Report on Chloroprocaine (DB01161): A Comprehensive Pharmacological and Clinical Monograph

Abstract and Drug Identification

Abstract

Chloroprocaine is a short-acting, small-molecule local anesthetic of the amino ester class, distinguished by its unique pharmacokinetic profile. Its defining characteristic is an extremely rapid hydrolysis in the plasma by the enzyme pseudocholinesterase, resulting in a very short half-life and a favorable safety profile with low systemic toxicity. This property allows for the administration of high concentrations, which produces a rapid onset of anesthesia (typically within 6 to 12 minutes) despite a chemically unfavorable high pKa. The duration of action is brief, generally lasting up to 60 minutes, making it an ideal agent for short surgical procedures, particularly in the ambulatory setting. Historically, its use in spinal anesthesia was curtailed due to reports of neurotoxicity in the 1980s, which were later attributed to preservatives, such as sodium bisulfite, and low pH in older formulations rather than the drug itself. The development of preservative-free formulations has led to a clinical renaissance for chloroprocaine, re-establishing its safety for neuraxial use. This resurgence is underscored by recent U.S. Food and Drug Administration (FDA) approvals of specific preservative-free preparations for intrathecal anesthesia (Clorotekal®) and, more recently, for topical ocular surface anesthesia (Iheezo®), solidifying its position as a key anesthetic in modern clinical practice.

Drug Identification and Classification

Chloroprocaine is a synthetic organic compound classified as an ester-type local anesthetic. It is a derivative of procaine, with a chlorine atom substituted on the benzene ring.

• Primary Name: Chloroprocaine [1]
• Systematic (IUPAC) Name: 2-(diethylamino)ethyl 4-amino-2-chlorobenzoate [1]
• DrugBank Accession Number: DB01161 [1]
• CAS Numbers:
• Base Molecule: 133-16-4 [2]
• Hydrochloride Salt: 3858-89-7 [2]
• Synonyms: 2-chloroprocaine, Chloroprocain, Chloroprocainum, Chlorprocaine, Cloroprocaina [1]
• Drug Type/Modality: Small Molecule [1]
• Pharmacological Class: Local Anesthetic (Ester type), Ester of aminobenzoic acid [1]
• Anatomical Therapeutic Chemical (ATC) Code: N01BA04 (Nervous System > Anesthetics > Anesthetics, local > Esters of aminobenzoic acid) [4]
• Regulatory Status: Prescription-only (℞-only) in the United States and Canada [2]

Physicochemical Properties and Formulation

Chemical Structure and Properties

The chemical structure and physicochemical properties of chloroprocaine are fundamental to its pharmacological behavior, influencing its onset of action, potency, duration, and metabolic fate. It is structurally defined as the 2-(diethylamino)ethyl ester of 4-amino-2-chlorobenzoic acid.[3] The molecule is achiral, meaning it does not have stereoisomers.[8]

The addition of a chlorine atom to the procaine structure is a key modification. This electron-withdrawing group pulls electron density from the adjacent ester carbonyl carbon, rendering it more electrophilic and thus more susceptible to hydrolysis by plasma cholinesterases. This chemical feature is directly responsible for its significantly faster metabolism compared to procaine.[5]

A critical property influencing its clinical behavior is its acid dissociation constant (pKa), which is relatively high, with reported values ranging from 8.7 to 9.14.[5] This high

pKa dictates that at physiological pH (approximately 7.4), the equilibrium between the ionized (cationic) and non-ionized (uncharged base) forms heavily favors the ionized state. Since only the non-ionized, lipid-soluble form can diffuse across the nerve membrane to reach its intracellular site of action, a high pKa would theoretically predict a slow onset of anesthesia.[9] However, as will be discussed, chloroprocaine exhibits a rapid clinical onset, a phenomenon explained by a unique interplay between its pharmacokinetics and the high concentrations used in clinical practice.

