Action potential 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). 

The exact reason for the differential susceptibility of nerve fibers based on their axonal diameter is not known. One possible explanation is that the anesthetic is able to affect a critical length of the axon more quickly in unmyelinated fibers, or small myelinated neurons with nodes of Ranvier that are spaced closely together compared to larger fibers where the nodes are farther apart.17 As indicated earlier, a specific length of the axon must be affected by the anesthetic so that action potentials cannot be transmitted past the point of blockade. Other factors such as the firing rate of each axon or the position of the axon in the nerve bundle (e.g., in the outer part of the bundle versus buried toward the center of the nerve) may also affect susceptibility to local anesthesia.62 In any event, from a clinical perspective the smaller-diameter fibers appear to be affected first, although the exact reasons for this phenomenon remain to be determined. 

In some types of rhythm disorders, antiar-rhythmics of the local anesthetic, Na+-channel blocking type are used for both prophylaxis and therapy. These substances block the Na+ channel responsible for the fast depolarization of nerve and muscle tissues. Therefore, the elicitation of action potentials is impeded and impulse conduction is delayed. This effect may exert a favorable influence in some forms of arrhythmia, but can itself act arrhythmogenically. Unfortunately, antiarrhythmics of the local anesthetic, Na+-channel blocking type lack suf -cient specificity in two respects (1) other ion channels of cardiomyocytes, such as K1 and Ca+ channels, are also affected (abnormal QT prolongation) and (2) their action is not restricted to cardiac muscle tissue but also impacts on neural tissues and brain cells. Adverse effects on the heart include production of arrhythmias and lowering of heart rate, AV conduction, and systolic force. CNS side effects are manifested by vertigo, giddiness, disorientation, confusion, motor disturbances, etc. 

Chloroprocaine, like other local anesthetics, blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve by slowing the propagation of the nerve impulse and by reducing the rate of the rise of action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows pain, temperature, touch, proprioception, and skeletal muscle tone. 

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... 

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. 

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