Bupivacaine

Mechanism of Action

All local anesthetics consist of 3 structural components: a lipophilic aromatic ring, an intermediate connecting chain containing either an ester (eg, procaine) or an amide linkage (eg, bupivacaine), and a hydrophilic ionizable amine group. These structural features determine their pharmacokinetic and pharmacodynamic properties.

Two key physicochemical properties influence the activity of local anesthetics: lipid solubility and the ionization constant (pKa). Lipid solubility primarily correlates with anesthetic potency, while protein binding is a major determinant of duration of action. Local anesthetics exist in equilibrium between ionized and unionized forms. The unionized (lipid-soluble) form facilitates diffusion across neuronal membranes, whereas the ionized (cationic) form binds to voltage-gated sodium (Na⁺) channels on the intracellular surface, thereby inhibiting ion conduction. Agents with a lower pKa have a faster onset of action, as a greater proportion exists in the unionized form at physiological pH.

Voltage-gated Na⁺ channels are transmembrane proteins responsible for the initiation and propagation of action potentials in excitable tissues, including neurons, cardiac myocytes, and skeletal muscle. Structurally, these channels consist of a large α-subunit (which forms the ion-conducting pore) and one or more auxiliary β-subunits. The α-subunit comprises 4 homologous domains, each containing 6 transmembrane segments. The extracellular surface is glycosylated, facilitating proper channel orientation within the membrane. In contrast to local anesthetics, toxins such as tetrodotoxin and scorpion venom bind to extracellular sites on the Na⁺ channel.[3]

Local anesthetics exert their effect by reversibly binding to voltage-gated Na⁺ channels, preferentially in their open and inactivated states, thereby reducing Na⁺ permeability and preventing depolarization. This results in inhibition of action potential propagation and nerve impulse conduction. In peripheral nerves, effective blockade requires inhibition of conduction across at least 2 to 3 consecutive nodes of Ranvier. Smaller, myelinated fibers are more susceptible to blockade because of their shorter internodal distances.

Local anesthetics not only have neural effects, but they also affect other excitable tissues in the body. In vascular smooth muscle, vasodilation may occur through direct smooth muscle relaxation and modulation of autonomic tone. In cardiac tissue, Na⁺ channel blockade reduces the rate of depolarization (Vmax), decreases pacemaker activity, and prolongs refractory periods. Bupivacaine, in particular, exhibits high affinity and slow dissociation from cardiac Na⁺ channels, contributing to its increased risk of cardiotoxicity, including ventricular arrhythmias. At higher concentrations, local anesthetics may also inhibit calcium (Ca^²+) and potassium (K⁺) channels, leading to dose-dependent myocardial depression.

In the central nervous system (CNS), local anesthetics initially produce excitation by selectively inhibiting inhibitory pathways, followed by generalized CNS depression at higher concentrations.[4]

Pharmacokinetics

Absorption: Systemic absorption of bupivacaine depends on the total dose and concentration administered, the route of administration, the vascularity of the site of administration, and the presence or absence of epinephrine in the anesthetic solution. The addition of epinephrine may reduce the rate of absorption and peak plasma concentration, thereby prolonging the duration of action.

Distribution: Following absorption, bupivacaine is distributed widely throughout body tissues. The drug is highly bound to plasma proteins, primarily alpha-1-acid glycoprotein. Bupivacaine crosses the placenta by passive diffusion.

Metabolism: Bupivacaine is metabolized in the liver. The rate of metabolism may be affected by hepatic function, and reduced hepatic function may result in increased plasma concentrations and prolonged elimination.

Elimination: Bupivacaine is excreted primarily via the kidneys as metabolites, with a small fraction excreted unchanged. The elimination half-life in adults is approximately 2.7 hours, but may be prolonged in neonates and in patients with impaired hepatic function.

Administration

Available Dosage Forms and Strengths

Bupivacaine is available in preservative-free single-use or multidose formulations as listed below.

