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Pharmacology of Local Anesthetics
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
However, sodium channel blockade is the main mechanism of action. The initiation and subsequent propagation of an action potential involves the opening of sodium channels in the nerve cell membrane. This process leads to a massive flow of sodium ions from the outside to the inside of the cell membrane, which depolarizes the membrane. Immediately after depolarization the membrane is actively repolarized by ion pumps back to its resting membrane potential. It is then available for another depolarization.
Neurotoxicology
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Sean D. McCann, Trevonne M. Thompson
The use of other antiepileptic drugs (AEDs) in the management of toxin-induced seizures is not supported by current literature. The use of any AED with sodium channel blocking properties is contraindicated in this setting. Many toxins that cause seizures do so by interfering with axonal transmission via sodium channel blockade; therefore, administration of an AED with sodium channel blocking properties may paradoxically worsen seizures. Sodium channel blockade also causes cardiotoxicity by a similar mechanism: impaired conductance through the sodium channel prolongs initial depolarization of the cardiac myocyte leading to a prolonged QRS interval and eventually ventricular dysrhythmia. Administration of an AED with sodium channel blocking properties could precipitate or worsen these effects and should be avoided. Given the unreliable nature of the history in poisoned patients, as discussed above, these agents should be avoided in toxin-induced seizures because of the risk of potential unidentified coingestants and the availability of safe and effective alternative therapies as outlined above. Table 19.1 lists common AEDs with sodium channelblocking activity.
Antidepressant Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
TCAs have three-ring chemical structure common to them (Santarsieri and Schwartz, 2015). TCAs inhibit the reuptake of NA, DA, and 5-HT in to the presynaptic neurons and exerts marked earlier response due to the dual inhibition of both 5-HT and NA reuptake (Thase et al., 2001; Thompson, 2002) and this is also further responsible for the unwanted side effects of TCAs (Pacher and Kecskemeti, 2004). The unwanted effects of these drugs is due to their action on various other receptors including adrenergic receptors (α1), histamine (H1), and muscarinic (M) receptors (Glassman, 1984; Goodman et al., 2001; Pacher et al., 1999) and these unwanted effects result in the discontinuation of TCAs in approximately 27% patients (Montgomery et al., 1994). Despite of their effectiveness in the treatment of the depression, the adverse effects accompanied by the TCAs imposed limitations regarding their use for the treatment of depression (Feighner, 1999; Holm and Markham, 1999). Adverse effects include dryness of mouth, blurred vision, dizziness, lethargy, sedation (Cohen, 1997), seizures, cardiac block or arrhythmias (Feighner, 1999), due to the blockade of cardiac sodium channels (Stahl, 2000).
Association of sodium voltage-gated channel genes polymorphisms with epilepsy risk and prognosis in the Saudi population
Published in Annals of Medicine, 2022
Mansour A. Alghamdi, Laith N. AL-Eitan, Ashwag Asiri, Doaa M. Rababa’h, Sultan A. Alqahtani, Mohammed S. Aldarami, Manar A. Alsaeedi, Raghad S. Almuidh, Abdulbari A. Alzahrani, Ahmad H. Sakah, Eman Mohamad El Nashar, Mansour Y. Otaif, Nawal F. Abdel Ghaffar
Epilepsy is a complex neurological condition that impacts the brain and cause seizure [24]. Genetic predisposition to epilepsy has been a fundamental part of the disorder aetiology [25]. Voltage-gated sodium channels are critical for genetics epilepsy, and these channels play a key role in mediating the electrical excitability. Thus, it is lucid that any genetic mutations in these gene coding channels can interfere the epilepsy development or progression. When the channels are activated by membrane depolarization, it will cause conformational change that increases the sodium ion influx in addition to cell depolarization and later the channels will be deactivated ending in resting of membrane potential [11]. This study investigated several genetic variants of SCN genes (SCN1A, SCN2A, SCN3A, SCN1B, SCN2B, SCN3B and SCN8A) and their association with epilepsy risk; these genes have been studied in this regard and conflicted results were reported [7]. rs3812718 is a common intronic variant that located in splice donor site, and it modifies alternative splicing of exon 5. We suggest that TT genotype of rs3812718 in SCN1A may be a protective factor against epilepsy and may decrease the risk of the disease in Saudi population. In contrast to our finding, rs3812718 was reported as a risk factor for GEFS + in Chinese population [26,27]. In one meta-analysis they revealed that the rs3812718 TT genotype was involved in high risk of developing drug resistance in epilepsy children [28].
Tefluthrin: metabolism, food residues, toxicity, and mechanisms of action
Published in Critical Reviews in Toxicology, 2022
Xiaohui Wang, Houpeng Li, Simeng Wang, María-Aránzazu Martínez, Irma Ares, Marta Martínez, María-Rosa Martínez-Larrañaga, Xu Wang, Arturo Anadón, Jorge-Enrique Maximiliano
As mentioned above, there are many different subtypes of sodium channels in mammals. The VGSCs of rats include Nav1.2a, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, and Nav1.8. Each subtype has substantial differences, and tefluthrin has a very effective modifying effect on all seven subtypes (Spencer et al. 2001; Soderlund 2010; Cao, Shafer, Murray 2011; He and Soderlund 2011; Tan et al. 2011; McCavera and Soderlund 2012; Soderlund et al. 2017; So et al. 2018). These seven channel subtypes combine with the β1 subunit to form a VGSC. Nav1.6 is the most sensitive to tefluthrin, and Nav1.3 and Nav1.7 are important targets for the neurotoxic effects of tefluthrin (Tan and Soderlund 2011; Wu et al. 2021). Overall, the sodium channel targets of all pyrethroids including tefluthrin remain to be studied further. This information could provide a direction to screen potential antagonists of pyrethroids, including tefluthrin. This endeavour could lead to a treatment for pyrethroid poisoning.
Why are sodium channel modulators not yet pharmacotherapeutic trailblazers for neuropathic pain?
Published in Expert Opinion on Pharmacotherapy, 2021
The finding that mammals have 9 sodium channels and that in the main, three, namely, 1.7, 1.8 and 1.9 are rather selectively found in peripheral pain pathways, gives rise to the possibility of systemic yet pain selective sodium channel blockers [1]. A number of preclinical studies using transgenic approaches revealed key roles in pain, in particular neuropathic pain models. Generally, proof of concept arises when a drug has been developed, but here and rapidly, strong proof of concept arrived from recognition of a number of inherited pain disorders involving mutations in Nav 1.7 in particular where the abnormal sodium channel proteins caused a loss or gain of function and corresponding pain abnormalities [1]. Similar inherited changes in Nav 1.8 have been reported indicating that this channel could be an important target too [2]. This provided an impetus for the development of novel pain related 1.7 sodium channel blockers. But some important messages were not taken into account as the field progressed.