Bupivacaine Hydrochloride Injection, Solution

The dosage of bupivacaine varies significantly based on the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, and the individual patient's physical status. Healthcare providers use the lowest dosage necessary to achieve the desired result.

• Local Infiltration: Typically 0.25% concentration. Doses up to 175 mg (70 mL) are common, depending on the size of the area.
• Lumbar Epidural Anesthesia:
• For surgery: 10-20 mL of 0.5% (50-100 mg) or 0.75% (75-150 mg).
• For labor/pain management: 10-20 mL of 0.25% (25-50 mg).
• Peripheral Nerve Block: 5 mL to 35 mL of 0.25% or 0.5% (up to 175 mg).
• Spinal Anesthesia: 7.5 mg to 15 mg of a hyperbaric solution (0.75% in dextrose).

Maximum Recommended Dose: The maximum single dose for an average healthy adult should not exceed 175 mg without epinephrine, or 225 mg with epinephrine. In any 24-hour period, the total dose should generally not exceed 400 mg.

Bupivacaine is used in pediatric patients for infiltration, nerve blocks, and caudal or epidural anesthesia. Dosing is strictly weight-based to avoid systemic toxicity.

• Caudal/Epidural Block: Concentrations of 0.125% to 0.25% are typically used. The dose is usually 1 mg/kg to 2.5 mg/kg of body weight.
• Note: The 0.75% concentration is NOT recommended for use in pediatric patients due to the high risk of systemic toxicity.

Renal Impairment

While bupivacaine is primarily metabolized by the liver, its metabolites are excreted by the kidneys. No specific initial dose adjustment is usually required for a single dose, but repeated doses or continuous infusions should be monitored closely in patients with severe renal impairment to prevent metabolite accumulation.

Hepatic Impairment

Because bupivacaine is metabolized by the liver, patients with hepatic disease (e.g., cirrhosis, hepatitis) have a reduced ability to clear the drug. Healthcare providers typically reduce the dose or increase the interval between doses to avoid toxic systemic levels.

Elderly Patients

Geriatric patients often require lower doses. Age-related decreases in cardiac output and hepatic blood flow can slow the clearance of bupivacaine. Furthermore, the elderly may be more sensitive to the cardiovascular and central nervous system effects of the drug.

Bupivacaine is administered exclusively by healthcare professionals via injection or infusion. It is not for self-administration.

• Administration: It may be injected into the skin, near a nerve, or into the space around the spinal cord.
• Monitoring: During and after administration, your provider will monitor your heart rate, blood pressure, and oxygen levels.
• Storage: In a clinical setting, bupivacaine vials are stored at room temperature (20°C to 25°C or 68°F to 77°F) and protected from light. It should not be frozen.

Since bupivacaine is administered by a healthcare professional for a specific procedure or as a continuous hospital-based infusion, a missed dose by the patient is not possible. If a continuous infusion is interrupted, the medical staff will restart it according to the protocol.

An overdose of bupivacaine leads to Local Anesthetic Systemic Toxicity (LAST). This is a medical emergency.

• Early Signs: Metallic taste in the mouth, numbness of the tongue or lips, tinnitus (ringing in the ears), lightheadedness, and blurred vision.
• Advanced Signs: Muscle twitching, tremors, generalized seizures, and loss of consciousness.
• Cardiovascular Signs: Severe hypotension (low blood pressure), bradycardia (slow heart rate), and potentially fatal cardiac arrest.
• Emergency Measures: Treatment involves stopping the injection, maintaining the airway, providing oxygen, and administering 'Intralipid' (lipid emulsion therapy), which acts as a 'sink' to pull bupivacaine out of the cardiac tissue.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance.

Side effects from bupivacaine are often related to the technique of administration (such as an epidural) rather than the drug itself. Common experiences include:

• Nausea and Vomiting: Frequently reported following epidural or spinal administration, often due to changes in blood pressure.
• Hypotension (Low Blood Pressure): A very common effect of spinal or epidural blocks as the medication relaxes blood vessels in the lower body.
• Headache: Specifically 'post-dural puncture headache' if the spinal fluid sac is punctured during an epidural.
• Back Pain: Mild soreness at the site of injection for 24-48 hours.
• Dizziness: Often associated with the initial onset of the block or changes in blood pressure.

