Andrew Grace
Synopsis
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 electrophysiologyas 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–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.
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 IKr, 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 IKr. 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 (t½ 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 t½ 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 t½ 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 (t½ 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 t½ 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
For long-term use, any of the oral preparations of β-blocker are suitable. In emergencies, esmolol is used (see Table 25.1), its short t½ (9 min) rendering it suitable for administration by intravenous infusion with rapid alterations in dose, according to response.
Adverse reactions
Cardiac effects from overdosage include heart block or even cardiac arrest. Heart failure may be precipitated in a patient dependent on sympathetic drive to maintain cardiac output.
Interactions
Concomitant intravenous administration of a calcium channel blocker that affects conduction (verapamil, diltiazem) increases the risk of bradycardia and AV block. In patients with depressed myocardial contractility, the combination of oral or intravenous β-blockade and calcium channel blockade (nifedipine, verapamil) may cause hypotension or heart failure.
Class III (lengthening of refractoriness due to potassium channel blockade)
Amiodarone
Amiodarone is the most powerful antiarrhythmic drug available for the treatment and prevention of both atrial and ventricular arrhythmias. Even short-term use can result in serious toxicity, and its use should always follow a consideration or a trial of alternatives. Amiodarone prolongs the effective refractory period of myocardial cells, the AV node and of anomalous pathways. It also blocks β-adrenoceptors non-competitively.
Amiodarone is used in chronic ventricular arrhythmias and in atrial fibrillation, in which condition it both slows the ventricular response and may restore sinus rhythm (chemical cardioversion). It may also be used to maintain sinus rhythm after cardioversion for atrial fibrillation or flutter. Amiodarone has been used for the management of re-entrant supraventricular tachycardias associated with the WPW syndrome, but radiofrequency ablation is now the treatment of choice and amiodarone should not in general be used.
Pharmacokinetics
Amiodarone is effective given orally; its enormous apparent distribution volume (70 L/kg) indicates that little remains in the blood. It is stored in fat and many other tissues and the t½ of 54 days after multiple dosing signifies slow release from these sites (and slow accumulation to steady state means that a loading dose is necessary; see Table 25.1). The drug is metabolised in the liver and eliminated through the biliary and intestinal tracts.
Adverse reactions
Cardiovascular effects include bradycardia, heart block and induction of ventricular arrhythmia associated with QT prolongation. Other effects include nausea, vomiting, taste disturbances and the development of corneal microdeposits, which may rarely cause visual halos, night glare and photophobia; the latter are dose related, resolve on discontinuation and do not threaten vision. Sleep disturbance and vivid dreams may be prominent and problematic. Plasma transaminase levels may rise (requiring dose reduction or withdrawal if accompanied by acute liver disorders). Amiodarone contains iodine, and both hyperthyroidism and hypothyroidism are quite common; monitoring thyroid function before and during therapy is essential (see chapter 37).
Photosensitivity reactions are common, may be severe and patients should be warned explicitly when starting the drug. Amiodarone may also cause a bluish discoloration on exposed areas of the skin (occasionally reversible on discontinuing the drug). Less commonly, pneumonitis and pulmonary fibrosis occur and hepatitis, sometimes rapidly during short-term use of the drug; these may be fatal, so vigilance should be high. Cirrhosis is reported. Peripheral neuropathy and myopathy occur (usually reversible on withdrawal).
Interaction
with digoxin (by displacement from tissue binding sites and interference with its elimination) and with warfarin (by inhibiting its metabolism) increases the effect of both these drugs. β-blockers and calcium channel antagonists augment the depressant effect of amiodarone on SA and AV node function.
Dronedarone
While amiodarone is less pro-arrhythmic than other conventional antiarrhythmic drugs, e.g. flecainide (possibly because it is a ‘multi-channel blocker’), it has substantial non-cardiac toxic effects. Dronedarone is structurally similar to amiodarone but has no iodine component and reduced lipophilicity. Dronedarone thus has a shorter half-life and appears better tolerated, with low pro-arrhythmic risk.
Dronedarone has been shown to reduce the time to first recurrence of atrial fibrillation. In the EURIDIS and ADONIS clinical trials,6 patients taking dronedarone had a 25% reduction in the risk of AF recurrence over one year, compared with placebo. In the ATHENA study,7 dronedarone also reduced the combined risk of cardiovascular hospitalisation or all-cause death by 24% in patients with current or recent AF and an additional risk factor for death, compared with placebo. A post hoc analysis found that dronedarone, compared with placebo, was associated with a significant reduction in the risk of stroke in paroxysmal and persistent AF patients. Data from the DIONYSOS trial8suggest that dronedarone may have an improved safety profile when compared to amiodarone, mainly driven by fewer thyroid and neurologic events and less premature discontinuation due to adverse events.
