i.v.: 6 mg initially; if no conversion after 1 2 minutes, give 1 2 mg and repeat once if necessary. Follow each bolus with saline flush.
Prolongs PR Transient heart block
Not clinically useful
* Doses based on British National Formulary recommendations. Patients with decreased hepatic or renal function may require lower doses (see text).
This table is adapted from that published in the Medical Letter on Drugs and Therapeutics (USA) 1996. We are grateful to the Chairman of the Editorial Board for allowing us to use this material.
tricular arrhythmias, especially those complicating myocardial infarction. Its kinetics render it unsuitable for oral administration and therefore restrict its application to the treatment of acute arrhythmias.
Pharmacokinetics. Lignocaine is used by the i.v, or occasionally the i.m. route; dosing by mouth is unsatisfactory because the tl/2 (90 min) is too short to maintain a constant plasma concentration by repeated administration and because the drug undergoes extensive presystemic (first-pass) elimination in the liver.
Adverse reactions are uncommon unless infusion is rapid or there is significant cardiac failure; they include hypotension, dizziness, blurred sight, sleepiness, slurred speech, numbness, sweating, confusion and convulsions.
Mexiletine is similar to lignocaine (lidocaine) but is effective by the oral route (t[/2 10 h). It has been used for ventricular arrhythmias especially those complicating myocardial infarction. The drug is usually poorly tolerated. Adverse reactions are almost universal and dose-related and 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 slows conduction in all cardiac cells including the anomalous pathways responsible for the Wolff-Parkinson-White (WPW) syndrome. Together with encainide and moricizine, it underwent clinical trials to establish if suppression of asymptomatic premature beats with antiarrhythmic drugs would reduce the risk of death from arrhythmia after myocardial infarction.4 The study was terminated after preliminary analysis of 1727 patients revealed that mortality in the groups 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 lethal ventricular arrhythmias possibly due to ischaemia by flecainide and encainide, i.e. a proarrhythmic effect. In the light of these findings the indications for flecainide are restricted to patients with no evidence of structural heart disease. The most common indication, indeed where it is the drug of choice, is atrioventricular 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. Flecainide may also be useful in patients with paroxysmal atrial fibrillation.
Pharmacokinetics. Its action is terminated by metabolism in the liver and by elimination unchanged in the urine. The t '/2 is 14 h in healthy adults but may be over 20 h in patients with cardiac disease, in the elderly and in those with poor renal function.
Adverse reactions. Flecainide is contraindicated in patients with sick sinus syndrome, with cardiac failure, and in those with a history of myocardial infarction who have asymptomatic ventricular ectopic
4 Cardiac Arrhythmia Suppression Trial (CAST) investigators 1989 New England Journal of Medicine 321: 406.
beats or asymptomatic nonsustained ventricular tachycardia. Minor adverse effects include blurred vision, abdominal discomfort, nausea, dizziness, tremor, abnormal taste sensations and paraesthesiae.
In addition to the defining properties of this class, propafenone also has ^-adrenoceptor blocking activity equivalent to a low dose of propranolol. It is occasionally used to suppress nonsustained ventricular arrhythmias in patients whose left ventricular function is normal.
Pharmacokinetics. It is metabolised by the liver and 7% of Caucasian patients are poor metabolisers (it is a substrate for CYP 2D6, see p. 123) who for equivalent doses thus have higher plasma concentrations than the remainder of the population who are extensive metabolisers.
Adverse reactions are similar to those of flecainide and are commoner in poor metabolisers. In addition, conduction block may occur, cardiac failure may worsen and ventricular arrhythmias may be exacerbated, and it should not be used in patients with sustained ventricular tachycardia and poor left ventricular function.
CLASS II (catecholamine blockade)
^-adrenoceptor antagonists (see also Ch. 23)
p-adrenoceptor blockers are effective 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 p-adrenoceptor activation and this effect is abolished by P-blockers. Some ectopic pacemakers appear to be dependent on adrenergic drive.
• P-blockers prolong the refractoriness of the AV node which may prevent re-entrant tachycardia at this site.
