Arrhythmia

Abstract An arrhythmia occurs as a result of abnormal electrical conduction and genesis of an abnormal electrical current. There are various types of arrhythmias that can be classified in terms of their origin as, atrial, junctional or ventricular arrhythmias. Many arrhythmias are initiated by ectopic foci. 

Keywords Arrhythmias Hutter Fibrillation Arrest rhythms Reentry Ectopic s 

EARLY PHARMACOTHERAPY FOR ST-SEGMENT-ELEVATION ACUTE CORONARY SYNDROME  

3 hours in patients with STE ACS who are treated with fibrinolytics and at 

Fish Oils (Marine-Derived Omega-3 Fatty Acids) 

See Chap. 18, Acute Coronary Syndromes, authored hy Sarah A. Spinier and Simon de Denus, for a more detailed discussion of this topic. 

Arrhythmia is defined as loss of cardiac rhythm, especially irregularity of heartbeat. This chapter covers the group of conditions caused by an abnormality in the rate, regularity, or sequence of cardiac activation. 

Asymptomatic sinus bradyarrhythmias (heart rate less than 60 heats/min) are common especially in young, athletically active individuals. However, some patients have sinus node dysfunction (sick sinus syndrome) because of underlying organic heart disease and the normal aging process, which 

Supraventricular tachycardias may cause a variety of clinical manifestations ranging from no symptoms to minor palpitations and/or irregular pulse to severe and even life-threatening symptoms. Patients may experience dizziness or acute syncopal episodes symptoms of HF anginal chest pain or, more often, a choking or pressure sensation during the tachycardia episode. 

AF or atrial flutter may be manifested by the entire range of symptoms associated with other supraventricular tachycardias, but syncope is not a common presenting symptom. An additional complication of AF is arterial embolization resulting from atrial stasis and poorly adherent mural thrombi, which accounts for the most devastating compUcation embolic stroke. Patients with AF and concurrent mitral stenosis or severe systolic HF are at particularly high risk for cerebral embolism. 

PVCs often cause no symptoms or only iruld palpitations. The presentation of VT may vary from totally asymptomatic to pulseless hemodynamic collapse. Consequences of proarrhythmia range from no symptoms to worsening of symptoms to sudden death. VF results in hemodynamic collapse, syncope, and cardiac arrest. 

At the SA node, electrical impulses generate a cardiac contraction at regular intervals and with a frequency of one beat per second. This impulse then spreads rapidly through the atria and enters the AV node. The conduction through the AV node takes 0.2 seconds, which is relatively slow. The impulse then propagates over the His-Purkinje system and contracts the entire ventricular muscle in 

1 seconds in an anatomically synchronous and hemo-dynamically effective fashion. Arrhythmias deviate from this pattern and result from abnormalities in either impulse generation or impulse conduction, whereby the normal impulse conduction rate is slowed somewhere in the specialized conducting system of the heart. This disturbance is frequently, but not always, found in the AV node or in the bundles of His (heart block), or both. 

The major electrophysiologic manifestation of impulse generation is found in the properties of automaticity (slope of phase 4 or diastolic depolarization) and of impulse conduction in conduction velocity. Drugs that alter pacemaker automaticity have a direct effect on the heart rate. 

Rapid diastolic depolarization leads to a rapid rate of firing, whereas a lowered slope of phase 4 diastolic depolarization elicits fewer action potentials in the same time interval. Similarly, drugs that increase conduction velocity in the heart can help alleviate heart block, whereas those that decrease conduction velocity may slow a rapid heart rate. 

Disopyramide Anticholinergic effects (urinary retention, aggravation of glaucoma, constipation), hypotension, heart failure, tachyarrhythmias, torsade de pointes, heart block, nausea, vomiting, diarrhea, hypoglycemia, nervousness 

---

Ca waves in systems [ike Xenopus laevis oocytes and pancreatic (3 cells fall into this category Electrochemical waves in cardiac and nerve tissue have this origin and the appearance and/or breakup of spiral wave patterns in excitable media are believed to be responsible for various types of arrhythmias in the heart [39, 40]. Figure C3.6.9 shows an excitable spiral wave in dog epicardial muscle [41]. 

Eupatin (69, R = H) and Eupatoretin (69, R = CH3), which are isolated from thistle perennials, show moderate cytotoxicity against human carcinoma of the nasopharynx (236). Baicaleia (70) salts exhibit antiallergic and antiinflammatory activity. 3,4,5-Trimethoxyphenoxyacetamides are hypotensives and diuretics and are useful for controlling arrhythmia duting anesthesia (237). 

Historical Inhalation Agents. Diethyl ether produces excellent surgical anesthesia, but it is flammable (see Ethers). Chloroform is a nonflammable, sweet smelling, colorless Hquid which provides analgesia at nonanesthetic doses and can provide potent anesthesia at 1% (see Chlorocarbons AND CHLOROHYDROCARBONs). However, a metabohte causes hepatic cell necrosis. Tdlene, a nonflammable colorless Hquid, has a slower onset and recovery and a higher toxicity and chemical reactivity than desirable. Cyclopropane is a colorless gas which has rapid induction (2 —3 min) and recovery characteristics and analgesia is obtained in the range of 3—5% with adequate skeletal muscle relaxation (see Hydrocarbons). The use of cyclopropane has ceased, however, because of its flammabiHty and marked predisposition to cause arrhythmias. 