• Urinary Retention: Difficulty urinating after the procedure, common with spinal/epidural use as the nerves controlling the bladder are temporarily numbed.
• Pruritus (Itching): More common if the bupivacaine is mixed with opioid medications.
• Paresthesia: A 'pins and needles' sensation as the block wears off.
• Bradycardia: A slight slowing of the heart rate.
• Shivering: Often occurs during the recovery phase of regional anesthesia.

• Nerve Injury: Extremely rare, but localized nerve damage can occur from the needle or the pressure of the injection.
• Methemoglobinemia: A condition where the blood cannot carry oxygen effectively; though more common with other anesthetics, it has been reported with bupivacaine.
• Toxicity (LAST): Systemic absorption leading to CNS or cardiac symptoms.

> Warning: Stop the administration (if on a pump) and alert medical staff immediately if you experience any of these symptoms.

• Seizures: Sudden, uncontrolled electrical activity in the brain caused by high systemic levels of bupivacaine.
• Cardiac Arrest: Bupivacaine is notoriously cardiotoxic in high doses, making it difficult to restart the heart if it stops.
• Difficulty Breathing: This can occur if a spinal or epidural block 'travels' too high and affects the nerves controlling the diaphragm.
• Severe Allergic Reaction (Anaphylaxis): Symptoms include hives, swelling of the face or throat, and difficulty swallowing.
• Loss of Sensation that Does Not Return: Prolonged numbness or weakness well beyond the expected duration of the drug.

Bupivacaine is generally intended for short-term use. However, some long-term concerns exist:

• Chondrolysis: There have been reports of permanent damage to joint cartilage (chondrolysis) when bupivacaine is administered via a continuous intra-articular infusion pump (e.g., into the shoulder joint) after surgery. This is NOT an approved use of the drug.
• Persistent Neuropathy: In very rare cases, patients may experience long-term tingling or weakness in the area where a nerve block was performed.

0.75% Bupivacaine Concentration Warning: The FDA has issued a Black Box Warning for the 0.75% concentration of bupivacaine. It is strictly contraindicated for obstetrical anesthesia (epidural use during labor). There have been reports of cardiac arrest with difficult resuscitation or death during epidural anesthesia in obstetrical patients using this high concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. The 0.75% concentration should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary.

Report any unusual symptoms to your healthcare provider.

Bupivacaine must only be administered by clinicians who are well-versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.

Obstetrical Anesthesia Restriction: The 0.75% concentration of bupivacaine hydrochloride is not recommended for obstetrical anesthesia. There have been reports of cardiac arrest with difficult resuscitation or death during epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. This concentration should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary.

• Local Anesthetic Systemic Toxicity (LAST): High plasma levels can cause central nervous system (CNS) toxicity (seizures) and cardiovascular toxicity (arrhythmias, arrest). Clinicians must perform frequent aspirations before and during injection to ensure the drug is not being injected into a blood vessel.
• Cardiovascular Disease: Patients with impaired cardiovascular function (e.g., heart block, hypotension) are at higher risk of bupivacaine-induced myocardial depression.
• Chondrolysis: Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis (cartilage death) in patients receiving such infusions.
• Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. Patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, or those taking certain medications are at higher risk.

During bupivacaine administration, the following must be monitored continuously:

• Electrocardiogram (ECG): To detect early signs of cardiac rhythm changes.
• Blood Pressure: To manage hypotension, especially during epidural or spinal use.
• Oxygen Saturation (Pulse Oximetry): To ensure adequate oxygenation.
• Mental Status: Changes in consciousness or 'feeling funny' can be early signs of CNS toxicity.

Bupivacaine can temporarily impair motor function and coordination. Patients should not drive or operate heavy machinery until the full effects of the anesthesia have worn off and they have regained full sensation and muscle strength. This typically takes several hours after the last dose.

Alcohol should be avoided for at least 24 hours after receiving bupivacaine. Alcohol can enhance the central nervous system depressant effects of any residual anesthetic and may increase the risk of falls or injury while sensation is still impaired.