• Many p-blocking drugs (propranolol, oxprenolol, alprenolol, acebutolol, labetalol) also possess membrane stabilising (class I) properties. Sotalol prolongs cardiac refractoriness (class III) but has no class I effects; it is often preferred when a (3-blocker is indicated but should be used with care. Esmolol (below) is a short-acting P1-selective agent, whose sole use is in the treatment of arrhythmias. Its short duration and Pj-selectivity mean that it could be considered in some patients with contraindications to other P-blocking drugs. • P-adrenoceptor antagonists are effective for a range of supraventricular arrhythmias, in particular those associated with exercise, emotion or hyperthyroidism. Sotalol may be used to suppress ventricular ectopic beats and ventricular tachycardia possibly in conjunction with amiodarone.
Pharmacokinetics. For long-term use, any of the oral preparations of P-blocker is suitable. In emergencies, esmolol may be given i.v. (see Table 24.1). Esmolol has a tl/2 of 9 min, which justifies administration by infusion with rapid alterations in dose, possibly titrated against response.
Adverse reactions. Adverse cardiac effects from overdosage include heart block or even cardiac arrest. Heart failure may be precipitated when a patient is dependent on sympathetic drive to maintain cardiac output (see Ch. 23 for an account of other adverse effects).
Interactions: concomitant i.v. 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 i.v. p-blockade and calcium channel blockade (nifedipine, verapamil) may cause hypotension or cardiac failure.
CLASS III (lengthening of refractoriness due to potassium channel blockade)
Amiodarone is the most powerful antiarrhythmic drug available for the treatment and prevention of both atrial and ventricular arrhythmias. Even short-
term use, however, can cause 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 P-adrenoceptors noncompetitively.
Amiodarone is used in chronic ventricular arrhythmias; in atrial fibrillation it both slows the ventricular response and may restore sinus rhythm; it may be used to maintain sinus rhythm after cardioversion for atrial fibrillation or flutter. Amiodarone should no longer be used for the management of reentrant supraventricular tachycardias associated with the Wolff-Parkinson-White syndrome as radio-frequency ablation is preferable.
Pharmacokinetics. Amiodarone is effective given orally; its enormous apparent distribution volume (701/kg) indicates that little remains in the blood. It is stored in fat and many other tissues and the t\ 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 24.1). The drug is metabolised in the liver and eliminated through the biliary and intestinal tracts.
Adverse reactions. Adverse cardiovascular effects include bradycardia, heart block and induction of ventricular arrhythmia. Other effects are the development of corneal microdeposits which may rarely cause visual haloes and photophobia. These are dose-related, resolve when the drug is discontinued and are not a threat to vision. Amiodarone contains iodine and both hyperthyroidism and hypothyroidism are quite common; thyroid function should be monitored before and during therapy. Photosensitivity reactions are universal. These may be very severe and should be pointed out explicitly to patients when starting this drug. Amiodarone may also cause a bluish discoloration on exposed areas of the skin (occasionally reversible on discontinuing the drug). Less commonly, pulmonary fibrosis and hepatitis occur, sometimes rapidly during short-term use of the drug, and both may be fatal so vigilance should be high. Cirrhosis is reported.
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, p-blockers and calcium channel antagonists augment the depressant effect of amiodarone on SA and AV node function.
CLASS IV (calcium channel blockade)
Calcium is involved in the contraction of cardiac and vascular smooth muscle cells, and in the auto-maticity of cardiac pacemaker cells. Actions of calcium channel blockers on vascular smooth muscle cells are described with the main account of these drugs in Chapter 23. 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 the benzothiazepine, diltiazem, slow conduction in the SA and AV nodes.
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 Fig. 24.1); 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. These actions can be separated; nifedipine, at therapeutic concentrations, acts almost exclusively on noncardiac ion channels and has no clinically useful antiarrhythmic activity whilst verapamil is a useful antiarrhythmic.
Verapamil (see also p. 466) 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 alternative to it for the termination of narrow complex paroxysmal supraventricular tachycardia. Verapamil should not be given intravenously to patients with broad complex tachyarrhythmias in whom it may be lethal but with due care is very safe in those with narrow complex tachycardia. Adverse effects include nausea, constipation, headache, fatigue, hypotension, bradycardia and heart block.
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