Other cardiovascular diseases cover a long Hst of circulatory problems, including heart faHure, peripheral vascular disease, cardiomyopathy, and arrhythmias. 

Economic Aspects. The cardiovascular devices market is estimated to be approximately 2.9 biUion annually on a worldwide basis. This market can be further segmented as follows angiography and angioplasty, 644 x 10 arrhythmia control, 1500 x 10 cardiovascular surgery, 700 x 10 cardiac assist (intra-aortic balloon pump), 80 x 10 and artificial hearts, which are experimental. 

Lethal Arrhythmias. Arrhythmias are a second significant source of cardiovascular problems. An arrhythmia is an abnormal or irregular heart rhythm. Bradyarrhythmias result in heart rates that are too slow tachyarrhythmias cause abnormally fast rates. A bradyarrhythmia can be debiUtating, causing a person to be short of breath, unable to climb stairs, black out, or even to go into cardiac arrest. Tachyarrhythmias can be un settling and painful at best, life-threatening at worst. 

There is a close correlation between myocardial infarctions and tachyarrhythmias, illustrated by the presence of complex ventricular arrhythmias among heart attack victims which are estimated to affect one-third of the survivors each year. Frequendy, the immediate cause of sudden death is ventricular fibrillation, an extreme arrhythmia that is difficult to detect or treat. In the majority of cases, victims have no prior indication of coronary heart disease. 

Cardiomyopathy. Cardiomyopathy, or diseased heart muscle, may reach a point at which the heart can no longer function. It arises from a combination of factors, including hypertension, arrhythmias, and valve disease. Other problems, such as congestive heart failure, cause the interrelated heart—lung system to break down. Because the heart can no longer adequately pump, duid builds up in the lungs and other areas. 

Arrhythmias. The first solution to cardiovascular problems arising from arrhythmias came about as a result of a complication caused by open-heart surgery. During procedures to correct congenital defects in children s hearts, the electrical conduction system often became impaired, and until it healed, the heart could not contract sufficiently without outside electrical stimulation. A system that plugged into a wall outlet was considered adequate until an electrical storm knocked out power, lea ding to the development of the first battery-powered external pacemaker. 

Devices for the 1990s. The 1990s may turn out to be the decade of active arrhythmia-control devices. Implantable devices to pace, cardiovert, and defibrillate the heart without the need for open-heart surgery should become widely accepted before the year 2000. Dramatic developments and... 

Fig. 6. A pacemaker provides electrical impulses to the heart in an effort to correct potentially fatal arrhythmias.

Implantable tachyrhythmia devices, available for some years, address far less dangerous atrial tachyarrhythmias and fibrillation. The technical barriers to counteracting ventricular tachyarrhythmias and fibrillation using massive shocks have been formidable and are compounded by the possibiUty of causing the very problem the shock is designed to overcome. Newer tachyrhythmia devices are being readied that can safely regulate arrhythmias across the hiU spectmm. 

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

Side Effects and Toxicity. Adverse effects to the tricycHc antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricycHcs concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as weU as to be certain that the patient has taken enough dmg to be effective, the steady-state semm levels of tricycHc antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of stmcture—activity relationships among the tricycHc antidepressants is available (42). 

Agent or class CNS effects Orthostatic hypotension Arrhythmias Anticholinergic effects Weight change... 

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). 

Enhanced automaticity occurs in hypoxia, hypokalemia, hypercarbia, excessive sympathetic nervous system stimulation, or high concentrations of catecholamines. These conditions may lead to arrhythmias. Decreased automaticity may also lead to production of arrhythmias by enhancing ectopic activity in latent pacemakers (ectopic foci) or by altering conductivity and refractoriness in conduction pathways of myocardium. 

Cardiac arrhythmias or dysrhythmias are disturbances of the normal regular rhythm which may be caused by an abnormality in the site of impulse generation, its rate or regularity, or its propagation or conduction (1,2). The more commonly encountered cardiac arrhythmias are... 

Arrhythmias Originating in the Sinus Node Sinus bradycardia Sick sinus syndrome Sinus tachycardia Disorders of Impulseformation ... 

Additionally, the electrophysiological effects are often obtained from normal myocardial preparations and the abnormalities of cellular electrophysiology which cause arrhythmias in a diseased myocardium may be uniquely related to the disease process (10). Nevertheless, antiarrhythmic agent classifications have been useful as a mnemonic device. 

The Class I agents have many similar side effects and toxicities. The anticholinergic side effects include dry mouth, constipation, and urinary hesitancy and retention. Common gastrointestinal (GI) side effects include nausea, vomiting, diarrhea, and anorexia. Cardiovascular adverse effects are hypotension, tachycardia, arrhythmias, and myocardial depression, especially in patients with congestive heart failure. Common central nervous system (CNS) side effects are headache, dizziness, mental confusion, hallucinations, CNS stimulation, paraesthesias, and convulsions. 

