Bupivacaine, lidocaine, ropivacaine and levobupivacaine (the S-enantiomer of bupivacaine) are all licensed for obstetric epidural use in the UK, and heavy (hyperbaric) 0.5% bupivacaine and heavy 2% prilocaine are the only local anaesthetics licensed for obstetric spinal use (levobupivacaine is licensed for non-obstetric spinal anaesthesia). These local anaesthetics are all amides. There are no local anaesthetics in the ester group in use in British obstetric anaesthesia, although chloroprocaine is used in the USA owing to its speedy onset and offset, and possible reduced incidence of fetal ion trapping because of its rapid breakdown by plasma esterases in the maternal circulation (see Chapter 16, Placental transfer of drugs).
Pharmacology
Local anaesthetics act by reducing permeability of the nerve cell membrane to sodium, preventing development of a propagated action potential. The local anaesthetic binds to receptor sites within the sodium channels of the nerve membrane. Increasing lipid solubility allows the local anaesthetic drug to penetrate the nerve membrane more readily, and is associated with increased potency (bupivacaine and levobupivacaine have greater lipid solubility than lidocaine and ropivacaine).
Increased capacity for protein binding increases the duration of action of the local anaesthetic. Bupivacaine and levobupivacaine are 95% protein-bound and ropivacaine is 94% protein-bound, and these drugs therefore have a longer duration of action than lidocaine, which is only 64% protein-bound.
The speed of onset of local anaesthetic activity is related to the degree of ionisation of the drug. The non-ionised form of the drug diffuses across the nerve sheath to reach the nerve membrane. The degree of ionisation is dependent on the pKa of the drug. Bupivacaine, ropivacaine and levobupivacaine all have a pKa of 8.2 and are therefore more ionised (and thus have a slower onset of anaesthetic action) at body pH than lidocaine, which has a pKa of 7.7. Addition of bicarbonate to local anaesthetic solutions speeds onset time and may improve the quality of the block.
The development of the minimum local analgesic concentration/dose (MLAC/D) technique, using an up-down sequential allocation model, has enabled relative analgesic potency ratios to be determined for epidural analgesia (and to a lesser extent, spinal analgesia/anaesthesia). In this technique, the first patient in a study group is given a set volume of a certain concentration (MLAC) or a set volume containing a certain dose (MLAD). If the target response is achieved (e.g. pain scores < 1 cm on a scale of 0-10 cm), the next patient receives a 20% decrease in concentration/dose; if the target response is not achieved the next patient receives a 20% increase. The process is repeated and the median effective dose (ED50) may be derived from the resultant graph of responses. This technique has allowed the potencies of different local anaesthetics and the effect of additives (e.g. opioids) to be compared. Studies have suggested the relative potencies of epidural ropivacaine : levobupivacaine : bupivacaine to be 0.7:0.9:1.0. They have also shown that the MLAC of bupivacaine increases as labour progresses, suggesting increased analgesic requirements as further pain fibres are recruited.
The amide local anaesthetics are metabolised by the liver and excreted via the kidney.
Toxicity
Systemic toxicity of local anaesthetics is manifest as central nervous system (CNS) excitability (caused by inhibition of inhibitory fibres) that may lead to convulsions and, later, to CNS depression. Local anaesthetics also affect the cardiovascular system. Toxic doses cause depolarisation of cardiac cell membranes and systemic vasodilatation; this may lead to cardiovascular collapse. The parturient appears to be particularly sensitive to local anaesthetic toxicity; suggested reasons for this include greater uptake due to increased vascularity and cardiac output, increased free fraction of the drug due to altered protein binding, and altered cardiomyocyte electrophysiology and neuronal susceptibility due to hormonal changes.
Resuscitation of the pregnant patient is notoriously difficult. In recent years, lipid rescue has become established as the treatment of choice in local anaesthetic toxicity; experience in pregnancy is limited, but its use is advocated in parturients as for nonpregnant patients.
The margin between the systemic concentration of local anaesthetic causing CNS symptoms and signs and that causing cardiovascular signs is smaller for bupivacaine than for the other local anaesthetic agents in clinical use, and it is this problem that has stimulated the development of newer local anaesthetics. Bupivacaine appears to be particularly cardiotoxic in pregnancy, causing ventricular arrhythmias and asystolic cardiac arrest. Both ropivacaine and levobupivacaine appear to have a wider safety margin than bupivacaine.
The addition of adrenaline to lidocaine reduces its systemic absorption and therefore permits administration of larger doses (up to 7 mg/kg body weight, compared with 3 mg/kg if adrenaline is not used), while prolonging its action. This is not the case with bupivacaine, the maximum dose of which is 2 mg/kg.
Amide local anaesthetics have a minimal chance of causing allergic reactions, unlike the ester group.
Differential block
The ideal local anaesthetic for obstetric analgesia would provide complete sensory analgesia of rapid onset and long duration without any motor blockade. Although bupivacaine provides long-lasting sensory block, this is accompanied (especially at increasing dosage) by motor blockade. Ropivacaine has similar action at higher concentrations, but at lower concentrations is claimed to produce differential sensory block by preferential action on C fibres. The extent to which this is clinically significant is still unproven, and the increasing use of very low concentrations of local anaesthetic combined with opioids for labour analgesia may make any difference clinically irrelevant.
Key points
• All the local anaesthetics used in British obstetric anaesthetic practice are amides.
• Anaesthetic potency is proportional to lipid solubility.
• Duration of action is proportional to extent of protein binding.
• Speed of onset of action is proportional to the amount of non-ionised drug present.
• Systemic toxicity is manifest by CNS excitability followed by cardiovascular depression. The margin of safety between CNS and cardiovascular toxicity is lowest for bupivacaine. Lipid rescue is recommended for local anaesthetic toxicity.
Further reading
Association of Anaesthetists of Great Britain and Ireland. Management of Severe Local Anaesthetic Toxicity. London: AAGBI, 2010. www.aagbi.org/sites/default/files/la_toxicity_2010_0.pdf (accessed December 2018).
Bern S, Weinberg G. Local anesthetic toxicity and lipid resuscitation in pregnancy. Curr Opin Anaesthesiol 2011; 24: 262-7.