Bupivacaine

Bupivacaine, marketed under the brand name Marcaine among others, is a long-acting, potent local anesthetic from the amide class. It is a cornerstone of regional anesthesia and pain management, valued for its duration of action but respected for its narrow therapeutic index and potential for severe cardiotoxicity.

Chemical Structure

Bupivacaine is an amide local anesthetic. Its structure consists of three key components:

1. Aromatic Ring: A lipophilic (fat-soluble) portion that allows the molecule to penetrate the lipid bilayer of the nerve cell membrane.
2. Amide Linkage: The connecting chain (-CONH-). This linkage makes it more stable and less likely to cause allergic reactions compared to ester anesthetics.
3. Tertiary Amine: A hydrophilic (water-soluble) portion that becomes charged (ionized) at physiological pH. This charged form is what binds to the intracellular portion of the sodium channel.

Bupivacaine has a pKa of 8.1. At physiological pH (7.4), approximately 85% of the molecules are in the ionized (cationic) form. It is also highly protein-bound (~95%), primarily to alpha-1-acid glycoprotein (AAG). This high protein binding contributes significantly to its long duration of action and potency.

Pharmacokinetics

• Absorption: The rate of absorption into the systemic circulation is highly dependent on the vascularity of the injection site and the presence of a vasoconstrictor (e.g., epinephrine). The order of absorption from fastest to slowest is generally: Intercostal > Caudal/Epidural > Brachial Plexus > Sciatic > Subcutaneous. The addition of epinephrine (1:200,000) causes local vasoconstriction, which slows systemic absorption, lowers peak plasma concentrations, prolongs the duration of action, and serves as a marker for intravascular injection.
• Distribution: Following absorption, bupivacaine distributes into a three-compartment model. The initial distribution is to highly perfused organs (brain, heart, liver, kidney), followed by distribution to muscle and finally to adipose tissue. Its high protein binding limits the amount of free (pharmacologically active) drug in the plasma, but this binding is competitive and can be displaced by other drugs.
• Metabolism: As an amide, bupivacaine is metabolized almost exclusively in the liver by microsomal enzymes, primarily the CYP3A4 isoenzyme. The main metabolite is pipecolylxylidide (PPX), which is less potent than the parent compound but still possesses some pharmacological activity.
• Excretion: The metabolites are excreted renally. In patients with severe hepatic dysfunction, the clearance of bupivacaine is significantly reduced, increasing the risk of systemic toxicity.

Pharmacodynamics

• Mechanism of Action: Bupivacaine's primary mechanism is the reversible blockade of voltage-gated sodium channels (Naᵥ) in the neuronal cell membrane. It binds to a specific site on the alpha-subunit of the channel from the intracellular side of the membrane. This binding stabilizes the inactive state of the channel, preventing the influx of Na⁺ ions, which is necessary for the depolarization phase (Phase 0) of the action potential. Without this depolarization, nerve impulse propagation is halted.
• Use-Dependent Block: Bupivacaine exhibits a phenomenon known as "use-dependent" or "phasic" block. It preferentially binds to and blocks sodium channels that are actively opening or firing (i.e., in an open or inactivated state). This is why rapidly firing pain fibers (C and A-delta fibers) are blocked more effectively than resting motor fibers (A-alpha fibers), leading to differential sensory > motor blockade.
• Differential Blockade: Bupivacaine is known for its profound differential blockade. It blocks small, myelinated (A-delta) and unmyelinated (C) fibers (pain and temperature) more effectively than large, myelinated (A-alpha and A-beta) fibers (motor and proprioception). This property is highly desirable for analgesia without complete paralysis.

Clinical Uses

Bupivacaine's long duration makes it ideal for procedures requiring prolonged pain relief:

• Local Infiltration: Injected directly into the tissue for minor surgical procedures.
• Peripheral Nerve Blocks: Used to anesthetize specific nerves or plexuses (e.g., brachial plexus block for arm surgery, femoral nerve block for knee surgery).
• Epidural Anesthesia/Analgesia: Widely used for childbirth labor, cesarean sections, and lower extremity surgeries.
• Spinal Anesthesia (Subarachnoid Block): Injected into the cerebrospinal fluid for rapid and profound anesthesia of the lower body.

Side Effects and Toxicity

While highly effective, bupivacaine has a narrow therapeutic window, and its systemic toxicity is a major concern, particularly its cardiotoxicity.

• Central Nervous System (CNS) Toxicity: Early signs are a direct result of cortical inhibition followed by disinhibition: a metallic taste, tinnitus (ringing in the ears), perioral numbness, anxiety, and restlessness. This can progress to muscle twitching (myoclonus), seizures, and ultimately, coma and respiratory arrest.
• Cardiovascular (CV) Toxicity: This is the most feared complication. Bupivacaine is a potent cardiotoxin. It can cause severe arrhythmias (like ventricular tachycardia and fibrillation), profound hypotension, and a decrease in cardiac contractility. Its high affinity and slow dissociation from cardiac sodium channels can lead to intractable arrhythmias. Bupivacaine-induced cardiac arrest is notoriously difficult to resuscitate with standard Advanced Cardiac Life Support (ACLS) protocols.

Treatment of Severe Toxicity: The primary antidote for bupivacaine-induced cardiac arrest is the immediate administration of a 20% intravenous lipid emulsion (Intralipid), often following the "Lipid Emulsion Therapy" algorithm (e.g., 1.5 mL/kg bolus, followed by an infusion at 0.25 mL/kg/min). The proposed mechanism is the creation of a "lipid sink" in the bloodstream, which sequesters the lipid-soluble bupivacaine away from the heart and brain, mitigating its toxic effects.

