Cardiac arrhythmia

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Chapter 25 Cardiac arrhythmia

The pathophysiology of cardiac arrhythmias is complex and the actions of drugs that are useful in stopping or controlling them may seem equally so. Nevertheless, many patients with arrhythmias respond well to therapy with drugs and a working knowledge of their effects and indications pays dividends, for disturbance of the heartbeat is at least inconvenient and at worst can be fatal. Drug therapy for arrhythmias has a place beside radiofrequency ablation and the use of implanted devices, e.g. pacemakers or implantable defibrillators (ICDs), which may often provide better treatment options. In view of the current complex range of choices for individuals with heart rhythm problems specialist referral should be considered in all cases.

We still have few drug options for patients with cardiac arrhythmias and new often-novel approaches are being developed. Carefully selected and monitored drugs may have useful impacts on morbidity and trials with newer agents, e.g. dronedarone, are now also showing measureable effects on major cardiovascular endpoints. Patients with heart disease die of either pump failure or arrhythmia and much of the risk they encounter is due to ventricular arrhythmias, which in selected cases can be minimised with implantable devices such as ICDs rather than with drugs.

• Drugs for cardiac arrhythmias.

• Principal drugs by class.

• Specific treatments, including those for cardiac arrest.

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

Fig. 25.1 The action potential of a cardiac cell that is capable of spontaneous depolarisation (SA or AV nodal, or His–Purkinje) indicating phases 0–4. The gradual increase in transmembrane potential (mV) during phase 4 is shown; cells that are not capable of spontaneous depolarisation do not exhibit increased voltage during this phase (see text). The modes of action of antiarrhythmic drugs of classes I, II, III and IV are indicated in relation to these phases.

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:

• slowed conduction in part of the system leading to the formation of re-entry circuits (more than 90% of tachycardias), or

• altered rate of spontaneous discharge in conducting tissue. Some ectopic pacemakers appear to depend on adrenergic drive.

Classification of drugs

The Vaughan–Williams ² 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.

Class I: sodium channel blockade

These drugs restrict the rapid inflow of sodium during phase 0 and thus slow the maximum rate of depolarisation. Another term for this property is membrane stabilising activity; the action may contribute to stopping arrhythmias by limiting the responsiveness to excitation of cardiac cells. The class subdivides into drugs that:

1A. lengthen action potential duration and refractoriness (adjunctive class III action), e.g. quinidine, disopyramide, procainamide

1B. shorten action potential duration and refractoriness, e.g. lidocaine and mexiletine

1C. have negligible effect on action potential duration and refractoriness, e.g. flecainide, propafenone.

One value of using the classification is the knowledge that drugs in class 1B are ineffective for supraventricular arrhythmias, whereas they all have some action in ventricular arrhythmias. One feature is that it is not useful in explaining why the classes differ anatomically in their efficacy.

Class II: catecholamine blockade

Propranolol and other β-adrenoceptor antagonists reduce background sympathetic tone in the heart, reduce automatic discharge (phase 4) and protect against adrenergically stimulated ectopic pacemakers.

Class III: lengthening of refractoriness

(without effect on sodium inflow in phase 0). Prolongation of the cardiac action potential and increased cellular refractoriness beyond a critical point may stop a re-entrant circuit being completed and thereby prevent or halt a re-entrant arrhythmia (see above), e.g. amiodarone, sotalol. These drugs act by inhibiting I_Kr, the rapidly activating component of the delayed rectifier potassium current (phase 3). The gene hERG (the human ether-à-go-go related gene) encodes a major subunit of the protein responsible for I_Kr. These are the most commonly used antiarrhythmic drugs and while some newer agents in this class, e.g. dofetilide and azimilide, have not achieved wide use, dronedarone is being increasingly prescribed.

Class IV: calcium channel blockade

These drugs depress the slow inward calcium current (phase 2) and prolong conduction and refractoriness particularly in the SA and AV nodes, which helps to explain their effectiveness in terminating paroxysmal supraventricular tachycardia, e.g. verapamil.

Antiarrhythmic drugs are classified here according to a characteristic major action but most have other effects as well. For example, quinidine (class I) has major class III effects, propranolol (class II) has minor class I effects, and sotalol (class II) has major class III effects. Amiodarone and dronedarone both have class I, II, III and IV effects but are usually placed under class III.

Principal drugs by class

For further data see Table 25.1.

Table 25.1 Drugs for cardiac arrhythmia

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).

Pharmacokinetics

Absorption of quinidine from the gut is rapid; 75% of the drug is metabolised and the remainder is eliminated unchanged in the urine (t_½ 7 h). Active metabolites may accumulate when renal function is impaired.