Pharmacokinetics
The absolute bioavailability of dronedarone (given with food) is 15%. It undergoes extensive first-pass metabolism through the CYP 450 3A4 system; hence strong inhibitors of this enzyme should not be co-administered with dronedarone. After oral administration in fed conditions, peak plasma concentrations of dronedarone are reached within 3–6 hours. Steady state is reached within 4–8 days. Dronedarone is mostly excreted in the faeces with only 6% excreted renally, and it has an elimination half-life of 28 h.
Contraindications
Dronedarone is contraindicated in patients with unstable haemodynamic conditions, including patients with symptoms of heart failure at rest or with minimal exertion (corresponding with NYHA class IV and unstable class III patients). Dronedarone is not recommended in stable patients with recent (1–3 months) NYHA class III heart failure, or left ventricular ejection fraction < 35%. Patients should consult their doctor if they experience worsening heart failure symptoms.
Due to pharmacokinetic and possible pharmacodynamic interactions, both β-blockers and calcium channel blockers with depressant effects on the sinus and atrioventricular nodes (such as verapamil and diltiazem) should be used with caution when prescribed with dronedarone. They should be initiated at low dose, which should only be increased after ECG assessment. In patients already taking β-blockers or calcium channel blockers, an ECG should be performed and the β-blocker/calcium channel blocker dose should be adjusted if needed.
Unwanted effects
Common side-effects include diarrhoea, abdominal discomfort, nausea, vomiting, and prolonged QT interval. Supportive symptomatic treatment should be provided, and attention should be paid to hydration in those most severely affected. In a proportion of patients, dronedarone may need to be discontinued because of intolerance. There is an increased incidence of skin rash and bradycardia.
Plasma creatinine should be measured 7 days after starting dronedarone, as an increase of approximately 10 micromol/L has been observed with dronedarone 400 mg twice daily in both healthy controls and in patients. This occurs early after treatment initiation and reaches a plateau after 7 days.
Recently released European Society of Cardiology guidelines have included dronedarone as a treatment option for non-permanent AF for rhythm and rate control (see below, Fig. 25.6).
Class IV (calcium channel blockade)
Calcium is involved in the contraction of cardiac and vascular smooth muscle cells, and in the automaticity of cardiac pacemaker cells. Actions of calcium channel blockers on vascular smooth muscle cells appear with the main account of these drugs in Chapter 24. Although the three classes of calcium channel blocker have similar effects on vascular smooth muscle in the arterial tree, their cardiac actions differ. The phenylalkylamine, verapamil, depresses myocardial contraction more than the others, and both verapamil and diltiazem slow conduction in the AV node.
Calcium and cardiac cells
Cardiac muscle cells are normally depolarised by the fast inward flow of sodium ions, following which there is a slow inward flow of calcium ions through the L-type calcium channels (phase 2 in Figure 25.1); the consequent rise in free intracellular calcium ions activates the contractile mechanism.
Pacemaker
cells in the SA and AV nodes rely heavily on the slow inward flow of calcium ions (phase 4) for their capacity to discharge spontaneously, i.e. for their automaticity.
Calcium channel blockers
inhibit the passage of calcium through the membrane channels; the result in myocardial cells is to depress contractility, and in pacemaker cells to suppress their automatic activity. Members of the group therefore may have negative cardiac inotropic and chronotropic actions, which can be separated: nifedipine, at therapeutic concentrations, acts almost exclusively on non-cardiac ion channels and has no clinically useful antiarrhythmic activity, whereas verapamil is an effective rate control agent.
Verapamil
Verapamil (see also p. 397) prolongs conduction and refractoriness in the AV node and depresses the rate of discharge of the SA node. If adenosine is not available, verapamil is a very attractive and, with due care, safe alternative for terminating narrow complex paroxysmal supraventricular tachycardia. Verapamil should not be given intravenously to patients with broad complex tachyarrhythmias whatever the presumptive mechanism, for it may prove lethal.
Adverse effects
include nausea, constipation, headache, fatigue, hypotension, bradycardia and heart block.
