The Pharmaceutical Journal Vol 264 No 7094 p659-663
April 29, 2000 Continuing education

Atrial fibrillation

(2) Antiarrhythmic agents

By Gregory Y. H. Lip, MD, FRCPE and Sridhar Kamath, MRCP

Table 3 gives details of the drugs and dosages commonly used in AF.

Table 3: Drugs commonly used in atrial fibrillation
Drug	Route of administration (if required)	Loading dose	Maintenance dose
Class I
Quinidine	Oral	Nil	200-400mg three to four times a day
Flecainide	Oral	Nil	50mg twice a day. Maximum 150mg twice a day
	Intravenous	2mg/kg over 10-30 minutes. Maximum 150mg	1.5mg/kg for one hour. Then, 100-250µg/kg/hour up to a maximum of 600mg/day
Propafenone	Oral	Nil	150mg three times/day, increased gradually over days to maximum of 300mg three times a day
Class II
(eg) Metoprolol	Oral	Nil	25-100mg twice a day
	Intravenous	5-15mg, at rate of 1-2mg/minute
Class III
Sotalol	Oral	Nil	40mg twice a day increased gradually over days to maximum 160mg twice a day
Amiodarone	Oral	200 mg three times a day for one week. 200mg twice a day for next week	200mg/day
	Intravenous	5mg/kg over 20-120 minutes	Maximum 1.2g/day (including loading dose)
Class IV
Diltiazem	Oral	Nil	60-180mg three times a day
Verapamil	Oral	Nil	40-160mg three times a day
	Intravenous	5-10mg
Other
Digoxin	Oral	1-1.5 mg/day in divided doses	62.5-500µg /day
	Intravenous	0.5-1 mg maximum, given in fractions over 10-20 minutes up to 4 hourly	Nil

Cardiac glycosides

In the United Kingdom, digoxin is the most widely used single drug in AF. While it has been predominantly used to control the ventricular rate in fast AF, or in permanent AF, it has often been prescribed (erroneously) in other patients with AF, for example, in paroxysmal AF or for cardioversion to sinus rhythm.
Digoxin and the cardiac glycosides have a weak positive inotropic action, which is a useful characteristic when managing patients with AF who are in cardiac failure.
Cardiac glycosides were first used by William Withering over 200 years ago for the treatment of the "dropsy", which we now recognise as cardiac failure, although we suspect that many of his patients also had AF. Commercially available digoxin is obtained from the white foxglove, Digitalis lanata. The cardiac glycosides exert prominent vagotonic actions, resulting in the inhibition of calcium currents in the atrioventricular node, increasing the atrio- ventricular nodal refractoriness. The latter property is used in controlling the ventricular rate in patients with AF. Digitalis also inhibits the Na+/K+ pump, causing the accumulation of intracellular Na+. This Na+ is exchanged for Ca++ thus increasing the intracellular Ca++ levels, providing cardiac inotropic effects.
While digoxin can be administered both orally and intravenously in acute AF, there is little advantage of giving digoxin intravenously except in instances when the patient is unable to take oral tablets (for example, post-operatively) or there is likely malabsorption.¹ Indeed, due to its slow distribution and long half life (36 hours), it has a slow onset of action. More than 80 per cent of digoxin is eliminated through the kidneys unchanged.
The drug has a narrow therapeutic range. Factors that predispose to toxicity include renal impairment, old age, concurrent administration of certain other medication, such as amiodarone and quinidine, hypokalemia, hypercalcaemia and hypothyroidism. Digitoxicity could induce any kind of cardiac arrhythmias, ranging from varying degrees of atrio-ventricular block, inhibition of the sino-atrial node and ventricular extrasystoles to ventricular tachycardia or fibrillation. Of the different arrhythmias seen in digitoxicity, atrial tachycardia with block is a characteristic feature. Extracardiac side effects can include nausea, vomiting, visual disturbances such as yellow vision (xanthopsia), visual hallucinations and general confusion.^1,2
Clinically, digoxin and other cardiac glycosides are useful in controlling the resting ventricular rate in AF. However, digoxin has limited value in patients with AF secondary to an accessory pathway (such as the Wolff-Parkinson-White syndrome) and may even accelerate the ventricular response. In addition, digoxin poorly controls the ventricular response in exercise and conditions of high sympathetic drive, such as uncontrolled heart failure, thyrotoxicosis, chronic lung disease, stress and pyrexia.¹ In such conditions, adequate rate control requires the concomitant use of a beta-blocker or calcium channel blocker with actions at the atrio-ventricular node, such as verapamil or diltiazem. Digoxin is no better than placebo in cardioverting AF to sinus rhythm^3-5 and may even exacerbate paroxysmal AF by increasing the number of paroxysms which tend to occur at faster heart rates.¹