The drug's lipophilicity, quantified by its partition coefficient (logP), is relatively low, with values around 2.46 to 2.72.[11] This low lipid solubility is a primary determinant of its low intrinsic potency compared to more lipophilic agents like bupivacaine.[9] Chloroprocaine hydrochloride, the salt form used in clinical preparations, is highly soluble in water (up to 61 mg/mL) but insoluble in ethanol.[6] This high aqueous solubility is essential for its formulation as a stable injectable solution.

Table 1: Drug Identification and Physicochemical Properties of Chloroprocaine
Property	Value
IUPAC Name	2-(diethylamino)ethyl 4-amino-2-chlorobenzoate 3
CAS Number (Base)	133-16-4 5
CAS Number (HCl Salt)	3858-89-7 2
Molecular Formula	C13​H19​ClN2​O2​ 4
Molecular Weight (Base)	Average: 270.755 g/mol; Monoisotopic: 270.11351 g/mol 1
Molecular Weight (HCl Salt)	307.22 g/mol 6
Melting Point	42°C 5
pKa	8.7 - 9.14 5
logP (Lipophilicity)	2.46 - 2.72 11
Water Solubility (HCl Salt)	57 - 61 mg/mL 13
SMILES	CCN(CC)CCOC(=O)C1=C(Cl)C=C(N)C=C1 2
InChIKey	VDANGULDQQJODZ-UHFFFAOYSA-N 2

Formulations and Commercial Preparations

The clinical use and safety of chloroprocaine are inextricably linked to its specific formulation. The distinction between preparations containing preservatives and those that are preservative-free is of paramount importance, particularly for neuraxial anesthesia.

• Injectable Solutions (Systemic):
• Nesacaine®: This formulation is available in 1% and 2% solutions, supplied in multidose vials. A critical feature of Nesacaine® is the inclusion of methylparaben as a preservative.[16] Due to the potential neurotoxicity of preservatives when administered into the epidural or subarachnoid space, this formulation is strictly indicated only for local anesthesia by infiltration and peripheral nerve block. It is explicitly contraindicated for lumbar or caudal epidural anesthesia.[16]
• Nesacaine-MPF® (Methylparaben-Free): Available in 2% and 3% solutions in single-dose vials, this formulation is free of preservatives like methylparaben.[16] Its preservative-free nature allows for a broader range of applications, including infiltration, peripheral nerve block, and central neuraxial blocks such as lumbar and caudal epidural anesthesia.[2]
• Clorotekal®: This is a 1% (10 mg/mL) preservative-free, sterile, isotonic solution specifically developed, formulated, and approved by the FDA for intrathecal (spinal) anesthesia in adults.[4] Its approval marked a significant milestone in re-establishing the safety of chloroprocaine for subarachnoid administration.
• Ophthalmic Formulation:
• Iheezo®: A 3% ophthalmic gel, Iheezo® is the first topical formulation of chloroprocaine approved for ocular surface anesthesia. It provides rapid anesthesia (onset in 1-1.5 minutes) for short ophthalmic procedures.[4]

The history of chloroprocaine vividly illustrates that formulation can be a critical determinant of drug safety. In the 1980s, reports of permanent neurological injury after large, accidental intrathecal injections of chloroprocaine intended for epidural use led to its withdrawal from spinal anesthesia for many years.[2] Subsequent research suggested that the neurotoxic effects were not caused by chloroprocaine itself but were instead linked to the high concentration of the drug combined with the low pH and the presence of preservatives, particularly the antioxidant sodium bisulfite, in the older epidural formulations.[9] This understanding paved the way for the development of modern, preservative-free, pH-balanced formulations. The eventual FDA approval of Clorotekal® for intrathecal use in 2017 was the culmination of this reformulation effort, officially validating the safety of preservative-free chloroprocaine for neuraxial anesthesia and marking its full clinical rehabilitation.[21] This history serves as a crucial lesson in clinical pharmacology: the excipients within a formulation can be as clinically significant as the active pharmaceutical ingredient, a fact clearly reflected in the distinct and non-interchangeable indications for Nesacaine® and its preservative-free counterparts.

