• Anesthetics
  • Pharmacology

Bupivacaine (Marcaine): MOA, Uses, Dosage and Side Effects

  • 6 minutes, 27 seconds
  • Anesthetics
  • 2022-07-21 23:53:03

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Bupivacaine is a long-acting amide local anesthetic agent that is used for epidural and spinal anesthesia. Bupivacaine has a slower onset but a longer duration when compared to lidocaine.

The duration of epidural blockade of bupivacaine is much shorter, at about 2 hours, but is still longer than for lidocaine.

This short duration of epidural block is due to the high vascularity of the epidural space and consequent rapid uptake of anesthetic into the bloodstream.

Bupivacaine is the agent of choice for continuous epidural blockade in obstetrics, due to a slower rise in maternal plasma concentration than lidocaine.

Bupivacaine is sold with a generic name, Marcaine or Sensorcaine. It is available in 0.25, 0.5, 0.75% for injection; 0.25, 0.5, 0.75% with  1:200,000 epinephrine, as hyperbaric 0.5% preservative-free solution with 8% dextrose for use in spinal anaesthesia and as 0.1% and 0.125% solution for epidural analgesia.

Bupivacaine molecules exist in two forms known as stereoisomers (mirror images of each other), these forms are based on the ability to rotate polarized light to either + or d( dextrorotatory and – l(levorotatory).

Bupivacaine is found as a racemic mixture with both isomers in equal quantities. Of the two levobupivacaine is the pure L isomer with significantly low cardiotoxicity.

The first sign of toxicity can be cardiac arrest from ventricular fibrillation, which is often resistant to defibrillation.
For this reason, it should not be used in intravenous regional anesthesia.

Why adrenaline is added to bupivacaine local anesthetic

Adrenaline is a potent vasoconstrictor due to its effect on alpha-adrenergic receptors.  The addition of an adrenaline vasoconstrictor to a local anesthetic creates relative ischemia in the surgical field by reducing the blood flow to the site of the injection. This causes:

  • A reasonably long-lasting local anesthetic effect,
  • Reduced rate of absorption,
  • Minimal systemic action and toxicity by confining the drug to its site of action.

Norepinephrine or a vasopressin derivative ie felypressin is sometimes used for the same purpose.

The effects are useful in nerve blocks and infiltration anesthesia but not in epidural or spinal.

Coadministration of adrenaline should not be used intrathecally.

As blood flow is diminished, diffusion from the endoneural space into the capillary blood decreases because the critical concentration gradient between endoneural space and blood quickly becomes small when an inflow of drug-free blood is reduced.

Catecholamine-type vasoconstrictors are associated with side effects such as:

Reactive hyperemia following washout of the constrictor agent and cardiostimulation when epinephrine gains entry to the systemic circulation.

In the absence of epinephrine, felypressin (analog of vasopressin) can be used as an adjunctive vasoconstrictor with less pronounced reactive hyperemia and no arrhythmogenic action, but the danger of coronary constriction is higher.

Coadministration of local anesthetics with vasoconstrictors should not be used in local anesthesia involving the extremities (e.g., fingers, toes) because of the risk of necrosis due to vasoconstriction.

To obtains the required intense vasoconstrictor effect, a very small concentration of adrenaline is needed. Usually, adrenaline used ranges from 1:80 000 to 1:200 000. Adrenaline is expressed as the weight of adrenaline in grams per volume of solution in Ml.

20 mL of 1:80 000 is the maximum safe dose representing 250 micrograms or 50mL of 1:200 000.

Bupivacaine is less dependent on the administration of a vasoconstrictor due to its longer duration of action.

Uses of bupivacaine

Bupivacaine is used in:

  1. Infiltration anesthesia
  2. Epidural and caudal anesthesia
  3. Dental anesthesia
  4. Spinal anesthesia
  5. Peripheral and sympathetic nerve block

The use of epidural and caudal anesthesia produces prolonged regional anesthesia, therefore the technique should be used by only experienced anesthetists or anesthesiologists.

Bupivacaine is unsuitable for intravenous regional anesthesia and topical application

Mechanism of action of bupivacaine

Bupivacaine works by blocking voltage-dependent sodium channels and reducing the efflux of sodium ions preventing the depolarization of the membrane and blocking the initiation and transmission of nerve impulses at the site of application by stabilizing the neuronal membrane.