Class I antiarrhythmic agents

Class Ia The class Ia agents, such as quinidine, procainamide and disopyramide, are a popular choice, especially in North America, for cardioversion of AF, the maintenance of sinus rhythm post cardioversion or the reduction of paroxysms of AF. These agents have an inhibitory effect on the sinus node function and the cardiac conducting tissue, leading to heart block or sinus arrest, and thus should be used cautiously in patients with evidence of these abnormalities. In addition to the class I antiarrhythmic properties, these agents often have ancillary effects. For example, quinidine has an alpha-adrenergic blocking action and a mild anticholinergic effect.⁶
The alpha-blocking action of quinidine can cause vasodilatation, which could result in hypotension, especially if nitrates and any other vasodilators are co-administered. The anticholinergic action of the class Ia agents may facilitate conduction through the atrioventricular node and, on occasion, treatment leads to 1:1 conduction through the atrioventricular node resulting in a very fast ventricular rate. This is more common in patients with atrial flutter and in young patients with intact atrioventricular conduction. Concomitant administration of drugs such as beta-blockers, calcium channel blockers or digoxin is recommended.
Disopyramide also has significant dose-related anticholinergic activity, which can cause urinary retention, constipation, dry mouth, oesophageal reflux and precipitation of acute glaucoma.⁷ Great care must therefore be employed in administering this drug to somebody with urinary outflow obstruction or glaucoma or even a family history of glaucoma.
The most serious adverse effect of the class I agents is proarrhythmia, which is the development of new arrhythmia or the worsening of the existing arrhythmia, following the institution of anti-arrhythmic therapy at doses or plasma concentrations below those considered toxic.⁸
A meta-analysis of six randomised control trials comparing quinidine against placebo in maintaining sinus rhythm following cardioversion of AF demonstrated that quinidine was more effective than placebo (although only 50 per cent in the quinidine group were still in sinus rhythm at one year) but was associated with higher mortality.⁹ One likely mechanism is the precipitation of ventricular arrhythmias, especially polymorphic ventricular tachycardia or torsades des pointes, which is more likely in some congenital disorders (Romano-Ward syndrome, Jeville-Lange-Neilson syndrome), with concomitant drug therapy (such as tricyclic antidepressants, other class I and III agents, some macrolide antibiotics and antihistamines) and with electrolyte abnormalities (hypokalaemia, hypomagnesaemia, etc). The so-called "quinidine syncope" is probably due to self-terminating torsade de pointes; it has been reported to occur in 1.5 per cent of patients taking quinidine per year, and is unrelated to the plasma quinidine level or the duration of therapy, occuring when plasma concentrations are normal or below the therapeutic range.^10,11 Proarrhythmia is best avoided by removing the precipitating factor.
Non-cardiac adverse effects of the class Ia agents can include diarrhoea, nausea, vomiting and abdominal pain with quinidine. Cinchonism is the term used to describe the cluster of neurological side effects associated with quinidine, such as tinnitus, deafness, delirium and confusion.⁶
Procainamide is partly metabolised by acetylation in the liver and almost all patients taking the drug develop antinuclear antibodies; in slow acetylators, 15-20 per cent develop a lupus-like syndrome, which requires discontinuation of the drug to avoid potentially serious complications such as cardiac tamponade or pleural effusions.

Class Ic agents Class Ic agents are increasingly used for the management of AF. Flecainide and propafenone are effective for cardioversion, maintenance of sinus rhythm post-cardioversion and for suppressing paroxysmal AF. These agents are also the drugs of choice in patients with Wolff-Parkinson-White syndrome. The mild beta-blocking properties of propafenone may also help for rate control.¹²
A systematic review of flecainide reported that the short-term efficacy in terminating AF was 65 per cent, while the long-term efficacy was 49 per cent.¹³ Furthermore, the use of flecainide in paroxysmal AF significantly decreased the number of attacks, increased the duration between attacks and improved quality of life. Similar efficacy has been reported for propafenone.¹⁴
Oral administration seems to be as efficient as the intravenous route and this has led to the "pill in the pocket" approach to treating paroxysmal AF, where the patient does not take regular drug treatment, but takes one or more oral doses of flecainide or propafenone at the start of a paroxysm of AF, with termination of the arrhythmia in most cases within eight to 12 hours.^15,16 However, this approach should only be used in patients in whom the drug has been shown to work, and where the patient is sensible and compliant with therapy.
Like the class Ia agents, the major adverse effects associated with class Ic agents also relate to proarrhythmia.¹⁷ Some caution must be employed in the use of these drugs in patients with underlying ischaemic or structural heart diseases. For example, in the Cardiac Arrhythmia Suppression Trial (CAST), flecainide and encainide were used for treating ventricular arrhythmias post-myocardial infarction, with a significant increase in all cause mortality, which was probably due to drug-induced proarrhythmias.¹⁸ However, another overview of flecainide for the treatment of supraventricular tachycardias, where 48 per cent of subjects had structural heart disease, concluded that adverse effects with flecainide were probably low.¹⁹