Clinical Pharmacology

Mechanism of Action

Chloroprocaine is a membrane-stabilizing agent that produces local anesthesia by reversibly blocking nerve impulse generation and conduction.[16] Its primary molecular target is the voltage-gated sodium channel, which is essential for the propagation of action potentials along nerve axons.[1]

The mechanism involves several key steps. First, the non-ionized, lipid-soluble form of the chloroprocaine molecule must diffuse across the lipid-rich nerve cell membrane to access the axoplasm.[9] Once inside the cell, it re-equilibrates, and the cationic (ionized) form of the drug binds to a specific receptor site on the inner (cytoplasmic) portion of the alpha subunit of the voltage-gated sodium channel.[9] This binding action locks the channel in its inactivated state, preventing the conformational change required for channel opening. By blocking this channel, chloroprocaine prevents the large, transient influx of sodium ions that underlies the rapid depolarization phase of the action potential.[9] The net effect is an increase in the threshold for electrical excitation, a slowing of the rate of nerve impulse propagation, and a reduction in the rate of rise of the action potential, culminating in a complete, albeit reversible, conduction blockade.[1]

Pharmacodynamics

The clinical effects of chloroprocaine are a direct result of its interaction with sodium channels and are characterized by a rapid onset, short duration, and a predictable pattern of sensory and motor blockade.

• Differential Blockade: Like other local anesthetics, chloroprocaine exhibits a differential blockade, meaning it affects different types of nerve fibers at different rates and concentrations, largely based on fiber diameter and myelination status.[9] Small, unmyelinated fibers that transmit autonomic signals (sympathetic block) and pain/temperature sensations are blocked first and at the lowest concentrations. Larger fibers responsible for touch, pressure, proprioception, and finally, motor function are progressively more resistant and require higher concentrations for blockade.[7] This results in a clinically observable progression of anesthesia, beginning with a loss of pain and temperature sensation, followed by loss of touch and proprioception, and culminating in skeletal muscle paralysis.[16]
• Onset of Action: The onset of anesthesia with chloroprocaine is notably rapid, typically occurring within 6 to 12 minutes following administration.[1] This rapid onset presents a pharmacological paradox. The drug's high pKa of ~8.7 means that at physiological pH, very little of the drug exists in the non-ionized form required to cross the nerve membrane.[9] This property should theoretically result in a slow onset. The paradox is resolved by considering the drug's exceptional safety profile, which stems from its ultra-rapid metabolism. Because the risk of systemic toxicity is very low, clinicians can safely administer chloroprocaine in high concentrations (e.g., 2% or 3% solutions).[9] This high initial concentration creates a steep diffusion gradient across the nerve sheath, which drives a sufficient absolute quantity of the non-ionized fraction into the nerve to initiate a block quickly, effectively compensating for the unfavorable ionization ratio.[9]
• Potency and Duration of Action: Chloroprocaine's intrinsic potency is low, a direct consequence of its relatively low lipid solubility (low logP).[9] More lipophilic drugs can more easily partition into the nerve membrane, leading to higher potency. Furthermore, the duration of action of local anesthetics is strongly correlated with their degree of protein binding, which serves as a surrogate for their affinity for the sodium channel protein receptor. Chloroprocaine has the lowest protein binding of all clinically used local anesthetics and, consequently, is among the shortest in its duration of action.[9] The anesthetic effect typically lasts for up to 60 minutes, depending on the dose, concentration, and specific block performed.[15]

Pharmacokinetics

The pharmacokinetic profile of chloroprocaine is unique among local anesthetics and is the primary determinant of its clinical utility and safety.