QuinidJne. Quinidine, an alkaloid obtained from cinchona bark (Sinchona sp.), is the dextrorotatory stereoisomer of quinine [130-95-0] (see Alkaloids). The first use of quinidine for the treatment of atrial fibrillation was reported in 1918 (12). The sulfate, gluconate, and polygalacturonate salts are used in clinical practice. The dmg is given mainly by the oral (po) route, rarely by the intravenous (iv) route of adniinistration. It is the most frequentiy prescribed po antiarrhythmic agent in the United States. The clinical uses of quinidine include suppression of atrial and ventricular extrasystoles and serious ventricular arrhythmias (1 3). 

Procainamide. Procainamide hydrochloride is a ben2amide, synthesized to prolong the therapeutic effects of the local anesthetic procaine [59-46-1] (13) (see Anesthetics). The dmg is effective in a wide range of supraventricular and ventricular arrhythmias (14). 

Disopyr mide. Disopyramide phosphate, a phenylacetamide analogue, is a racemic mixture. The dmg can be adininistered po or iv and is useful in the treatment of ventricular and supraventricular arrhythmias (1,2). After po administration, absorption is rapid and nearly complete (83%). Binding to plasma protein is concentration-dependent (35—95%), but at therapeutic concentrations of 2—4 lg/mL, about 50% is protein-bound. Peak plasma concentrations are achieved in 0.5—3 h. The dmg is metabolized in the fiver to a mono-AJ-dealkylated product that has antiarrhythmic activity. The elimination half-life of the dmg is 4—10 h. About 80% of the dose is excreted by the kidneys, 50% is unchanged and 50% as metabolites 15% is excreted into the bile (1,2). 

Lldoc ine. Lidocaine hydrochloride, an anilide, was originally introduced as a local anesthetic in 1943 and found to be a potent antiarrhythmic in 1960. The compound is a reverse amide of procainamide. Lidocaine is generally considered to be the dmg of choice in the treatment of ventricular arrhythmias and those originating from digitalis glycoside toxicity (1,2,15—17). 

Phenytoin. Phenytoin sodium is sodium diphenylhydantoin [630-93-3] which is stmcturally related to the barbiturates. It was originally introduced as an anticonvulsant (18) (see Hypnotics, sedatives, and anticonvulsants) and later found to have antiarrhythmic properties (19), although not approved by the PDA for any arrhythmic indications. Phenytoin is effective in the treatment of ventricular arrhythmias associated with acute MI and with digitalis toxicity (20). It is not very effective in treatment of supraventricular arrhythmias (20). 

Mexilltene. Mexifitene hydrochloride, a phenyl ether, is a po active congener of lidocaine. It is used clinically for suppression of ventricular arrhythmias (1,2). 

MoriciZine. Moricizine, a phenothiazine derivative, was synthesized and developed in Russia, where it has been in general use since 1971. EDA approval of the new dmg application (NDA) for use in the United States was granted in 1991. It is effective against atrial and ventricular arrhythmias (1,2,21). 

The dmg is effective in the treatment of ventricular arrhythmias, especially those following acute myocardial infarctions (1,2,22). 

Fleca.inide, Elecainide acetate, a fluorobenzamide, is a derivative of procainamide, and has been reported to be efficacious in suppressing both supraventricular and ventricular arrhythmias (26—29). The dmg is generally reserved for patients with serious and life-threatening ventricular arrhythmias. Elecainide depresses phase 0 depolarization of the action potential, slows conduction throughout the heart, and significantly prolongs repolarization (30). The latter effect indicates flecainide may possess some Class III antiarrhythmic-type properties (31). 

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). 

Pirmenol. Pirmenol hydrochloride, a pyridine methanol derivative, is a racemic mixture. It has Class lA antiarrhythmic activity, ie, depression of fast inward sodium current, phase 0 slowing, and action potential prolongation. The prolongation of refractory period may be a Class III property. This compound has shown efficacy in converting atrial arrhythmias to normal sinus rhythm (34,35). 

Propranolol. Propranolol hydrochloride, considered the prototype of the P-adrenoceptor blocking agents, has been in use since 1964. It is a nonselective, highly Hpid-soluble P-adrenoceptor blocker having no ISA. It is a mixture of (+) and (—) enantiomers, and the (—) enantiomer is the active moiety. The local anesthetic effects of propranolol are equipotent to those of Hdocaine [137-58-6] C 4H22N20, (see Anesthetics). Therapeutic effects include termination of catecholamine-induced arrhythmias, conversion of SA nodal tachycardias (including flutter and fibrillation) and AV nodal tachyarrhythmias to normal sinus rhythm, digitahs-induced arrhythmias, and ventricular arrhythmias (1,2). The dmg also has cardioprotective properties (37,39). 

Acebutolol. Acebutolol hydrochloride is a hydrophilic, cardioselective P-adrenoceptor blocker that has about 1/25 the potency of propranolol in this regard. The dmg has moderate ISA and weak membrane stabilizing activities. It is approved for the treatment of hypertension and ventricular arrhythmias, especially PVCs. Acebutolol should produce minimal depression of heart rate because of its ISA (32). 

---