Injection solutions (as hydrochloride)

• Marcaine: 0.25% (50 mL) and 0.5% (50 mL) (contains methylparaben)
• Sensorcaine: 0.25% (50 mL) and 0.5% (50 mL) (contains methylparaben)
• Generic: 0.25% (50 mL) and 0.5% (30 mL, 50 mL)

Preservative-free injection solutions (as hydrochloride)

• Bupivacaine Fisiopharma: 2.5 mg/mL (5 mL, 10 mL) and 0.5% (5 mL, 10 mL)
• Marcaine preservative-free: 0.25% (10 mL, 30 mL), 0.5% (10 mL, 30 mL), and 0.75% (30 mL)
• Sensorcaine-MPF (methylparaben-free): 0.25% (10 mL, 30 mL), 0.5% (10 mL, 30 mL), and 0.75% (10 mL, 30 mL)
• Generic (preservative-free): 0.25% (10 mL, 30 mL), 0.5% (10 mL, 30 mL), and 0.75% (10 mL, 30 mL)

Intrathecal (spinal) solutions (preservative-free)

• BUPivacaine spinal: 0.75% (7.5 mg/mL, 2 mL)
• Marcaine spinal: 0.75% (7.5 mg/mL, 2 mL)
• Generic: 0.75% (7.5 mg/mL, 2 mL)

Adult Dosage

Dose varies based on procedure, depth, tissue vascularity, duration, and patient condition. Preservative-containing solutions should not be used for caudal or epidural block.

Table 2. Adult Dosage of Bupivacaine by Indication, Concentration, and Route of Administration

Abbreviations: IV, intravenous; PF, preservative-free.

Administration of bupivacaine includes local infiltration (eg, postsurgical analgesia), peripheral nerve blocks (for dental or other minor surgical procedures, including orthopedic surgery), spinal anesthesia (injected into the cerebrospinal fluid [CSF] for procedures such as orthopedic or abdominal surgery and cesarean delivery), epidural anesthesia or analgesia for labor pain, and caudal block (providing anesthesia and analgesia below the umbilicus, commonly in pediatric surgery).[5] 

Adjuvants are often added to local anesthetics to prolong the duration of nerve block compared with local anesthetics alone. Alpha-2 agonists such as clonidine and dexmedetomidine have been shown to significantly extend the duration of anesthesia. Additionally, dexamethasone, when mixed with the local anesthetic for nerve blocks, has been shown to increase the duration of anesthesia. However, the mechanism is unclear: whether it is a direct neural effect or simply the systemic effect of the steroid's anti-inflammatory processes. Magnesium has also been associated with a prolonged duration of action of local anesthetics during nerve blocks, likely due to its N-methyl-D-aspartate (NMDA) receptor antagonist effects. Ongoing studies continue to evaluate the effects of these and other potential adjuvants to local anesthetics to enhance efficacy while minimizing toxicity risk.[6]

In the last decade, it has been shown that ultrasound-guided nerve blocks are associated with a decreased risk of local anesthetic systemic toxicity (LAST). Presumably, visualization of the nerve and surrounding structures decreases the likelihood of injecting into a vascular structure and increases early recognition of this occurrence, thereby reducing the risk of reaching toxic levels of bupivacaine in the bloodstream.[7]

Liposomal bupivacaine is a newer formulation of the drug, which creates a sustained-release formulation. Bupivacaine is encapsulated in multivesicular liposomes, allowing for gradual release at the site and providing prolonged analgesia lasting 72 to 96 hours.[8][9][10][11][12] Studies comparing the efficacy of this technique with other methods for prolonged analgesia have yielded mixed results, and further evaluations are ongoing. Mixing liposomal preparations with other local anesthetics should be done cautiously. Liposomal bupivacaine may be mixed with standard bupivacaine. However, coadministration with lidocaine can cause rapid release of bupivacaine, potentially increasing the risk of local anesthetic toxicity.[13]

Specific Patient Populations

Hepatic impairment: Although specific dosage adjustments are not provided in the manufacturer’s labeling, bupivacaine is extensively metabolized in the liver, and patients with hepatic impairment may be at increased risk of systemic toxicity. Therefore, cautious use and close monitoring are recommended. In patients with moderate or severe hepatic impairment, dose reduction may be considered, along with close monitoring for signs of systemic toxicity.

Renal impairment: No dosage adjustments are provided in the manufacturer’s labeling.

Pregnancy considerations: Bupivacaine crosses the placenta and may result in maternal, fetal, or neonatal effects involving the CNS and cardiovascular systems. This is commonly used in obstetric anesthesia and analgesia, including labor epidural anesthesia, cesarean delivery, and pudendal nerve block. However, use of a paracervical block is contraindicated due to the risk of fetal bradycardia. Higher concentrations, particularly 0.75%, are not recommended in obstetric patients because of the increased risk of severe cardiotoxicity, including cardiac arrest following systemic toxicity.

