Cardiac Arrhythmias

1. Introduction
2. A Brief Electrophysiology Recap
   • The Fast Cardiac Action Potential
   • The Slow (Pacemaker) Action Potential
3. The Vaughan-Williams Classification
   • Class I: Sodium Channel Blockers
   • Class II: Beta-Blockers
   • Class III: Potassium Channel Blockers
   • Class IV: Calcium Channel Blockers
4. Drugs Outside the Vaughan-Williams Classification
   • Adenosine
   • Digoxin
   • Atropine
   • Ivabradine
   • Magnesium
5. Pharmacological Management of Common Arrhythmias
   • Atrial Fibrillation
   • Supraventricular Tachycardia
   • Ventricular Tachycardia and Ventricular Fibrillation
   • Torsades de Pointes
   • Symptomatic Bradycardia
6. Summary
7. Drug Summary Table
8. Quiz

• An arrhythmia is a disturbance of cardiac rate, rhythm or conduction. Antiarrhythmic drugs are best understood through the Vaughan-Williams classification of action on the cardiac action potential.
• The four classes are I (sodium channel blockers), II (beta-blockers, which block the effects of adrenaline and noradrenaline on the heart), III (potassium channel blockers, mainly amiodarone) and IV (non-dihydropyridine calcium channel blockers: verapamil and diltiazem, which slow the heart, unlike the dihydropyridines such as amlodipine, which mainly relax blood vessels). A useful memory aid is "Some Block Potassium Channels": Sodium, Beta, Potassium, Calcium.
• Adenosine, digoxin, atropine, ivabradine and magnesium sit outside the Vaughan-Williams classes but are part of routine UK practice.
• The two clinical decisions in any arrhythmia are rate control (slowing the heart rate while the abnormal rhythm continues) versus rhythm control (restoring and keeping the normal heart rhythm, called sinus rhythm), and whether the patient needs anticoagulation (treatment to prevent blood clots). Anticoagulation is covered in detail in Antiplatelets, Anticoagulants and Thrombolysis.

Introduction

An arrhythmia is any disturbance of the rate, rhythm or conduction of the electrical impulse through the heart. Some are entirely benign, such as occasional atrial ectopics (extra beats arising early from the upper chambers of the heart) in healthy adults. Others are immediately life-threatening, such as ventricular fibrillation (a chaotic quivering of the lower chambers that pumps no blood). Drugs are central to the management of many arrhythmias, although some need an electric shock, a catheter procedure or a pacemaker. The principles are easier to learn than the long list of drugs first suggests.

This article assumes the cardiac electrophysiology covered in Cardiac Conduction and Contraction, the ECG basics in Electrocardiograms, and the mechanisms of arrhythmogenesis (how arrhythmias arise) in Electrocardiogram Pathology.

A Brief Electrophysiology Recap

Two distinct cardiac action potentials need to be remembered, because the antiarrhythmic drugs target different phases of each.

The Fast Cardiac Action Potential

This is the action potential of working atrial and ventricular myocytes (muscle cells). It has five phases:

• Phase 0: Depolarisation. Voltage-gated sodium channels (channels that open when the voltage across the cell membrane changes) open, sodium rushes in, and the membrane potential rapidly swings positive.
• Phase 1: Initial repolarisation. Sodium channels close (inactivate). A brief outward flow of potassium (the transient outward potassium current) then partly repolarises the cell, meaning that the membrane potential starts to return towards its negative resting value.
• Phase 2: Plateau. Calcium flowing in through L-type calcium channels (the long-lasting type of voltage-gated calcium channel) balances potassium flowing out. The plateau is the cardiac action potential's distinguishing feature. It is responsible for the long refractory period (the time during which the cell cannot be excited again). This prevents tetany (a sustained, fused contraction that would stop the heart pumping).
• Phase 3: Repolarisation. Calcium channels close; potassium channels are now dominant; the cell repolarises.
• Phase 4: Resting potential. The Na⁺/K⁺ ATPase (the sodium-potassium pump, an enzyme that moves sodium out of the cell and potassium in) restores the resting ionic gradient.

