Sodium channels recovery

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Elestolol sulfate is a nonselective, ultrashort acting P-adrenoceptor blocker. It has no ISA and produces weak inhibition of the fast sodium channel. The dmg is under clinical investigation for supraventricular tachyarrhythmias, unstable angina, and acute MI. In humans, flestolol has hemodynamics and electrophysiologic effects similar to those of other P-adrenoceptor blockers. The pharmacokinetics of flestolol are similar to those of esmolol. It is 50 times more potent than esmolol and the elimination half-life is 7.2 min. Recovery from P-adrenoceptor blockade is 30—45 min after stopping iv infusions. The dmg is hydrolyzed by tissue esterases and no active metabohtes of flestolol have been identified (41). 

Clarkson CW, Hondeghem LM (1985) Mechanism for bupivacaine depression of cardiac conduction fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62 396-405... 

At the cellular level, the major electrophysiological effect appears to be rate-dependent blockade of sodium channels [22]. The onset for this Class I effect (64 + 9% of the final depression of between the first and second beat of the train) was similar to that for Class IB agents [23]. The offset rate (recovery of from rate-dependent depression) for amiodarone was 1.48 s. This value falls between those seen for Class IB agents (200-500 ms) and lA agents (2.3-12.2 s) [23]. Amiodarone inhibited the binding of pH]ba-trochotoxinin A 20a-benzoate to the sodium channel, suggesting that it binds to inactivated sodium channels [24]. 

As with other members of class IB, mexiletine slows the maximal rate of depolarization of the cardiac membrane action potential and exerts a negligible effect on repolarization. Mexiletine demonstrates a rate-dependent blocking action on the sodium channel, with rapid onset and recovery kinetics suggesting that it may be more useful for the control of rapid as opposed to slow ventricular tachyarrhythmias. 

Lidocaine blocks activated and inactivated sodium channels with rapid kinetics (Figure 14-9) the inactivated state block ensures greater effects on cells with long action potentials such as Purkinje and ventricular cells, compared with atrial cells. The rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction. The increased inactivation and slower unbinding kinetics result in the selective depression of conduction in depolarized cells. 

Dofetilide has class 3 action potential prolonging action. This action is effected by a dose-dependent blockade of the rapid component of the delayed rectifier potassium current, IKr, and the blockade of IKr increases in hypokalemia. Dofetilide produces no relevant blockade of the other potassium channels or the sodium channel. Because of the slow rate of recovery from blockade, the extent of blockade shows little dependence on stimulation frequency. However, dofetilide does show less action potential prolongation at rapid rates because of the increased importance of other potassium channels such as IKs at higher frequencies. 

The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of -90 to -60 mV. During excitation, the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about -95 mV) repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. 

Between successive action potentials, a portion of the sodium channels will recover from the local anesthetic block (see Figure 14-9). The recovery from drug-induced block is 10 to 1000 times slower than the recovery of channels from normal... 

Mechanism of Action. These drugs are believed to exert their primary antiepileptic effects in a manner similar to phenytoin—that is, they stabilize the neuronal membrane by slowing the recovery of sodium channels firing too rapidly. Carbamazepine may also inhibit the presynaptic uptake and release of norepinephrine, and this effect may contribute to its antiseizure activity. 

In healthy cardiac cells, the recovery time from inactivation of sodium channels (back to the resting state) is quite rapid, so that the maximum number of channels is available for activation. In contrast, in sick cells, the recovery time is quite slow. In these sick cells, the action potential develops from the opening of fewer sodium channels, so the action potential is a slow sluggish upstroke as opposed to the fast upstroke in a healthy cell. A slow sluggish upstroke results in poor and perhaps no propagation of the action potential. Chronically depolarized or ischemic cells may (1) fail to conduct an action potential and therefore fail to contract or to transmit the action potential to neighboring cells or (2) become an ectopic pacemaker (due to a... 

Epilepsy affects 0.5% of the world s population and can have a multitude of underlying etiologies, including several mutations in CNS sodium channels. Sodium channel mutations linked to human epileptic syndromes typically shift activation to more hyperpolarized potentials, slow inactivation kinetics, accelerate recovery from inactivation, and/or increase the persistent current [48]. Seemingly paradoxically, some mutations appear to result in non-functional channels [48-50]. 

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

Pyrethroid compounds formulated with the insect repellant DEBT were responsible for numerous deaths in cats and dogs in the past decade. Pyrethroids interfere with sodium channels in nerves causing them to fire repetitively. Clinical signs of pyrethroid poisoning in small animals include ataxia, excitement, and muscle fasciculations and tremors. There is no antidote for pyrethrin poisoning, but symptomatic treatment, such as decontamination procedures and sedation, usually results in full recovery. 

E. Delays recovery of voltage-dependent sodium channel... 

At the end of the plateau, causes rapid repolarization. The refractory period of the cardiac cell is a function of how rapidly sodium channels recover from inactivation. Recovery from inactivation depends on both the membrane potential (which varies with repolarization time and the extracellular potassium concentration) and the actions of drugs that bind to the sodium channel, ie, sodium channel blockers. The carrier processes (sodium pump and sodium/calcium exchanger) contribute little to the shape of the action potential (but they are critical for the maintenance of the ion gradients on which the sodium, calcium, and potassium currents depend). Antiairhythmic drugs act on one or more of the three major currents (1, Ij, ) or on... 

Local anesthetics bind preferentially to sodium channels in the open and inactivated states. Recovery from drug-induced block is 10-1000 times slower than recovery of channels from normal inactivation. Resting channels have a lower affinity for local anesthetics. The answer is (B). Since the drug is a weak base, it will be more ionized (protonated) at pH values lower than its pKjj. Since the pH given is 1 log unit lower (more acid) than the pK, the ratio of ionized to nonionized drug will be approximately 90 10. The answer is (D). (Recall from Chapter 1 that at a pH equal to pK, the ratio is 1 1 at 1 log unit difference, the ratio is [approximately] 90 10 at 2 units difference, 99 1 etc.)... 

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