Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Local anaesthetics
ATC code: N01BB01
Bupivacaine Grindeks 5 mg/ml contains bupivacaine, which is a long-acting amide-type local anaesthetic . Bupivacaine reversibly blocks impulse transmission in the nerve fibres by inhibiting the transport of sodium ions through the nerve membrane. Similar effects can also be seen on excitatory membranes in the brain and cardiac muscle.
The most prominent characteristic of bupivacaine is the long duration of action; and the difference in duration of action between bupivacaine with and without adrenaline is relatively small.
Bupivacaine is well suited to continuous epidural blockage. Lower concentrations have less effect on motor nerve fibres and a shorter duration of action, and may be appropriate for prolonged analgesia such as in childbirth or postoperatively.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
The rate of absorption is dependent on dose, route of administration and vascularisation of the injection site. Intercostal blocks lead to the highest plasma concentrations (4 mg/l following a dose of 400 mg) due to rapid absorption; subcutaneous abdominal injections lead to the lowest plasma concentrations. Rapid absorption and high plasma concentrations are seen in children following caudal block (approx. 1-1.5 mg/l after a dose of 3 mg/kg).

Bupivacaine has complete and biphasic absorption from the epidural space, with half-lives of approx. 7 minutes and 6 hours respectively. The slow absorption is rate- limited by the elimination of bupivacaine, which explains why the elimination half-life is longer following epidural administration than that intravenous administration.

The distribution volume of bupivacaine at steady state is 73 litres; the hepatic extraction ratio is 0.40; total plasma clearance is 0.58 l/min; the elimination half-life is 2.7 hours. The elimination half-life in newborns is up to 8 hours longer than in adults. The half-life in children over 3 months is equivalent to that in adults.
The pharmacokinetics in children are similar to those in adults.

Plasma protein binding is 96% and primarily involves alpha-1-glycoprotein. There may be an elevated level of this protein following major surgery, giving a higher total plasma concentration of bupivacaine. The unbound concentration of bupivacaine will however remain unchnaged. This explains why plasma concentrations above toxic levels can be well tolerated.
Bupivacaine is metabolised almost entirely in the liver, primarily through aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to pipecolylxylidine, both of which are mediated by cytochrome P450 3A4. Clearance is thus dependent on the hepatic blood flow and the activity of the metabolising enzyme.

Bupivacaine crosses the placenta and the concentration of unbound bupivacaine is the same in the mother and the foetus. However, the total plasma concentration is lower in the foetus, due to a lower degree of protein binding.