Breastfeeding considerations: According to the manufacturer's recommendations, the decision to breastfeed during bupivacaine therapy should balance potential infant exposure with the benefits of breastfeeding and maternal treatment. The Academy of Breastfeeding Medicine considers local anesthetics, including bupivacaine, to be compatible with breastfeeding. When feasible, elective procedures may be deferred until lactation is established, and expressing milk before surgery may be considered. In general, breastfeeding may be resumed once the mother has recovered from anesthesia; however, additional caution may be warranted in infants at higher risk for respiratory or cardiovascular instability.[14]

Older patients: Bupivacaine should be used with caution in this population; dose reduction may be required.

Adverse Effects

Immunologic reactions to local anesthetics are rare. Allergic reactions to preservative-free amide-type local anesthetics are rare and usually not reported. True anaphylactic response appears to be more common with ester local anesthetics or preservatives, whereas reactions to epinephrine-containing local anesthetics are often misdiagnosed as allergic reactions. Patients may also react to preservatives, such as methylparaben, included in local anesthetic formulations.

Frequently reported adverse reactions occurring in more than 10% of patients include pruritus (ocular and anorectal), gastrointestinal effects such as constipation, dysgeusia, nausea, and vomiting, nervous system effects such as dizziness, drowsiness, headache, and paresthesia, and tinnitus. Other common adverse effects of bupivacaine involve the CNS and cardiovascular systems. Early manifestations may include tinnitus, blurred vision, chills or shivering, back pain, anxiety, vertigo, restlessness, and tremors, which may progress to convulsions, coma, and cardiovascular collapse in cases of systemic toxicity.[2]

Warnings and Precautions

Risk of cardiac arrest in obstetrical anesthesia: Resuscitation has often been challenging or unsuccessful, even with proper preparation and management. Cardiac arrest has occurred following convulsions due to systemic toxicity, typically after accidental IV injection. The 0.75% (7.5 mg/mL) concentration of bupivacaine hydrochloride injection is not recommended for obstetrical anesthesia and should be used only for surgical procedures requiring deep muscle relaxation and a long-lasting effect.

Methemoglobinemia: Methemoglobinemia has been reported with local anesthetics. Although all patients are at risk, certain populations may be more susceptible, including patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, infants younger than 6 months, patients with pulmonary or cardiac compromise, and those concurrently exposed to oxidizing agents. In these at-risk populations, if local anesthetics are required, careful monitoring for signs and symptoms of methemoglobinemia is recommended.

Symptoms may appear immediately or may be delayed by several hours after exposure. The symptoms typically include bluish discoloration of the skin (cyanosis) and/or abnormal blood color. Methemoglobin levels can continue to rise, making prompt intervention essential to prevent serious CNS and cardiovascular complications such as seizures,  arrhythmias, coma, or death. Bupivacaine hydrochloride injection and any other oxidizing agents should be discontinued. Depending on symptom severity, patients may respond to supportive measures such as oxygen therapy and hydration. Severe cases may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen therapy. 

Risk of systemic toxicities with unintended intravascular or intrathecal injection: Accidental injection of bupivacaine hydrochloride into a blood vessel or the intrathecal space can lead to systemic toxicities, such as CNS or cardiorespiratory depression, coma, and, ultimately, respiratory arrest. Unintentional intrathecal injection during procedures intended as caudal, lumbar epidural, or paraspinal nerve blocks may result in inadequate ventilation or apnea, referred to as “total” or “high spinal.” This severe complication may lead to bradycardia, lower extremity paralysis, loss of consciousness, and respiratory paralysis. To minimize this risk, aspiration for blood or CSF should be performed before administration of each dose of bupivacaine hydrochloride injection. However, a negative aspiration does not guarantee that inadvertent intravascular or intrathecal injection will not occur.

Risk of toxicity in patients with hepatic impairment: As amide local anesthetics such as bupivacaine are metabolized in the liver, patients with moderate to severe hepatic impairment may be at increased risk of systemic toxicity, particularly with repeated dosing. Dose reduction and enhanced monitoring are recommended in these patients.

