Access and binding of local anesthetics in the closed sodium channel.

Local anesthetics (LAs) are known to bind Na+ channels in the closed, open, and inactivated states and reach their binding sites via extracellular and intracellular access pathways. Despite intensive studies, no atomic-scale theory is available to explain the diverse experimental data on the LA actions. Here we attempt to contribute to this theory by simulating access and binding of LAs in the KcsA-based homology model of the closed Na+ channel. We used Monte Carlo minimizations to model the channel with representative local anesthetics N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium (QX-314), cocaine, and tetracaine. We found the nucleophilic central cavity to be a common binding region for the ammonium group of LAs, whose aromatic group can extend either along the pore axis (vertical binding mode) or to the III/IV domain interface (horizontal binding mode). The vertical mode was earlier predicted for the open channel, but only the horizontal mode is consistent with mutational data on the closed-channel block. To explore hypothetical access pathways of the permanently charged QX-314, we pulled the ligand via the selectivity filter, the closed activation gate, and the III/IV domain interface. Only the last pathway, which leads to the horizontal binding mode, did not impose steric obstacles. The LA ammonium group mobility within the central cavity was more restricted in the vertical mode than in the horizontal mode. Therefore, occupation of the selectivity-filter DEKA locus by a Na+ ion destabilizes the vertical mode, thus favoring the horizontal mode. LA binding in the closed channel requires the resident Na+ ion to leave the nucleophilic central cavity through the selectivity filter, whereas the LA egress should be coupled with reoccupation of the cavity by Na+. This hypothesis on the coupled movement of Na+ and LA in the closed channel explains seemingly contradictory data on how the outer-pore mutations as well as tetrodotoxin and micro-conotoxin binding affect the ingress and egress of LAs.

Iontophoretic drug delivery using the IOMED Phoresor system.

Iontophoresis, or electromotive drug administration, is a process that enhances the delivery of drugs through a biological membrane via the application of low-intensity electrical current. This technology offers several advantages over oral and injection drug delivery. Key advantages of iontophoretic drug delivery include the avoidance of pain and potential for infection associated with needle injection, the ability to control the rate of drug delivery, the ability to programme the drug-delivery profile and the minimisation of local tissue trauma. Research using iontophoresis has shown delivery of a number of drug classes. By controlling the applied electric current one can tailor a dosage regimen with a drug delivery profile specific for an indication and the needs of the patient. Advances in iontophoretic electrode design, microelectronics and methods to optimise iontophoretic drug delivery have improved the ability to safely deliver both older, off-patent drugs, as well as new chemical entities being developed to treat a variety of diseases. In addition to transdermal applications, current research indicates that iontophoresis may prove to be a viable noninvasive drug delivery method for treating conditions that affect the back of the eye.

Ropivacaine: a pharmacological review.

Ropivacaine (Naropin, AstraZeneca) a new long-acting amide local anaesthetic agent, is a pure S-enantiomer, with a high pKa and relatively low-lipid solubility. Since its clinical introduction in 1996, it has been the focus of intense interest because of its increased CNS and cardiovascular safety compared with bupivacaine. This article reviews the pharmacology of ropivacaine with particular emphasis placed on toxicological issues. Compared with bupivacaine (the drug of choice for many years), ropivacaine is equally effective for subcutaneous infiltration, epidural, intrathecal and peripheral nerve block surgery, and obstetrics and postoperative analgesia. Ropivacaine is virtually identical to bupivacaine in terms of onset, quality and duration of sensory block, but seems to produce less motor block. The lesser toxicity of ropivacaine compared with bupivacaine has been confirmed in numerous animal experiments as well as human studies, including studies considering the presumed lower potency of ropivacaine. In fact, the reduced cardiovascular toxicity compared with bupivacaine may be a distinct feature of ropivacaine. So far, the increased cost of ropivacaine compared with bupivacaine has limited its wider clinical use -- in spite of the improved safety profile. During the last few years, cost differences between bupivacaine and ropivacaine have been minimized, thus making pharmacoeconomical speculations a much lesser concern when choosing a local anaesthetic drug. In conclusion, ropivacaine appears to be a safer local anaesthetic agent than bupivacaine. It seems particularly indicated for major peripheral nerve blocks and obstetrics. Ropivacaine should be considered when regional blocks are used in neonates and young infants. With the current trend in the cost development, ropivacaine will most likely be used increasingly in the future.

Rapid and specific precolumn extraction high-performance liquid chromatographic assay for bupivacaine in human serum.

A rapid and specific HPLC assay for quantiative determination of bupivacaine in human serum is described. The technique incorporates an on-line sample clean-up system followed by reversed-phase chromatography with UV detection. The proposed method uses a column-switching technique and protein-coated Lichrosorb RP-8 as a precolumn together with Lichrosorb RP-18 as an analytical column. The total run time for an injection of serum sample was 10 min. This procedure offers a sensitive assay without the need for time-consuming extractions. The average bupivacaine recoveries over a concentration range of 150-600 ng/mL ranged from 99.12 to 101.02%, and relative standard deviations ranged from 1.15 to 1.78%.