Bupivacaine (Marcaine): MOA, Uses, Dosage and Side Effects
Bupivacaine is a long-acting amide local anesthetic agent that is used for epidural and spinal anaesthesia. Bupivacaine has a slower onset but a longer duration of 5–12 hours 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 slower rise in maternal plasma concentration than with 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 sterioisomers (mirror images of each other), these forms are based on 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 levo-bupivacaine is the pure L isomer with a 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 anaesthesia.
Why adrenaline is added to bupivacaine local anesthetic
Adrenaline is a potent vasoconstrictor due to its effect on alpha adrenergic receptors. Addition of adrenaline vasoconstrictor to a local anaesthetic creates a relative ischemia in the surgical field by reducing the blood flow to the site of the injection. This causes:
- A reasonably long-lasting local anaesthetic 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 anaesthesia 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 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 (analogue of vasopressin) can be used as an adjunctive vasoconstrictor with less pronounced reactive hyperemia and no arrhythmogenic action, but danger of coronary constriction is higher.
Coadministration of local anaesthetics with vasoconstrictors should not be used in local anaesthesia involving the extremities (e.g., fingers, toes) because of the risk of necrosis due to vasoconstriction.
To obtains 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:
- Infiltration anaesthesia
- Epidural and caudal anaesthesia
- Dental anaesthesia
- Spinal anaesthesia
- Peripheral and sympathetic nerve block
The use of epidural and caudal anaesthesia produces prolonged regional anaesthesia, therefore the technique should be used by only experienced anesthetists or anesthesiologists.
Bupivacaine is unsuitable for intravenous regional anaesthesia and topical application
Mechanism of action of bupivacaine
Bupivacaine works by blocking voltage dependent sodium channels and reduce 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 inhibits the whole cell potassium ion currents in a 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 shown to inhibit aerobic ATP synthesis by uncoupling of 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), that inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia.
The drug is employed as 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 anaesthetic activity whereas elevated extracellular calcium ions antagonizes its effect.
Pharmacokinetics of bupivacaine
Bupivacaine is the longest acting amide local anaesthetic 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, anaesthesia 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 anaesthesia, absorption rate, weight and status of the patient.
A higher initial blood levels are attained with more concentrated anaesthetic 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 anaesthesia.
The administration of spinal anaesthesia should be done by a trained and competent anaesthetist 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 anaesthesia and analgesia.
Local infiltration use 0.25% concentration with a maximum of 175 mg
Peripheral nerve block use 5 ml of 0.25-0.5%: 400mg/day maximum
Dental anaesthesia use 0.5%
Retrotubular anaesthesia: 2-4Ml OF 0.75%
Spinal anaesthesia use preservative free anaesthesia 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 anaesthesia 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 preliminary intravenous infusion of 500-1000ml of physiological saline (9mg/ml) 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
Lumbar epidural has largely replaced caudal epidural for relief of pain in labor.
It requires less local anaesthetic, less risk of infection and is readily extended should 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.
Paracervical block is no longer recommended during labour 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, sedation, nystagmus, unconsciousness and tonic-clonic convulsions.
They develop due to the use of excessive dosage, inadvertent intravascular injection or injection into highly vascular tissues.
Initial signs of light headedness, dizziness, blurred vision, restlessness, tremors and rapidly followed drowsiness, coma and respiratory failure.
A racemic mixture of bupivacaine isomers may produce cardiovascular toxicity such as arrhythmias and hypotension.
Myocardial depression and hypotension can result in hypoxia, acidosis, heart block and cardiac arrest.
Hypersensitivity and allergic reactions may also occur
Levobupivacaine is less cardiotoxic.
Epidural analgesia is occasionally complicated by urinary retention, fecal incontinence, headache, backache, loss of perineal sensation,
Transient paraesthesia and paraplegia are rare.
Co-administration of oxytotic drugs post-partum may cause severe and prolonged hypertension.
The use of bupivacaine preparations containing adrenaline during or following the administration of halothane or trichloroethylene creates a risk of cardiac dysrhythmias
Overdosage or accidental intravascular injection is characterized by systemic effects. Its treatment is symptomatic
There is no specific antidote to manage toxicity.
A clear airway should be maintained and hyperventilation with oxygen is required
Convulsions may be controlled with intravenous diazepam 5-10 mg or thiopental 100-150 mg IV which is a short acting barbiturate.
Neuromuscular blocking agents may be used to treat violent convulsive activity.
Hypotension should be used by use of vasopressors such as ephedrine 10-15 mg intravenously and intravenous fluids.
What is heavy and plain Marcaine?
Heavy Marcaine is composed of 0.5% bupivacaine and 8% dextrose
Plain bupivacaine is dextrose free.
To understand the role of dextrose in Marcaine we need to understand baricity. Baricity is a specific gravity that is important in determining the extent at which the local anaesthetic drug spreads within the cerebrospinal fluid during a subarachnoid block.
Dextrose or glucose acts as an adjunt to alter the baricity of a given local anaesthetic and in this case it is bupivacaine. When glucose 8% is added to 0.5% bupivacaine, the resultant drug is known as heavy bupivacaine (Heavy Marcaine) or hyperbaric Marcaine. Therefore its initial spread in the intrathecal space is affected by gravity
When using heavy Marcaine it is recommended to monitor blood pressure levels for the first two minutes and adequate early intravenous fluids should be given.
Marcaine heavy produces moderate muscular relaxation of lower limbs for 2-2.5 hours.
The duration of motor blockade doesn’t exceed the duration of analgesia. Heavy Marcaine is usually well tolerated by all tissues.
Its motor blockade of the abdominal muscles makes heavy Marcaine to be effective for use in abdominal surgery.
This drug is contraindicated in patients with:
- Known or suspected hypersensitivity to bupivacaine
- Skin infections adjacent to the intended site of injection,
- Concomitant anticoagulant therapy or an
- Abnormal bleeding tendency.
- Severe anaemia or
- Heart disease
Spinal and epidural anaesthetics should never be administered to patients with hypovolemia.
Preservative-containing solutions should not be used for caudal or epidural block.
Resuscitation equipment should be ready and available at all times.
Assurance should be obtained that the patient is psychologically stable to undergo the procedure.
High blood levels of bupivacaine should be avoided in patients with hepatic impairment.
Care must be taken to avoid inadvertent intravascular injection
Safety in pregnancy has not been established. However there is no evidence to suggest that exposure of the mother to bupivacaine is harmful to the fetus