Cardiac arrhythmia

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Chapter 25 Cardiac arrhythmia

Objectives of treatment

In almost no other set of conditions is it so clearly obvious to remember the dual objectives, which are to reduce morbidity and mortality.

Arrhythmias are frequently asymptomatic but may be fatal even at first presentation. Indeed, an estimated 70 000 deaths per year are ascribed to ventricular arrhythmias just in the UK. Antiarrhythmic drugs themselves are also capable of generating arrhythmias (see below) and find use only in the presence of clear indications. In addition, antiarrhythmic agents are to a variable degree negatively inotropic (except for digoxin and possibly amiodarone). These observations provide important primary reasons for caution in the use of these drugs.

A background reason for a careful approach to antiarrhythmic treatment is the gulf between knowledge of their mechanism of action and their clinical uses. On the side of normal physiology, we can see the spontaneous generation and propagation of the cardiac impulse requiring a combination of specialised conducting tissue and inter-myocyte conduction. The heart also has backstops in case of problems with a sequential hierarchy of intrinsic pacemakers. By contrast, the available drugs are at an early stage of evolution, and useful antiarrhythmic actions are yet discovered by chance.

Doctors and drugs have historically generally interfered with cardiac electrophysiology at their peril. In emergencies, the most junior doctor in the team often needs to take action, and some rote recommendations are clearly necessary. The diagnosis and elective treatment of chronic or episodic arrhythmias require experience to achieve the best balance between risk and benefit and this realisation has led to the development of cardiac electrophysiology as a distinct therapeutically effective subspeciality of cardiology.

Antiarrhythmic drugs in general have had a hard time proving superior safety or efficacy over other therapeutic (non-drug) options.

Some physiology and pathophysiology

There are broadly two types of cardiac tissue.

The first type is ordinary myocardial (atrial and ventricular) muscle, responsible for the pumping action of the heart.

The second type is specialised conducting tissue that initiates the cardiac electrical impulse and determines the order in which the muscle cells contract. The important property of being able to form impulses spontaneously (automaticity) is a feature of certain parts of the conducting tissue e.g. the sinoatrial (SA) and atrioventricular (AV) nodes. The SA node has the highest frequency of spontaneous discharge, usually around 70 times per minute, and thus controls the contraction rate of the whole heart, making the cells more distal in the system fire more rapidly than they would do spontaneously, i.e. it is the pacemaker. If the SA node fails to function, the next fastest component takes over. This is often the AV node (approx. 45 discharges per min) or sites in the His–Purkinje system (discharge rate about 25 per min).

Altered rates of automatic discharge or an abnormality in the mechanism by which an impulse is generated from a centre in the nodes or conducting tissue, is one cause of cardiac arrhythmia, e.g. atrial fibrillation, atrial flutter or atrial tachycardia.

Ionic movements into and out of cardiac cells

Nearly all cells in the body exhibit a difference in electrical voltage between their interior and exterior, the membrane potential. Some cells, including the conducting and contracting cells of the heart, are excitable; an appropriate stimulus alters the properties of the cell membrane, ions flow across it and thereby elicit an action potential. This spreads to adjacent cells, i.e. it is conducted as an electrical impulse and, when it reaches a muscle cell, causes it to contract; this is excitation–contraction coupling.

In the resting state the interior of the cell (conducting and contracting types) is electrically negative with respect to the exterior, owing to the disposition of ions (mainly sodium, potassium and calcium) across its membrane, i.e. it is polarised. The ionic changes of the action potential first result in a rapid redistribution of ions such that the potential alters to positive within the cell (depolarisation); subsequent and slower flows of ions then restore the resting potential (repolarisation). These ionic movements separate into phases, which are briefly described here and in Figure 25.1, as they help to explain the actions of antiarrhythmic drugs.1

Classification of antiarrhythmic drugs

The classification still used partially relates to the phases of the cardiac cycle depicted in Figure 25.1.

