease the rate of systemic absorption and prolong the local duration of action.[1]

• Topical and Mucosal Administration: Lidocaine is readily absorbed across mucous membranes (e.g., oral, pharyngeal, tracheobronchial) and damaged or inflamed skin.[1] Absorption through intact skin is generally poor unless specialized formulations are employed, such as eutectic mixtures (e.g., EMLA cream) or transdermal patches (e.g., Lidoderm 5% patch) designed to enhance penetration.[42] For instance, peak blood levels following endotracheal administration of a 4% lidocaine solution can be observed within 5 to 30 minutes.[39]
• Parenteral Administration: Lidocaine is completely absorbed following parenteral injection. The rate of absorption, however, varies with the injection site, reflecting differences in tissue vascularity. Systemic absorption is generally greatest after intercostal nerve blocks, followed in decreasing order by caudal/epidural blocks, brachial plexus blocks, and subcutaneous or intramuscular injections.[1] An intravenous (IV) bolus results in very rapid attainment of systemic levels [3], while intramuscular (IM) injection typically leads to an onset of systemic effects in about 15 minutes.[1]
• Oral Administration: Although well-absorbed from the gastrointestinal tract, lidocaine undergoes extensive first-pass hepatic metabolism, resulting in a low oral bioavailability of approximately 35%.[1] This makes the oral route unsuitable for achieving systemic therapeutic concentrations.

4.2. Distribution

Once absorbed into the systemic circulation, lidocaine distributes rapidly and extensively throughout the body.

• Tissue Distribution: It initially distributes to highly perfused organs such as the brain, heart, liver, and kidneys, followed by slower distribution into tissues with lower blood flow, including skeletal muscle and adipose tissue.[1] Due to its large mass, skeletal muscle accounts for the highest percentage of distributed drug, rather than specific affinity.[1]
• Volume of Distribution (Vd): The apparent volume of distribution for lidocaine is reported to be in the range of 0.7 to 1.5 L/kg.[1] Its pharmacokinetics are often described by a two- or even three-compartment model. This model includes a rapid initial distribution phase (alpha phase, with a half-life of approximately 8 minutes) representing uptake by rapidly equilibrating, highly perfused tissues, and one or more slower phases (beta and sometimes gamma phases) reflecting distribution to more slowly equilibrating tissues and subsequent elimination.[1] This compartmental behavior is clinically significant, particularly for IV antiarrhythmic dosing, as it explains why loading doses are necessary to quickly achieve therapeutic concentrations in the central compartment, followed by maintenance infusions to counteract elimination and maintain steady-state levels.
• Plasma Protein Binding: Lidocaine is approximately 60% to 80% bound to plasma proteins.[1] The primary binding protein is alpha-1-acid glycoprotein (AAG), with albumin contributing to a lesser extent.[1] This binding is concentration-dependent, meaning the fraction of bound drug decreases as the total lidocaine concentration increases.[22] The levels of AAG can vary significantly in different physiological and pathological states (e.g., inflammation, post-surgery, myocardial infarction, cancer), which can lead to inter-individual variability in the free (pharmacologically active) fraction of lidocaine. This variability can impact both efficacy and the risk of toxicity, as higher AAG levels may decrease the free fraction, potentially reducing efficacy, while lower AAG levels can increase the free fraction, raising toxicity risk at standard total drug concentrations.
• Barrier Penetration: Lidocaine readily crosses the blood-brain barrier and the placental barrier, likely via passive diffusion.[1]

4.3. Metabolism

Lidocaine is extensively and rapidly metabolized, primarily in the liver.

• Primary Site: Approximately 90% of an administered dose of lidocaine undergoes biotransformation in the liver.[1]
• Enzymatic Pathways: The main cytochrome P450 (CYP) isoenzymes responsible for lidocaine metabolism are CYP1A2 and CYP3A4.[3] Some involvement of CYP2B6 and CYP2D6 has also been suggested, and lidocaine itself can inhibit CYP1A2.[3]
• Metabolic Reactions: Key metabolic pathways include oxidative N-dealkylation (or N-deethylation), ring hydroxylation, cleavage of the amide linkage, and subsequent conjugation.[1]
• Active Metabolites:
• Monoethylglycinexylidide (MEGX): This is a major active metabolite formed through N-deethylation. MEGX possesses both antiarrhythmic and convulsant properties, with a potency estimated to be about 80-90% that of lidocaine. It is further metabolized to glycinexylidide.[1] The half-life of MEGX in dogs has been reported as approximately 0.9-1.0 hour [55], but can be longer in humans and may accumulate in patients with impaired renal or hepatic function.
• Glycinexylidide (GX): Formed by the subsequent deethylation of MEGX, GX is also pharmacologically active but is considerably less potent than lidocaine (around 10% of its antiarrhythmic potency).[1] Its half-life in dogs is around 2.6-3.2 hours.[55] The formation of these active metabolites is clinically relevant because their accumulation, particularly in patients with renal or severe hepatic impairment, can contribute to both the therapeutic effects and the toxicity profile of lidocaine, potentially complicating dose adjustments and patient monitoring.[1] Other metabolites include 3-hydroxylidocaine and 2,6-xylidine. While 2,6-xylidine has shown carcinogenic potential in rats, its systemic levels following topical Lidoderm application are negligible.[56]

4.4. Excretion

Lidocaine and its metabolites are primarily eliminated from the body via the kidneys.