Other antiarrhythmics
Digoxin and other cardiac glycosides9
Crude digitalis is a preparation of the dried leaf of the foxglove plants Digitalis purpurea or lanata. Digitalis contains a number of active glycosides (digoxin, lanatosides) whose actions are qualitatively similar, differing principally in rapidity of onset and duration of action; the pure individual glycosides are used. The following account refers to all the cardiac glycosides, but digoxin is the principal one.
Mode of action
Cardiac glycosides affect the heart both directly and indirectly in a series of complex actions, some of which oppose one another. The direct effect is to inhibit the membrane-bound sodium–potassium adenosine triphosphatase (Na+, K+-ATPase) enzyme that supplies energy for the system that pumps sodium out of and transports potassium into contracting and conducting cells. By reducing the exchange of extracellular sodium with intracellular calcium, digoxin raises the store of intracellular calcium, which facilitates muscular contraction. The indirect effect is to enhance vagal activity by complex peripheral and central mechanisms. The clinically important consequences are on:
• the contracting cells: increased contractility and excitability
• SA and AV nodes and conducting tissue: decreased impulse generation and propagation.
Uses
Digoxin is not strictly an antiarrhythmic agent but rather it modulates the response to arrhythmias. Its most useful property, in this respect, is to slow conduction through the AV node. The main uses are in the following:
• Atrial fibrillation, benefiting chiefly by the vagal effect on the AV node, reducing conduction through it and thus slowing the ventricular rate. Its use in this setting is limited and treatment with β-blockers and calcium channel blockers is generally preferred as they are more effective and less likely to cause adverse effects.
• Atrial flutter, benefiting by the vagus nerve action of shortening the refractory period of the atrial muscle so that flutter may occasionally be converted to fibrillation (in which state the ventricular rate is more readily controlled). Electrical cardioversion followed by referral for radiofrequency ablation is the preferred option when ablation is available.
• Heart failure, benefiting chiefly by the direct action to increase myocardial contractility. Digoxin is still used occasionally in chronic heart failure due to ischaemic, hypertensive or valvular heart disease, especially in the short term. This is no longer a major indication following the introduction of other groups of drugs.
Pharmacokinetics
Digoxin is eliminated 85% unchanged by the kidney and the remainder is metabolised by the liver. The t½ is 36 h. Digoxin is usually administered by mouth.
Dose and therapeutic plasma concentration
(See Table 25.1.) Reduced dose of digoxin is necessary in: renal impairment (see above); the elderly (probably due to the decline in renal clearance with age); electrolyte disturbances (hypokalaemia accentuates the potential for adverse effects of digoxin, as does hypomagnesaemia); hypothyroid patients (who are intolerant of digoxin).
Adverse effects
Abnormal cardiac rhythms due to digoxin usually take the form of ectopic arrhythmias (ventricular ectopic beats, ventricular tachyarrhythmias, paroxysmal supraventricular tachycardia) and heart block. Gastrointestinal effects include anorexia, which usually precedes vomiting and is a warning that dosage is excessive. Diarrhoea may also occur. Visual effects include disturbances of colour vision, e.g. yellow discolouration (xanthopsia) but also red or green vision, photophobia and blurring. Gynaecomastia in men and breast enlargement in women is seen with long-term use (cardiac glycosides have structural resemblance to oestrogen). Mental effects include confusion, restlessness, agitation, nightmares and acute psychoses.
Acute digoxin poisoning causes initial nausea and vomiting and hyperkalaemia because inhibition of the Na+, K+-ATPase pump prevents intracellular accumulation of potassium. The ECG changes (see Table 25.1) of prolonged use of digoxin may be absent. There may be exaggerated sinus arrhythmia, bradycardia and ectopic rhythms with or without heart block.
Treatment of overdose
For severe digoxin poisoning, infusion of the digoxin-specific binding (Fab) fragment of an antibody to digoxin (Digibind) neutralises digoxin in the plasma and is an effective treatment. Because it lacks the Fc segment, this fragment is relatively non-immunogenic and is sufficiently small to be eliminated as the digoxin–antibody complex in the urine. Intravenous phenytoin has been used for ventricular arrhythmias although formal efficacy has not been established, with atropine used for bradycardia. Temporary electrical pacing may be needed.
Interactions
Verapamil, nifedipine and amiodarone raise steady-state plasma digoxin concentrations (see above) and the digoxin dose should be lowered when any of these is added. The likelihood of AV block due to digoxin is increased by verapamil and by β-adrenoceptor blockers.
Adenosine
Adenosine is an endogenous purine nucleotide that slows atrioventricular conduction and dilates coronary and peripheral arteries. It is rapidly metabolised by circulating adenosine deaminase and is also taken up by cells; hence its residence in plasma is brief (t½ < 2 s) and it must be given rapidly intravenously.