• Absorption: Systemic absorption from the injection site is influenced by factors such as the vascularity of the tissue, the total dose administered, and the co-administration of vasoconstrictors like epinephrine. However, the clinical impact of systemic absorption is significantly attenuated by the drug's rapid metabolism.[1]
• Distribution: Once absorbed systemically, chloroprocaine is distributed throughout the body, with higher concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.[15]
• Metabolism: The metabolism of chloroprocaine is its most defining pharmacokinetic feature. As an ester-type local anesthetic, it is rapidly and extensively hydrolyzed in the plasma by the enzyme pseudocholinesterase (also known as plasma cholinesterase or butyrylcholinesterase).[5] This process is remarkably efficient, with an in vitro plasma half-life of only 21 to 25 seconds in adults and 43 seconds in neonates.[2] This ultra-rapid clearance is the cornerstone of its safety profile, as it prevents the accumulation of the drug in the plasma and minimizes the risk of systemic toxicity.[9] The primary metabolites produced by this hydrolysis are 2-chloro-4-aminobenzoic acid (ACBA) and β-diethylaminoethanol.[1]
• Excretion: The metabolites, ACBA and β-diethylaminoethanol, are primarily eliminated from the body via renal excretion.[1] Very little chloroprocaine is excreted as the unchanged parent drug in the urine.[24]

This unique pharmacokinetic profile is not merely a descriptive characteristic; it is the central factor that dictates chloroprocaine's entire clinical role. Its rapid metabolism confers a wide margin of safety against systemic toxicity, which is a major concern with more slowly metabolized amide-type anesthetics. This safety allows for the use of high concentrations needed for a rapid onset. In obstetrics, this rapid maternal metabolism is a profound advantage, as it severely limits the amount of active drug that can cross the placenta and affect the fetus.[2] Unlike amide anesthetics, which can become "trapped" in an ionized state in an acidotic fetus, ester-linked chloroprocaine is rapidly cleared from the maternal circulation, making it a preferred agent when fetal distress is a concern.[2]

However, this metabolic pathway also introduces a specific pharmacological limitation. One of the primary metabolites, ACBA, is structurally similar to para-aminobenzoic acid (PABA).[5] PABA is a known antagonist of sulfonamide antibiotics, which work by inhibiting bacterial folic acid synthesis. The presence of the PABA-like ACBA metabolite can therefore competitively inhibit the action of sulfonamides, potentially rendering them ineffective.[5] This creates a clinically significant drug interaction and forms the basis for the recommendation to avoid chloroprocaine in patients being treated with sulfonamide drugs. Furthermore, this PABA-like structure is the reason for the contraindication of chloroprocaine in patients with a known allergy to the PABA ester group of drugs.[16]

Clinical Applications and Efficacy

Approved Indications and Off-Label Use

The clinical indications for chloroprocaine are highly dependent on the specific commercial formulation, with the presence or absence of preservatives being the key differentiating factor for neuraxial applications.

Table 2: FDA-Approved Formulations, Brand Names, and Indications for Chloroprocaine
Brand Name	Formulation	FDA-Approved Indication(s)
Nesacaine® 4	1% and 2% Injection with methylparaben 16	Production of local anesthesia by infiltration and peripheral nerve block. CONTRAINDICATED for lumbar or caudal epidural anesthesia.16
Nesacaine-MPF® 4	2% and 3% Injection, methylparaben-free 16	Production of local anesthesia by infiltration, peripheral nerve block, and central nerve block (including lumbar and caudal epidural blocks).2
Clorotekal® 4	1% (10 mg/mL) Injection, preservative-free 18	Intrathecal injection in adults for the production of subarachnoid block (spinal anesthesia) for short-duration surgical procedures.1
Iheezo® 4	3% Ophthalmic Gel 19	Ocular surface anesthesia prior to ophthalmic surgical procedures.4

The range of applications is broad. For peripheral nerve blocks, it can be used for procedures such as brachial plexus, intercostal, sciatic, pudendal, and paracervical blocks.[2] Its most common application in central neuraxial anesthesia is in obstetrics, where the preservative-free 3% solution is often used to rapidly extend an existing epidural block for an urgent Cesarean section.[9] A recent study also highlighted the efficacy of 1.5% epidural chloroprocaine for managing breakthrough pain during labor analgesia.[27] The approval of Clorotekal® has solidified its role in spinal anesthesia for short procedures (up to 40 minutes) in the ambulatory setting.[2]

Administration and Dosage Guidelines

The administration of chloroprocaine requires careful attention to dosage, concentration, and technique to ensure efficacy while minimizing the risk of toxicity. The guiding principle is to use the lowest dosage and concentration required to produce the desired anesthetic effect.[16] Doses should be reduced for elderly, debilitated, and pediatric patients, as well as those with significant cardiovascular disease.[24]

