Bupivacaine receptor interactions

Receptor interactions bupivacaine binds to the intracellular portions of sodium channels and blocks sodium influx into nerve cells which therefore prevents nerve cell depolarization. Since pain-transmitting nerve fibers tend to be thinner (small diameter) and either unmyelinated or only lightly myelinated (myelin is non-polar and lipophilic), the local anesthetic agent can diffuse more readily into them than into thicker and more heavily myelinated nerve fibers such as touch and proprioception. 

The local anesthetics can be broadly categorized on the basis of the chemical nature of the linkage contained within the intermediate alkyl chain group. The amide local anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine (7.8), prilocaine (7.9), and ropivacaine (7.10) the ester local anesthetics include cocaine (7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmacodynamic interaction of both amide and ester local anesthetics with the same Na" channel receptor is essentially idenhcal, the amide and ester functional groups are bioisosterically equivalent. However, amide and ester local anesthetics are not equal from a pharmacokinetic perspective. Since ester links are more susceptible to hydrolysis than amide links. 

In small doses, local anesthetics can depress posttetanic potentiation via a prejunctional neural effect. In large doses, local anesthetics can block neuromuscular transmission. With higher doses, local anesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channel-blocking antiarrhythmic drugs such as quinidine. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Higher concentrations of bupivacaine (0.75%) have been associated with cardiac arrhythmias independent of the muscle relaxant used. 

Some studies suggest that both cimetidine and ranitidine can raise plasma bupivacaine levels, whereas other evidence suggests that no significant interaction occurs. Ranitidine does not appear to significantly affect lidocaine. Some studies found that cimetidine does not affect lidocaine when used as an anaesthetic. Other studies found that cimetidine increased plasma lidocaine levels and that famotidine had less effect. See also Lidocaine + H2-receptor antagonists , p.264 for interactions of lidocaine used as an an-tiarrhythmic. 

A confusing situation. No clinically important interaction has been established, but be alert for any evidence of increased bupivacaine toxicity resulting from raised total plasma levels and rises in unbound bupivacaine levels during the concurrent use of cimetidine and possibly ranitidine. Cimetidine (but not ranitidine) has been shown to raise plasma lidocaine levels when lidocaine is used as an antiarrhythmic (see Lidocaine + H2-receptor antagonists , p.264), but some of the studies cited above found cimetidine did not affect lidocaine levels when lidocaine is used as an anaesthetic. However, in the studies comparing the effects of cimetidine and famotidine, cimetidine was found to increase lidocaine levels and it was suggested that famotidine may be preferable to cimetidine as pretreatment before epidural lidocaine. ... 

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