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Topical Pain Medications and Their Role in Pain Management
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Topical baclofen acts as an agonist at the GABA-B receptor. By the activation of tetraethylammonium-sensitive K+ channels on GABA-B, peripheral antinociceptive effects are observed. The intracellular increase in K+ is accompanied by a decrease in calcium ions, which alter membrane permeability, leading to a slow and prolonged inhibitory transmission.13 Baclofen is used mostly in combination with other topical formulations for combined analgesia, as efficacy has not been established for monotherapy.
Overview of Ion Channels, Antiepileptic Drugs, and Seizures
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Inward (anomalous) rectifying K+ channels also are common in neurons and other excitable cell types.22 Conductance in this type of channel increases with hyperpolarization, allowing K+ entry. Rectification is probably due to blockade of the channel by intracellular Mg2+ through competition of the two cations for the pore.22,29 Quaternary ammonium ions, such as tetraethylammonium, block this type of current. This channel type also is important in regulating neuronal firing frequency, and is affected by neurotransmitters and second messengers.30 The excitability of an individual neuron can be influenced by multiple different types of K+ conductances within the same cell.23
Physiology, Biochemistry, and Pathology of Neuromuscular Transmission
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
Neural K+ channels exist in several forms and can be identified by a number of “diagnostic” toxins (charybdo- and noxius toxin derived from scorpion venom, and apamine from the venom of the honey bee). At the neuromuscular junction, the nerve terminals contain K+ channels that can be blocked completely by 3,4-aminopyridine and tetraethylammonium.
Renal tubular transporter-mediated interactions between mirogabalin and cimetidine in rats
Published in Xenobiotica, 2023
Naotoshi Yamamura, Tomoki Imaoka, Misa Hoshi, Makiko Yamada, Ken-ichi Itokawa
Metformin is a known substrate of rOct2 rather than rOct1 (Kimura et al. 2005). The mRNA expression level of rOct2 in the kidney was higher than that in the liver and the mRNA expression of rOct1 was not detected in the kidney (Kimura et al. 2005). The Ki values of cimetidine were reported to be 632 μM and 9.4 μM for the uptake of [14C]tetraethylammonium by rOct2-overexpressing HEK293 cells (Umehara et al. 2007) and by rOct2-overexpressing MDCK cells (Urakami et al. 1998), respectively. As the Ki value of cimetidine of 9.4 μM for rOct2 was comparable to or somewhat higher than the observed plasma unbound concentration (7.0 μM), it cannot be ruled out that cimetidine inhibited rOct2 to some extent in rats in vivo. However, this effect is considered to be negligible or limited based on our in vivo observation in rats. Specifically, cimetidine coadministration significantly increased the cellular accumulation of metformin in the renal cortex and kidney, suggesting that the effect of inhibition of the apical efflux transporter rMate1, rather than the basolateral uptake transporter rOct2, is more dominant in vivo. In the same manner, cimetidine coadministration resulted in the intracellular accumulation of mirogabalin in kidney cortex, accompanied by a decrease in CLr/Ckidney.
Electromagnetic field affects the voltage-dependent potassium channel Kv1.3
Published in Electromagnetic Biology and Medicine, 2020
C. Cecchetto, M. Maschietto, P. Boccaccio, S. Vassanelli
Evidence exists that electromagnetic fields in the 0.03–300 Hz frequency range (ELF-EMF) can affect fundamental cellular processes such as proliferation and differentiation. Nevertheless, molecular mechanisms underlying interactions of ELF-EMF with living cells have remained elusive (Funk et al. 2009). Theoretical and experimental studies have suggested that voltage-gated calcium and sodium channels may be involved. ELF-EMF may modulate channel gating – either directly acting on the channels voltage sensors or, indirectly, through interposed biochemical signaling pathways – or affect ions percolation through the channel pore (Cui et al. 2014; Funk et al. 2009; Gartzke and Lange 2002; He et al. 2013; Pall 2013; Prucha et al. 2018; Sun et al. 2016). Yet, voltage-gated potassium channels remained largely unexplored, with the exception of the observation that an AC low-frequency (8 Hz) and low-intensity (100 µT) field was not altering Tetraethylammonium (TEA)-sensitive potassium currents in neuroblastoma cells (Gavoçi et al. 2013).
The human organic cation transporter OCT1 and its role as a target for drug responses
Published in Drug Metabolism Reviews, 2019
Nicolas Brosseau, Dindial Ramotar
Uptake analysis using the two different prototypical substrates, tetraethylammonium and 1-methyl-4-phenylpyridinium revealed that the OCT1 variant Trp218Phe decreased the uptake of tetraethylammonium, but increased the uptake for 1-methyl-4-phenylpyridinium (Popp et al. 2005). A similar observation was reported for the substitution Pro283Leu, which has been shown to reduce the uptake of lamivudine, but not of metformin (Choi and Song 2012). These observations underscore the possibility that different substrates require unique amino acid residues for binding and uptake. Thus, it would appear that OCT1 possesses multiple substrate binding sites (Koepsell 2011), which may explain its ability to transport a range of cationic molecules, but becomes predispose to drug-drug interactions (Zhang and Hagenbuch 2019). It is noteworthy that drug binding and transport by the rat OCT1 are also dependent on the amino acid residues Phe160 in TMH2, Trp218 in TMH4, and Asp475 in TMH11 in a manner similar to the human OCT1 (Koepsell 2011).