• Route: Approximately 90% of an administered dose of lidocaine is excreted in the urine in the form of various metabolites. Less than 10% of the parent drug is excreted unchanged.[1]
• Major Urinary Metabolite: The primary metabolite found in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline.[1]
• Renal Clearance Mechanisms: The renal clearance of unchanged lidocaine is inversely related to its plasma protein binding and is influenced by urinary pH, suggesting that non-ionic diffusion plays a role in its tubular reabsorption.[1]

4.5. Half-Life

• Elimination Half-Life (Parent Drug): The terminal elimination half-life of lidocaine following an intravenous bolus is typically in the range of 1.5 to 2.0 hours in healthy adults.[1] This half-life can be significantly prolonged (e.g., two-fold or more) in patients with hepatic dysfunction, owing to the liver's primary role in its metabolism, and also in conditions such as congestive heart failure or with co-administration of certain drugs that inhibit its metabolism.[1] When administered subcutaneously with epinephrine, the absorption rate is slowed, which can prolong the apparent terminal half-life (e.g., reported as 3.78 hours in horses under such conditions).[56]
• Distribution Half-Life (Alpha Phase): The initial rapid distribution phase has a much shorter half-life, estimated at around 8 to 17 minutes.[28]

Table 4.1: Key Pharmacokinetic Parameters of Lidocaine

Parameter	Value	Key Considerations/Source(s)
Bioavailability (Oral)	~35%	Extensive first-pass hepatic metabolism 1
Bioavailability (Topical Patch - Lidoderm 5%)	~3 ± 2% of applied dose systemically absorbed	Low systemic absorption from intact skin over 12h 44
Bioavailability (IM)	Complete	1
Onset of Action (IV)	~1 minute (anesthetic/antiarrhythmic)	1
Onset of Action (IM)	~15 minutes	1
Onset of Action (Topical Mucosal/Ointment)	3-5 minutes	3
Onset of Action (Topical Patch - Lidoderm 5%)	~30 minutes for local numbing	43
Duration of Action (IV)	~10-20 minutes (anesthetic)	1
Duration of Action (IM)	~60-90 minutes (anesthetic)	1
Duration of Action (Topical Patch - Lidoderm 5%)	Up to 12 hours of local analgesia per application	43
Volume of Distribution (Vd​)	0.7 - 1.5 L/kg	1
Plasma Protein Binding	60-80%	Primarily to alpha-1-acid glycoprotein (AAG) 1
Metabolism	Liver (~90%) via CYP1A2 and CYP3A4	1
Major Active Metabolites	Monoethylglycinexylidide (MEGX), Glycinexylidide (GX)	Both have antiarrhythmic/convulsant activity 1
Elimination Half-Life (Parent drug, IV)	1.5 - 2.0 hours	Prolonged in hepatic/cardiac impairment 1
Elimination Half-Life (MEGX)	~0.9-1.0 hours (dogs, IV/SC); may be longer in humans	55
Elimination Half-Life (GX)	~2.6-3.2 hours (dogs, IV/SC); may be longer in humans	55
Excretion	Primarily renal (metabolites); <10% unchanged in urine	1

5. Pharmacodynamics

The pharmacodynamic effects of lidocaine encompass its desired therapeutic actions as well as potential systemic effects, particularly on the central nervous and cardiovascular systems.

5.1. Onset and Duration of Anesthetic Action

Lidocaine is characterized by a rapid onset of local anesthetic action and an intermediate duration of efficacy.[2] These parameters vary significantly depending on the route of administration, the concentration of the solution, the specific formulation used, and physiological factors at the site of application.

• Intravenous (IV) Anesthesia/Analgesia: When administered intravenously, for instance as an adjunct for pain or during certain procedures, the onset of action is very rapid, typically within about one minute.[1] The duration of this effect is relatively short, lasting approximately 10 to 20 minutes.[1]
• Intramuscular (IM) Injection: Following IM injection, the onset of anesthetic effect is around 15 minutes, with a duration of action of about 60 to 90 minutes.[1]
• Topical Application (Mucous Membranes/Ointment): For application to mucous membranes or as an ointment, lidocaine generally produces local anesthesia within 3 to 5 minutes.[3] The duration of effect is variable; for example, topical lidocaine used for awake tracheal intubation can provide analgesia for up to 40 minutes.[3]
• Topical Patch (Lidoderm® 5%): The Lidoderm 5% patch, indicated for postherpetic neuralgia, typically begins to numb the application area within 30 minutes.[43] It is designed for sustained local analgesic delivery and is worn for up to 12 hours within a 24-hour period.[43] The formulation ensures that lidocaine penetration is sufficient to produce analgesia but results in systemic absorption that is generally less than that required for a complete sensory block or systemic antiarrhythmic effects (only about 3 ± 2% of the applied dose is absorbed systemically from an intact skin application).[44] The development of such patch formulations illustrates how pharmaceutical engineering can modulate the pharmacodynamic profile of an established drug to suit specific therapeutic needs, such as providing prolonged, localized pain relief with minimal systemic exposure.
• Retrobulbar Injection: A 4% lidocaine solution used for retrobulbar injection provides an average duration of action of 1 to 1.5 hours.[39]
• Factors Influencing Duration: The duration of anesthetic action is influenced by several factors including the total dose administered, the concentration of the solution, the vascularity of the application site (higher blood flow leads to faster removal), and importantly, the co-administration of vasoconstrictors such as epinephrine. Epinephrine constricts local blood vessels, reducing systemic absorption of lidocaine and thereby prolonging its presence and action at the nerve site.[3]

5.2. Pharmacodynamic Effects as an Antiarrhythmic

When used as an antiarrhythmic agent, lidocaine's pharmacodynamic effects are primarily observed on the cardiovascular system.

