L12 Clinical Pharmacology Anti-arrhythmics

Overview

This lecture covers the drug treatment of cardiac arrhythmias, with atrial fibrillation as the worked clinical example. It begins with the electrophysiology the drugs act on (nodal versus cardiomyocyte action potentials, and how these map onto the ECG), then the mechanisms by which arrhythmias arise (defective impulse generation, defective conduction, re-entry). The pharmacology is organised by the Vaughan Williams classification, classes I to IV plus the agents that do not fit it (digoxin, adenosine, atropine), and the four drugs to know in depth are metoprolol, amiodarone, diltiazem and digoxin. The final part applies these to AF: rate control algorithms by ejection fraction, rhythm control and ablation, and stroke prevention using CHA2DS2-VASc.

Learning objectives and framing

• Outline the properties of the different classes of antiarrhythmic drugs (Vaughan Williams classes I to IV and miscellaneous agents) and their pharmacological profiles.
• Explain the role of pharmacotherapy in managing arrhythmias, focused on AF, with particular attention to rate control.
• Focus drugs: metoprolol, amiodarone, diltiazem, digoxin.
• An effective anticoagulant strategy may also be vital as an immediate prophylactic measure prior to cardioversion.
• Adverse effects of overdoses of these drugs often include arrhythmia.
• Prior learning assumed: ionic basis of cardiac action potentials, electrophysiological differences between nodal cells and cardiomyocytes, and the relationship between cellular electrical activity and the ECG.
• Further reading given: Goodman and Gilman’s Manual of Pharmacology and Therapeutics chapter 29; AccessMedicine ECG Library; CVS physiology lecture notes on Electrical Properties of Heart and ECG; Integrated Case 8; clinical case “Palpitations”.

Cardiac electrophysiology underpinning the drugs

Pacemaker and conduction cells

• Action potentials are rhythmically generated within cells of the excitation conduction system.
• SA node is the primary pacemaker, discharging at 70 to 80 bpm.
• AV node and His bundles are secondary, discharging at 40 to 60 bpm, but are overridden by the SA node.
• Nodal cells have only phases 0, 3 and 4 (no phase 1 or 2).
• Normal conduction sequence: SA node → atria → AV node → bundles of His and Purkinje fibres → ventricles. AF and SVT arise at the atrial level of this sequence; VT and VF arise at the ventricular level.
• The orderly sequence can be disrupted by heart disease (IHD), hormones, drugs or anatomical anomaly, producing arrhythmias and reduced cardiac efficiency.

Nodal (pacemaker) action potential

Steps in order:

1. Phase 4: “funny” sodium channels ($I_f$) open, raising $P_{N{a}^{+}}$, while K+ channels close. This is the pacemaker potential, a slow drift upward from about $-60$ mV with no stable resting potential.
2. Phase 0a: transient (T-type) Ca2+ channels open, pushing the membrane to threshold (about $-40$ mV).
3. Phase 0b: long-lasting (L-type) Ca2+ channels open, generating the action potential upstroke (slow and rounded, peaking around 0 to $+5$ mV).
4. Phase 3: K+ channels open (↑$P_{K^{+}}$, K+ efflux) and L-type Ca2+ channels close, hyperpolarising the cell back to about $-60$ to $-65$ mV.

The cycle shown runs at roughly 800 ms per beat. Currents mapped onto the SA node trace: $i_f$ under phase 4, $i_{Ca,T}$ and $i_{Ca,L}$ around threshold and upstroke, $i_K$ over repolarisation.

Ventricular myocyte action potential

• Phase 0: rapid upstroke from a stable resting potential of about $-90$ mV to about $+15$ mV, caused by opening of Na+ channels ($i_{Na}$).
• Phase 1: early rapid repolarisation, seen as a notch ($i_{Kto}$).
• Phase 2: plateau, marked by slow inward Ca2+ ($i_{Ca(L)}$) and transient outward K+.
• Phase 3: late repolarisation, secondary to outward K+ current repolarising the membrane plus gradual inactivation of Ca2+ channels.
• Phase 4: return to the stable resting membrane potential; repolarisation mostly due to outward passage of K+.

The ECG and what each part means

Recorded using surface electrodes.

• P wave: depolarisation of the atria.
• QRS complex: depolarisation of the ventricles, and the time taken for ventricular depolarisation.
• T wave: repolarisation of the ventricles.
• PR interval: time for electrical activity to propagate from the SA node through the AV node.
• ST segment: time until ventricular repolarisation; represents the plateau phase of the ventricular action potential.
• QT interval: time for ventricular depolarisation and repolarisation.

