Cardiac arrhythmias mechanisms

The anticipated outcome from this change in paradigm is the development of a non-clinical, standardised in vitro assay that determines the effects of drugs on the major cardiac ion channels and provide an assessment of the potential to precipitate clinical proarrhythmia, obviate conduct of the clinical TQT study and facilitate more efficient drug discovery efforts. In order to understand the fundamentals of this novel paradigm, it is important to review fundamental cardiac electrophysiology including basic ion channel biophysics as well as review some fundamental cardiac arrhythmia mechanisms to achieve this alternate approach. 

Cardiac arrhythmias are an important cause of morbidity and mortality approximately 400,000 people per year die from myocardial infarctions (MI) in the United States alone. Individuals with MI exhibit some form of dysrhythmia within 48 h. Post-mortem examinations of MI victims indicate that many die in spite of the fact that the mass of ventricular muscle deprived of its blood supply is often quite small. These data suggest that the cause of death is ventricular fibrillation and that the immediate availability of a safe and efficacious antiarrhythmic agent could have prolonged a number of Hves. The goals of antiarrhythmic therapy are to reduce the incidence of sudden death and to alleviate the symptoms of arrhythmias, such as palpitations and syncope. Several excellent reviews of the mechanisms of arrhythmias and the pharmacology of antiarrhythmic agents have been pubflshed (1,2). 

Facilitates GI transit/mechanical intestinal allodynia Cardiac arrhythmia... 

Molecular and cellular mechanisms of cardiac arrhythmias. Cell, 104, 569-580. 

Keating, M.T. and Sanguinetti, M.C. (2001) Molecular and cellular mechanisms of cardiac arrhythmias. Cell, 104, 569-580. 

The mechanism of action of phenol in the body is not well understood. Reports of cardiac arrhythmias resulting from phenol exposure are not uncommon (Gross 1984 Horch et al. 1994 Truppman and Ellenby 1979 Warner and Harper 1985). Methods to interfere with the mechanism of action for phenol were not identified. 

Hill. J.L. (1985) in Mechanism and Treatment of Cardiac Arrhythmias Relevance of Basic Studies to Clinical Management (Reiser, H.J. and Horowitz, L.N., eds.), pp. 173-182, Urban Schwarzenberg, Baltimore. 

Optimal therapy of cardiac arrhythmias requires documentation, accurate diagnosis, and modification of precipitating causes, and if indicated, proper selection and use of antiarrhythmic drugs. These drugs are classified according to their effects on the action potential of cardiac cells and their presumed mechanism of action. 

Bennett, P.B., Yazawa, K., Makita, N. and George, A.L. (1995) Molecular mechanism for an inherited cardiac-arrhythmia. Nature, 376, 683-685. 

Most of the indications for -blockers concern the -adrenoceptor. This subtype is predominantly present in the heart, mediating all typical cardiac effects like positive inotropy, chronotropy and dro-motropy. The main indications are hypertension, ischemic heart disease, cardiac arrhythmias and some forms of congestive heart failure. The mechanism by which -blocker, when administered chronically, can reduce the blood pressure is not completely understood yet. Most probably several mechanisms. 

Make a firm diagnosis. A firm arrhythmia diagnosis should be established. For example, the misuse of verapamil in patients with ventricular tachycardia mistakenly diagnosed as supraventricular tachycardia can lead to catastrophic hypotension and cardiac arrest. As increasingly sophisticated methods to characterize underlying arrhythmia mechanisms become available and are validated, it may be possible to direct certain drugs toward specific arrhythmia mechanisms. 

In addition to their antianginal (see Chapter 12 Vasodilators the Treatment of Angina Pectoris) and antiarrhythmic effects (see Chapter 14 Agents Used in Cardiac Arrhythmias), calcium channel blockers also dilate peripheral arterioles and reduce blood pressure. The mechanism of action in hypertension (and, in part, in angina) is inhibition of calcium influx into arterial smooth muscle cells. 

Crosstalk Mechanism of NMDAR and GPCRs in Hcy-Induced Cardiac Arrhythmias... 

---