Fast channel blockers

Remacemide, which chemically is ( )-2-aini-no-iV-( 1-methyl- l,2-diphenylethyl)acetamide (58), and its principal active desglycinyl metabolite (58a), are low-affinity, noncompetitive NMDA receptor blockers and Na+ fast-channel blockers (242). Remacemide is rapidly absorbed on oral administration and achieves a peak plasma level in 1 h, whereas the active metabolite (58a) takes 2-3 h. The parent has a half-life of 3-4 h, compared to 12-15 h for the active metabolite (243). Comedication with enzyme-inducing anticonvulsants (i.e., phe-nytoin, carbamazepine, and phenobarbital) induces the metabolism of both remacemide and (68a), thus reducing their plasma concentration. The agent has been studied for its anticonvulsant effect, and because of its neuro-... 

Known as sodium channel blockers or fast channel blockers. 

Channel blockers are often classified as slow, intermediate, or fast blockers, based on the very wide range of values that have been found for the microscopic dissociation rate constant of different... 

Bepridil also inhibits fast sodium inward channels. Galcium channel blockers are classified by structure as follows Diphenylalkylamines - verapamil benzothiazepines - diltiazem dihydropyridines - amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine. 

Remacemide from AstraZeneca is a pro-drug which is converted by hydrolysis and removal of glycine to its active desglycinyl derivative FPL-12,495 which is a low affinity fast kinetics channel blocker (Heyn et al., 1994 Subramaniam et al., 1996 Monaghan et al., 1997 Ahmed et al., 1999). 

Houghton, A. K., Parsons, C. G., Headley, P. M. Mrz2/576, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats, Pain 2001, 91, 201-207. 

In contrast, amiodarone and sotalol are effective in most supraventricular and ventricular tachycardias. Amiodarone displays electrophysiologic characteristics consistent with each type of antiarrhythmic drug, ft is a sodium channel blocker with relatively fast on-off kinetics, has nonselec-tive j8-blocking actions, blocks potassium channels, and has slight calcium antagonist activity. The impressive effectiveness and low proarrhythmic potential of amiodarone have challenged the notion that selective ion channel blockade is preferable. Sotalol is a potent inhibitor of outward... 

Four categories of calcium channel blockers can be defined based on their chemical structures and actions diphenylalkylamines, benzothiazepines, dihydropyridines, and bepridil. Both diphenylalkylamines (verapamil) and benzothiazepines (diltiazem) exhibit effects on both cardiac and vascular tissue. With specificity for the heart tissue, these two types of calcium channel blockers can slow conduction through the AV node and are useful in treating arrhythmias. The dihydropyridines (nifedipine is the prototypical agent) are more potent peripheral and coronary artery vasodilators. They do not affect cardiac conduction, but can dilate coronary arteries. They are particularly useful as antianginal agents. Bepridil is unique in that it blocks both fast sodium channels and calcium channels in the heart. All calcium channel blockers, except nimodipine and bepridil, are effective in treating HTN. 

Smooth muscle exhibits very diverse behaviors depending on which control mechanisms are present. Vascular smooth muscle, for example, lacks fast voltage-dependent Na+ or Ca + channels and so does not have action potentials or Ca + spikes. It has slow voltage-dependent Ca + channels that admit calcium in a graded fashion in response to fluctuations in membrane potential induced by humoral or transmitter effects on membrane ion conductances, and it has several membrane receptor-initiated second-messenger cascades that control Ca " " entry and Ca + release from its limited SR, and which moderate the effectiveness of Ca +. Vascular smooth muscle contraction is thus tonic rather than phasic, and is very dependent on extracellular Ca + therefore Ca + channel blockers effectively inhibit contraction. In contrast, gut smooth muscle does have fast voltage-dependent channels sufficient to produce action potentials and more SR than vascular smooth muscle, and also has gap junctions through which ion fluxes can occur. It also has receptor-mediated Ca +... 

XM, and almost complete inhibition of Na" -channels was attained with 400 IM (+)-kavain and the potent Na channel blocker tetrodotoxin (10 XM) (Figure 6.3). The local anesthetic procaine (400 XM) reduced veratridine-elevated [Na i to 30.4% of control, whereas the centrally acting muscle relaxant mephenesin (400 XM) produced no effect. The data indicated a fast and specific inhibition of voltage-dependent Na -channels by (+)-kavain (Gleitz etal., 1995). 

The calcium channel blockers have been found to affect several different subcellular processes (see Figure 7.2) and these effects may contribute to the pharmacological profile of the drugs. However, these actions are mainly seen at higher concentrations of the drugs than the concentrations required for calcium channel blockade. For example, high concentrations of D600, nitrendipine and verapamil have been shown to block the fast sodium channels present in cardiac tissue [44, 153-156], On the other hand, lower concentrations of verapamil do not decrease the maximum rate of depolarization of phase 0 of the action potential (Fmax) [156, 157], Neither diltiazem nor nisoldipine reduces Kmax [7,42]. Since influx of Na+ into the cell via the fast sodium... 

---