• Therapeutic Plasma Levels: The generally accepted therapeutic plasma concentration range for lidocaine's antiarrhythmic effects is 1.5 to 5 µg/mL (or approximately 6 to 25 µmol/L).[22] This range is relatively narrow, as concentrations exceeding 5 to 6 µg/mL are increasingly associated with CNS and cardiovascular toxicity. This proximity between therapeutic and toxic levels underscores the need for careful dosing, individualized therapy, and vigilant monitoring, especially during IV infusions for arrhythmias.[3]
• Effects on Electrocardiogram (ECG): At therapeutic doses, lidocaine typically produces no significant change in myocardial contractility, systemic arterial pressure, or the absolute refractory period of cardiac tissue. It may slow conduction velocity and decrease the action potential duration as part of its Class Ib mechanism.[25] However, at toxic concentrations, ECG changes such as prolongation of the PR interval and widening of the QRS complex can occur, indicating excessive cardiac depression.[52]
• Hemodynamic Effects: At usual therapeutic doses for arrhythmias, lidocaine generally causes modest hypotension or no significant alteration in hemodynamics. However, excessive plasma levels can lead to direct myocardial depression, vasodilation, significant hypotension, and bradycardia.[1]

6. Clinical Applications

Lidocaine's broad utility stems from its dual action as a local anesthetic and an antiarrhythmic agent, leading to a wide range of approved and off-label clinical uses. The diversity of available formulations further enhances its applicability across various medical specialties.

6.1. Approved Indications

• Local and Regional Anesthesia: This is the most extensive area of lidocaine application.
• Infiltration Anesthesia: Used for numbing localized areas via percutaneous injection.[1]
• Peripheral Nerve Blocks: Employed for anesthesia of specific body regions, such as brachial plexus blocks for upper limb surgery or intercostal nerve blocks for chest wall analgesia.[1]
• Central Neural Blockade: Includes epidural (lumbar or caudal) and spinal anesthesia for surgical procedures and labor analgesia.[1]
• Topical Anesthesia: Applied to mucous membranes of the mouth, pharynx, larynx, trachea, esophagus, and genitourinary tract for diagnostic and therapeutic procedures. It is commonly used in dental procedures and for short ophthalmic procedures.[1] Specific topical formulations like the Lidoderm® 5% patch and ZTLido® 1.8% topical system are approved for the relief of pain associated with postherpetic neuralgia (PHN).[2]
• Intravenous Regional Anesthesia (Bier Block): A technique used for short surgical procedures on the extremities.[3]
• Ventricular Arrhythmias:
• Lidocaine is indicated for the acute management of ventricular arrhythmias, such as those occurring during cardiac manipulations (e.g., cardiac surgery) or in the setting of acute myocardial infarction.[1] It is often considered if amiodarone is not available or is contraindicated, and is typically administered after initial measures like defibrillation, cardiopulmonary resuscitation (CPR), and vasopressors have been attempted in cases of ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT).[2]

6.2. Off-Label and Other Uses

The therapeutic applications of lidocaine extend beyond its formally approved indications:

• Premature Ejaculation: Topical application of lidocaine (e.g., creams or sprays) to the glans penis is used to reduce sensitivity and prolong ejaculatory latency.[1]
• Chronic Pain Management: Intravenous lidocaine infusions are increasingly used off-label for the management of various chronic pain conditions, including neuropathic pain. It is also employed as an opioid-sparing analgesic technique in the perioperative setting for acute surgical pain.[2] The Lidoderm patch is also commonly used off-label for other types of localized neuropathic pain beyond PHN.[58] The growing exploration of lidocaine for these conditions suggests a recognition of its more complex analgesic mechanisms, potentially involving central effects or its known NMDA receptor antagonism, rather than solely peripheral nerve blockade.[3]
• Cough Suppression: Inhaled lidocaine can be used to suppress the cough reflex, particularly as a comfort and safety measure during endotracheal intubation or extubation procedures.[2]
• Status Epilepticus: Intravenous lidocaine has been used in the management of refractory status epilepticus.[60] It has also been recommended as a second-line treatment for neonatal seizures if phenobarbital is ineffective.[2]
• Miscellaneous Uses: Other reported off-label uses include treatment for intractable cough and hiccups.[60] Viscous lidocaine formulations may provide symptomatic relief for gastritis or pain from jellyfish stings.[2] Lidocaine jelly (e.g., Xylocaine® jelly) is used for painful urethritis and as a lubricant for intubation and other procedures involving the urethra, nose, mouth, or throat.[42] Intravesical lidocaine is used for interstitial cystitis/bladder pain syndrome, and intraosseous lidocaine is administered for pain relief during trauma resuscitation.[3]

The role of lidocaine in arrhythmia management has evolved. While historically a primary antiarrhythmic, current guidelines often position it as an alternative to amiodarone for VF/pVT, or for specific scenarios such as witnessed cardiac arrest where rapid administration is feasible.[2] Routine prophylactic use of lidocaine following myocardial infarction is no longer recommended due to a lack of clear mortality benefit and the potential for harm (e.g., increased risk of asystole).[2] This shift reflects a more nuanced understanding of its risk-benefit profile in different cardiac conditions.

6.3. Formulations and Dosage Regimens

The wide array of available lidocaine formulations is a key factor contributing to its ubiquitous use across diverse medical and dental specialties. This pharmaceutical versatility allows for tailored drug delivery according to the specific clinical need, site of action, and desired onset and duration of effect.

