Sodium channel block

Propafenone. Propafenone hydrochloride, an arylketone, is stmcturaHy similar to the P-adrenoceptor blocking agents. It has been in use in the former West Germany since 1977 and was introduced in the United States in 1990. Its effects may result from a combination of weak calcium channel blocking, weak nonselective -adrenoceptor blocking, and sodium channel blocking activity. Propafenone is effective in treating supraventricular tachyarrhythmias, ventricular ectopic beats, and ventricular arrhythmias. It is the most frequendy prescribed medication for ventricular arrhythmias in Europe (32). 

Sensitive to toxins, in this case means that the assay presents no false negative results. Primary hepatocytes can elucidate hepatotoxins, and mouse neuroblastoma cells can elucidate sodium channel-blocking neurotoxins therefore these assays can be used to screen for the appropriate toxins. 

The primary electrophysiological effects of moricizine relate to its inhibition of the fast inward sodium channel. Moricizine reduces the maximal upstroke of phase 0 and shortens the cardiac transmembrane action potential. The sodium channel blocking effect of moricizine is more significant at faster stimulation rates an action referred to as use dependence. This phenomenon may explain the efficacy of moricizine in suppressing rapid ectopic activity. An interesting effect of moricizine is its depressant effect on automaticity in ischemic... 

It is an alkaloid obtained from the bark of cinchona and is a dextro isomer of anti-malarial drug quinine. Its sodium channel blocking property results in an increased threshold for excitability and decreased automaticity. As a consequence of its potassium channel blocking properties, it prolongs action potential in most cardiac cells. 

Action potential propagation Local anesthetics, tetrodotoxin,1 saxitoxin2 Nerve axons Block sodium channels block conduction... 

Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Sodium channel block is modest with verapamil, and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. (See Chapter 14 for additional details.) On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects they are therefore less depressant on the heart than verapamil or diltiazem. 

Propafenone has some structural similarities to propranolol and possesses weak 3-blocking activity. Its spectrum of action is very similar to that of quinidine, but it does not prolong the action potential. Its sodium channel-blocking kinetics are similar to that of flecainide. Propafenone is metabolized in the liver, with an average half-life of 5-7 hours. The usual daily dosage of propafenone is 450-900 mg in three divided doses. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation arrhythmia exacerbation can also occur. 

Propranolol 13- Adrenoceptor blockade Direct membrane effects (sodium channel block) and prolongation of action potential duration slows SA node automaticity and AV nodal conduction velocity Atrial arrhythmias and prevention of recurrent infarction and sudden death Oral, parenteral duration 4-6 h Toxicity Asthma, AV blockade, acute heart failure Interactions With other cardiac depressants and hypotensive drugs... 

In small doses, local anesthetics can depress posttetanic potentiation via a prejunctional neural effect. In large doses, local anesthetics can block neuromuscular transmission. With higher doses, local anesthetics block acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channel-blocking antiarrhythmic drugs such as quinidine. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Higher concentrations of bupivacaine (0.75%) have been associated with cardiac arrhythmias independent of the muscle relaxant used. 

In overdose, 3 blockers block both and 32 adrenoceptors selectivity, if any, is lost at high dosage. The most toxic blocker is propranolol. As little as two to three times the therapeutic dose can cause serious toxicity. This may be because propranolol has additional properties At high doses it may cause sodium channel blocking effects similar to those seen with quinidine-like drugs, and it is lipophilic, allowing it to enter the CNS (see Chapter 10). 

As in the previous section, only drugs with sodium channel blocking activities are considered. 

Lidocaine is chemically similar to cocaine it is also a sodium channel-blocking drug, which is why it is an effective topical pain reliever that is commonly sold over the counter in drug stores. However, in contrast to cocaine, it has no reinforcing, euphoric effect at all, and animals, including humans, will not self-administer it. This confirms the validity of the finding that... 

The results showed that mortality among patients treated with the drugs flecainide and encainide (the latter is no longer available) was increased more than twofold compared with those treated with placebo. The mechanism underlying this effect is not known, although an interaction between conduction depression by sodium channel block and chronic or acute myocardial ischemia seems likely. Indirect evidence suggests that other sodium channel blockers may produce a similar effect. 

The state of the sodium channel varies in healthy ventricular cells and those damaged by ischemia. This variability in the state has implications for antiarrhymic therapy with sodium channel blocking agents. In sick or damaged ventricular cells (i.e., from ischemia or blockade of the sodium/potassium-ATPase [sodium/potassium pump]), the resting membrane is more positive than the healthy resting membrane potential (Figure 12.10). 

Several other therapeutic effects of sodium channel blockers have been suggested. Most of these stem from clinical activities of approved anticonvulsants and antiarrhythmics with sodium channel blocking activity. Beneficial effects of sodium channel blockers for the treatment of bipolar disease are suggested by clinical data with lamotrigine [63-67], phenytoin [68], topiramate [69], and carbamazepine [70,71]. In addition, clinical studies with lidocaine suggest efficacy in the treatment of tinnitus [72] and, as an inhaled formulation, in the suppression of cough [73,74]. 

The biosynthetic pathway for ajmaline in R. serpentina is one of the best-characterized terpenoid indole alkaloid pathways. Much of this progress has been detailed in a recent extensive review (78). Like all other terpenoid indole alkaloids, ajmaline, an antiarrhythmic drug with potent sodium channel-blocking properties (79), is derived from deglycosylated strictosidine (Fig. 2c). 

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