Table 3: Recommended Dosage Guidelines for Anesthetic Procedures with Chloroprocaine
Anesthetic Procedure	Recommended Concentration	Recommended Volume/Dose	Maximum Recommended Dose (Adults)
Spinal Anesthesia (Clorotekal®)	1%	50 mg (5 mL) for T10 block 18	50 mg 18
Lumbar Epidural Anesthesia (Nesacaine-MPF®)	2% or 3%	15 - 25 mL total volume (2 - 2.5 mL per segment) 17	Without epinephrine: 11 mg/kg (max 800 mg) 16
Brachial Plexus Block	2%	30 - 40 mL (600 - 800 mg) 16	With epinephrine: 14 mg/kg (max 1000 mg) 16
Pudendal Block	2%	10 mL per side (400 mg total) 16
Infiltration (Pediatric, >3 years)	0.5% - 1%	Dose varies	11 mg/kg 24
Peripheral Nerve Block (Pediatric, >3 years)	1% - 1.5%	Dose varies	11 mg/kg 24

For epidural administration, a test dose is critically important to detect accidental intravascular or subarachnoid injection. A typical test dose is 3 mL of 3% or 5 mL of 2% Nesacaine-MPF®.[15] Injections should always be made slowly with frequent aspiration to avoid intravascular administration.[16]

Comparative Efficacy Analysis (vs. Lidocaine and Bupivacaine)

The clinical value of chloroprocaine is best understood in comparison to other commonly used local anesthetics, particularly lidocaine and bupivacaine, in the context of neuraxial anesthesia for short-duration surgery. The rise of ambulatory (day-case) surgery has created a strong demand for an ideal spinal anesthetic—one that provides a rapid, reliable block but also allows for swift patient recovery and discharge.[2] In this specific niche, chloroprocaine has emerged as a superior agent by overcoming the limitations of its main competitors.

Lidocaine, while offering a rapid onset and short duration, has fallen out of favor for spinal anesthesia due to its association with an unacceptably high incidence of Transient Neurologic Symptoms (TNS), a painful condition characterized by pain or dysesthesia in the buttocks and lower extremities after the block resolves.[20] Bupivacaine is a reliable alternative that avoids TNS, but its long duration of action, particularly its prolonged motor block, significantly delays patient ambulation, urination, and ultimate hospital discharge, making it suboptimal for an efficient ambulatory setting.[28]

Chloroprocaine effectively solves this clinical dilemma. Multiple comparative studies have demonstrated its distinct advantages:

• Onset of Action: Chloroprocaine provides a motor block onset that is significantly faster than bupivacaine, while its sensory block onset is comparable to or faster than bupivacaine and lidocaine.[20]
• Recovery and Discharge: This is the defining advantage of chloroprocaine. Clinical trials consistently show that patients receiving spinal chloroprocaine have a significantly shorter time to complete recovery of both sensory and motor function compared to those receiving either lidocaine or bupivacaine.[30] This translates directly into superior clinical outcomes for ambulatory surgery: significantly shorter times to unaided ambulation, spontaneous urination, and readiness for hospital discharge when compared to bupivacaine.[20]
• Safety Profile: The modern, preservative-free formulation of chloroprocaine has a very low incidence of TNS, making it a much safer alternative to lidocaine in this regard.[21]

The one notable trade-off is that due to its short duration, chloroprocaine provides less postoperative analgesia than a longer-acting agent like bupivacaine, meaning patients may require systemic rescue analgesics sooner.[30] However, in the context of ambulatory surgery, this is often considered an acceptable compromise for the substantial benefits of faster functional recovery and earlier discharge.