Risk in patients with impaired cardiovascular function: Bupivacaine hydrochloride injection should be administered at lower doses in patients with compromised cardiovascular function (such as hypotension or heart block) because these individuals may have a diminished ability to compensate for the effects of prolonged AV conduction. Close monitoring of blood pressure, heart rate, and electrocardiographic changes is essential.[15]

Drug-Drug Interactions

Bupivacaine may interact with ergot medications used for migraine headaches, blood thinners, antidepressants, or monoamine oxidase inhibitors.[16][17]

Local anesthetics: As toxic effects are cumulative, if it is necessary to use other local anesthetics together with bupivacaine hydrochloride injection, patients should be carefully monitored for signs of neurologic and cardiovascular toxicity associated with LAST.

Drugs associated with methemoglobinemia: The risk of developing methemoglobinemia is increased in patients receiving bupivacaine hydrochloride injection when it is used alongside certain other drugs, including other local anesthetics, as listed below.[18]

• Nitrates/nitrites: Nitric oxide, nitroglycerin, nitroprusside, and nitrous oxide
• Local anesthetics: Articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine
• Antineoplastic agents: Cyclophosphamide, flutamide, hydroxyurea, isofamide, and rasburicase
• Antibiotics: Dapsone, nitrofurantoin, para-aminosalicylic acid, and  sulfonamides
• Antimalarials: Chloroquine and primaquine
• Anticonvulsants: Phenobarbital, phenytoin, and sodium valproate
• Other drugs: Acetaminophen, metoclopramide, quinine, and sulfasalazine

Contraindications

Contraindications include hypersensitivity to the drug or its components, hypersensitivity to amide anesthetics, infection at the injection site, obstetric paracervical block, obstetric anesthesia using 0.75% concentration, intravenous (IV) regional anesthesia, and intra-articular continuous infusion. Clinicians should exercise caution in patients with sulfite hypersensitivity, hepatic impairment (because the liver clears amides), renal impairment, impaired cardiac function, heart block, hypovolemia, hypotension, and older, debilitated, or acutely ill patients.[19]

Box Warnings

Use of bupivacaine hydrochloride injection in obstetrical epidural anesthesia has been associated with rare cases of cardiac arrest, often following systemic toxicity due to inadvertent intravascular injection. These events have been reported more frequently with the 0.75% concentration, which is not recommended for obstetrical use and should be reserved for procedures requiring profound muscle relaxation.

Cardiac arrest with intravenous regional anesthesia (Bier Block): Cardiac arrest and death have been reported when bupivacaine has been used for IV regional anesthesia (Bier Block). Because there is insufficient information on safe dosing and administration techniques for bupivacaine hydrochloride injection using this method, its use is contraindicated in Bier Block procedures.

Adverse reactions with use in the head and neck area: Even small amounts of local anesthetics injected into the head and neck region (eg, retrobulbar or stellate ganglion blocks) can cause adverse effects resembling systemic toxicity, similar to those seen with accidental intravascular injection of larger doses. These include confusion, seizures, respiratory depression or arrest, and cardiovascular stimulation or depression. Such reactions may result from intra-arterial injection with retrograde flow to the brain, or from puncture of the optic nerve’s dural sheath during retrobulbar block, leading to anesthetic diffusion toward the midbrain. Procedures in these areas require extreme caution, close patient monitoring, and immediate access to resuscitation equipment, medicines, and trained personnel. Recommended dosages should not be exceeded.

Respiratory arrest in ophthalmic surgery: Respiratory arrest has been reported following retrobulbar blocks with local anesthetics. Before such procedures are performed, resuscitation equipment, medications, and trained personnel should be immediately available to manage potential respiratory or cardiac complications, as well as convulsions. Patients should be monitored continuously after ophthalmic blocks, as adverse reactions can occur even at relatively low doses. A 0.75% concentration of bupivacaine is approved for retrobulbar block but is not approved for other peripheral nerve blocks (including facial nerve blocks) or for local infiltration (such as conjunctival use).

Antimicrobial preservatives in multiple-dose vials: Bupivacaine hydrochloride injection solutions that contain antimicrobial preservatives (eg, those in multiple-dose vials) should not be used for epidural or caudal anesthesia, as their safety for these routes of administration has not been established.

Chondrolysis with intra-articular infusion: Intra-articular infusions of local anesthetics, including bupivacaine hydrochloride injection, following arthroscopic or other surgical procedures, are not approved. Postmarketing reports have identified cases of chondrolysis in patients receiving these infusions, most commonly involving the shoulder joint. Both pediatric and adult patients have developed glenohumeral chondrolysis after continuous intra-articular infusions lasting 48 to 72 hours. Whether shorter infusion durations carry the same risk remains unclear.