Adverse reactions

Quinidine must not be used alone to treat atrial fibrillation or flutter as its antimuscarinic action enhances AV conduction and the heart rate may accelerate. Other cardiac effects include serious ventricular tachyarrhythmias associated with electrocardiographic QT prolongation, i.e. torsade de pointes (Fig. 25.2), the cause of ‘quinidine syncope’. Non-cardiac effects, called ‘cinchonism’, include diarrhoea and other gastrointestinal symptoms, rashes, thromobocytopenia and fever, and these have substantially limited its use.

Fig. 25.2 Torsade de pointes ventricular arrhythmia. This patient had received the potassium channel blocking drug, amiodarone, which prolonged the QTc interval and produced this characteristic ‘twisting about the points’ pattern.

Disopyramide

Disopyramide was the most commonly used drug in this class but is much less so now. It has significant antimuscarinic activity.

Pharmacokinetics

Disopyramide is used orally (see Table 25.1) and is well absorbed. It is in part excreted unchanged and in part metabolised. The t_½ is 6 h.

Adverse reactions

The antimuscarinic activity is often a significant clinical problem causing dry mouth, blurred vision, glaucoma, micturition hesitancy and retention. Gastrointestinal symptoms, rash and agranulocytosis can also occur. Effects on the cardiovascular system include hypotension and heart failure (negative inotropic effect).

Class IB (sodium channel blockade with shortened refractoriness)

Lidocaine

Lidocaine finds use principally for ventricular arrhythmias, especially those complicating myocardial infarction or occurring, e.g., after cardiothoracic surgery. Its kinetics render it unsuitable for oral administration and its application is restricted to the treatment of acute ventricular arrhythmias.

Pharmacokinetics

Lidocaine is used intravenously and has occasionally been used intramuscularly; dosing by mouth is unsatisfactory because its t_½ is short (1.5 h) and the drug undergoes extensive pre-systemic (first-pass) elimination in the liver.

Adverse reactions

are uncommon unless infusion is rapid or there is significant heart failure; they include hypotension, dizziness, blurred sight, sleepiness, slurred speech, numbness, sweating, confusion and convulsions.

Mexiletine

is similar to lidocaine but is effective orally (t_½ 10 h). It has been used for ventricular arrhythmias, especially those complicating myocardial infarction, but is usually poorly tolerated and has been withdrawn in many jurisdictions.

Adverse reactions,

almost universal and dose related, include nausea, vomiting, hiccough, tremor, drowsiness, confusion, dysarthria, diplopia, ataxia, cardiac arrhythmia and hypotension.

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.

Pharmacokinetics

Metabolism in the liver and renal elimination of unchanged metabolites terminates its action. The t_½ is 14 h in healthy adults but may be over 20 h in patients with heart disease, in the elderly and in those with poor renal function.

Adverse reactions

Flecainide is contraindicated in patients with sinus node disease, heart failure, and in those with a history of myocardial infarction, especially if they have a history of ventricular arrhythmias. Minor adverse effects include blurred vision, abdominal discomfort, nausea, dizziness, tremor, abnormal taste sensations and paraesthesiae.

Propafenone

In addition to the defining properties of this class, propafenone has β-adrenoceptor blocking activity equivalent to a low dose of propranolol. It is occasionally used to suppress non-sustained ventricular arrhythmias in patients whose left ventricular function is normal.

Pharmacokinetics

Propafenone is metabolised by the liver and is a substrate for CYP 2D6. Some 7% of Caucasian patients are poor metabolisers who, for equivalent doses, thus have higher plasma concentrations than the remainder of the population.

Adverse reactions

are similar to those of flecainide and are commoner in poor metabolisers. In addition, conduction block may occur, heart failure may worsen and ventricular arrhythmias may be exacerbated, and propafenone should not be used in patients with sustained ventricular tachycardia and poor left ventricular function.

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:

• The rate of automatic firing of the SA node is accelerated by β-adrenoceptor activation and this effect is abolished by β-blockers. Some ectopic pacemakers appear to be dependent on adrenergic drive.

• β-blockers prolong the refractoriness of the AV node, which may prevent re-entrant tachycardias that are dependent on the AV node for their perpetuation.

• Many β-blocking drugs (propranolol, oxprenolol, acebutolol, labetalol) also possess membrane stabilising (class I) properties. Sotalol also prolongs cardiac refractoriness (class III effect) but has no class I effects; it is often preferred when a β-blocker is indicated for arrhythmias, but should be used with care. Esmolol (below) is a short-acting β₁-selective agent, whose sole use is in the treatment of arrhythmias. Its short duration and β₁ selectivity make it an option for some patients with contraindications to other β-blocking drugs.

• β-Adrenoceptor antagonists are effective for a range of supraventricular arrhythmias, in particular those associated with exercise, emotion or hyperthyroidism. Sotalol finds use to suppress ventricular ectopic beats and ventricular tachycardia although care should be taken with careful monitoring of the QT interval whenever it is used.

Pharmacokinetics

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