Table 4: Comparative Profile of Chloroprocaine, Lidocaine, and Bupivacaine for Spinal Anesthesia
Parameter	Chloroprocaine	Lidocaine	Bupivacaine
Onset of Action	Rapid (motor faster than bupivacaine) 20	Rapid 28	Slower than chloroprocaine/lidocaine 20
Duration of Motor Block	Very Short (~40-60 min) 2	Short 29	Long (>2 hours) 28
Time to Ambulation/Discharge	Fastest 1	Faster than bupivacaine 30	Slowest (prolonged recovery) 28
Potency	Low 9	Intermediate	High
Key Adverse Effect Profile	Low risk of TNS; shorter post-op analgesia 21	High risk of TNS 20	Low risk of TNS; risk of prolonged motor block and urinary retention 28

Safety, Tolerability, and Risk Management

Adverse Drug Reactions

The adverse reactions associated with chloroprocaine are similar to those of other local anesthetics and are primarily related to excessive plasma concentrations or the physiological consequences of the anesthetic technique itself.

Table 5: Summary of Adverse Drug Reactions by System Organ Class
System Organ Class	Adverse Reactions
Nervous System Disorders	Systemic (Dose-Related): Restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, shivering, progressing to seizures, drowsiness, unconsciousness, coma, and respiratory arrest.1
Cardiac Disorders	Systemic (Dose-Related): Myocardial depression, bradycardia, ventricular arrhythmias, cardiac arrest.31
Vascular Disorders	Systemic/Neuraxial: Hypotension.18
Immune System Disorders	Allergic: Rash, itching, hives (urticaria), angioedema (swelling of face, lips, throat), sneezing, anaphylaxis.15
Blood and Lymphatic System Disorders	Methemoglobinemia: Cyanosis (pale, gray, or blue skin/lips), confusion, headache, tachycardia, fatigue (rare).16
Gastrointestinal Disorders	Nausea, vomiting.31
Renal and Urinary Disorders	Loss of bladder control, difficulty passing urine (dribbling), painful urination.31
Reproductive System and Breast Disorders	Loss of genital sensation and sexual function, abnormal ejaculation.32
General Disorders	Excessive sweating, elevated temperature, shivering, feeling of heat.31

Systemic reactions are the most common acute adverse events and are generally dose-dependent. They typically result from rapid systemic absorption, accidental intravascular injection, or diminished patient tolerance (e.g., due to acidosis or plasma cholinesterase deficiency).[15] Complications specific to neuraxial anesthesia, such as a high spinal block, can lead to profound cardiovascular and respiratory depression due to extensive blockade of sympathetic and respiratory motor nerves.[18]

Contraindications, Warnings, and Precautions

Safe use of chloroprocaine requires adherence to specific contraindications and precautions.

• Absolute Contraindications:
• Known hypersensitivity to chloroprocaine, other PABA ester-group anesthetics, or any excipients in the formulation.[16]
• General contraindications to neuraxial anesthesia, including local infection at the puncture site, septicemia, serious cardiac conduction problems, and severe hypotension.[18]
• Formulation-Specific Contraindications:
• Formulations containing preservatives (e.g., Nesacaine® with methylparaben) are strictly contraindicated for epidural or spinal administration.[16]
• Nesacaine® and Nesacaine-MPF® are not intended for subarachnoid (spinal) administration.[16]
• Warnings and Precautions:
• Resuscitative equipment, oxygen, and emergency drugs must be immediately available whenever local anesthetics are administered.[16]
• Extreme caution is advised when performing epidural anesthesia in patients with pre-existing neurological disease, spinal deformities, severe hypertension, or sepsis.[16]
• Patients with a genetic deficiency in plasma cholinesterase may have a diminished tolerance to ester anesthetics, leading to a prolonged block and increased risk of toxicity.[31]
• There is a risk of methemoglobinemia, particularly in infants under 6 months of age and patients with specific enzyme deficiencies (e.g., G6PD deficiency).[32]

Drug-Drug Interactions

Several clinically significant drug interactions can occur with chloroprocaine:

• Sulfonamides: The ACBA metabolite of chloroprocaine can inhibit the antibacterial action of sulfonamides. Concurrent use should be avoided.[1]
• Methemoglobinemia-Inducing Agents: The risk of methemoglobinemia is increased when chloroprocaine is used concurrently with other agents known to cause this condition, such as nitrates/nitrites, dapsone, and other local anesthetics.[31]
• Vasopressors: Co-administration of local anesthetic solutions containing vasopressors (e.g., epinephrine) with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants may result in severe, prolonged hypertension.[31]
• Hyaluronidase: When added to local anesthetic solutions, hyaluronidase hastens the onset of analgesia but also increases systemic absorption, which shortens the duration of action and increases the risk of systemic reactions.[17]

The History and Resolution of Neurotoxicity Concerns

The clinical history of chloroprocaine is marked by a significant safety controversy that has since been resolved through advances in pharmaceutical formulation. In the early 1980s, several case reports emerged describing prolonged or permanent neurological deficits, including cauda equina syndrome, following the administration of chloroprocaine for epidural anesthesia.[2] These reports led to widespread concern about the drug's intrinsic neurotoxicity and caused it to fall out of favor for neuraxial use for many years.[20]

However, further investigation revealed a more complex picture. It became apparent that these neurological injuries were not associated with routine epidural use but occurred after accidental, massive-dose injections into the subarachnoid space (i.e., unintentional spinal anesthesia with a large epidural dose).[2] The neurotoxicity was ultimately attributed not to the chloroprocaine molecule itself, but to the formulation's excipients. The older epidural solutions had a low pH and contained the antioxidant preservative sodium bisulfite, which was subsequently shown in animal models to be neurotoxic when applied directly to neural tissue at high concentrations.[2]

This understanding prompted the development of new, preservative-free formulations of chloroprocaine with a pH closer to physiological levels.[20] Extensive preclinical and clinical research on these new formulations demonstrated a lack of neurotoxic effects, even with intrathecal administration, paving the way for the drug's reintroduction into neuraxial practice.[20] The culmination of this decades-long effort was the FDA's approval of Clorotekal®, a preservative-free chloroprocaine solution, specifically for spinal anesthesia in 2017.[21] This regulatory validation officially resolved the historical safety concerns and confirmed that, when properly formulated and dosed, chloroprocaine is a safe and effective agent for modern neuraxial anesthesia.

Use in Specific Patient Populations

Obstetrics and Perinatal Care

Chloroprocaine holds a prominent and vital role in modern obstetric anesthesia, largely due to its favorable pharmacokinetic profile. It is frequently used to provide rapid and effective epidural anesthesia for urgent or emergent Cesarean deliveries, especially when a laboring patient already has an epidural catheter in place.[9]

The primary advantage in this population is its ultra-rapid metabolism in maternal plasma. This rapid hydrolysis severely limits the amount of active drug that crosses the placenta, thereby minimizing fetal exposure and the risk of neonatal toxicity.[2] The

in vitro plasma half-life in neonates is short (43 seconds), though longer than in adults.[15] This safety margin is particularly crucial in cases of fetal distress. Amide-type local anesthetics can cross the placenta and, in the presence of fetal acidosis, can become "ion-trapped" in their ionized form on the fetal side, leading to accumulation and potential toxicity. Chloroprocaine, being an ester, is rapidly metabolized before significant placental transfer can occur and is not subject to this ion-trapping phenomenon, making it a drug of choice when the fetus is compromised.[2]

However, like any regional anesthetic technique in obstetrics, its use requires careful monitoring. Maternal hypotension is a common side effect, and continuous monitoring of maternal vital signs and fetal heart rate is essential.[25] The anesthetic block may also alter the forces of parturition and prolong the second stage of labor.[25] It is not known if chloroprocaine is excreted in human milk, but given its rapid maternal metabolism, significant adverse effects on a breastfed infant are considered highly unlikely.[9]

Pediatric Anesthesia

The use of chloroprocaine in the pediatric population requires caution and precise dosing. Its safety and efficacy have not been established in children younger than 3 years of age.[25] For children aged 3 years and older, the dose must be carefully calculated based on the patient's age and weight and should not exceed a maximum of 11 mg/kg.[24] To minimize the risk of systemic toxicity in this vulnerable population, it is recommended to use the lowest effective concentrations, typically 0.5% to 1% for infiltration and 1% to 1.5% for peripheral nerve blocks.[17]