Symptoms such as joint pain, stiffness, and reduced range of motion can appear as early as 2 months following surgery. Effective treatment for chondrolysis does not exist, and affected patients often require further diagnostic or therapeutic intervention, with some ultimately needing arthroplasty or joint replacement surgery.

Monitoring

Standard monitoring required during the administration of bupivacaine includes:

• Continuous electrocardiographic monitoring
• SpO₂ monitoring
• Blood pressure monitoring

Patients should be instructed to report symptoms such as numbness around the lips or mouth, metallic taste, ringing in the ears, tremors, or ominous feelings, as these may indicate impending LAST. If any of these symptoms are reported, LAST should be considered, bupivacaine administration should be discontinued immediately, and treatment should proceed according to established guidelines.[2]

Dose-Related Toxicity

The safety and effectiveness of bupivacaine injection depend on the administration of the appropriate dose, proper technique, implementation of necessary precautions, and readiness to manage emergencies. Following administration, the patient’s cardiovascular and respiratory status (including adequacy of ventilation) and level of consciousness should be monitored continuously and carefully.

Early signs of CNS toxicity may include restlessness, anxiety, slurred speech, lightheadedness, metallic taste, perioral numbness or tingling, tinnitus, blurred vision, dizziness, tremors, muscle twitching, drowsiness, or CNS depression. Delayed recognition of toxicity, inadequate ventilation, or altered patient sensitivity may lead to acidosis, cardiac arrest, or death.

For major regional nerve blocks, such as brachial plexus or lower extremity blocks, IV access should be maintained with an indwelling catheter. The lowest effective dose should be used to minimize plasma concentrations and reduce the risk of serious adverse effects. Large volumes should not be injected rapidly; instead, the drug should be administered in small, incremental doses whenever possible. Repeated injections of bupivacaine hydrochloride may result in significant increases in plasma concentrations with each dose because of slow accumulation of the drug and its metabolites or reduced metabolic clearance. Tolerance to elevated blood concentrations varies according to the patient’s clinical condition. Older, debilitated adults or acutely ill patients should receive lower doses tailored for age and overall health status.

Toxicity

Most local anesthetics produce similar signs and symptoms of toxicity; however, the ratio of neurotoxicity to cardiotoxicity differs among agents, with bupivacaine having greater cardiotoxic potential. The reported incidence of toxicity is rare, ranging from approximately 1 in 1,000 to 1 in 10,000 cases. LAST should be suspected in patients presenting with abnormal cardiovascular or neurologic signs and symptoms.

The site of administration of a local anesthetic also influences the risk of toxicity. Unintended direct IV injection or rapid vascular uptake of the drug is the most common cause of bupivacaine toxicity, which has maximum dosing recommendations of 2.5 to 3.5 mg/kg. Depending on the vascularity of the injection site and the technique, toxicity of the medication can occur if administering the upper limit of the dosing recommendations. Signs and symptoms of toxicity may occur rapidly or be delayed and typically present as neurologic or cardiovascular symptoms.  

Rarely, patients may develop bupivacaine toxicity at doses well below the recommended upper dosing limits. This toxicity has been associated with rare conditions involving L-carnitine deficiency. Carnitine deficiency may be congenital (autosomal recessive) or acquired (eg, secondary to dietary causes such as a ketogenic diet or severe malnutrition). Affected patients may develop cardiac toxicity at cutaneous bupivacaine doses as low as 1.1 mg/kg. Case reports have described low-dose toxicity in patients later found to have L-carnitine deficiency. A rat study demonstrated this model and found that administering supplemental L-carnitine could reverse this effect.[20]

Other patient groups that may be more susceptible to LAST include patients who have low total body weight (low muscle mass, including infants less than 6 months and frail older patients with low muscle mass), patients with advanced cardiovascular or liver disease, or the presence of acidosis.[15]

Sites Associated With Highest to Lowest Toxicity Risk 

IV>Intercostal>Caudal>Epidural>Interfascial plane blocks of the abdominal wall (TAP)> Psoas compartment blocks>Sciatic blocks>Cervical plexus block>Brachial plexus block.