Administered as a bolus injection, adenosine is effective for terminating paroxysmal supraventricular (re-entrant) tachycardias, including episodes in patients with Wolff–Parkinson–White syndrome. The initial dose in adults is 6 mg over 2 s with continuous ECG monitoring, with doubling increments every 1–2 min. The average total dose is 125 micrograms/kg.
Adenosine is an alternative to verapamil for supraventricular tachycardia and possibly safer because adenosine is short acting and not negatively inotropic; verapamil is dangerous if used mistakenly in a ventricular tachycardia.
Adverse effects
from adenosine are usually not serious because of the brevity of its action, but it may cause distressing dyspnoea, facial flushing, chest pain and transient arrhythmias, e.g. bradycardia. Adenosine should not be given to asthmatics or to patients with second- or third-degree AV block or sick sinus syndrome (unless a pacemaker is in place).
Cardiac effects of the autonomic nervous system
Some drugs used for arrhythmias exert their actions through the autonomic nervous system by mimicking or antagonising the effects of the sympathetic or parasympathetic nerves that supply the heart. The neurotransmitters in these two branches of the autonomic system, noradrenaline/norepinephrine and acetylcholine, are functionally antagonistic by having opposing actions on cyclic AMP production within the cardiomyocyte. Their receptors are coupled to the two trimeric GTP-binding proteins, Gs and Gi, which stimulate and inhibit adenylyl cyclase, respectively.
The sympathetic division
(adrenergic component of the autonomic nervous system), when stimulated, has the following (receptor) effects on the heart:
• Tachycardia due to increased rate of discharge of the SA node.
• Increased automaticity in the AV node and His–Purkinje system.
• Increase in conductivity in the His–Purkinje system.
• Increased force of contraction.
• Shortening of the refractory period.
Isoprotenerol,
a β-adrenoceptor agonist has been used to accelerate the heart when there is extreme bradycardia due to heart block, prior to the insertion of an implanted pacemaker, although this is now rarely used. It is also used by interventional cardiac electrophysiologists to induce cardiac arrhythmias both for diagnosis and both before and after ablation procedures. Adverse effects are those expected of β-adrenoceptor agonists and include tremor, flushing, sweating, palpitation, headache and diarrhoea.
The vagus nerve
(cholinergic, parasympathetic), when stimulated, affects the heart in ways that are useful in the therapy of arrhythmias, by causing:
• bradycardia due to depression of the SA node
• slowing of conduction through and increased refractoriness of the AV node
• shortening of the refractory period of atrial muscle cells
• decreased myocardial excitability.
There is also reduced force of contraction of atrial and ventricular muscle cells.
Vagal stimulation can slow or terminate supraventricular arrhythmias, reflexly by physical manoeuvres (under ECG control, if possible).
Carotid sinus massage activates stretch receptors: external pressure is applied gently to one side at a time (but not to both sides at once). Some individuals are very sensitive to the procedure and develop severe bradycardia and hypotension.
Other methods include the Valsalva manoeuvre (deep inspiration followed by expiration against a closed glottis, which both stimulates stretch receptors in the lung and reduces venous return to the heart); the Müller procedure(deep expiration followed by inspiration against a closed glottis); production of nausea and retching by inviting patients to put their own fingers down their throat.
The effects of vagus nerve activity are blocked by atropine (antimuscarinic action), an action that is used to accelerate the heart during episodes of sinus bradycardia as may occur after myocardial infarction. The dose is 600 micrograms i.v. and repeated as necessary to a maximum of 3 mg.
Adverse effects are those of muscarinic blockade, namely dry mouth, blurred vision, urinary retention, confusion and hallucination.
Proarrhythmic drug effects
All antiarrhythmic drugs can also cause arrhythmia; they should be used with care and almost invariably following advice from a specialist (heart rhythm specialist/electrophysiologist). Such proarrhythmic effects most commonly occur with drugs that prolong the QTc interval or QRS complex of the ECG; hypokalaemia aggravates the danger. Quinidine may cause tachyarrhythmias, torsade de pointes (see Fig. 25.2) in an estimated 4–6% of patients. The Cardiac Arrhythmia Suppression Trial (CAST) revealed a probable pro-arrhythmic effect of flecainide resulting in fatalities (see p. 432). Digoxin can induce a variety of bradyarrhythmias and tachyarrhythmias (see above).