• Overview of Formulations:
• Injectable Solutions: Available in various concentrations (e.g., 0.5%, 1%, 1.5%, 2%, 4%), often as the hydrochloride salt, with or without epinephrine. These are used for infiltration, nerve blocks, epidural anesthesia, and as intravenous solutions for antiarrhythmic therapy.[3] Lidocaine Hydrochloride and 5% Dextrose Injection, USP, is specifically formulated for IV infusion in arrhythmia management.[25]
• Topical Solutions: Examples include 2% viscous solutions for oral and pharyngeal anesthesia and 4% solutions for topical anesthesia of airway mucous membranes.[3]
• Gels/Jellies: Typically 1% or 2% aqueous gels, often containing an antiseptic like chlorhexidine, used for urethral lubrication and anesthesia prior to procedures such as catheterization.[3]
• Ointments: Commonly 5% lidocaine, sometimes combined with hydrocortisone, for topical application to skin or mucous membranes (e.g., rectal).[3]
• Sprays: Metered-dose atomizers delivering, for example, 10% lidocaine solution for airway anesthesia.[3] A 5% spray formulation is also used for premature ejaculation.[2]
• Patches: Lidoderm® (lidocaine patch 5%) and ZTLido® (lidocaine topical system 1.8%) are adhesive patches for the treatment of postherpetic neuralgia.[2]
• Creams: Various over-the-counter (OTC) strengths (e.g., 4%) are available for temporary relief of minor pain and itching.[64]
• EMLA® (Eutectic Mixture of Local Anesthetics): A cream combining lidocaine and prilocaine, designed to penetrate intact skin for cutaneous anesthesia, often used prior to needle punctures.[3]
• Powder Intradermal Injection System: A novel delivery system providing 0.5 mg of lidocaine hydrochloride monohydrate for topical local analgesia prior to venipuncture or peripheral intravenous cannulation in children aged 3–18 years.[66]
• Typical Dosage Regimens: Dosages are highly variable and must be individualized based on the specific procedure, the area to be anesthetized, the patient's age, weight, and physical condition, and the formulation used. The guiding principle is always to use the lowest dose and concentration that will produce the desired result.
• Local Anesthesia (Injectable):
• Infiltration: Maximum individual dose is typically 4.5 mg/kg (without epinephrine) or 7 mg/kg (with epinephrine), not to exceed a total dose of around 300 mg (without epinephrine) or 500 mg (with epinephrine) in adults.[23]
• IV Regional Anesthesia (Bier Block): Maximum dose around 4 mg/kg.[24]
• Epidural Anesthesia: Dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome). A test dose (e.g., 2-3 mL of 1.5% lidocaine HCl, possibly with epinephrine) is usually administered prior to the full dose to detect unintentional subarachnoid or intravascular injection.[23] For continuous epidural or caudal anesthesia, maximum recommended doses should not be administered at intervals of less than 90 minutes.[24]
• Paracervical Block: Maximum recommended dose per 90-minute period is 200 mg total.[24]
• Ventricular Arrhythmias (Adult IV):
• Loading Dose: Typically 1 to 1.5 mg/kg administered as an IV bolus (e.g., 50 to 100 mg) over 2-3 minutes. This may be repeated with doses of 0.5 to 0.75 mg/kg every 5 to 10 minutes if necessary, up to a maximum cumulative dose of 3 mg/kg or 300 mg within a 1-hour period.[24]
• Maintenance Infusion: Following the loading dose, a continuous IV infusion is administered at a rate of 1 to 4 mg/min (or 20 to 50 mcg/kg/min).[24] The infusion rate should be reduced after 24 hours or in patients with hepatic impairment or congestive heart failure to avoid accumulation and toxicity.[25]
• Topical Anesthesia:
• Lidoderm® 5% Patch / ZTLido® 1.8% Topical System: Apply 1 to 3 patches/systems to the most painful area of intact skin for up to 12 hours within a 24-hour period.[42]
• Viscous Solution (2% for mouth/throat): For adults, approximately 15 mL (1 tablespoonful) swished and expectorated (or swallowed if indicated by physician for pharyngeal anesthesia) every 3 hours as needed. Maximum 8 doses in a 24-hour period. For children, dosage is based on body weight and must be determined by a physician.[42]
• OTC Topical Creams/Ointments (e.g., 4%): Applied to the affected area 3 to 4 times daily as needed.[64]

Table 6.1: Overview of Selected Lidocaine Formulations and Common Dosage Regimens

Formulation Type	Common Strengths	Typical Approved Indication(s)	General Dosage Range/Regimen (Adults, unless specified)	Key Administration Notes/Source(s)
Injectable Solution (HCl salt)	0.5%, 1%, 1.5%, 2% (with/without epinephrine)	Local/Regional Anesthesia (infiltration, nerve block, epidural)	Highly variable; e.g., Infiltration: up to 4.5 mg/kg (plain), 7 mg/kg (with epi). Max 300mg (plain), 500mg (with epi). Epidural: 2-3 mL/dermatome.	Lowest effective dose. Test dose for epidural. Reduce dose in elderly, debilitated, hepatic/cardiac disease. 23
Injectable Solution (HCl salt in D5W)	0.4% (4 mg/mL), 0.8% (8 mg/mL)	Acute Ventricular Arrhythmias	Loading: 1-1.5 mg/kg IV bolus. Maintenance: 1-4 mg/min IV infusion.	Constant ECG monitoring. Reduce infusion rate after 24h or in hepatic/cardiac impairment. 25
Topical Patch (Lidoderm®, ZTLido®)	5% (Lidoderm), 1.8% (ZTLido)	Postherpetic Neuralgia	Apply 1-3 patches/systems to intact painful skin for up to 12h in a 24h period.	Apply to intact skin only. Avoid external heat sources. 42
Topical Viscous Solution	2%	Topical anesthesia of irritated/inflamed oral/pharyngeal mucous membranes; reducing gagging.	~15 mL (1 tbsp) swished and expectorated/swallowed q3h PRN. Max 8 doses/24h.	Do not eat for 60 min after use in mouth/throat due to impaired swallowing. 38
Topical Ointment	5%	Anesthesia of accessible mucous membranes; relief of pain/itching from minor skin conditions.	Apply thin film to affected area 3-4 times daily. Max 5g per application for 5% ointment.	For external/mucosal use only. 3
Topical Cream (OTC)	e.g., 4%	Temporary relief of minor pain, itching, burning.	Apply to affected area 3-4 times daily.	For external use only. 64