The Slow (Pacemaker) Action Potential

This is the action potential of pacemaker tissue (the cells that set the heart rate) at the sinoatrial (SA) and atrioventricular (AV) nodes. It differs from the fast action potential in two ways:

• There is no stable resting potential: phase 4 is a slow, spontaneous depolarisation driven principally by the "funny" current (I_f), a slow inward flow of positive ions through special channels. This current is responsible for automaticity, the ability of the cell to generate its own impulses without outside stimulation.
• Phase 0 depolarisation is mediated by L-type calcium channels, not sodium channels.

This is why different drugs act at different sites. Calcium channel blockers slow the heart at the SA and AV nodes because phase 0 there depends on calcium. Beta-blockers reduce sympathetic drive and slow phase 4 at the SA and AV nodes. Sodium channel blockers act mainly on working myocardium (the atrial and ventricular muscle that contracts to pump blood), where phase 0 depends on sodium.

Diagram: The fast cardiac action potential (working myocardium, sodium-driven phase 0) and the slow pacemaker action potential (SA/AV node, calcium-driven phase 0 with phase 4 funny-current automaticity), with the sites of action of the Vaughan-Williams antiarrhythmic classes labelled. In the diagram, AP means action potential and non-DHP CCBs means non-dihydropyridine calcium channel blockers (verapamil and diltiazem).

The Vaughan-Williams Classification

The classical classification by Miles Vaughan-Williams divides antiarrhythmic drugs into four classes by their action on the cardiac action potential. A useful memory aid is "Some Block Potassium Channels": in order, Sodium, Beta-blocker, Potassium, Calcium.

Class I: Sodium Channel Blockers

Class I drugs block voltage-gated sodium channels in working myocardium, slowing phase 0 depolarisation. They are subdivided by their effect on action potential duration and the kinetics of channel binding:

• Class IA (e.g. quinidine, procainamide, disopyramide): intermediate dissociation (they unbind from the sodium channel at a moderate speed); lengthen action potential duration. Largely historical in UK practice, with two exceptions. Disopyramide is still listed in the BNF (British National Formulary) for ventricular and supraventricular arrhythmias. In the Resuscitation Council UK (RCUK) algorithm for fast abnormal rhythms (tachyarrhythmias), procainamide is the first drug named for stable ventricular tachycardia (VT, a fast abnormal rhythm arising in the ventricles), but only when a shock under sedation or anaesthesia would carry too much risk. In the UK it is available from specialist importing companies (BNF).
• Class IB (e.g. lidocaine): rapidly dissociating; preferentially block sodium channels in fast-firing or ischaemic tissue. Lidocaine is given intravenously and has been used for ventricular tachycardia, particularly in the context of ischaemia, but the BNF says it is no longer the anti-arrhythmic drug of first choice. Side effects are predominantly central nervous system: dizziness, drowsiness and, in toxicity, seizures.
• Class IC (e.g. flecainide): slowly dissociating; markedly slow phase 0 in normal tissue, slow conduction throughout the heart. Flecainide is used orally as a "pill in the pocket" for paroxysmal atrial fibrillation in patients without structural heart disease, and is occasionally given intravenously for cardioversion. Strictly contraindicated after myocardial infarction (the CAST trial showed increased mortality) and in any patient with structural heart disease.

An important pitfall: flecainide can slow atrial flutter (a fast, regular, organised rhythm of the atria) so that every atrial beat is conducted through the AV node to the ventricles (1:1 conduction), producing a dangerously fast ventricular rate. Flecainide should therefore be prescribed together with a drug that slows the AV node, such as a beta-blocker, diltiazem or verapamil. Verapamil needs caution with flecainide, because both can slow the heart (BNF).

