Core pharmacology

Class Group

Amide Local Anaesthetic

Legacy Cicm Level

Level 1

Indications Uses

local anaesthetic

Chemical Pharmaceutics

amide which is a structural homologue of mepivacaine

Presentation

- clear, colourless solution containing racemic bupivacaine (s- and R-enantiomers) in concentrations of 0.25% (2.64 mg/ml
equivalent to bupivacaine hydrochloride anhydrous 2.5 mg/ml) and
0.5% (5.28 mg/ml equivalent to bupivacaine hydrochloride anhydrous
5.0 mg/ml).
- The 0.25/0.5% solutions are available combined with
1:200 000 adrenaline, which contain the preservative sodium metabisulfite.
- A 0.5% (‘hyperbaric’ or ‘heavy’) solution containing 80 mg/ml of glucose
(with a specific gravity of 1.026) is also available.
- Bupivacaine 0.1% is available as a mixture with 2 micrograms/ml of fentanyl for epidural use.

The s-enantiomer is available as levobupivacaine hydrochloride in the following
concentrations: 2.5 mg/ml, 5 mg/ml, and 7.5 mg/ml.
- Levobupivacaine is also
available for epidural use in the following concentrations: 0.625 mg/ml and
1.25 mg/ml.

The pKa of bupivacaine is 8.1, and it is 15% unionized at a pH
of 7.4. The heptane:buffer partition coefficient is 27.5.

Main Action

Local anaesthetic

Mechanism of action

Local anaesthetics diffuse in their uncharged base form
through neural sheaths and the axonal membrane to the internal surface
of cell membrane Na+ channels; here they combine with hydrogen ions
to form a cationic species which enters the internal opening of the Na+
channel and combines with a receptor. This produces blockade of the Na+
channels, thereby decreasing Na+ conductance and preventing the depolarization of the cell membrane

Physiological effects

CVS Bupivacaine is markedly cardiotoxic; it binds specifically to myocardial
proteins, in addition to blocking cardiac sodium channels and decreasing
the rate of increase of phase 0 during the cardiac action potential. In toxic
concentrations, the drug decreases the peripheral vascular resistance and
myocardial contractility, producing hypotension and possibly cardiovascular collapse. K+ and Ca2+ channels may also be affected at toxic doses.
Levobupivacaine-induced cardiotoxicity requires a greater dose to be
administered, compared with racemic bupivacaine.
CNS The principal effect of bupivacaine is reversible neural blockade; this
leads to a characteristically biphasic effect in the CNs. Initially, excitation
(light-headedness, dizziness, visual and auditory disturbances, and seizure
activity) occurs due to inhibition of inhibitory interneurone pathways in the
cortex. With increasing doses, depression of both facilitatory and inhibitory
pathways occurs, leading to CNs depression (drowsiness, disorientation,
and coma). Local anaesthetic agents block neuromuscular transmission
when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible
conductance. Levobupivacaine produces less motor blockade, but longer
sensory blockade, following epidural administration.

Adverse Effects Toxicity

Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described
above. The use of the drug for intravenous regional blockade is no longer
recommended, as refractory cardiac depression, leading to death, has been
reported when it is used for this purpose.

Absorption

The absorption of local anaesthetic agents is related to:
1. the site of injection (intercostal > caudal > epidural > brachial plexus >
subcutaneous)
2. the dose—a linear relationship exists between the total dose and the
peak blood concentrations achieved, and
3. the presence of vasoconstrictors which delay absorption.

The addition of adrenaline to bupivacaine solutions does not influence the
rate of systemic absorption, as:
1. the drug is highly lipid-soluble, and therefore its uptake into fat is rapid,
and
2. the drug has a direct vasodilatory effect.

Protein binding

95%
albumin and
alpha-1 acid glycoprotein; (Levo: >97%)

Volume of distribution

21–103 L

Metabolism

occurs in the liver by N-dealkylation, primarily to pipecoloxylidide. N-desbutyl bupivacaine and 4-hydroxy bupivacaine are also formed.
There is no evidence of in vivo racemization of levobupivacaine. In vitro
studies of levobupivacaine demonstrate that CYP3A4 and CYP1A2 are
responsible for its metabolism to desbutyl levobupivacaine and 3-hydroxy
levobupivacaine, respectively

Excretion

5% of the dose is excreted in the urine as pipecoloxylidide; 16% is excreted unchanged.

Clearance

0.47 l/min

Half-life

elimination halflife (after IV administration) is 0.31–0.61 hours.

Special Points

The onset and duration of conduction blockade are
related to the pKa, lipid solubility, and the extent of protein binding. A low
pKa and high lipid solubility are associated with a rapid onset time; a high
degree of protein binding is associated with a long duration of action. In
infants under 6 months of age, the low level of albumin and alpha-1 acid
glycoprotein results in an increase in the free fraction of bupivacaine.
Local anaesthetic agents significantly increase the duration of action of
both depolarizing and non-depolarizing relaxants. Levobupivacaine may
precipitate if diluted in alkaline solutions. Clonidine (8.4 micrograms/ml),
morphine (0.05 mg/ml), and fentanyl (4 micrograms/ml) have been shown
to be compatible with levobupivacaine

Route And Dose

Bupivacaine may be administered
topically, by infiltration, intrathecally, or epidurally;

the toxic dose of bupivacaine is 2 mg/kg (with or without adrenaline).
The maximum dose is 150 mg.

The drug acts within 10–20 minutes and has a duration of action
of 5–16 hours.