Mechanisms of arrhythmia

An arrhythmia is an abnormal rhythm. It may originate in the atria or AV node (supraventricular) or the ventricles (ventricular), can cause sudden death, and has clinical consequences ranging from asymptomatic to life threatening. Causes are numerous, for example myocardial ischaemia or infarction, hypokalaemia, drug toxicity and thyroid disease.

The two major categories are:

• Defects in impulse generation (SA node), which may produce tachy- or brady-arrhythmias.
• Defects in impulse conduction (propagation), which may produce dropped beats or heart block.

1. Defects in impulse generation

A. Enhanced or altered automaticity

• Automatic tissue beside the SA node begins to pace the heart because of increased permeability to Na+ (AV node, His bundles, Purkinje fibres).
• Latent pacemaker cells in atria and ventricles produce ectopic beats.
• Examples: sinus and atrial tachycardias, premature ventricular beats.

B. Triggered activity, where a normal action potential triggers extra abnormal depolarisations:

• Early after-depolarisations: associated with an abnormally prolonged action potential; ion channel mechanisms may be unknown, with K+ rectifier currents involved in torsades de pointes. On the trace, repolarisation is interrupted by a depolarising hump as Na+ channels recover from inactivation, which can progress to repetitive after-depolarisations and then a triggered arrhythmia. Torsades de pointes appears on the ECG as normal complexes breaking into a rapid continuous run whose amplitude waxes and wanes.
• Delayed after-depolarisations: typically the result of cellular Ca2+ overload (see digitalis). The action potential repolarises fully, then a small bump appears because high intracellular Ca2+ triggers an inward Na+ current; if a delayed after-depolarisation reaches threshold voltage it generates an action potential with a slow upstroke velocity.

2. Defects in impulse conduction

Heart block: loss of SA control of cardiac contraction because of impaired conduction from SA node to ventricles through ischaemic or refractory tissue. Manifests as bradycardia (first degree), decreased heart rate with missing beats (second degree), or complete block (third degree), which places the emphasis on ventricular nodal cells.

Re-entry through ischaemic or infarcted tissue

• Major cause of ventricular tachycardia and fibrillation, and a common cause of tachyarrhythmias generally.
• Requires unidirectional block of an impulse and re-excited tissue beyond the block.
• Circuit as drawn: the impulse travels down the Purkinje fibres to a branch point; at that site the effective refractory period is prolonged so antegrade conduction down one limb is blocked; the impulse passes down the unblocked limb into ventricle, then conducts retrogradely back up the blocked limb through a region of slow conduction; by the time it returns to the branch point the tissue has recovered, so the wave re-enters recently excited tissue and a self-sustaining circuit is established.
• Propagation depends on conduction velocity and refractory period, and drugs including antiarrhythmics can adversely alter both.

Accessory tract pathways: a short circuit activated during fast nodal firing, manifested as tachyarrhythmias. AVRT is illustrated as a mechanism of SVT, with the re-entry loop running between atrium and ventricle via the AV node and an accessory pathway, with block on one limb of the circuit.

Structural substrate: a myocardial histology section shows patchy blue-staining fibrous tissue infiltrating and replacing red-stained cardiomyocytes, that is fibrosis interrupting the myocardium, as the arrhythmogenic substrate (illustrated for stress cardiomyopathy).

Warning

The substrate slide carried no text beyond its title, so the interpretation of the stain rests only on what is visible in the image.

Atrial fibrillation

Burden, causes and classification

• AF remains one of the major causes of stroke, heart failure, sudden death and cardiovascular morbidity worldwide, with numbers expected to increase. Despite pharmacotherapeutic advances, morbidity remains substantially high.
• Causes: IHD, hypertension, heart failure, hyperthyroidism, diabetes, old age, excess alcohol intake, pneumonia, pericarditis.
• Classification:
  • Paroxysmal: self-terminating episodes.
  • Persistent: sinus responsive to treatment.
  • Successful AF ablation: free from AF.
  • Permanent: long standing, sinus cannot be maintained; requires early rhythm control.
• Prevalence rises steeply with age, from well under 1% in those aged under 55 to roughly 9 to 11% in those 85 and over. Men have higher prevalence than women in every age band except the oldest, where the two converge.
• Risk: AF causes hypokinetic atria, leading to blood stasis and thrombus formation, increasing the risk of ischaemic stroke.