7. Safety Profile

The safety profile of lidocaine is well-characterized, with adverse effects being generally dose-related and arising from high plasma concentrations. Systemic toxicity primarily affects the central nervous system (CNS) and the cardiovascular system (CVS).[1]

7.1. Adverse Effects

• Local Reactions:
• At the site of injection, reactions such as swelling, redness, pain, and petechiae can occur.[73]
• With topical application (e.g., Lidoderm patch), common reactions include erythema, edema, bruising, papules, vesicles, skin discoloration, burning sensation, pruritus, dermatitis, petechiae, blisters, or exfoliation. These are typically mild and transient, resolving within minutes to hours after patch removal.[42]
• Systemic Toxicity:
• Central Nervous System (CNS) Effects: CNS manifestations are often the first signs of systemic toxicity and can be both excitatory and depressant.
• Early/Mild Symptoms: These include lightheadedness, dizziness, nervousness, apprehension, euphoria, confusion, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold, or numbness, circumoral (around the mouth) paresthesia, numbness of the tongue, metallic taste in the mouth, and dysarthria (difficulty speaking).[1] The relatively high cardiovascular collapse to CNS toxicity (CC/CNS) dose ratio for lidocaine (approximately 7.1) compared to more lipophilic local anesthetics like bupivacaine means that these CNS symptoms often precede severe cardiovascular compromise in awake patients, serving as an important early warning.[3] However, in patients under general anesthesia or heavy sedation, these early CNS signs may be masked, and cardiovascular toxicity might be the first overt manifestation.[3]
• Severe Symptoms: As plasma concentrations rise, more severe CNS effects can develop, including muscle twitching, tremors, tonic-clonic seizures, leading to unconsciousness, coma, respiratory depression, and ultimately respiratory arrest.[1] Seizures are a common and significant sign of major CNS toxicity.[69]
• Cardiovascular System (CVS) Effects: These typically occur at higher plasma concentrations of lidocaine than those causing initial CNS symptoms, although they can manifest concurrently or even precede CNS signs in situations of rapid intravascular injection or in anesthetized patients.[3]
• Effects: Cardiovascular toxicity can manifest as bradycardia, hypotension, various arrhythmias (including ventricular tachycardia, ventricular fibrillation, asystole, and heart block), direct myocardial depression (reduced contractility), and in severe cases, cardiovascular collapse and cardiac arrest.[1] Paradoxically, early cardiovascular signs can sometimes include transient hypertension and tachycardia due to initial sympathetic stimulation before depressive effects predominate.[71]
• Methemoglobinemia: This is a rare but potentially life-threatening adverse effect where the iron in hemoglobin is oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state, rendering it incapable of binding and transporting oxygen effectively. Lidocaine, particularly its metabolite o-toluidine, can induce methemoglobinemia.[1] The risk is increased with high doses, especially with topical application to large mucosal areas, and in susceptible individuals such as infants (particularly those younger than 6 months), the elderly, patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, pre-existing hemoglobinopathies, or those concomitantly receiving other oxidizing agents (e.g., nitrates, sulfonamides).[1] Clinical signs include cyanosis (often described as "chocolate brown" or grayish-blue) that is unresponsive to oxygen therapy, confusion, headache, tachycardia, and fatigue.[43] Pulse oximetry readings can be misleadingly normal or falsely low in the presence of significant methemoglobinemia.
• Allergic Reactions: True IgE-mediated allergic reactions to amide-type local anesthetics like lidocaine are extremely rare, occurring in less than 1% of cases.[78] Symptoms can range from mild cutaneous reactions such as urticaria, erythema, and pruritus, to more severe manifestations like angioedema, bronchospasm, and, in very rare instances, life-threatening anaphylactic shock characterized by hypotension and loss of consciousness.[1] Many reactions attributed to "allergy" are often vasovagal responses (fainting due to anxiety), toxic effects from inadvertent intravascular injection, or reactions to preservatives (such as methylparaben, which can be metabolized to PABA-like compounds known to be allergenic) or co-administered epinephrine.[78]

7.2. Contraindications

Lidocaine is contraindicated in the following situations:

• Patients with a known history of hypersensitivity to lidocaine or other local anesthetics of the amide type.[1]
• Patients with Stokes-Adams syndrome (a type of heart block causing fainting spells).[2]
• Patients with Wolff-Parkinson-White syndrome (a condition that can cause rapid heart rates).[2]
• Patients with severe degrees of sinoatrial, atrioventricular (AV), or intraventricular heart block, unless an artificial pacemaker is in place.[2]
• Application of the Lidoderm patch (lidocaine patch 5%) is contraindicated on non-intact (broken or inflamed) skin.[44]