Phase 0 is the rapid depolarisation of the cell membrane that is associated with a fast inflow of sodium ions through channels that are selectively permeable to these ions.

Phase 1 is a short initial period of rapid repolarisation brought about mainly by an outflow of potassium ions.

Phase 2 is a period when there is a delay in repolarisation caused mainly by a slow movement of calcium ions from the exterior into the cell through channels that are selectively permeable to these ions (‘long-opening’ or L-type calcium channels).

Phase 3 is a second period of rapid repolarisation during which potassium ions move out of the cell.

Phase 4 begins with the fully repolarised state. For cells that discharge automatically, potassium ions then progressively move back into, and sodium and calcium ions move out of, the cell. The result is that the interior becomes gradually less negative until a certain (threshold) potential is reached, which allows rapid depolarisation (phase 0) to occur, and the cycle is repeated; the prevailing sympathetic tone also influences automaticity. Cells that do not discharge spontaneously rely on the arrival of an action potential from another cell to initiate depolarisation.

In phases 1 and 2 the cell is in an absolutely refractory state and is incapable of responding further to any stimulus, but during phase 3, the relative refractory period, the cell will depolarise again if a stimulus is sufficiently strong. The orderly transmission of an electrical impulse (the action potential) throughout the conducting system may be retarded in an area of disease, e.g. localised ischaemia or scar tissue due to previous myocardial infarction. An impulse travelling down a normal Purkinje fibre may spread to an adjacent fibre that has transiently failed to transmit, and pass up it in the reverse direction. Should such a retrograde impulse in turn re-excite the cells that provided the original impulse, re-entrant excitation becomes established and may cause an arrhythmia, e.g. ventricular tachycardia, paroxysmal supraventricular tachycardia, atrial flutter, etc.

Most cardiac arrhythmias are due to either:

Classification of drugs

The Vaughan–Williams2 classification of antiarrhythmic drugs is still commonly used despite its many peculiarities, and on occasion provides a useful shorthand for referring to particular groups or actions of drugs.

Principal drugs by class

For further data see Table 25.1.

Class 1A (sodium channel blockade with lengthened refractoriness)

Quinidine

Quinidine is considered the prototype antiarrhythmic drug,3 although it is now used quite rarely and indeed is not available in some jurisdictions. It has a newly identified use that is unique in that it appears to be effective in reducing the risks of sudden cardiac death in those with Brugada syndrome.4 In addition to its class IA activity, quinidine slightly enhances contractility of the myocardium (positive inotropic effect) and reduces vagus nerve activity on the heart (antimuscarinic effect).

Class IC (sodium channel blockade with minimal effect on refractoriness)

Flecainide

Flecainide slows conduction in all cardiac cells including the accessory pathways responsible for the Wolff–Parkinson–White (WPW) syndrome.

One common indication – indeed where it is the drug of choice – is atrioventricular (AV) re-entrant tachycardia, such as AV nodal tachycardia or in the tachycardias associated with the WPW syndrome or similar conditions with anomalous pathways. This should be as a prelude to definitive treatment with radiofrequency ablation, which is the overall treatment approach of choice. Flecainide is also very useful in patients with paroxysmal atrial fibrillation, used in conjunction with an agent that blocks the AV node to protect against rapid conduction to the ventricle. Following the salutary findings of the CAST study,5 flecainide is now restricted to patients without evidence of coronary or structural heart disease. Indeed before it is used an echocardiogram is essential, and in patients at potential risk of coronary artery disease an exercise test or an alternative test of ischaemia is often conducted.

Class II (catecholamine blockade)

β-Adrenoceptor antagonists

(See also Ch. 24.)

β-Adrenoceptor blockers are effective in the prophylaxis of cardiac arrhythmia probably because they counteract the arrhythmogenic effect of catecholamines. The following actions appear to be relevant:

Pharmacokinetics
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