Mechanisms causing AF

Predisposing conditions feeding in: diabetes, heart failure, obesity, coronary artery disease, hypertension, ageing, genetic predisposition. These act at two levels:

• Atrial cavity: reduced fibrinolysis, thrombocyte activation and raised fibrinogen produce a hypercoagulable state leading to stroke. Endothelial and luminal factors involved are shear, PAI-1 (plasminogen activator inhibitor 1), VCAM-1 (vascular cell adhesion molecule 1), FXII (factor XII), IL-6 (interleukin 6) and TF (tissue factor).
• Atrial myocardium: hypocontractility, atrial stretch, AngII (angiotensin II), inflammation, vascular remodelling, ischaemia, fatty infiltration, fibrosis and atrial tachycardia.
• At myocyte level, Ca2+-handling instability → ectopy and conduction heterogeneities plus ion channel remodelling → re-entry. Ectopy and re-entry converge on AF, and a feedback arrow runs from AF back to the atrial myocardium, so AF begets AF.

The two aims of pharmacological treatment

1. Treatment of rate or rhythm (the subject of this lecture).
2. Prevention of embolic complications (ischaemic stroke), covered in the anticoagulant lecture and ELM3 stroke management.

AF treatment pathways

Three goals, each with pharmacological and non-pharmacological options:

Goal	Pharmacological	Non-pharmacological
Rate control	β-blockers, Ca2+ blockers, digoxin, amiodarone	Ablate and pace
SR (sinus rhythm) maintenance	Class IA, Class IB, Class III, β-blockers, amiodarone	Catheter ablation, pacing, surgery, implantable devices
Stroke prevention (high risk, CHA2DS2-VASc ≥2)	DOACs (dabigatran, rivaroxaban); VKAs (warfarin)	Surgical isolation of the left atrium

Caveats attached to this pathway chart:

• Avoid CCBs in AF associated with heart failure with systolic dysfunction.
• Amiodarone is not first line for rate control without heart failure.
• Catheter ablation is now a major AF treatment strategy.
• Compelling data that ACE inhibitors and statins may help prevent recurrence of AF.
• Do not use antiplatelets for stroke prevention in AF unless an in-stent thrombotic risk exists.
• DOACs are preferred over warfarin except in patients with mitral stenosis or mechanical heart valves.
• In symptomatic AF where antiarrhythmic drugs have been ineffective, contraindicated, not tolerated or not preferred, catheter ablation is useful to improve symptoms.

Both rate and rhythm control measures improve AF-related symptoms and may preserve cardiac function, but have not demonstrated a reduction in long-term morbidity or mortality. Oral anticoagulation (VKAs and direct thrombin inhibitors) markedly reduces stroke and mortality in AF patients. Addition of ACE inhibitors and statins has shown added benefit.

Acute rate control

• In the absence of hypotension or heart failure symptoms, either an IV beta-blocker or a cardioselective non-dihydropyridine CCB (diltiazem or verapamil) is a reasonable initial acute approach.
• Where it is uncertain what the patient will tolerate safely, an ultra short-acting IV beta-blocker (esmolol) can be trialled.
• If monotherapy with a beta-blocker or CCB gives an inadequate response, discontinue the initial agent and try the other class; digoxin can be added as a second agent.
• Combination of a beta-blocker and a CCB, with or without digoxin, must be done with caution and only in patients without heart failure symptoms or hypotension.
• IV amiodarone may be effective short term for ventricular rate control in critically ill or post-operative patients.
• In patients with significant hypotension or symptomatic heart failure, the first approach can be IV digoxin, IV amiodarone, or emergent/urgent cardioversion.

Acute algorithm branching on LVEF:

• LVEF <40% or signs of congestive heart failure: smallest dose of beta-blocker to achieve rate control (amiodarone is an option in haemodynamic instability or severely reduced LVEF), then add digoxin.
• LVEF ≥40%: beta-blocker or diltiazem or verapamil (check previous drug history to avoid concomitant administration), then add digoxin.
• Initial resting heart rate target at every step is <110 bpm.
• Both branches converge on: avoid bradycardia; perform echocardiogram to determine further management and choice of maintenance therapy; consider need for anticoagulation.