7.3. Warnings and Precautions

• Hepatic Impairment: Since lidocaine is primarily metabolized in the liver, patients with severe hepatic disease are at a greater risk of developing toxic blood concentrations due to reduced clearance. Dosage reduction and careful monitoring are essential in these patients.[2]
• Renal Impairment: While mild to moderate renal impairment generally does not significantly affect lidocaine kinetics, severe renal dysfunction can lead to decreased clearance of lidocaine and accumulation of its active metabolites (particularly GX), increasing the risk of toxicity. Dose adjustments and cautious use are warranted.[3]
• Congestive Heart Failure (CHF), Cardiogenic Shock, Reduced Cardiac Output: These conditions can reduce hepatic blood flow and thus lidocaine clearance, necessitating lower doses and careful monitoring.[3]
• Bradycardia and Heart Block: In patients with pre-existing sinus bradycardia or incomplete heart block, intravenous administration of lidocaine for ventricular arrhythmias without prior acceleration of the heart rate (e.g., with isoproterenol or electrical pacing) may precipitate more severe arrhythmias or complete heart block.[52]
• Pregnancy (FDA Pregnancy Category B): Lidocaine crosses the placenta. While animal reproduction studies have not shown evidence of harm to the fetus, there are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Fetal effects such as bradycardia or CNS depression can occur, and neonatal elimination of lidocaine is slower than in adults.[1]
• Lactation: Lidocaine is excreted in human milk in small amounts (milk:plasma ratio reported as 0.4 to 1.1). Caution should be exercised when administering lidocaine to nursing mothers. Some sources advise temporary discontinuation of breastfeeding for a period after administration to minimize infant exposure.[1]
• Pediatric Use: Dosages in children must be carefully calculated and reduced based on age, body weight, and physical condition. Infants, particularly those younger than 6 months, are at an increased risk of methemoglobinemia. Viscous lidocaine 2% carries an FDA boxed warning regarding life-threatening events (including seizures and cardiopulmonary arrest) in children younger than 3 years if improperly used, especially for teething pain.[3]
• Geriatric Use: Elderly patients may be more susceptible to the toxic effects of lidocaine due to age-related decreases in hepatic, renal, or cardiac function, as well as a higher likelihood of polypharmacy. Dose selection should be cautious, often starting at the lower end of the dosing range.[23]
• Accidental Exposure (Especially Transdermal Patches): Lidocaine patches (both new and used) contain a significant amount of lidocaine (e.g., at least 665 mg in a used Lidoderm patch). Accidental ingestion or chewing by children or pets can lead to serious adverse effects or fatality. Strict adherence to instructions for proper storage and disposal (e.g., folding used patches so the adhesive sides stick together) is crucial.[43]
• External Heat Sources with Patches: Applying external heat sources (e.g., heating pads, electric blankets) over lidocaine patches is not recommended, as this has not been thoroughly evaluated and may increase the rate and extent of lidocaine absorption from the patch, potentially leading to toxic systemic levels.[44]
• Eye Exposure: Contact with the eyes should be avoided with all lidocaine preparations not specifically formulated for ophthalmic use, as it can cause severe irritation. If accidental eye contact occurs, the eye should be immediately irrigated with water or saline, and protected until sensation returns.[44]
• Application to Non-Intact Skin: For products intended for use on intact skin (like Lidoderm patches), application to broken, inflamed, or compromised skin may result in increased systemic absorption and a higher risk of systemic toxicity.[42]
• Monitoring: Constant ECG monitoring is essential during intravenous administration of lidocaine for antiarrhythmic purposes. Patients should be monitored for signs and symptoms of CNS and CVS toxicity whenever systemic exposure is anticipated.[24]

7.4. Drug Interactions

Lidocaine is subject to numerous clinically significant drug interactions, primarily related to its metabolism via CYP1A2 and CYP3A4, and additive pharmacodynamic effects with other cardioactive or CNS-active drugs.

• CYP1A2 and CYP3A4 Inhibitors: Drugs that inhibit these enzymes (e.g., cimetidine, fluvoxamine, erythromycin, itraconazole, ketoconazole, ritonavir, amiodarone, propofol) can decrease the hepatic clearance of lidocaine, leading to increased plasma concentrations and an elevated risk of lidocaine toxicity. Careful monitoring and potential dose reduction of lidocaine may be necessary.[2]
• CYP1A2 and CYP3A4 Inducers: Conversely, drugs that induce these enzymes (e.g., phenytoin, carbamazepine, rifampin, St. John's Wort, barbiturates, and factors like cigarette smoking) can increase the metabolism of lidocaine, potentially reducing its plasma concentrations and therapeutic efficacy. Higher doses of lidocaine may be required in such situations.[52]
• Other Antiarrhythmic Drugs: Co-administration of lidocaine with other Class I antiarrhythmic agents (e.g., tocainide, mexiletine, procainamide, quinidine, flecainide, disopyramide) or other drugs with antiarrhythmic properties (e.g., amiodarone) can result in additive or synergistic cardiac effects, potentially increasing the risk of proarrhythmia or other cardiotoxic manifestations. Close monitoring is crucial, and some combinations may be contraindicated.[2]
• Beta-Adrenergic Blockers: Beta-blockers (e.g., propranolol, metoprolol, nadolol) can increase lidocaine plasma levels by reducing hepatic blood flow (thereby decreasing lidocaine clearance) and potentially by inhibiting its metabolism. This combination increases the risk of lidocaine toxicity, and careful monitoring or dose adjustment is advised.[2]
• Drugs Increasing Methemoglobinemia Risk: Concomitant use of lidocaine with other drugs known to cause methemoglobinemia (e.g., nitrates, nitrites, local anesthetics like benzocaine, prilocaine; antimalarials like chloroquine, primaquine; antineoplastics like cyclophosphamide, flutamide; antibiotics like dapsone, sulfonamides; antiepileptics like phenobarbital, phenytoin, valproic acid; and others like acetaminophen, metoclopramide, quinine, sulfasalazine) can potentiate the risk of this adverse effect.[1]
• Succinylcholine: Lidocaine may prolong the neuromuscular blockade produced by succinylcholine, possibly by inhibiting plasma cholinesterase activity. A comprehensive list of potential drug interactions with lidocaine is extensive, involving numerous medications across various therapeutic classes.[67] Clinicians must carefully review a patient's complete medication profile before administering lidocaine.