Choice between drugs and electroconversion
Direct current (DC) electric shock applied externally is often the best way to convert cardiac arrhythmias to sinus rhythm. Many atrial or ventricular arrhythmias start from transiently operating factors but, once they have begun, the abnormal mechanisms are self-sustaining. With a successful electric shock, the heart is depolarised, the ectopic focus is extinguished and the SA node, the part of the heart with the highest automaticity, resumes as the dominant pacemaker.
Electrical conversion has the advantage that it is immediate, unlike drugs, which may take days or longer to act; also, the effective doses and adverse effects of drugs are largely unpredictable, and can be serious.10
Uses of electrical conversion: in supraventricular and ventricular tachycardia, ventricular fibrillation and atrial fibrillation and flutter. Drugs can be useful to prevent a relapse, e.g. sotalol, amiodarone. See also the UK Resuscitation Council's guidelines (Figs 25.3-25.5).
Specific treatments11
Sinus bradycardia
Acute sinus bradycardia requires treatment if it is symptomatic, e.g. where there is hypotension or escape rhythms; extreme bradycardia may allow a ventricular focus to take over and lead to ventricular tachycardia. The foot of the bed should be raised to assist venous return and atropine should be given intravenously. Chronic symptomatic bradycardia is an indication for the insertion of a permanent pacemaker.
Atrial ectopic beats
Reduction in the use of tea, coffee and other methylxanthine-containing drinks, and of tobacco, may suffice for ectopic beats not due to organic heart disease. For persistent symptoms, a small dose of a β-adrenoceptor blocker may be effective.
Paroxysmal supraventricular (AV re-entrant or atrial) tachycardia
For acute attacks, if vagal stimulation (by carotid sinus massage, or swallowing ice) is unsuccessful, adenosine has the dual advantage of being effective in most such tachycardias, while having no effect on a ventricular tachycardia. The response to adenosine is therefore also of diagnostic value. Intravenous verapamil is an alternative for the acute management of a narrow complex tachycardia. If the patient is in circulatory shock from the tachycardia, or drug treatment fails, DC conversion delivers immediate effects. Flecainide and sotalol are the drugs of choice for prophylaxis, but patients should also be referred to heart rhythm specialists for the definitive treatment of their arrhythmia with radiofrequency ablation.
Atrial fibrillation (AF)
Atrial fibrillation (AF) is the most commonly encountered arrhythmia. Its incidence increases with age and is estimated to affect approximately 6% of people over 65 years. AF increases the risk of stroke by four- to five-fold and death by around two-fold. The health-care costs associated with AF are substantial.
What management options are available?
Treatment can be divided into rhythm or rate control, utilising pharmacological and/or non-pharmacological therapies. Thromboembolic prevention is strongly advocated in all patients, the level of risk determining the degree to which this is pursued. Rhythm control should theoretically be superior to rate control, as the former maintains the physiological, sequential and coordinated pumping actions of the atria and ventricles. At the same time it should reduce the risk of thrombus formation in the atria. Clinical trials fail to support these arguments, although the use of differing anticoagulation regimens complicates interpretation of results. The potential side-effects of currently available anti-arrhythmic agents may negate any benefit conferred by maintenance of sinus rhythm (see below).
The therapeutic options for the management of atrial fibrillation are therefore complex and include asking questions that concern:
• Treatment or no treatment?
• Conversion or rate control?
• Immediate or delayed conversion?
• Drugs, DC conversion or radiofrequency ablation?
The information that should be considered is extensive and includes:
• Ventricular rate (‘normal’ or high).
• Haemodynamic state (‘normal’ or compromised).
• Atrial size (‘normal’ or enlarged).
In many patients, AF is an incidental finding on the background of some existing cardiovascular disease, and with a large atrium. With a prolonged history of symptoms, rate-controlling medication such as a β-blocker, digoxin or calcium antagonist may suffice.
If the history appears shorter, and the atrium is of normal size, i.e. is unlikely to contain thrombus, or there has been recent onset of heart failure or shock, cardioversion should be considered. Electrical (DC) conversion is often favoured where treatment is either urgent or likely to be successful in holding the patient in sinus rhythm. Amiodarone can often provide pharmacological conversion over hours to days, and is also effective for patients who revert rapidly to AF after DC conversion. In cases in which the AF duration exceeds 48 h cardioversion should be delayed for at least a month to permit anticoagulation with warfarin, which should be continued for 4 weeks thereafter. If cardioversion is deemed urgent, then transoesophageal echocardiography should be used to show there is no thrombus visible in the left atrium.