Long-term rate control

• Beta-blockers and CCBs were equally effective in the AFFIRM trial. Consider switching from one drug class to the other where response is inadequate. Patients initially treated with a beta-blocker were less likely than those on CCBs to have their regimen changed. Digoxin is often added to a beta-blocker or CCB to avoid high doses of either agent.
• Algorithm first step: perform echocardiogram (IC); choose initial rate control therapy (IB) and combination therapy if required (IIaC); target initial resting heart rate <110 bpm (IIaB), avoiding bradycardia.
• LVEF <40%: start beta-blocker or digoxin → consider early low-dose combination therapy → add digoxin (if started on a beta-blocker) or add a beta-blocker (if started on digoxin).
• LVEF ≥40%: start diltiazem/verapamil, a beta-blocker, or digoxin → add therapy to reach target heart rate or if symptoms continue → add digoxin (after diltiazem/verapamil or after a beta-blocker), or add diltiazem, verapamil or a beta-blocker (after digoxin).
• Digitoxin is a suitable alternative to digoxin where available.

Pacing and ablation versus drugs

• Used when pharmacological intervention fails or because of adverse drug effects.
• Interventions depend on the irregularity, for example ablation of extra-nodal tissue (such as around the pulmonary veins), or AV junctional ablation (leaving the AV node and His bundles intact) to produce complete heart block with ventricular support from a pacemaker.
• Advantage: pharmacological intervention can be withdrawn. Anticoagulants are still needed.

Stroke prevention in AF

AF is associated with increased stroke risk, so always assess patients for stroke risk and consider treatment.

• The CHA2DS2-VASc score should be systematically assessed in all patients with AF to identify stroke risk and decide on oral anticoagulation. Technology tools may assist.
• Oral anticoagulation is recommended in all male patients scoring 2 or more, and all female patients scoring 3 or more.
• Oral anticoagulation should be considered in males scoring 1 and females scoring 2, considering individual characteristics and patient preferences.
• When initiating anticoagulation a non-vitamin K antagonist (NOAC/DOAC) is preferred, with exceptions (see warfarin use).
• Do not use aspirin or other antiplatelets for stroke prevention in AF.

CHA2DS2-VASc scoring

Risk factor	Definition given	Points
Congestive heart failure	Signs/symptoms of heart failure or objective evidence of reduced LV ejection fraction	1
Hypertension	Resting BP >140/90 mmHg on at least two occasions, or current antihypertensive treatment	1
Age ≥75 years		2
Diabetes mellitus	Fasting glucose >7 mmol/L (>125 mg/dL) or treatment with an oral hypoglycaemic and/or insulin	1
Previous stroke, TIA or thromboembolism		2
Vascular disease	Previous MI, peripheral artery disease, or aortic plaque	1
Age 65 to 74 years		1
Sex category (female)		1

Stroke prevention algorithm (ESC AF guidelines, European Heart Journal 2016;37:2893-2962):

1. Mechanical heart valves, or moderate or severe mitral stenosis? If yes, go directly to a VKA.
2. If no, estimate stroke risk by CHA2DS2-VASc:
   • Score 0, or women with no other risk factors: no antiplatelet or anticoagulant treatment.
   • Score 1: oral anticoagulation should be considered (a weaker recommendation).
   • Score ≥2: oral anticoagulant indicated; assess for contraindications and correct reversible bleeding risk factors.
3. Options from the anticoagulation-indicated branch: DOAC (the preferred option), VKA, or other options, meaning no anticoagulation or left atrial appendage exclusion where there are clear contraindications to anticoagulation.

Definitions: DOAC = direct oral anticoagulant (apixaban, dabigatran, edoxaban, rivaroxaban). VKA = vitamin K oral anticoagulant, for example warfarin, targeting INR 2.0 to 3.0 with time in therapeutic range kept as high as possible and closely monitored.

Principles of antiarrhythmic drug therapy

• Antiarrhythmic agents suppress arrhythmias by inhibiting automaticity, triggered activity and re-entry.
• They generally show use-dependency, with greater efficacy in abnormal tissue at high heart rates. Therapeutic effects are more pronounced with tachycardia or loss of a normal resting membrane potential, for example in ischaemic cardiac tissue.
• Success rate is variable, depending on the type of arrhythmia and on the drug or drug combination used.
• Where indicated they are used to treat and prevent arrhythmias, but adverse effects are common and most can induce arrhythmias.
• There is a small difference between therapeutic and toxic doses (narrow therapeutic index).

Mortality by class

Reported side effect burden: class I can cause many problems; class II decrease heart rate and affect lifestyle; class III after 5 years cause side effects in up to 75% of patients (GI and vision related); class IV have side effects similar to class II.

Forest plot of mortality odds ratios (reference line 1.0):

• Class Ia: increased risk.
• Class Ib: point estimate slightly above 1.0, interval roughly 0.85 to 1.25.
• Class Ic: OR 1.79, the largest increase.
• Class I total: increased, P = 0.05.
• Class II beta-blockers: reduced mortality, P = 0.00001.
• Class III amiodarone: about 0.7, reduced, P = 0.05.
• Class IV calcium channel blockers: close to 1.0, not significant.