Table 7.1: Clinically Significant Drug Interactions with Lidocaine

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Consequence	Management Recommendation/Source(s)
CYP1A2/CYP3A4 Inhibitors (e.g., cimetidine, fluvoxamine, erythromycin, ketoconazole, ritonavir, amiodarone, propofol)	Decreased hepatic metabolism of lidocaine	Increased lidocaine plasma levels, increased risk of toxicity	Monitor for lidocaine toxicity; consider lidocaine dose reduction. 52
CYP1A2/CYP3A4 Inducers (e.g., phenytoin, carbamazepine, rifampin, St. John's Wort, barbiturates)	Increased hepatic metabolism of lidocaine	Decreased lidocaine plasma levels, reduced efficacy	Monitor for efficacy; may require higher lidocaine doses. 52
Other Antiarrhythmic Drugs (e.g., Class I agents like mexiletine, tocainide; amiodarone)	Additive or synergistic cardiac effects	Increased risk of cardiotoxicity, proarrhythmia	Use with caution; close monitoring. Some combinations may be contraindicated. 45
Beta-Adrenergic Blockers (e.g., propranolol, metoprolol)	Decreased hepatic blood flow and/or inhibition of lidocaine metabolism	Increased lidocaine plasma levels, increased risk of toxicity	Monitor for lidocaine toxicity; consider lidocaine dose reduction. 52
Drugs Increasing Methemoglobinemia Risk (e.g., nitrates, sulfonamides, dapsone, other local anesthetics)	Additive effect on methemoglobin formation	Increased risk of clinically significant methemoglobinemia	Avoid concomitant use if possible, especially in at-risk patients; monitor for signs of methemoglobinemia. 1
Succinylcholine	Potential inhibition of plasma cholinesterase by lidocaine	Prolongation of neuromuscular blockade	Monitor neuromuscular function. [General pharmacology knowledge]

7.5. Overdose Management

Overdosage of lidocaine can lead to severe systemic toxicity, primarily affecting the CNS and CVS. Prompt recognition and management are crucial to prevent life-threatening complications.

• Recognition of Overdose:
• CNS Symptoms: Early signs include circumoral numbness, tongue paresthesia, lightheadedness, dizziness, tinnitus, blurred vision, and restlessness. These can progress to muscle twitching, tremors, confusion, disorientation, and eventually tonic-clonic seizures, unconsciousness, coma, and respiratory arrest.[1]
• CVS Symptoms: Cardiovascular manifestations may include hypotension, bradycardia, conduction disturbances (e.g., AV block, widened QRS), ventricular arrhythmias (tachycardia or fibrillation), myocardial depression, and ultimately cardiovascular collapse or cardiac arrest.[1]
• Immediate Management Steps (LAST Protocol):

1. Stop Lidocaine Administration: Immediately discontinue the administration of lidocaine or any suspected local anesthetic.[3]
2. Call for Help: Alert appropriate personnel and activate emergency response systems.[40]
3. Airway Management: Ensure a patent airway. Administer 100% oxygen and assist ventilation as necessary to prevent hypoxia and hypercapnia, as acidosis can exacerbate local anesthetic toxicity.[3] Early intubation may be required, especially if seizures occur or respiratory depression is evident.
4. Seizure Control: If seizures occur, they should be treated promptly. Benzodiazepines (e.g., diazepam, midazolam) are the preferred agents. Propofol may be used but should be avoided if there are signs of cardiovascular instability due to its cardiodepressant effects.[22]
5. Cardiovascular Support:

• Treat hypotension with intravenous fluids and vasopressors if necessary. Epinephrine doses may need to be reduced (<1 mcg/kg) in the context of LAST. Vasopressin should generally be avoided.[40]
• Treat bradycardia with atropine.
• For ventricular arrhythmias, standard ACLS algorithms should be modified. Amiodarone may be considered. Avoid further administration of lidocaine or other Class I antiarrhythmics. Sodium bicarbonate (1–2 mmol/kg IV) can be beneficial for QRS widening or ventricular dysrhythmias secondary to sodium channel blockade.[40]
• Prolonged resuscitation efforts may be necessary. Alert the nearest facility with cardiopulmonary bypass capability, as this may be required in refractory cases.[40]
• Intravenous Lipid Emulsion (ILE) Therapy: The administration of a 20% intravenous lipid emulsion (e.g., Intralipid®) is a cornerstone of treatment for severe local anesthetic systemic toxicity (LAST), particularly in cases of cardiovascular collapse or cardiac arrest that are refractory to standard resuscitative measures.[3]
• Mechanism: ILE is thought to act as a "lipid sink" or "lipid shuttle," effectively creating an expanded lipid compartment within the plasma that sequesters the lipophilic local anesthetic molecules, drawing them away from their sites of action in the heart and brain. Additionally, ILE may have direct beneficial cardiotonic and metabolic effects, such as improving myocardial energy substrate availability.[85] The advent of ILE therapy represents a significant paradigm shift in managing LAST, offering a more specific antidote beyond purely supportive care.
• Dosing (Example Protocol):
• Initial bolus: 1.5 mL/kg of 20% lipid emulsion administered intravenously over 1 minute (e.g., approximately 100 mL for a 70 kg patient).
• Continuous infusion: Follow the bolus with an infusion at a rate of 0.25 mL/kg/min.
• Repeat bolus: If cardiovascular stability is not achieved, the bolus can be repeated once or twice (e.g., every 5 minutes).
• Adjust infusion: If blood pressure remains low, the infusion rate can be doubled to 0.5 mL/kg/min.
• Duration: Continue the infusion for at least 10 minutes after circulatory stability has been achieved.
• Maximum dose: There is a recommended upper limit for the total dose of lipid emulsion (e.g., approximately 10-12 mL/kg over the first 30 minutes).[40] Facilities performing regional anesthesia or administering large doses of local anesthetics should have ILE readily available and staff trained in its administration.
• Management of Methemoglobinemia: If methemoglobinemia is suspected (e.g., cyanosis unresponsive to oxygen, "chocolate brown" arterial blood), treatment involves the intravenous administration of methylene blue (1 to 2 mg/kg given over 5 minutes). Methylene blue is contraindicated in patients with G6PD deficiency, who may require alternative treatments such as exchange transfusion or dialysis.[59]

