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Pharmacology: 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. Local anaesthetics of the amide type are thought to act within the sodium channels of the nerve membrane.
Local anaesthetic drugs may have similar effects on excitable membranes in the brain and myocardium. If excessive amounts of drug reach the systemic circulation rapidly, symptoms and signs of toxicity will appear, emanating mainly from the central nervous system (CNS) and cardiovascular system.
Central nervous system toxicity usually precedes the cardiovascular effects as it 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 eg, hypotension and bradycardia, may occur after epidural or spinal administration depending on the extent of the concomitant sympathetic block.
Pharmacokinetics: Bupivacaine is a long-acting, amide-type local anaesthetic chemically related to lignocaine and mepivacaine. It is approximately 4 times as potent as lignocaine.
In concentrations of 5 mg/mL, it has a long duration of action from 2-5 hrs following a single epidural injection and up to 12 hrs after peripheral nerve blocks. The onset of the blockade is slower than with lignocaine, especially when anaesthetising large nerves.
When used in low concentrations (≤2.5 mg/mL), there is less effect on motor nerve fibres and the duration of action is shorter. Low concentrations may, however, be used with advantage for prolonged pain relief eg, in labour or postoperatively.
The plasma concentration of bupivacaine depends upon the dose, the route of administration and the vascularity of the injection site.
After injection of Marcain for caudal, epidural or peripheral nerve block in man, peak plasma levels of bupivacaine in the blood are reached within 30-45 min, followed by a decline to insignificant levels during the next 3-6 hrs.
Intercostal blocks give the highest peak plasma concentration due to rapid absorption (maximum plasma concentrations in the order of 1-4 mg/L after a 400-mg dose), while abdominal SC injections give the lowest plasma concentrations. Epidural and major plexus blocks are intermediate. In children, rapid absorption (plasma concentrations are in the order of 1-1.5 mg/L after a dose of 3 mg/kg) is seen with caudal block.
Bupivacaine has a total plasma clearance of 0.58 L/min, a volume of distribution at steady state of 73 L, an elimination half-life of 2.7 hrs and an intermediate hepatic extraction ratio of 0.4 following experimental IV administration in adults. The terminal elimination half-life is prolonged in the newborn to approximately 8 hrs. In children >3 months, the elimination half-life is similar to that in adults. Bupivacaine is mainly bound to α1-acid glycoprotein in plasma with a plasma-binding of 96%.
Absorption of bupivacaine from the epidural space occurs in 2 phases; the 1st phase is in the order of 7 min and the 2nd is in 6 hrs. The slow absorption is rate-limiting in the elimination of bupivacaine, which explains why the apparent elimination half-life after epidural administration is longer than after IV administration.
An increase in α1-acid glycoprotein, which occurs postoperatively after major surgery, may cause an increase in the total plasma concentration of bupivacaine. The level of free drug will remain the same. This explains why total plasma concentrations above the apparent toxic threshold level of 2.6-3 mg/L are apparently well tolerated in this situation.
Bupivacaine is excreted in the urine principally as metabolites with about 6% as unchanged drug. Following epidural administration, the urinary recovery of unchanged bupivacaine is about 0.2%, of pipecolylxylidine (PPX) about 1% and of 4-hydroxy-bupivacaine about 0.1% of the administered dose.
Various pharmacokinetic parameters can be significantly altered by a number of factors including the presence of hepatic and renal disease, route of administration, age of the patient, presence or absence of adrenaline in the solution and certain concomitant medication.