For single-dose blocks, the drug naturally wears off. For continuous infusions, the dose is typically tapered or stopped once oral pain medications are sufficient. There is no 'withdrawal' syndrome, but a rebound increase in pain (breakthrough pain) may occur if alternative analgesia is not provided.

> Important: Discuss all your medical conditions with your healthcare provider before starting Bupivacaine.

• IV Regional Anesthesia (Bier Block): Bupivacaine must never be used for Bier blocks. Because bupivacaine is highly cardiotoxic, the accidental release of the tourniquet during this procedure can lead to immediate cardiac arrest.
• Concurrent Amide Local Anesthetics: Using bupivacaine with other amide-type local anesthetics (e.g., lidocaine, ropivacaine) is generally avoided as the toxic effects are additive.

• Anti-arrhythmic Drugs: Medications like Amiodarone or Mexiletine can have additive effects on the heart's electrical conduction when bupivacaine is in the system, increasing the risk of myocardial depression.
• Class III Anti-arrhythmics: These should be used with extreme caution as they may potentiate the cardiotoxic effects of bupivacaine.
• Propranolol and Beta-Blockers: These drugs can reduce hepatic blood flow, potentially slowing the metabolism of bupivacaine and increasing the risk of toxicity.

• CYP3A4 Inhibitors: Drugs like Ketoconazole, Ritonavir, or Clarithromycin inhibit the enzyme responsible for breaking down bupivacaine. This can lead to higher-than-expected levels of bupivacaine in the blood, especially during long-term infusions.
• Hyaluronidase: Sometimes added to local anesthetics to increase spread, but it may also increase the rate of systemic absorption, potentially shortening the block and increasing toxicity risk.

Since bupivacaine is administered via injection for acute procedures, food interactions are generally not a concern. However, patients should follow their surgeon's 'NPO' (nothing by mouth) instructions prior to any procedure involving anesthesia.

• St. John's Wort: May induce CYP3A4 enzymes, potentially leading to faster clearance of bupivacaine, though this is rarely clinically significant for a single dose.
• Garlic, Ginkgo, Ginseng: These supplements can increase bleeding risk. While they don't interact with bupivacaine directly, they can increase the risk of a hematoma (blood clot) at the site of a spinal or epidural injection.

Bupivacaine does not typically interfere with standard laboratory blood tests. However, the presence of epinephrine in some bupivacaine formulations may cause a transient increase in blood glucose levels.

For each major interaction, the management strategy involves:

• Mechanism: Usually additive pharmacodynamic effects (on the heart/nerves) or pharmacokinetic changes (CYP3A4 inhibition).
• Consequence: Increased risk of LAST or reduced duration of anesthesia.
• Management: Dose reduction of bupivacaine and continuous ECG monitoring.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking.

Bupivacaine must NEVER be used in the following circumstances:

1. 1Hypersensitivity: Known allergy to bupivacaine or any other local anesthetic of the amide class (e.g., lidocaine, mepivacaine). An allergic reaction can lead to life-threatening anaphylaxis.
2. 2Intravenous Regional Anesthesia (Bier Block): The risk of cardiac arrest upon tourniquet release is unacceptably high.
3. 3Obstetrical Epidural (0.75% Concentration): Due to the high risk of maternal cardiac arrest.
4. 4Severe Hypotension or Shock: For spinal anesthesia, as the drug can further drop blood pressure to dangerous levels.
5. 5Septicemia: Infection in the blood is a contraindication for spinal or epidural blocks due to the risk of introducing infection into the central nervous system.

Conditions requiring careful risk-benefit analysis:

• Coagulopathy: Patients on blood thinners (like warfarin) or those with low platelets are at high risk for spinal/epidural hematoma, which can cause permanent paralysis.
• Pre-existing Neurological Disease: Conditions like Multiple Sclerosis may be exacerbated by regional anesthesia, though data is inconclusive.
• Heart Block: Bupivacaine can slow electrical conduction in the heart, worsening existing arrhythmias.
• Liver Disease: Reduced metabolism increases the risk of systemic toxicity.