Geriatric and Debilitated Patients

Elderly and debilitated patients often exhibit altered pharmacokinetics and may have a heightened sensitivity to the systemic effects of local anesthetics. Therefore, dosages of chloroprocaine should be reduced in these populations.[24] Caution is particularly warranted in elderly patients with co-existing conditions such as severe hypertension, advanced cardiac disease, or significant hepatic or renal impairment, as these can further diminish their tolerance to the drug.[24]

Regulatory and Commercial Landscape

FDA Approval History

Chloroprocaine has a long history of use in the United States, with initial approvals for Nesacaine® dating back to before 1982, possibly as early as 1955.[21] However, its modern clinical role has been shaped by a series of recent, significant FDA approvals that reflect its resurgence based on reformulated, preservative-free preparations.

• September 26, 2017: The FDA approved Clorotekal® (manufactured by Sintetica S.A. and marketed by B. Braun Medical).[21] This approval was a landmark event, as it was for a 1% preservative-free solution specifically indicated for intrathecal (spinal) anesthesia in adults. It officially marked the end of the long-standing neurotoxicity concerns and re-established chloroprocaine as a safe and valuable option for spinal anesthesia after decades of disuse in this application.[21]
• September 27, 2022: The FDA approved Iheezo® (marketed by Harrow). This approval was for a 3% ophthalmic gel for ocular surface anesthesia. It represented two milestones: it was the first ophthalmic formulation of chloroprocaine to be approved, and it was the first branded ocular anesthetic to be approved in the U.S. market in nearly 14 years, signaling an expansion of chloroprocaine's utility into a new therapeutic area.[19]

Commercial Preparations and Manufacturers

Chloroprocaine is available in the United States under several brand names and as a generic product, marketed by a number of pharmaceutical companies.

• Brand Names: Clorotekal®, Iheezo®, Nesacaine®, Nesacaine-MPF®.[4]
• Primary Marketers and Manufacturers:
• Fresenius Kabi USA: Nesacaine® and Nesacaine-MPF® [35]
• Hikma Pharmaceuticals USA: Generic Chloroprocaine HCl injections [36]
• B. Braun Medical: Clorotekal® [36]
• Harrow: Iheezo® [19]
• Hospira (a Pfizer company) is also listed as a marketer of chloroprocaine products.[36]

Conclusion and Future Perspectives

Chloroprocaine is a unique local anesthetic whose entire clinical profile—its rapid onset, short duration, and exceptional safety—is dictated by its defining feature: ultra-rapid hydrolysis by plasma pseudocholinesterase. This pharmacokinetic property provides a robust defense against systemic toxicity, a critical advantage that allows for the administration of high drug concentrations. This, in turn, enables a rapid onset of anesthesia, effectively overcoming the kinetic barrier imposed by the molecule's high pKa.

After a period of clinical disfavor stemming from now-resolved neurotoxicity concerns linked to preservatives in older formulations, chloroprocaine has undergone a significant and well-deserved renaissance. The development and validation of preservative-free preparations have not only restored confidence in its safety for neuraxial anesthesia but have also positioned it as a first-line agent for specific, modern clinical needs. Today, chloroprocaine is recognized as an ideal anesthetic for the high-turnover environment of ambulatory surgery, where its ability to provide a reliable, short-duration block with the fastest recovery profile among common agents facilitates procedural efficiency and timely patient discharge. Its established role in obstetrics as a safe, rapid-acting agent for urgent procedures remains a cornerstone of its utility.

The recent FDA approval of a topical ophthalmic formulation demonstrates the ongoing innovation and expansion of chloroprocaine's clinical applications. It stands as a compelling example of how the careful reformulation of an established drug can address historical safety issues and meet the evolving demands of contemporary medical practice, transforming an older molecule into a new standard of care. Future perspectives may involve exploring its utility in other clinical scenarios where a profound, rapid, and brief anesthetic effect is advantageous.

Works cited

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