Introduction and development ofanti-arrhythmic drugsAuthor：赵恒军84Instructor：刘静庭Abstract Objective：summaries of the classification, progress and security applications of antiarrhythmic drugs. Methods:searching and retrieving relevant documents about the latestanti-arrhythmia at home and abroad. Results: this paperreviewed the classification, the latest progress and securityapplications of antiarrhythmic drugs. And it will help toformulate the proper treatment of rational anti-arrhythmia.Conclusions: the paper can be used to help people get basicknowledge of anti-arrhythmic drugs rapidly.Key words Antiarrhythmic agents, application, and development The concept of arrhythmiaUnder normal circumstances, the impulse of the heart comes from the sinus node, through the atrium, atrioventricular node, atrioventricular bundle and Purkinje fibers in turn and then to ventricular muscle finally which cause the contraction of the heart in a rhythm. Cardiac arrhythmia is a serious heart disease which is caused by abnormal of heartbeat law and frequency. At the same time, normal atrial and ventricular activationand movement sequence are disordered. The disease has slow and fast types, the former can be treated by isoprot erenol (β agonist or atropine (M receptor blocker). The drug therapy of the latter is more complex, we usually say that the anti- arrhythmic drugs is for the fast type of arrhythmia.MechanismThe mechanism of anti-arrhythmic drugs is mainly through the influence of the Na+, Ca2+ and K+ transport of myocardial cell membrane, affecting the period of cardiac action potential, inhibition of self-regulation and (or) stop reentry to correct the arrhythmias.Since the mechanism of arrhythmia is complex, the side effects of various anti-arrhythmic drugs are different in many aspects. So it must be fully taken into account when select drugs. We also should pay attention to the dose of medication and methods to achieve the desired effects.CategoriesThe classification of antiarrhythmic drugs, proposed by the Vaughan Williams and completed by Harris etc., has been used for nearly 30 years. Vaughan Williams classified drugs into four categories based on the electrophysiological characteristics of the drugs. Ⅰclass medicines block sodium channels and inhibit atrial, ventricular and Purkinje fiber of fast response organizations conduction velocity.Ⅱ class medicinescan be further divided into 3 categories. Ⅰa sodium channel block in a medium speed, extended the period of repolarization, such as quinidine, procainamide, double disopyramide.Ⅰb sodium channel block in a fast speed such as lidocaine , mexiletine, Ⅰc sodium channel block in a slow speed, such as fluorine Cain, propafenone. Ⅱclass is a β-receptor blocker.Ⅲclass medicines prolong cardiac repolarization process and block potassium channel in the action potential of 2,3 phase. Thereby prolong the refractory period of cardiac tissue, such as amiodarone, sotalol. Ⅳclass medicines block calcium channels and inhibit sinus node, slow response organizations of atrioventricular node, such as verapamil, diltiazem.Antiarrhythmic drug efficacy and potential hazardsAlthough antiarrhythmic drugs can reduce or eliminate the symptoms which caused by the arrhythmia itself and / or risk of death, it may cause some potential dangers, including non-cardiac adverse reactions (such as dizziness, nausea), organ toxicity (eg, agranulocytosis, hepatitis), cardiac events, post-induced arrhythmia or arrhythmic death.Cardiac adverse reactions of antiarrhythmic drugs including: ① "early" arrhythmogenic effect, which refers to the treatment of early antiarrhythmic drug induced arrhythmia, or new deterioration of the existing arrhythmia. ② induce congestive heart failure or to the dete rioration, ③ induce cardiac conduction disturbances, such as theheight of atrioventricular block or "sick sinus syndrome."The most serious potential risk of antiarrhythmic drugs is to increase risk of late arrhythmia death, which known as the "late proarr-hythmiceffect ". Organ toxicity, such as agranulocytosis or hepatitis, are specifically found in quinidine, procainamide, tocainide, as well as amiodarone treatment. Treatment cases of flecainide, encainide shown it can effectively suppress ventricular arrhythmia and also well tolerated, but the risk of death in the late arrhythmia is still higher than placebo 2 to 3 times.This dangerous of "late proarr-hythmiceffect", can be seen in 10 months later of follow-up visit. Quinidine, mexiletine, Morrissey throat, also can make the late cause arrhythmogenic risk of death increased. So far known only when the βblockers treatment can reduce the risk of cardiac arrhythmias sudden death and total cardiac death.Progress in anti-arrhythmic drugsThe advance in antiarrhythmic drug research is rapid. There are nearly 20 varieties clinical application drugs. Quinidine, which started for clinical purposes in 1918, is the broad-spectrum anti-arrhythmic drug. And it was used as standard drugs in this class of preparations. Due to side effects, earlier application such as Procainamide and Lidocaine current consumption diminished.After 80 years of the 20th