In patients who have reverted to AF after previous conversions, amiodarone is the drug of choice prior to further attempts at cardioversion. Amiodarone may also be used to suppress episodes of paroxysmal atrial fibrillation, but dronedarone, sotalol or flecainide are preferred12 (Fig. 25.6). Radiofrequency ablation is now established as the treatment of choice in many patients with both paroxysmal and persistent atrial fibrillation and patients with symptomatic atrial fibrillation should ideally be referred to heart rhythm specialists for advice on further management.
Fig. 25.6 Choice of antiarrhythmic drug for atrial fibrillation according to underlying pathology. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CAD = coronary artery disease; CHF = congestive heart failure; HT = hypertension; LVH = left ventricular hypertrophy; NYHA = New York Heart Association; unstable = cardiac decompensation within the prior 4 weeks. Antiarrhythmic agents are listed in alphabetical order within each treatment box. ? = evidence for ‘upstream’ therapy for prevention of atrial remodelling still remains controversial. Taken from the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) guidance. Camm A J, Kirchhof P, Lip G Y et al 2010 European Heart Journal 31:2369–2429. With permission.
Additional treatments in persistent atrial fibrillation
Long-term treatment with warfarin is almost mandatory to reduce embolic complications. The efficacy of aspirin as an antithrombotic agent is minimal and is little used in those not having a vascular indication.
Atrial flutter
It is doubtful whether this differs in any important way in its origins or sequelae from atrial fibrillation. The ventricular rate is usually faster (typically, half an atrial rate of 300 beats/min, where 2:1 block is present), which is too fast to leave without treatment. Previously, conversion without prior anticoagulation was undertaken occasionally, but transoesphageal echocardiography or anticoagulation is now mandatory. Patients should not remain in chronic atrial flutter, and DC conversion will usually either restore sinus rhythm or result in atrial fibrillation (treated as above). Patients who fail to convert, or who revert to atrial flutter, should be referred for radiofrequency ablation, which is highly effective and removes the cause of the atrial flutter in nearly all patients. The potential later recurrence of atrial fibrillation is much more readily managed than atrial flutter.
Atrial tachycardia with variable AV block
The atrial rate varies and commonly there is AV block. Digoxin is a possible cause of the arrhythmia, and should be withdrawn. If the patient is not taking digoxin, it may be introduced to control the ventricular rate. These patients should be referred to a heart rhythm specialist and be considered for radiofrequency ablation.
Heart block
In an emergency, antimuscarinic vagal block with atropine 600 micrograms i.v. or the β-adrenoceptor agonist, isoprenaline (0.5–10 micrograms/min i.v.) can improve AV conduction, but advanced heart block always requires implantation of a permanent pacemaker, possibly preceded by a temporary pacing wire.
Pre-excitation (Wolff–Parkinson–White) syndromes
These occur in otherwise healthy individuals who possess an anomalous (accessory) atrioventricular (AV) pathway; they often experience attacks of paroxysmal AV re-entrant tachycardia or atrial fibrillation. Drugs that both suppress the initiating ectopic beats and delay conduction through the accessory pathway are used to prevent attacks, e.g. flecainide, sotalol or amiodarone. Do not use verapamil or digoxin, which may increase conduction through the anomalous pathway. Electrical conversion restores sinus rhythm when the ventricular rate is very rapid. Radiofrequency ablation of aberrant pathways provides a cure and is the treatment of choice.
Ventricular premature beats
These are common after myocardial infarction. One particular significance in those with ischaemic heart disease is that the R-wave (ECG) of an ectopic beat, superimposed upon the early or peak phases of the T-wave of a normal beat, may precipitate ventricular tachycardia or fibrillation (the ‘R-on-T’ phenomenon). About 80% of patients with myocardial infarction who proceed to ventricular fibrillation have preceding ventricular premature beats. Lidocaine effectively suppresses ectopic ventricular beats but is not often used, as its addition increases overall risk.
Ventricular tachycardia
Ventricular tachycardia demands urgent treatment because it frequently leads to ventricular fibrillation and circulatory arrest. A powerful thump of the fist on the mid-sternum or praecordium may very occasionally stop a tachycardia. If there is rapid haemodynamic deterioration, electrical conversion is the treatment of choice. When the patient is in good cardiovascular condition, treatment may begin with intravenous lidocaine, failing which, intravenous amiodarone may be used. For recurrent ventricular tachycardia, amiodarone or sotalol is preferred. Patients should be referred to a heart rhythm specialist and be considered for the insertion of an implantable cardioverter defibrillator (ICD) that will often be combined with radiofrequency ablation directed at the arrhythmogenic substrate.
