Sodium channels and inhibition

Rapid-acting paralytic neurotoxins that blocks transient sodium channels and inhibits depolarization of nerve cells. They are some of the causative agents of paralytic shellfish poisoning (PSP). They are obtained from dinoflagellates (Gonyaulax spp., Alexandrium spp.) and cyanobacteria (Anabaena circinalis). 

Lamotrigine blocks voltage-dependent sodium channels and inhibits high-voltage activated Ca channels. 

This anticonvulsant drug blocks voltage-gated sodium channels and inhibits release of glutamate. A controlled study found efficacy in PTSD (Hertzberg et al. 1999). Important side-effects include fever and skin reactions. 

The mechanism of phenytoin s action probably involves a combination of actions at several levels. At therapeutic concentrations, the major action of phenytoin is to block sodium channels and inhibit the generation of repetitive action potentials. 

Lidocaine combines with fast voltage-gated sodium channels and inhibits recovery after repolarization. As a result, cellular conduction is blocked by... 

C. Lamotrigine blocks voltage-sensitive sodium channels, and Inhibits the release of excitatory neurotransmitters. 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Cocaine (8), from Erythroxylum coca Lam., besides causing euphoria by inhibiting the dopamine transport protein (DAT) responsible for its recreational and illegal use, exerts a local anesthetic activity through blocking sodium channels and is still used as a probe for this target. 

As with all members of its class, propafenone has its major effect on the fast inward sodium current. The IC agents depress over a wide range of heart rates and shift the resting membrane potential in the direction of hyperpolarization. The 1C agents bind slowly to the sodium channel and dissociate slowly. Therefore, they exhibit rate-dependent block. Inhibition of the sodium channel throughout the cardiac cycle will result in a decrease in the rate of ectopy and trigger ventricular tachycardia. 

Schematic diagram of a primary afferent neuron mediating pain, its synapse with a secondary afferent in the spinal cord, and the targets for local pain control. The primary afferent neuron cell body is not shown. At least three nociceptors are recognized acid, injury, and heat receptors. The nerve ending also bears opioid receptors, which can inhibit action potential generation. The axon bears sodium channels and potassium channels (not shown), which are essential for action potential propagation. Synaptic transmission involves release of substance P, a neuropeptide (NP) and glutamate and activation of their receptors on the secondary neuron. Alpha2 adrenoceptors and opioid receptors modulate the transmission process.

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

Lamotrigine. Lamotrigine is approved as an anticonvulsant but not as a mood stabilizer. It is postulated to inhibit sodium channels and to inhibit the release of glu-... 

Like other G-proteins, transducin has innate GTPase activity, and over a time course of seconds or less is autocatalytically converted to transducin-GDP, which does not interact with phosphodiesterase. This restores the normal inhibition of phosphodiesterase, permitting cGMP concentrations to rise again, reopening the sodium channels and restoring the dark current. 

Class lA agents (quinidine, procainamide, disopyramide) affect both atrial and ventricular arrhythmias. These drugs block both sodium channels and reduce potassium current. They increase action potential duration and effective refractory period, which results in slowed conduction velocity and inhibition of ectopic pacemakers. They may prolong the QT interval as a result of increased action potential duration. This may precipitate torsade de pointes. 

Phenytoin is a hydantoin derivative like dantrolene and the oldest non-sedative anticonvulsant drug known. It alters sodium, potassium and calcium conductance across cell membranes thereby altering membrane potentials and amino acid and neurotransmitter concentrations (i.e. norepinephrine (noradrenaline), acetylcholine and GABA). Its major mode of action appears to be the blockade of sodium channels and e inhibition of the generation of repetitive action potentials (membrane stabilization) (see Chs 9 and 12). 

Pharmacology and Mechanism of Action. The exact mechanism of action of ethosuximide remains elusive. Proposed mechanisms include inhibition of NADPH-linked aldehyde reductase, inhibition of the sodium-potassium ATPase system, a decrease in noninactivating Na+ currents, blocking of Ca +-dependent K+ channels, and inhibition of T-type Ca + channel currents." ... 

More than 30 different substances have been proven or proposed to act as neurotransmitters. Neurotransmitters are either excitatory or inhibitory. As noted, excitatory neurotransmitters (e.g., glutamate and acetylcholine) open sodium channels and promote the depolarization of the membrane in another cell (either another neuron or an effector cell, such as a muscle cell). If the second (post-synaptic) cell is a neuron, the wave of depolarization (referred to as an action potential) triggers the release of neurotransmitter molecules as it reaches the end of the axon. (Most neurotransmitter molecules are stored in numerous membrane-enclosed synaptic vesicles.) When the action potential reaches the nerve ending, the neurotransmitter molecules are released by exocytosis into the synapse. If the postsynaptic cell is a muscle cell, sufficient release of excitatory neurotransmitter molecules results in muscle contraction. Inhibitory neurotransmitters (e.g., glycine) open chloride channels and make the membrane potential in the postsynaptic cell even more negative, that is, they inhibit the formation of an action potential. 

Valproic acid is thought to increase concentrations of GABA, which decreases the frequency of neuronal firing. It may also have a direct effect on the neuronal membrane by the inhibition of voltage-gated sodium channels and the resulting decrease in sodium influx. 

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