Contraindications

• Absolute: Known hypersensitivity to bupivacaine or any amide-type local anesthetic. True allergy is rare.
• Relative:
  • Intravenous Regional Anesthesia (Bier Block): Bupivacaine is contraindicated for this technique due to the high risk of systemic toxicity from accidental release of the tourniquet.
  • Patients with severe hypovolemia or shock, as they are more susceptible to the cardiovascular depressant effects.
  • Patients with pre-existing severe cardiac conduction abnormalities (e.g., complete heart block) not treated with a pacemaker.

Special Considerations

• Maximum Recommended Doses: These are guidelines and must be individualized based on patient factors, site of injection, and use of epinephrine.
  • Without Epinephrine: 2 mg/kg (not to exceed 175 mg in a healthy adult).
  • With Epinephrine (1:200,000): 3 mg/kg (not to exceed 225 mg in a healthy adult).
• Pregnancy: Pregnant patients, particularly those at term, are more sensitive to bupivacaine's cardiotoxic effects. Hormonal changes can lower the seizure threshold, and the engorged epidural vasculature can lead to faster systemic absorption. Dose reduction is often warranted.
• Pediatrics: Infants have lower levels of alpha-1-acid glycoprotein (AAG), resulting in a higher free fraction of bupivacaine in the plasma. This makes them more susceptible to toxicity at lower total plasma concentrations. Dosing must be carefully calculated by weight.
• Test Dose: When performing epidural or spinal anesthesia, a test dose (e.g., 3 mL of 1.5% lidocaine with 1:200,000 epinephrine) is crucial to detect inadvertent intravascular or intrathecal placement before administering the full dose of bupivacaine.
• Aspiration and Fractionated Dosing: To minimize the risk of intravascular injection, always aspirate before injecting and administer the total dose in small, incremental (fractionated) amounts (e.g., 3-5 mL at a time), continuously monitoring the patient for signs of toxicity.

 
Next: Levobupivacaine & Liposomal Bupivacaine →
 

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Levobupivacaine

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Levobupivacaine, marketed as Chirocaine, is the pure S(-)-enantiomer of racemic bupivacaine. It was developed specifically to retain the desirable anesthetic properties of bupivacaine while reducing its potential for severe toxicity.

Why It Was Developed?

Standard bupivacaine is a racemic mixture, meaning it contains two mirror-image molecules (enantiomers): R(+) and S(-). Research showed that the R(+) enantiomer was significantly more responsible for the drug's cardiotoxic and neurotoxic effects. By isolating and using only the S(-)-enantiomer, levobupivacaine was created as a theoretically safer alternative.

Comparison to Bupivacaine

• Potency and Duration: Levobupivacaine provides analgesia that is clinically indistinguishable in potency and duration from bupivacaine when used at equipotent doses.
• Motor Blockade: It tends to produce a slightly less dense motor block than bupivacaine at the same dose, which can be advantageous in situations like labor epidurals, allowing the mother to retain more motor function.
• Safety Profile: This is the key difference. Levobupivacaine has a significantly wider safety margin. It is less likely to cause CNS and cardiovascular toxicity. In animal studies, the dose required to cause cardiac arrest was substantially higher for levobupivacaine than for bupivacaine.

Clinical Uses

Levobupivacaine is used for the same indications as bupivacaine (epidurals, nerve blocks, local infiltration). It is often preferred in clinical situations where large volumes or high doses of a local anesthetic are required, or in patients with pre-existing cardiac conditions, as its improved safety profile offers a significant advantage.

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Liposomal Bupivacaine

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Liposomal Bupivacaine, marketed as Exparel, is not a new chemical entity but a novel drug delivery system. It consists of bupivacaine encapsulated within multivesicular liposomes (DepoFoam technology).

Mechanism of Action (of the Formulation)

The drug itself still works by blocking sodium channels. The innovation lies in the liposomal carrier. After injection into the surgical site, these liposomes act like tiny drug reservoirs, slowly releasing bupivacaine over an extended period. This provides a sustained therapeutic level of the local anesthetic at the site of pain.

Key Characteristics

• Duration of Action: This is its defining feature. A single injection can provide analgesia for up to 72 to 96 hours (3-4 days), far exceeding the 6-12 hours typical of plain bupivacaine.
• Onset of Action: The onset is slower than plain bupivacaine because the drug must first be released from the liposomes before it can take effect. For this reason, it is sometimes used in combination with a short-acting local anesthetic (like lidocaine) for immediate pain relief.

Clinical Uses

Liposomal bupivacaine is specifically indicated for post-operative pain management via local infiltration into the surgical site. Common applications include:

• Hemorrhoidectomy
• Bunionectomy
• Inguinal hernia repair
• Total knee arthroplasty

It is not FDA-approved for use in major nerve blocks (e.g., brachial plexus) or epidural/spinal anesthesia, though it is used off-label in some nerve block settings by specialists.

Advantages and Disadvantages

• Advantages:
  • Prolonged, single-dose pain relief.
  • Can significantly reduce the need for post-operative opioids.
  • Improved patient satisfaction and recovery.
• Disadvantages:
  • Cost: It is significantly more expensive than plain bupivacaine.
  • Formulation Limitations: It cannot be mixed with other local anesthetics in the same syringe, as this would disrupt the liposomal structure and cause an immediate, uncontrolled release of the drug.

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Summary Comparison