Marcaine 0.5% Adrenaline Mechanism of Action

Pharmacotherapeutic class: Local anaesthetic. ATC code: N01B B51.
Pharmacology: Pharmacodynamics: Marcain with Adrenaline contains bupivacaine, which is a long-acting local anaesthetic of the amide type, and the vasoconstrictor adrenaline (epinephrine). Bupivacaine reversibly blocks impulse conduction in the nerves by inhibiting the transport of sodium ions through the nerve membrane. Similar effects can also be seen on excitatory membranes in the brain and myocardium.
The most prominent property of bupivacaine is its long duration of effect, and the difference in duration between bupivacaine with and without adrenaline is relatively small. Lower concentrations produce lesser effects on motor nerve fibres and a shorter duration of effect, and can be suitable for prolonged pain relief, e.g. during parturition or postoperatively.
Pharmacokinetics: The rate of absorption is dependent on dose, route of administration and perfusion at the injection site. The addition of adrenaline can reduce the rate of absorption, whereas the time to peak plasma concentration is little affected. The effect varies with the type of block, dose and concentration. In adults, adrenaline decreases peak plasma concentrations by up to 50% in brachial plexus block and by 5-25% in epidural block. Intercostal blockades produce the highest plasma concentrations (1-4 mg/l) after a dose of 400 mg), due to rapid absorption, while subcutaneous injections in the abdomen produce the lowest plasma concentrations. In children rapid absorption and high plasma concentrations are seen in cases of caudal block (approx. 1-1.5 mg/l after a dose of 3 mg/kg).
Bupivacaine is absorbed completely and bi-phasically from the epidural space with half-lives of approx. 7 minutes and 6 hours respectively. The slow absorption is rate-limiting in the elimination of bupivacaine, which explains why the elimination half-life after epidural administration is longer than after intravenous administration.
The volume of distribution of bupivacaine in steady state is 73 litres, the degree of hepatic extraction is 0.40, total plasma clearance is 0.58 l/min and the elimination half-life is 2.7 hours.
The elimination half-life in newborns is up to 8 hours longer than in an adult. In children over 3 months the half-life is equivalent to that in adults.
Plasma protein binding is 96% and binding is predominantly to alpha-1-glycoprotein. After a major operation the level of this protein may be increased and give a higher total plasma concentration of bupivacaine. However, the unbound concentration of bupivacaine remains the same. This explains why plasma concentrations above toxic levels can be well tolerated.
Bupivacaine is metabolised almost completely in the liver, predominantly through aromatic hydroxylation to 4-hydroxybupivacaine and N-dealkylation to pipecholylxylidine, which are both mediated by cytochrome P450 3A4. Clearance is thus dependent on hepatic perfusion and the activity of the metabolising enzyme.
Bupivacaine crosses the placenta and the concentration of free bupivacaine is the same in the mother and the foetus. However, the total plasma concentration is lower in the foetus, which has a lower degree of protein binding.