Marcain Spinal Heavy Mechanism of Action

Pharmacotherapeutic group (ATC code): N01B B01.
Pharmacology: Pharmacodynamics: Bupivacaine is a local anaesthetic of the amide type. Given as an intrathecal anaesthetic, it has a rapid onset and a medium to long duration. The duration is dose-dependent.
Bupivacaine, like other local anaesthetics, causes a reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the nerve membrane.
Marcain Spinal Heavy is hyperbaric and its initial spread in the intrathecal space is affected by gravity. Due to the small dose the intrathecal distribution results in a relatively low concentration and the duration of the local anaesthetic tends to be relatively short.
Plain solutions (without dextrose) produce a less predictable level of block, but of longer duration than the hyperbaric solutions.
Pharmacokinetics: Bupivacaine has a pKa of 8.2 and a partition coefficient of 346 (25°C n-octanol/phosphate buffer pH 7.4). The metabolites have a pharmacological activity that is less than that of bupivacaine.
Bupivacaine shows complete and biphasic absorption from the subarachnoid space with half-lives of the two phases of the order of 50 and 408 minutes. The slow absorption phase is the rate-limiting factor in the elimination of bupivacaine, which explains why the apparent terminal half-life is longer after subarachnoidal administration than after intravenous administration. The blood concentration of bupivacaine after intrathecal block is low compared with those after other regional anaesthetic procedures, due to the small dose required for intrathecal anaesthesia. Generally, the increment in maximum plasma concentration is approximately 0.4 mg/L for every 100 mg injected. This means that a dose of 20 mg would result in plasma levels in the order of 0.1 mg/L.
After i.v. injection bupivacaine has a total plasma clearance of 0.58 L/min, a volume of distribution at steady state of 73 L, a terminal half-life of 2.7 h and an intermediate hepatic extraction ratio of 0.38 after i.v. administration. It is mainly bound to alpha-l-acid glycoprotein in plasma with a plasma binding of 96%. Clearance of bupivacaine is almost entirely due to liver metabolism, and more sensitive to changes in intrinsic hepatic enzyme function than to liver perfusion.
Bupivacaine readily crosses the placenta and equilibrium with regard to the unbound concentration is rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus.
Bupivacaine is excreted in breast milk, but in such small quantities that there is no risk to the child.
Bupivacaine is extensively metabolized in the liver, predominately by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to PPX, both mediated by cytochrome P4503A4. About 1% of bupivacaine is excreted in the urine as unchanged drug in 24 h and approximately 5% as PPX. The plasma concentrations of PPX and 4-hydroxy-bupivacaine during and after continuous administration of bupivacaine are low as compared to the parent drug.
Toxicology: Preclinical safety data: Based on conventional studies with bupivacaine of safety pharmacology, single and repeated dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no hazards for humans were identified other than those which can be expected on the basis of the pharmacodynamic action of high doses of bupivacaine (e.g. CNS signs and cardiotoxicity).