Patients allergic to one amide local anesthetic are likely to be allergic to others in the same class. However, they may be able to safely receive 'ester-type' local anesthetics (like procaine or tetracaine), provided the allergy is confirmed to be class-specific. Always inform your anesthesiologist of any previous 'caine' allergies.

> Important: Your healthcare provider will evaluate your complete medical history before prescribing Bupivacaine.

Bupivacaine is classified as FDA Pregnancy Category C. It does cross the placenta. While it is widely used for epidural anesthesia during labor, it must be used with caution.

• Teratogenicity: Animal studies have shown some evidence of fetal harm at high doses, but there are no adequate, well-controlled studies in pregnant women.
• Paracervical Block: Use of bupivacaine for paracervical block in obstetrics can cause fetal bradycardia (slow heart rate) and acidosis.
• Obstetric Warning: As noted, the 0.75% concentration is strictly forbidden for epidural use in labor.

Bupivacaine is excreted in human milk in very small amounts. According to the American Academy of Pediatrics, the use of bupivacaine during breastfeeding is generally considered compatible, as the systemic levels in the mother are usually low and the infant's exposure is negligible. No adverse effects on nursing infants have been documented.

Bupivacaine is approved for use in children for various types of regional anesthesia. However, because children have different metabolic rates and higher body water content, weight-based dosing (mg/kg) is mandatory. The 0.75% concentration is not recommended for children. Safety and effectiveness in children under the age of 2 have not been fully established for all types of blocks.

Patients over age 65 are at a higher risk of bupivacaine-related complications.

• Pharmacokinetics: Reduced cardiac output and hepatic blood flow lead to slower clearance.
• Sensitivity: The elderly may experience more profound hypotension during spinal or epidural anesthesia.
• Dosing: Clinicians typically start at the lower end of the dosing range and titrate slowly.

In patients with kidney failure, the clearance of bupivacaine metabolites may be reduced. While a single dose is usually safe, continuous infusions require careful monitoring for signs of systemic toxicity, as the parent drug and its metabolites can accumulate over several days.

Patients with severe hepatic impairment (Child-Pugh Class C) have a significantly reduced ability to metabolize bupivacaine. This increases the half-life and the risk of Local Anesthetic Systemic Toxicity (LAST). Dose reductions of 25% to 50% may be necessary for these patients.

> Important: Special populations require individualized medical assessment.

Bupivacaine is a sodium channel blocker. It binds to the S6 segment of Domain IV of the voltage-gated sodium channel (Nav1.5 in the heart, and various isoforms in the nerves). By binding to the internal pore of the channel, it prevents the rapid influx of sodium ions necessary for the depolarization of the neuronal membrane. This stops the propagation of the action potential along the axon, effectively 'silencing' the nerve and preventing pain signals from reaching the brain.

• Onset of Action: Intermediate (5 to 20 minutes depending on the site).
• Duration of Effect: Long (3 to 9 hours for most blocks; up to 72 hours for liposomal forms).
• Differential Block: At low concentrations (0.125% - 0.25%), bupivacaine can provide sensory block (pain relief) while sparing motor function (ability to move), which is ideal for labor.

| Parameter | Value |

|---|---|

| Bioavailability | 100% (Systemic absorption from site) |

| Protein Binding | 95% (Alpha-1-acid glycoprotein) |

| Half-life | 2.7 hours (Adults), 8.1 hours (Neonates) |

| Tmax | 30 - 45 minutes (after infiltration) |

| Metabolism | Hepatic (CYP3A4) |

| Excretion | Renal (95% as metabolites, 5% unchanged) |

• Molecular Formula: C18H28N2O
• Molecular Weight: 288.43 g/mol
• Solubility: Soluble in water and ethanol.
• Structure: A white crystalline powder; chemically, it is 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide.

Bupivacaine is a member of the Amide Local Anesthetic class. It is structurally related to lidocaine and mepivacaine but is more lipid-soluble and potent. It is often compared to Ropivacaine, which is a pure S-enantiomer designed to have less cardiotoxicity than racemic bupivacaine.