Bupivacaine

Bupivacaine is a long acting local anaesthetic of the amide type with both anaesthetic and analgesic effects. At high doses it produces surgical anaesthesia, while at lower doses it produces sensory block (analgesia) with less pronounced motor block.

Onset and duration of the local anaesthetic effect of bupivacaine depends on the dose and site of administration.

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 cell membrane of the nerve fibres. The sodium channels of the nerve membrane are considered a receptor for local anaesthetic molecules.

Local anaesthetics may have similar effects on other excitable membranes e.g. in the brain and myocardium. If excessive amounts of drug reach the systemic circulation, symptoms and signs of toxicity may appear, emanating from the central nervous and cardiovascular systems.

Central nervous system toxicity usually precedes the cardiovascular effects as central nervous system toxicity occurs at lower plasma concentrations. Direct effects of local anaesthetics on the heart include slow conduction, negative inotropism and eventually cardiac arrest.

Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration depending on the extent of the concomitant sympathetic block..

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.

The plasma concentration of bupivacaine depends upon the dose, the route of administration and the vascularity of the injection site.

Bupivacaine shows complete and biphasic absorption from the epidural space with half-lives in the order of 7 min and 6 h respectively. The slow absorption is rate-limiting in the elimination of bupivacaine, which explains why the apparent half-life after epidural administration is longer than that after intravenous administration.

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 IV administration. It is mainly bound to alpha-l-acid glycoprotein with plasma binding of 96%. Clearance of bupivacaine is almost entirely due to liver metabolism and more sensitive to changes in intrinsic hepatic enzyme function that to liver perfusion.

Paediatric population

In children the pharmacokinetics are similar to that in adults.

An increase in total plasma concentration has been observed during continuous epidural infusion. This is related to a postoperative increase in alpha 1-acid glycoprotein. The unbound, i.e. pharmacologically active, concentration is similar before and after surgery.

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 extensively metabolised 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.

Bupivacaine is a well established active ingredient.