century, propafenone, flecainide, Encainidehave been applied in succession. These drugs, which can work directly on the cell membrane and make a difference, are the sodium channel blocker of strong activity. In 1995, pirmenol, anti-malignant ventricular arrhythmia drugs, go public in Japan. In 1999, the development of nifekalant by the Japanese Mitsui Corporation was approved listed on the treatment of ventricular arrhythmias which known as the only progress in drug.Looking from our antiarrhythmic drugs structure, the mature drug applying has little difference compared with abroad.Treatment of supraventricular, ventricular tachycardia drug propafenone, sotalol and amiodarone have high popularizing rate. Verapamil and diltiazem that control atrial fibrillation and atrial flutter also occupy a certain amount of market share. The new type Ⅲ class potassium channel Blockers has been the general concern of the indust.Type Ⅲnew potassium channel blocker ibutilide, dofetilide and sematilide is a recent development of products which is the class Ⅲantiarrhythmic drugs with a certain class Ⅰactivity. New Heart Ⅲdrugs has smaller side effects than amiodarone.However, the torsade type of tachycardia (TDP) incidence is not less than amiodarone. Ibutilide which belongs to methyl sulfonamide derivatives, is a new type of class Ⅲantiarrhythmic drugs with ion channel activity used on acute atrial fibrillation and atrial flutter patients. Pharmacia & Upjohnwhich researched and developed by the United States, come into the market in the United States in 1996. It has listed 11 countries in Europe and America. The treatment effect of intravenous administration is more significant. It provide a new type of good medicine to cure atrial fibrillation, atrial flutter to sinus rhythm.Duofeilite, which developed by the U.S. Pfizer and come into the market the first times in the United States in 2000, is the third-generation oral administration anti-arrhythmic drug. Duofeilite is a new type of potassium channel agonist with similar mechanism of action as ibutilide. The function on atrial is more obvious than ventricular.It is used in clinical to treat atrial fibrillation and atrial flapping and to make the rhythm of the heart to sinus rhythm. The main side effect is the torsade type of tachycardia. The occurrence rate of intravenous application is about 3%, while the incidence of oral administration is about 1%. Most adverse events happened within 3d after treatment. The torsade type of tachycardia risk factors are QT interval prolongation, hypokalemia, hypomagnesemia and bradycardia.Dronedarone is a new antiarrhythmic drug which was reported in the Europe heart meetingin the August 2004. It is an analogue of amiodarone, because they are free of iodine compared with amiodarone, there is no organ toxicity. It is easier to adjust the dose with the half-life of 1 ~ 2d. EURIDS study shown, 77 European Hospital with 612 patientswith 2: 1 randomized into the group were due to auricular fibrillation or atrial flapping to try this medicine. All patients confirmed atrial fibrillation or atrial flutter within the first 3 months of at least 1 ECG before taking part in the group. 411 patients received dronedarone 400mg, 2 times a day, 201 patients received placebo treatment for 12 months. The results observed from random assignment to the first occurrence of atrial fibrillation or atrial flutter recurrence time for comparison (ECG confirmed onset time at least more than 10min). The results, from the random assignment to first atrial fibrillation or atrial flutter onset, shown that dronedarone group was 2.3 times longer than placebo group. The dronedarone reduced the recurrence rate of 33%, while medication side effects was similar to the placebo group, medicine group 59.4%, 58.2% in the placebo group, no significant difference.The drug was well tolerated, so it is very promising in control of atrial fibrillation, atrial flutter episode. Because it improves the amine iodine AZD7009 which is the drug being developed with sodium, potassium channel blocking effect, it has obvious effect on atrial muscles and is effective in treating atrial arrhythmias. It also can prolong QT interval, but no the torsade type of tachycardia happened. AZD7009 will enter Phase Ⅲclinical trials.RSD1235 is a new, fast acting and can be intravenous administration antiarrhythmic drugs. It has been shown to be effective in treating atrialfibrillation. It is of high degree of selection in the atrium, and almost no effect on the ventricle. The drug is safe and relatively well tolerated and no drug-related the torsade type of tachycardia. Heart Rhythm Society (HRS) meeting announced the arrhythmia cardioversion trial, that RSD1235 AF cardioversion rate is about 50% to 60% in America in 2005. In summary, for a long period of time, represented by amiodarone class Ⅲantiarrhythmic drugs will remain our first line of drug clinical arrhythmia. And the complex class Ⅲantiarrhythmic drug therapy with multi-channel block (IKr, IKs, Ito, INa etc.) effects may shed light on arrhythmic drugs.References[1] Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. 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