Class II agents

Beta-blockers are useful agents as monotherapy or in combination with digoxin for heart rate control in permanent AF. These agents also have a role to play in maintaining sinus rhythm post-cardioversion and in reducing the paroxysms in paroxysmal AF.²⁰ Beta-blockers are probably the drugs of choice in patients with AF and concomitant ischaemic heart disease or hypertension. Although randomised trial data are lacking, the advantages of beta-blockers such as carvedilol, metoprolol and bisoprolol²¹ in improving prognosis in patients with mild to moderate heart failure may perhaps extend to heart rate control and reducing paroxysmal AF in this group of patients. A non-specific beta-blocker such as propranolol may also be useful in AF related to thyrotoxicosis.²²
In cases of concern with the administration of long-acting oral beta-blockers, the use of esmolol, a short- and rapidly-acting intravenous beta-blocker, either alone or with digoxin, is effective for rate control in acute AF; it can be titrated according to response, and may even cardiovert some patients.²³ Thus an infusion of esmolol would rapidly control the ventricular response in fast AF and on cessation of the infusion the effects would wear off rapidly. Esmolol would therefore be useful in the post-operative setting and post-myocardial infarction, especially with some uncertainty over the use of prolonged beta-blockade in the acute stages of myocardial infarction.
The side effect profile of beta-blockers is well known. Cardiac side effects are mainly due to the negative chronotropic and inotropic effects, which could worsen heart failure, hypotension and heart block. Non- selective beta-blockers could produce unwanted non-cardiac side effects, which include bronchospasm and intermittent claudication, as well as reducing the symptoms of hypoglycaemia in diabetics. Other side effects can include lethargy, depression, impotence and sleep disturbance. Sudden cessation of beta-blocker therapy could result in a withdrawal syndrome with severe hypertension and complications similar to phaeochromocytoma crisis.

Class III agents

The most widely used drugs for AF in this class include sotalol and amiodarone. Both agents can be used for heart rate control and maintenance of sinus rhythm post-cardioversion. Amiodarone is also effective for cardioversion and is the drug of choice in patients with resistant AF and in paroxysmal AF if poor cardiac function is present.
Sotalol combines class III activity with non-selective beta-blocking (class II) activity and is effective in maintaining sinus rhythm and decreasing the paroxysms of AF.^24,25 It has shown equivalent efficacy to propafenone and quinidine in preventing AF recurrences, and is better tolerated than quinidine.²⁴ Sotalol is also perceived to be better tolerated than other beta-blockers, probably due to enhanced inotropy associated with class III activity. However, at the low doses (under 80mg daily) commonly used in the UK, class II effects predominate over the class III activity. Thus, a recent randomised, crossover study comparing sotalol and atenolol in the treatment of symptomatic paroxysmal AF found no significant difference between the two agents in preventing recurrences of AF.²⁰ Sotalol has been used intravenously (not available in the UK) to cardiovert recent onset AF in patients with good left ventricular function,²⁶ although oral sotalol is relatively ineffective.²⁷ Sotalol is also useful in preventing AF following coronary artery bypass graft.²⁸ The drug has the side effect profile of beta-blockers and, importantly, can predispose to proarrhythmia. Indeed, sotalol causes life threatening torsade de pointes and ventricular tachycardia in 2 per cent of all patients treated.²⁹
Amiodarone is one of the most widely used antiarrhythmic drugs, especially in patients with underlying ischaemic and/or structural heart disease.³⁰ Administered both intravenously and orally, the drug appears to be safe and effective in the termination of persistent AF.^31-33 In contrast to oral administration, which may take weeks to achieve therapeutic concentrations in view of the long half-life, intravenous administration of amiodarone has a fast onset of action. It is preferably given via a central venous catheter as it may lead to inflammation of the peripheral veins.
The greatest advantage of amiodarone over other antiarrhythmic agents is the demonstrated safety in patients with structural heart disease and congestive cardiac failure. Nevertheless, amiodarone probably has the worst extra-cardiac side effect profile among all antiarrhythmic drugs, although most of the side effects are reversible on drug discontinuation.³⁰ For example, long- term administration of amiodarone can result in corneal microdeposits, slate grey or bluish discoloration of the skin³⁴ and photosensitivity. Amiodarone also inhibits the peripheral conversion of T4 to T3, resulting in disturbances in thyroid function in approximately 4 per cent of patients, which could manifest in the form of hypothyroidism or hyperthyroidism.³⁵ Amiodarone-induced thyroid disease can usually be managed with drugs and rarely results in cessation of amiodarone therapy. Rarely, there is liver damage (which may lead to cirrhosis) as well as interstitial pneumonitis and lung fibrosis.³⁰ Advanced age, maintenance doses higher than 300mg/day and pre-existing restrictive lung disease seem to predispose to lung toxicity with amiodarone. Baseline screening tests should include thyroid and liver function tests. Slit lamp eye examination may be necessary at times and a chest x-ray is advisable during follow up.

Class IV agents

The non-dihydropyridine calcium channel blockers, verapamil and diltiazem, reduce atrioventricular impulse conduction. They are useful for ventricular rate control in AF when administered orally and intravenously, either as monotherapy or in combination with digoxin. These drugs are not useful in cardioversion of AF and are ineffective in paroxysms of AF. The predominant adverse effects of these agents are related to negative inotropic and chronotropic effects. Toxicity could result in bradycardia, asystole and congestive cardiac failure.³⁶

Dr Lip is consultant cardiologist and reader in medicine and Dr Kamath is research fellow in the Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham

References