Ventricular fibrillation and cardiac arrest
Ventricular fibrillation is usually caused by myocardial infarction or ischaemia, or serious organic heart disease and is the main cause of cardiac arrest. Guidelines for the management of peri-arrest arrhythmias and cardiac arrest are issued by the UK Resuscitation Council and appear in Figures 25.3, 25.4 and 25.5. Patients suffering ‘failed’ sudden cardiac death (SCD) should be considered for the insertion of an ICD.
Fig. 25.3 Algorithm for the management of acute bradycardia. mcg, micrograms. Reproduced with the kind permission of the Resuscitation Council (UK). The latest version can be found at: http://www.resus.org.uk
Fig. 25.4 Algorithm for the management of acute tachycardia. Reproduced with the kind permission of the Resuscitation Council (UK). The latest version can be found at: http://www.resus.org.uk
Fig. 25.5 Adult advanced life support. Reproduced with the kind permission of the Resuscitation Council (UK). The latest version can be found at: http://www.resus.org.uk
Long QT syndromes
These are caused by malfunction of ion channels, leading to impaired ventricular repolarisation (expressed as prolongation of the QT interval) and a characteristic ventricular tachycardia, torsade de pointes(see Fig. 25.2).13 The symptoms range from episodes of syncope to cardiac arrest. Several drugs are responsible for the acquired form of the condition including antiarrhythmic drugs (see above), antimicrobials, histamine H1-receptor antagonists and serotonin receptor antagonists; predisposing factors are female sex, recent heart rate slowing, and hypokalaemia.14 Congenital forms of the long QT syndrome are due to mutations of the genes encoding ion channels, and exposure to drugs reveals some of these.
Summary
• The treatment of cardiac arrhythmias has advanced enormously and can be directly physical, electrical, pharmacological or surgical. Radiofrequency ablation and devices such as permanent pacemakers and ICDs increasingly provide the preferred approaches. The use of drugs alone is declining but they often constitute adjunctive treatments.
• The choice among drugs follows partly from theoretical predictions of their action on the cardiac cycle but substantially from short- and long-term observations of their efficacy and safety.
• All antiarrhythmics can be potentially dangerous, and should be used only in patients who have been properly and fully assessed.
• Adenosine is the treatment of choice for diagnosis and reversal of supraventricular arrhythmias. Verapamil is an alternative for the management of narrow complex tachycardias.
• Amiodarone is the most effective drug for reversing and preventing atrial fibrillation, and for preventing ventricular arrhythmias, but it has notable adverse effects. Dronedarone has been designed to provide the actions of amiodarone without the side-effects but is not so effective.
• New drugs are needed and several are in the pipeline.
• In view of the increasing complexity and range of treatment options all patients should be considered for referral to a heart rhythm specialist for a full discussion of the options available.
Guide to further reading
Camm A.J., Kirchhof P., Lip G.Y., et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur. Heart J.. 2010;31:2369–2429.
Crystal E., Connolly S.J. Role of oral anticoagulation in management of atrial fibrillation. Heart. 2004;90:813–817.
Delacretaz E. Clinical practice. Supraventricular tachycardia. N. Engl. J. Med.. 2006;354:1039–1051.
Dobrev D., Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet. 2010;375:1212–1223.
Lip G.Y., Halperin J.L. Improving stroke risk stratification in atrial fibrillation. Am. J. Med.. 2010;123:484–488.
Morady F. Catheter ablation of supraventricular arrhythmias: state of the art. J. Cardiovasc. Electrophysiol.. 2004;15(1):124–139.
Page R.L., Roden D.M. Drug therapy for atrial fibrillation: where do we go from here? Nat. Rev. Drug. Discov.. 2005;4(11):899–910.
Torp-Pedersen C., Pedersen O.D., Kober L. Antiarrhythmic drugs: safety first. J. Am. Coll. Cardiol.. 2010;55:1577–1579.
Zimetbaum P. Amiodarone for atrial fibrillation. N. Engl. J. Med.. 2007;356:935–941.
1 Dobrev D, Nattel S 2010 New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 375:1212–1223.
2 Roden D M 2003 Antiarrhythmic drugs: past, present and future. Journal of Cardiovascular Electrophysiology 14:1389–1396.