8. Regulatory Status

8.1. FDA Approval History

Lidocaine has a long history of use and regulatory approval in the United States. It was first discovered in 1943 and became available for sale in 1948.2 Over the decades, numerous formulations of lidocaine have received FDA approval for various anesthetic and antiarrhythmic indications.

A notable example of a formulation-specific approval is Lidoderm® (lidocaine patch 5%), which was approved by the FDA on March 19, 1999, specifically for the relief of pain associated with postherpetic neuralgia.58 Subsequently, ZTLido® (lidocaine topical system 1.8%), another patch formulation bioequivalent to Lidoderm 5%, also received FDA approval for the same indication.58 These formulation-specific approvals highlight how targeted drug delivery systems can enhance the therapeutic utility of an established drug like lidocaine, addressing specific clinical needs such as chronic localized neuropathic pain with minimized systemic exposure.44

8.2. Inclusion in WHO Model List of Essential Medicines

Lidocaine's fundamental importance in healthcare is underscored by its consistent inclusion in the World Health Organization's (WHO) Model List of Essential Medicines.[1] This list identifies medications considered essential for addressing the most significant public health needs in a basic healthcare system. Lidocaine's presence on this list for many years reflects its established efficacy, safety profile (when used correctly), and cost-effectiveness for critical anesthetic and antiarrhythmic applications worldwide.

According to the WHO Model List of Essential Medicines – 23rd List (2023), lidocaine is included under section "1.2 Local anaesthetics" in the following formulations [8]:

• Injection: 1% (hydrochloride) in vial; 2% (hydrochloride) in vial.
• Injection for spinal anaesthesia: 5% (hydrochloride) in a 2 mL ampoule (to be mixed with 7.5% glucose solution).
• Topical forms: 2% to 4% (hydrochloride).

Additionally, a combination of lidocaine with epinephrine (adrenaline) is listed:

• Dental cartridge: 2% (hydrochloride) + epinephrine 1:80,000.
• Injection: 1% (hydrochloride or sulfate) + epinephrine 1:200,000 in vial; 2% (hydrochloride or sulfate) + epinephrine 1:200,000 in vial.

This continuous endorsement by the WHO emphasizes lidocaine's indispensable role, particularly in resource-constrained settings where access to a broad range of pharmaceuticals may be limited. It serves as a benchmark drug for many basic procedures requiring local anesthesia or management of specific cardiac arrhythmias.

9. Conclusion

9.1. Summary of Key Characteristics, Benefits, and Risks

Lidocaine is a remarkably versatile and enduring pharmaceutical agent, distinguished by its dual utility as a local anesthetic and a Class Ib antiarrhythmic. Its rapid onset of action and intermediate duration, stemming from its physicochemical properties and mechanism of sodium channel blockade, have cemented its place in a vast array of medical and dental procedures for over seven decades. The benefits of lidocaine are manifold: it provides effective and reliable anesthesia for surgical and diagnostic interventions, manages life-threatening ventricular arrhythmias, and offers options for various types of pain relief through diverse formulations.

However, its widespread use necessitates a thorough understanding of its potential risks. Systemic toxicity, primarily affecting the central nervous and cardiovascular systems, can occur with excessive dosage, rapid absorption, or inadvertent intravascular injection. Symptoms range from mild CNS disturbances like dizziness and paresthesias to severe manifestations such as seizures, coma, arrhythmias, and cardiovascular collapse. Methemoglobinemia, though rare, is another serious potential adverse effect. Furthermore, lidocaine is subject to numerous drug interactions, particularly with agents affecting CYP1A2 and CYP3A4 metabolism, and with other cardioactive drugs, which can significantly alter its pharmacokinetic and pharmacodynamic profile. Therefore, appropriate patient selection, careful dosing, vigilant monitoring, and preparedness to manage adverse events are paramount for its safe and effective use.

9.2. Current Place in Therapy and Future Perspectives

Lidocaine remains an indispensable tool in modern medicine, particularly as a local anesthetic for a multitude of procedures. Its efficacy, rapid onset, and relatively low cost ensure its continued prominence globally, as evidenced by its consistent inclusion in the WHO Model List of Essential Medicines. In the realm of arrhythmia management, its role has become more nuanced, often serving as a second-line agent or for specific clinical scenarios, reflecting advancements in antiarrhythmic therapy and a refined understanding of its risk-benefit profile.

The future of lidocaine is likely to involve continued exploration of its off-label applications, especially in multimodal and chronic pain management. The growing understanding of its potential central analgesic mechanisms, including NMDA receptor antagonism, opens avenues for repurposing and further research. Pharmaceutical innovation will also continue to play a role, with the development of novel formulations and delivery systems aimed at enhancing target specificity, improving the therapeutic index, and expanding its utility for challenging clinical conditions. Lidocaine, despite its age, is a drug that embodies both ubiquitous utility and the need for pharmacological precision. Its legacy is a testament to its fundamental efficacy, yet its complex safety profile and interactions demand ongoing education and vigilance from healthcare professionals. As such, lidocaine is poised to remain a relevant and valuable medication for many years to come, continually adapting through new research and formulation advancements.

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