PubMed · 1914898
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A Schmidt. 1991. [Brachial plexus blockade].. https://pubmed.ncbi.nlm.nih.gov/1914898/
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Marijuana contains a complex mixture of compounds including tetrahydrocannabinol (THC), the major psychoactive constituent, and cannabidiol (CBD), a nonpsychoactive constituent. We have shown previously that CBD pretreatment of mice increases brain levels of THC and have now further characterized this effect and determined whether the brain pharmacokinetics of other drugs are also affected. CBD pretreatment of mice (30-60 min) increased brain levels of THC nearly 3-fold, whereas CBD co-administration did not. Because marijuana is often consumed with other drugs, the influence of cannabinoids on the brain levels of several other drugs of abuse was also determined. CBD pretreatment of mice increased brain levels (2- to 4-fold) of subsequently administered cocaine as well as phencyclidine (PCP). Although CBD pretreatment increased blood and brain levels of cocaine comparably, blood levels of PCP were only modestly elevated (up to 50%). Behavioral tests indicated that the CBD-mediated increases in the brain levels of THC, cocaine, and PCP correlated with increased pharmacological responses. Pretreatment with THC instead of CBD could similarly increase brain levels of cocaine, PCP, and CBD, although with a lower potency than CBD. On the other hand, pretreatment of mice with CBD had no effect on the brain levels of several other drugs of abuse including morphine, methadone, or methylenedioxyphenyl-methamphetamine. These findings demonstrate that cannabinoids can increase the brain concentrations and pharmacological actions of several other drugs of abuse, thereby providing a biochemical basis for the common practice of using marijuana concurrently with such drugs.
Local anesthetics, commonly used for treating cardiac arrhythmias, pain, and seizures, are best known for their inhibitory effects on voltage-gated Na(+) channels. Cardiovascular and central nervous system toxicity are unwanted side-effects from local anesthetics that cannot be attributed to the inhibition of only Na(+) channels. Here, we report that extracellular application of the membrane-permeant local anesthetic bupivacaine selectively inhibited G protein-gated inwardly rectifying K(+) channels (GIRK:Kir3) but not other families of inwardly rectifying K(+) channels (ROMK:Kir1 and IRK:Kir2). Bupivacaine inhibited GIRK channels within seconds of application, regardless of whether channels were activated through the muscarinic receptor or directly via coexpressed G protein G(beta)gamma subunits. Bupivacaine also inhibited alcohol-induced GIRK currents in the absence of functional pertussis toxin-sensitive G proteins. The mutated GIRK1 and GIRK2 (GIRK1/2) channels containing the high-affinity phosphatidylinositol 4,5-bisphosphate (PIP(2)) domain from IRK1, on the other hand, showed dramatically less inhibition with bupivacaine. Surprisingly, GIRK1/2 channels with high affinity for PIP(2) were inhibited by ethanol, like IRK1 channels. We propose that membrane-permeant local anesthetics inhibit GIRK channels by antagonizing the interaction of PIP(2) with the channel, which is essential for G(beta)gamma and ethanol activation of GIRK channels.
As part of a general study to improve the iontophoretic delivery of local anaesthetics of the amide type, the diffusion properties of the hydrochloride salts of bupivacaine, etidocaine, lidocaine, mepivacaine, prilocaine and ropivacaine, were studied in a 1% w/w agarose hydrogel. A source drug solution (25 mM) was placed in contact with the gel and, after an appropriate time, the drug concentration profile in the gel was analyzed to give a diffusion coefficient, D. The values of Dx10(10) expressed in m(2) s(-1) were: (bupi) 6.71, (eti) 6.71, (ropi) 6.39, (mepi) 7.31, (lido) 7.49 and (prilo) 7.76. For comparative reasons, the diffusion coefficient for LidHCl in an aqueous solution according to the Nernst-Hartley relation for the diffusion of ion-pairs was calculated, hereby taking into account ionic activity of LidH+ and Cl-. The diffusion coefficient thus obtained was 7.76x10(-10) m2 s-1 at infinite dilution. The relationship between the molecular weight of the compounds and the diffusion coefficient was investigated.