It does this by decreasing the current amplitude and inhibiting the whole cell potassium ion currents in calcium ion activated potassium channels and N-type voltage-gated (KCNA and KCNC) K+ channels. It is also known to inhibit voltage-gated Na+ channels and tandem pore domain (TASK-2/KCNK-5) K+ channels.

The compound is cytotoxic at high concentrations inducing apoptosis and/or necrosis by interfering with the mitochondrial energy transduction.

This agent has been shown to inhibit aerobic ATP synthesis by uncoupling the oxidative phosphorylation (OXPHOS) and by inhibiting of the complex I of the respiratory. Other mechanisms include inhibition of the carnitine-acyl carnitine translocase or activation of the mitochondrial permeability transition pore (MPTP).

The analgesic effect of bupivacaine is thought to be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia.

The drug is employed as a cAMP production inhibitor, it acts as a surfactant molecule possessing both hydrophilic and lipophilic properties, adrenergic antagonist, and cholinesterase inhibitor.

High extracellular potassium concentration enhances local anesthetic activity whereas elevated extracellular calcium ions antagonize its effect.

Pharmacokinetics of bupivacaine

Bupivacaine is the longest-acting amide local anesthetic with a half-life of 4.2 hours

The drug is metabolized in the liver.

Depending on the site of injection and the concentration used, anesthesia usually lasts 2-4 hours

Liver dysfunction increases the elimination half-life of bupivacaine and increases its risk of toxicity.

95% protein bound.

The onset of action is 1-17 minutes.

The drug is eliminated via urine

Dosage and administration of bupivacaine

The aim is to administer the smallest effective dosage, and this varies with the procedure adopted, the degree of required anesthesia, absorption rate, weight, and status of the patient.

Higher initial blood levels are attained with more concentrated anesthetic solutions

The maximum cumulative safe dose for adults and children of a 0.25% solution of bupivacaine is 1.5mg/kg
Smaller doses are used in elderly, epileptic, and acutely ill patients.

Bupivacaine is generally not recommended for children less than 12 years due to insufficient information on this age group.

The solution containing preservatives should not be used for spinal, epidural, or caudal anesthesia.

Spinal anesthesia

The administration of spinal anesthesia should be done by a trained and competent anesthetist able to treat the possible side effects or complications.

A heavy Marcaine solution containing 0.75% of bupivacaine in 8.25% glucose provides the required muscular relaxation for abdominal surgery.

A full aseptic procedure must be used for the injection and the patient must be appropriately tilted to ensure safety and the required level of anesthesia and analgesia.

Local infiltration use a 0.25% concentration with a maximum of 175 mg
Peripheral nerve block use 5 ml of 0.25-0.5%: 400mg/day maximum
Dental anesthesia use 0.5%

Retrotubular anesthesia: 2-4Ml OF 0.75%
Spinal anesthesia use preservative-free anesthesia 0.75 (8.25% glucose).

Caudal block use preservative free 15-30mL of 0.25% or 0.5%

Sympathetic nerve block: 20-50mL of 0.25%

Spinal anesthesia always causes hypotension due to sympathetic blockade.

It should never be used in any patient with a condition causing hypovolemia. The hypotensive response may be averted by a preliminary intravenous infusion of 500-1000ml of physiological saline (normal saline) but blood pressure should be always monitored every two minutes for at least 10 minutes.
Post-operative headache is prevented by instructing the patient to remain supine for 24 hours

Obstetric use

Lumbar epidural has largely replaced caudal epidural for relief of pain in labor.

It requires less local anesthetic, less risk of infection, and is readily extended should a caesarian section be required.

However because of the risk to both the mother and fetus. It should be attempted by an experienced anesthetist.
Concentrations of greater than 0.5% are contraindicated due to reports of cardiac arrest and maternal death.

Maternal blood pressure and fetal heart rate and uterine contractions should be monitored throughout the procedure.
The paracervical block is no longer recommended during labor because it results in very high levels of the drug in fetal blood.

Side effects of bupivacaine

Most side effects are in the CNS. These include lightheadedness, dizziness,

    NCBI, eMEDICINE, BNF, Atlas of pharmacology, Basic and clinical pharmacology by Katzung, Uptodate


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