Na+ channel blocking drugs

The common features of the local anaesthetic receptor site suggest that novel Na channel blocking drugs could be developed to fit this site that might have higher affinity and specificity than presently available compounds. Consistent with this idea, the novel compound Bill 890 CL, a complex ether of benzoyl and modified benzomorphan moieties, is a potent Na channel blocker binding at the local anaesthetic receptor site with a of 50 nM for the inactivated state (Carter et al 2000). It is aimed for neuroprotective therapy in the treatment of stroke and possibly neurodegenerative diseases. 

Propafenone (rythmol), a Na -channel blocking drug, is also a fi receptor antagonist (see Chapter 34). 

The effects of calcium channel blocking drugs on the ionic currents of cardiac cell membranes can be studied by recording action potentials. In most cells, a large, fast inward Na+ current is responsible for the early spike component and... 

Figure 7.2. Some intracellular processes that may be affected by calcium channel blocking drugs. Calcium channel blocking drugs inhibit calmodulin-dependent sarcolemmal Ca2 -A TPase (7), myosin light-chain kinase (MLCK) (2) and phosphodiesterase (PDE) (7). Passive Na -Ca2 exchange (4) may also be inhibited, whilst (Na +K )-ATPase (J) is stimulated. Ca2 release from mitochondria (MIT) in exchange for Na ( ) may be inhibited, but the effect of calcium channel blocking drugs on Ca2 uptake into sarcoplasmic reticulum (SR) via Ca2 -ATPase (7) is variable.

The effects of flecainide (Tambocor) therapy are thought to be attributable to the drug s very long Xrecovery from Na+ channel block, flecainide increased mortality in patients... 

Drug Na Channel Block T , State S econds Dependence Tapd Ca2+ Channel Block Autonomic Effects Other Effects... 

Na channel block occurs only in rapidly driven tissues, particularly in ischemia. Conversely, drugs such as flecainide have such long values (>10 s) that roughly the same number of Na chan-... 

Na Channel-Blocker Toxicity Conduction slowing in potential reentrant circuits can account for toxicity of drugs that block the Na+ channel (Table 34—1). For example, Na+ channel block decreases conduction velocity and hence slows atrial flutter rate. Normal AV nodal function permits... 

Cardiac Between 2% and 8% of patients who receive quinidine therapy will develop marked QT-interval prolongation and torsades de pointes. In contrast to sotalol, V-acetyl procainamide, and other drugs, quinidine-associated torsades de pointes usually occurs at therapeutic or subtherapeu-tic plasma concentrations. The reasons for individual susceptibility are not known. At high plasma concentrations of quinidine, marked Na+ channel block can occur, with resulting ventricular tachycardia. Quinidine can exacerbate heart failure or conduction system disease but usually is well tolerated in patients with congestive heart failure, perhaps because of its vasodilating actions. 

Answer A. Amiodarone is a highly effective antiarrhythmic drug, in part because of its multiple actions, which include Na channel block, beta adrenoceptor block, K channel block, and Ca channel block. Drugs that block channels (which include class lA and class III antiarrhythmics) prolong APD and ERP and predispose toward torsades de pointes ventricular arrhythmias. Flecamide is a class IC drug, lidocaine and phenytoin are class IB, and verapamil is class IV, none of which inhibits the delayed rectifier K+ current responsible for membrane repolarization during the cardiac action potential. 

Class IC antiarrhythmic drugs such as flecainide or propafenone block the Na+ channel (open state propafenone open and inactivated state) with a very long dissociation time constant so that they alter normal action potential propagation. Flecainide increased mortality of patients recovering from myocardial infarction due to its proarrhythmic effects (CAST study). Action potential is shortened in Purkinje fibres but is prolonged in the ventricles. 

Quaternary ammonium salts such as carcainium chloride (RSD 931) have been shown to be antitussive whilst having much reduced local anaesthetic activity. Whilst the molecular mechanisms underlying this antitussive activity is not understood, RSD 931 appears to be A8 fibre selective and may represent a novel class of antitussive drug. More recently JMF2-1 a lidocaine derivative that blocks Na+ channels has had beneficial effects in the airways without significant local anaesthetic activity. 

State-dependent block describes the binding of a drug to a certain state of an ionic channel. Tims, the fast Na+ channel switches between a resting and open and inactivated states, the latter being the state to which antiarrhythmic drugs like lidocaine bind. 

A 68-year-old female has AF, which is treated with an anti arrhythmic agent that blocks Na+ channels. On a recent office visit, she complained of recurrent attacks of feeling faint and of experiencing an episode of loss of consciousness. An EKG showed marked prolongation of the QT interval. Plasma concentration of the drug was in the therapeutic range. 

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