Class II: Beta-Blockers

Beta-blockers reduce sympathetic drive, slowing phase 4 depolarisation in pacemaker tissue and prolonging conduction through the AV node. They lengthen the PR interval (the time on the ECG from the start of atrial activity, the P wave, to the start of ventricular activity, the QRS complex; it mostly reflects delay in the AV node) and reduce heart rate. In the BNF, atenolol, metoprolol and propranolol have arrhythmia indications. Bisoprolol is licensed for hypertension, angina and heart failure, not for arrhythmias, but it is an off-label option (used for a purpose outside its licence) for rate control in atrial fibrillation (NICE CKS, Clinical Knowledge Summaries).

Class II drugs are the main drugs for many arrhythmias. They are effective and generally safe. They are used in atrial fibrillation, supraventricular tachycardia (SVT, a fast rhythm that starts above the ventricles), ventricular tachycardia, and arrhythmias caused by ischaemia (a reduced blood supply to the heart muscle) or thyrotoxicosis (an overactive thyroid gland).

Side effects are covered in Hypertension and Heart Failure. The main ones are bronchospasm (narrowing of the airways, which causes wheeze), bradycardia (a slow heart rate), fatigue, cold extremities, masking of hypoglycaemia (the warning symptoms of low blood sugar are hidden) and erectile dysfunction. Beta-blockers should usually be avoided in anyone with a history of asthma. If there is no suitable alternative, a specialist may start a cardioselective beta-blocker (one that acts mainly on the heart) at a low dose, with close monitoring (BNF).

Class III: Potassium Channel Blockers

Class III drugs block potassium channels involved in repolarisation, prolonging the action potential and the refractory period. The two main UK drugs are amiodarone and sotalol. A third drug, dronedarone, is a second-line option in NICE TA197 for keeping sinus rhythm after cardioversion in paroxysmal or persistent AF (persistent AF lasts longer than 7 days). It is not used in people with left ventricular systolic dysfunction or a history of, or current, heart failure.

Amiodarone is among the most effective antiarrhythmic drugs, with activity across all four Vaughan-Williams classes. It is used in atrial fibrillation, atrial flutter, ventricular tachycardia and ventricular fibrillation. It is also part of the RCUK Advanced Life Support algorithm (the cardiac arrest protocol) for shockable rhythms (ventricular fibrillation and pulseless VT, which can be treated with a defibrillator shock). It can be given orally or intravenously. The trade-off is its remarkable side-effect profile, which is worth committing to memory:

• Pulmonary fibrosis: potentially fatal; baseline and routine pulmonary monitoring needed.
• Hepatic injury (liver damage): liver function tests (LFTs, blood tests that reflect liver damage) are needed before treatment and then every 6 months.
• Thyroid disease: both hyperthyroidism (an overactive thyroid) and hypothyroidism (an underactive thyroid). Amiodarone is iodine-rich and blocks the conversion of thyroxine (T₄) to tri-iodothyronine (T₃). Thyroid function tests are needed before treatment, every 6 months and for several months after stopping.
• Photosensitivity (the skin burns easily in sunlight) and slate-grey skin discolouration.
• Corneal microdeposits (tiny deposits on the front of the eye, usually reversible when treatment stops), occasionally optic neuropathy (damage to the optic nerve). Amiodarone must be stopped if optic neuritis (inflammation of the optic nerve) or optic neuropathy occurs, to prevent blindness.
• Peripheral neuropathy (damage to the nerves of the limbs, causing numbness, tingling or weakness).
• QT prolongation (a long QT interval on the ECG, meaning that the ventricles take longer than normal to reset): risk of torsades de pointes (a dangerous twisting ventricular rhythm). This risk is lower than with other class III drugs, probably because its complex electrical effects make the heart muscle more electrically uniform.
• Drug interactions: potent inhibitor of multiple cytochrome P450 (CYP) enzymes, the liver enzymes that break down many drugs. It increases the anticoagulant effect of warfarin (the INR, the clotting test, needs monitoring), raises digoxin levels (the digoxin dose needs to be reduced) and raises levels of simvastatin and atorvastatin (the statin dose may need adjusting).