Pathophysiology

At therapeutic concentrations, local anesthetics block voltage-gated sodium channels by binding to the alpha subunit within the channel, thereby preventing sodium influx, membrane depolarization, and action potential generation. At toxic concentrations, local anesthetics also affect cardiac sodium channels and central nervous system neurons, and may inhibit potassium and calcium channels, as well as NMDA receptors. In addition, local anesthetics interfere with cellular processes such as oxidative phosphorylation, free fatty acid utilization, and cyclic AMP production. Toxic levels of local anesthetics on the heart lead to conduction irregularities, impaired cardiac contractility, and the loss of vascular tone secondary to extreme vasodilation.

Signs and Symptoms

Neurological

• Early manifestations may include perioral tingling, tinnitus, blurred vision, and tongue paresthesias, which can progress to CNS depression with slurred speech and drowsiness.
• Late manifestations may include agitation, confusion, altered mental status, and seizures.
• In the depressive phase, coma and respiratory depression may occur.

Cardiovascular

• Hypertension and tachycardia: Intermediate myocardial depression and hypotension.
• Terminal: Vasodilation, severe hypotension, dysrhythmias, conduction blocks, and asystole.

Hypercarbia

Hypercarbia lowers the seizure threshold and increases cerebral blood flow, resulting in greater delivery of local anesthetic to the brain. Acidosis further impairs protein binding of local anesthetics, increasing the free plasma fraction and enhancing delivery of local anesthetics to the brain.

Treatment

Treatment of bupivacaine toxicity has historically been challenging because of its profound neurologic and cardiac toxicity. In centers with readily available cardiopulmonary bypass, extracorporeal support was used to maintain the patient until the drug was adequately metabolized and cleared, a process that could take several hours. In the early 2000s, landmark research by Guy Weinberg demonstrated that lipid emulsions, such as those used as carriers in total parenteral nutrition formulations, were effective in reversing bupivacaine toxicity in laboratory animals (mice and dogs). These findings in mice and dogs led to several case reports describing the use of lipid emulsion therapy as rescue treatment in patients with profound cardiovascular collapse following nerve blocks with long-acting local anesthetics, including bupivacaine and ropivacaine.

Over the following 15 years, treatment with 20% lipid emulsion became widely accepted as effective therapy for LAST. The American Society of Regional Anesthesia and Pain Medicine adopted lipid emulsion therapy as the standard treatment for LAST and incorporated it into formal treatment algorithms. Once reserved as rescue therapy, lipid emulsion is now considered the first-line treatment in patients with suspected LAST. Facilities that administer local anesthetics should maintain immediate access to 20% lipid emulsion rescue kits for emergency use. Evidence also suggests that high-dose epinephrine may reduce the effectiveness of lipid emulsion therapy, further emphasizing the importance of early lipid emulsion administration when LAST is suspected. Detailed treatment algorithms are available through the American Society of Regional Anesthesia and Pain Medicine website.[21]

Current dosing recommendations for lipid emulsion 20% are as follows:

• In patients with a body weight greater than 70 kg, 100 mL of 20% lipid emulsion should be administered as a rapid bolus over 2 to 3 minutes, followed by an infusion of 200 to 250 mL over the next 15 to 20 minutes. Repeat dosing may be required up to a maximum total dose of 12 mL/kg.
• In patients with body weight less than 70 kg, 1.5 mL/kg of 20% lipid emulsion should be administered as a rapid bolus over 2 to 3 minutes, followed by a continuous infusion at 0.25 mL/kg/min, with a maximum total dose of 12 mL/kg.
• Cardiopulmonary bypass should still be considered early when other treatment measures are ineffective. 

Enhancing Healthcare Team Outcomes

Bupivacaine is administered to patients by a wide range of healthcare professionals, including surgeons, anesthesiologists, pain specialists, emergency medicine clinicians, nurse practitioners, and certified registered nurse anesthetists. All members of the interprofessional healthcare team involved in the administration or dispensing of bupivacaine should be familiar with its potential adverse effects and toxicity. Resuscitation equipment should be immediately available at the time of injection, and at least one team member should be trained in its proper use in the event of an emergency. The most common reason for complications is injecting the drug into an artery or vein, leading to adverse cardiac and CNS effects.[22][23]

Pharmacists play an important role in preparing the medication, verifying appropriate dosing and administration, and collaborating with anesthesiologists and nurse anesthetists. They may also assist in the management of toxicity by facilitating access to appropriate rescue medications. Safe and effective use of bupivacaine requires an interprofessional team approach involving physicians, specialists, nurses with specialty training, and pharmacists working collaboratively to optimize patient outcomes.