3 In 1912, K F Wenckebach, a Dutch physician (who described ‘Wenckebach block’) was visited by a merchant who wished to get rid of an attack of atrial fibrillation (he had recurrent attacks which, although they did not unduly inconvenience him, offended his notions of good order in life's affairs). On receiving a guarded prognosis, the merchant inquired why there were heart specialists if they could not accomplish what he himself had already achieved. In the face of Wenckebach's incredulity he promised to return the next day with a regular pulse, which he did, at the same time revealing that he had done it with quinine (an optical isomer of quinidine). Examination of quinine derivatives led to the introduction of quinidine in 1918 (Wenckebach K F 1923 Journal of the American Medical Association 81:472).
4 An inherited condition that is the major cause of sudden unexpected death syndrome (SUDS), commonly in young men.
5 Flecainide, encainide and moricizine underwent clinical trial to establish whether suppression of asymptomatic premature beats with antiarrhythmic drugs would reduce the risk of death from arrhythmia after myocardial infarction. The study was terminated after preliminary analysis of 1727 patients revealed that the mortality rate in patients treated with flecainide or encainide was 7.7% compared with 3.0% in controls. The most likely explanation for the result was the induction of fatal ventricular arrhythmias, possibly in conjunction with ischaemia by flecainide and encainide, i.e. a proarrhythmic effect (Cardiac Arrhythmia Suppression Trial (CAST) Investigators 1989 Preliminary report: effect of encainide and flecainide on mortality in a randomised trial of arrhythmia suppression after myocardial infarction. New England Journal of Medicine 321:406–412).
6 Singh B N, Connolly S J, Crijns H J et al; EURIDIS and ADONIS Investigators 2007 Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. New England Journal of Medicine 357:987–999.
7 Hohnloser S H, Crijns H J, van Eickels M et al; ATHENA Investigators 2009 Effect of dronedarone on cardiovascular events in atrial fibrillation. New England Journal of Medicine 360:668–678.
8 Le Heuzey J Y, De Ferrari G M, Radzik D et al 2010 A short-term, randomised, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. Journal of Cardiovascular Electrophysiology 21:597–605.
9 In 1775 Dr William Withering was making a routine journey from Birmingham (England), his home, to see patients at the Stafford Infirmary. While the carriage horses were being changed half-way, he was asked to see an old dropsical (oedematous) woman. He thought she would die and so some weeks later, when he heard of her recovery, was interested enough to enquire into the cause. Recovery was attributed to a herb tea containing some 20 ingredients, among which Withering, already the author of a botanical textbook, found it ‘not very difficult … to perceive that the active herb could be no other than the foxglove’. He began to investigate its properties, trying it on the poor of Birmingham, whom he used to see without fee each day. The results were inconclusive and his interest flagged until one day he heard that the principal of an Oxford College had been cured by foxglove after ‘some of the first physicians of the age had declared that they could do no more for him’. This put a new complexion on the matter and, pursuing his investigation, Withering found that foxglove extract caused diuresis in some oedematous patients. He defined the type of patient who might benefit from it and, equally importantly, he standardised his foxglove leaf preparations and was able to lay down accurate dosage schedules. His advice, with little amplification, served until relatively recently (Withering W 1785 An Account of the Foxglove. Robinson, London).
10 To the layperson, ‘shock’ treatment could be interpreted as frights (which stimulate the vagus, as described above), or as the electrical sort. Dr James Le Fanu quotes a Belfast doctor who reported a farmer with a solution that covered both possibilities. He had suffered from episodes of palpitations and dizziness for 30 years. When he first got them, he would jump from a barrel and thump his feet hard on the ground at landing. This became less effective with time. His next ‘cure’ was to remove his clothes, climb a ladder and jump from a considerable height into a cold water tank on the farm. Later, he discovered the best and simplest treatment was to grab hold of his high-voltage electrified cattle fence – although if he was wearing Wellington (rubber) boots he found he had to earth the shock, so besides grabbing the fence with one hand he simultaneously shoved a finger of the other hand into the ground.
11 See also UK Resuscitation Council guidelines (Figs 25.3-25.5).
12 The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) has issued guidance preferring these agents to amiodarone depending on the characteristics of the patient (see Fig. 25.6). A J Camm et al 2010 European Heart Journal 31:2369–2429.
13 French: torsade, twist; pointe, point. ‘Twisting of the points’, referring to the characteristic sequence of ‘up’ followed by ‘down’ QRS complexes. The appearance has been called a ‘cardiac ballet’.
14 Roden D M 2004 Drug-induced prolongation of the QT interval. New England Journal of Medicine 350:1013–1022.