Amiodarone has an enormous volume of distribution (it spreads widely out of the blood into the tissues) and a half-life (the time for the blood level to fall by half) measured in weeks. Its effects (and side effects) therefore persist long after stopping.

Sotalol combines class III action with non-selective beta-blockade (it blocks beta-1 receptors, mainly in the heart, and beta-2 receptors, mainly in the lungs and blood vessels). It is used for paroxysmal AF and some ventricular arrhythmias. The risk of torsades de pointes from QT prolongation is higher than with amiodarone.

Class IV: Calcium Channel Blockers

The non-dihydropyridine calcium channel blockers verapamil and diltiazem block L-type calcium channels in the AV node, slowing conduction and prolonging the refractory period. Their main uses in arrhythmia are rate control (slowing the heart rate) in atrial fibrillation and atrial flutter, and termination of AV-nodal re-entrant supraventricular tachycardia (a fast rhythm in which the impulse circles round a loop of tissue that includes the AV node).

The same drug class is covered for hypertension in Hypertension and Heart Failure. Two prescribing rules:

• Verapamil and diltiazem should be combined with a beta-blocker only with great care: the additive AV nodal blockade can cause complete heart block (the impulses no longer pass from the atria to the ventricles). The BNF advises caution or avoidance for verapamil with bisoprolol, and avoidance or monitoring for diltiazem with bisoprolol. Intravenous verapamil should be avoided in patients recently treated with a beta-blocker. NICE NG196 does allow any two of a beta-blocker, diltiazem and digoxin for rate control in atrial fibrillation when one drug does not control symptoms.
• Both verapamil and diltiazem are contraindicated in heart failure with reduced ejection fraction (HFrEF: the left ventricle pumps out a smaller fraction of its blood with each beat than it should) because of their negative inotropy (they weaken the force of the heart's contraction).

Drugs Outside the Vaughan-Williams Classification

Adenosine

Adenosine is given as a rapid intravenous bolus (a single dose pushed in quickly) into a large vein (typically in the crook of the elbow, the antecubital fossa). It binds adenosine A₁ receptors on the cells of the SA and AV nodes, opens potassium channels, and produces transient AV nodal block (a brief pause in conduction through the AV node).

The half-life (the time for the blood level to fall by half) is only about 8 to 10 seconds, so any AV block it causes wears off within seconds. The half-life is longer in people taking dipyridamole (a drug that stops platelets clumping together), so the BNF advises avoiding adenosine or adjusting the dose in these people. Adenosine has two main uses:

• Termination of AV-nodal re-entrant supraventricular tachycardia (SVT). The drug "breaks" the re-entrant circuit by transiently blocking the AV node.
• Diagnostic unmasking of underlying atrial activity: adenosine briefly blocks the AV node, which slows the ventricular rate so that the atrial activity on the ECG can be seen when the rhythm is unclear (e.g. distinguishing atrial flutter from SVT).

The patient should be warned about the brief but unpleasant feeling of impending doom and chest tightness during administration. Adenosine is contraindicated in asthma (it can cause bronchospasm, narrowing of the airways), chronic obstructive lung disease, decompensated heart failure (heart failure that has worsened and is not controlled), long QT syndrome and severe hypotension (very low blood pressure). It is also contraindicated in second- or third-degree AV block and in sick sinus syndrome (failure of the SA node to set the heart rate reliably), unless a pacemaker is fitted in either case. Verapamil may be preferable to adenosine in asthma (BNF).

Digoxin

Digoxin is a cardiac glycoside (a plant-derived drug that acts on the heart) derived from foxglove (Digitalis). It inhibits the Na⁺/K⁺ ATPase, which secondarily increases intracellular calcium and produces a positive inotropic effect (it strengthens the heart's contraction), and enhances vagal tone (the slowing influence of the vagus nerve on the heart), which slows AV nodal conduction.

