Sodium channels local anesthetics affecting

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). 

Local anesthetics decrease the excitability of nerve cells without affecting the resting potential. Because the action potential, or the ability of nerve cells to be excited, seems to be associated with the movement of sodium ions across the nerve membranes, anything that interferes with the movement of these ions interferes with cell excitability. For this reason, many hypotheses have been suggested to explain how local anesthetics regulate the changes in sodium permeability that underlie the nerve impulse. These hypotheses include direct action on ionic channels that interferes with ionic fluxes and interaction with phospholipids and calcium that reduces... 

A series of potent alkaloids were first isolated from den-drobatid frogs of western Colombia and northwestern Ecuador, but are now known to be more widespread in distribution. These alkaloids affect at least three classes of channels in nerve and muscle. The first two are receptor-regulated channels, in particular the nicotinic acetylcholine receptor channel. The histrionicotoxins are noncompetitive blockers of this receptor-channel complex (Daly et al, 1993). The second class of channels are the voltage-dependent sodium channels. Histrionicotoxins reduce conductances in a manner reminiscent of local anesthetics (Daly et al., 1993). Despite these effects, these alkaloids have relatively low toxicity (Daly et al., 1993). 

Local anesthetics exert their action by binding to sodium chaimels in nerve cell membranes and inhibiting the influx of sodium ions [39]. The limited influx of sodium ions reduces the rate of rise of the action potentials, increases the threshold for electrical excit-abihty and slows impulse conduction [40]. The action potential fails to reach the threshold level and no impulses are conducted if sufficient sodium channels are blocked. Local anesthetics, therefore, do not affect the resting membrane potential, but rather affect the formation and propagation of the action potential. 

Like all local anesthetics, ropivacaine binds directly to the intracellular voltage-dependent sodium channels. It blocks primarily open and inactive sodium channels. Thus, this blocks the generation and conduction of nerve impulses. Lipid solubility appears to be the primary determinant of intrinsic anesthetic potency and toxicity. The more lipid-soluble, the greater is the potency of the local anesthetic. Hence, ropivacaine is less potent and less toxic than bupivacaine. In addition, the progression of blockade is affected by the diameter, myelination, and conduction velocity of the nerve fibers. 

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