It is now used mainly for rate control in atrial fibrillation. NICE NG196 says to consider digoxin on its own for people with non-paroxysmal AF (AF that is not coming and going) only if they do very little or no physical exercise, or if other rate-limiting drugs (drugs that slow the heart rate) are contraindicated or not wanted. In heart failure with reduced ejection fraction, NICE NG106 says to offer digoxin for worsening or severe disease despite optimised treatment, after seeking specialist advice. Digoxin does not have negative inotropy (it does not weaken the heart's contraction), which is helpful in heart failure. It is not effective for exercise-induced rate control, because vagal tone falls during exercise.

Digoxin has a narrow therapeutic index (the effective dose is close to the toxic dose), a long half-life (around 40 hours, longer in renal impairment), and a high volume of distribution (around 500 L). A loading dose (a larger first dose, to reach an effective level quickly) can be used when rapid control is needed, although the BNF says an emergency loading dose is rarely necessary. Toxicity ("digitalis toxicity") is the classic presentation worth knowing:

• Cardiac: almost any arrhythmia, classically bradycardia with ventricular ectopy (extra beats arising early from the ventricles) or AV block.
• Gastrointestinal: nausea, vomiting, anorexia.
• Visual: the famous "yellow-green" colour vision (xanthopsia, a yellow tint to everything seen). This yellow tint is often said to have influenced Vincent van Gogh's paintings. However, one review (Arnold and Loftus, 1991) found that his use of digitalis cannot be substantiated and concluded that artistic preference is the best working hypothesis for the yellow in his work.
• Neurological: confusion, fatigue.

Risk factors for toxicity include renal impairment (digoxin is renally cleared), hypokalaemia (low blood potassium: potassium and digoxin compete for the Na⁺/K⁺ ATPase: low potassium amplifies digoxin effects), and drug interactions. Amiodarone and verapamil raise digoxin levels directly via P-glycoprotein inhibition (P-glycoprotein is a transport protein that pumps drugs such as digoxin out of the body); diuretics increase the risk of toxicity indirectly by causing hypokalaemia and hypomagnesaemia (low blood magnesium), even though serum digoxin itself is unchanged. Severe toxicity is treated with digoxin-specific Fab antibody fragments (DigiFab), which bind digoxin in the blood and neutralise it.

Atropine

Atropine is a competitive antagonist (it blocks a receptor without activating it) at muscarinic acetylcholine receptors, the receptors through which the vagus nerve acts on the heart. By blocking vagal influence on the SA and AV nodes, it speeds heart rate and AV conduction. The standard dose is 500 micrograms intravenously, repeated up to a maximum of 3 mg, for symptomatic bradycardia (Resuscitation Council UK guidance). Side effects are predictable from anticholinergic action (the effects of blocking acetylcholine): dry mouth, blurred vision, urinary retention, constipation and confusion.

Ivabradine

Ivabradine selectively blocks the I_f ("funny") current at the SA node, slowing the heart rate without affecting blood pressure or contractility. It is used in:

• Chronic stable angina in sinus rhythm (the normal rhythm set by the SA node), including when beta-blockers are not tolerated. The BNF says not to start it for angina if the resting heart rate is below 70 beats per minute (bpm).
• HFrEF when all of the following apply (NICE TA267): sinus rhythm with a heart rate of 75 bpm or more; a left ventricular ejection fraction of 35% or less; and New York Heart Association (NYHA) class 2 to 4 symptoms (symptoms that limit activity). The person must be on standard therapy including a beta-blocker, or be unable to take one. A heart failure specialist starts it after 4 weeks on optimised standard therapy.

Ivabradine should be avoided in pregnancy: the BNF gives toxicity in animal studies as the reason. Vision disorders are common side effects, including visual phosphenes (luminous phenomena such as flashes of light, due to a related I_h current, a similar pacemaker-type current, in the retina).

Magnesium

Intravenous magnesium sulfate is the first-line treatment for torsades de pointes regardless of serum magnesium level. It is also given as part of asthma management, and in pregnancy for pre-eclampsia (a pregnancy complication with high blood pressure) and eclampsia (seizures occurring with pre-eclampsia).

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