Important

Class I agents are associated with increased mortality (Ic worst), beta-blockers with a significant mortality reduction, amiodarone with a reduction, and calcium channel blockers with no significant difference.

Drugs to learn for AF, by territory

Drug	Territory
Metoprolol	Supraventricular and ventricular
Amiodarone	Supraventricular and ventricular
Diltiazem	Supraventricular
Digoxin	Supraventricular

Vaughan Williams classification

Based on the electrophysiology of normal His-Purkinje cells, classifying drugs by their ability to block specific ionic currents (Na+, K+, Ca2+) and beta-adrenergic receptor action. It is useful for describing modes of action because it is physiologically based and highlights beneficial and deleterious effects of specific drugs. Its limitation is that many commonly used antiarrhythmics do not fit, for example digoxin, adenosine and atropine.

Class	Target	Mechanism	Example and use
I (Ia to Ic)	Na+ channels	Block fast Na+ channels responsible for rapid depolarisation (phase 0); reduce slope and peak of the AP, reducing conduction velocity	Lignocaine
II	β-adrenoceptors	Block the effects of noradrenaline/adrenaline on the heart; block sympathetic activity at the SA node, reducing rate, conduction and contraction	Metoprolol, atenolol, bisoprolol; rate control in AF and stress-induced tachycardias
III	K+ efflux	Reduce K+ efflux, delaying repolarisation (phase 3), so increasing AP duration and refractory period	Amiodarone (used for most arrhythmias), sotalol (also a beta-blocker)
IV	L-type Ca2+ channels (non-dihydropyridine)	Slow Ca2+ entry through voltage-sensitive Ca2+ channels; act mainly on SA and AV nodes; impair impulse propagation in nodal and damaged tissue	Diltiazem; rate control, atrial tachycardia and flutter
Others	Various	Slow the ventricular response rate to AF and give positive inotropic support in HF	Digoxin, adenosine (A1 receptor agonist), atropine (muscarinic antagonist)

Summary diagram mapping classes onto the ventricular action potential:

• Phase 0 (Na+, depolarisation): class I / lignocaine.
• Phase 2 (Ca2+, contraction): class II beta-blockers and class IV Ca2+ channel blockers.
• Phase 3 (K+, repolarisation): class III / amiodarone.
• Phase 4: class II / metoprolol.

Warning

On the classification slide the class I drug list ended with a trailing comma after “Lignocaine,” so a second drug name appears to have been cut off.

Singh-Vaughan Williams classification (for future use)

Class	Subtype	Examples	Clinical use
0	HCN channel modulators	Ivabradine	Heart rate control for tachycardia
1	1a, intermediate dissociation kinetics	Quinidine, procainamide	SVT, AF, VT/VF; not commonly used
1	1b, fast dissociation kinetics	Lidocaine, mexiletine, phenytoin	VT, particularly after MI
1	1c, slow dissociation kinetics	Flecainide	AF and atrial flutter
1	1d, late Na+ current ($I_{NaL}$) blocker	Ranolazine	AF treatment and prevention
2	β-blockers, non-selective	Propranolol	Prevention of supraventricular tachyarrhythmia
2	β-blockers, selective	Metoprolol, esmolol	Rate control of atrial and ventricular tachyarrhythmias
2	Muscarinic (M1) blockers	Atropine, glycopyrrolate	Bradycardia, atrioventricular block
2	Muscarinic (M2) activators	Digoxin	Rate control of AF
2	A1 receptor activators	Adenosine	SVT
3	Selective $I_{Kr}$ blockers	Sotalol, ibutilide, amiodarone	Supraventricular arrhythmias including AF, AVNRT, PVC, VF, VT; rate control of AF
3	Non-selective ($I_{Kr}$ and $I_{Ks}$) blockers	Vernakalant	Termination of AF
3	Multi-ion channel blocker	None listed	None listed
4	L-type Ca2+ channel blockers	Verapamil, diltiazem	Paroxysmal SVT, rate control of AF and atrial flutter
5	Mechanosensitive channel blockers	No drugs available clinically
6	Gap junction channel blockers	No drugs available clinically
7	Upstream target modulators	ACE inhibitors and angiotensin II receptor blockers

Warning

Row alignment within the class 3 block of this table was ambiguous at slide resolution: vernakalant and “termination of AF” may belong to the non-selective row or the multi-ion channel blocker row, and the multi-ion channel row appears to have no example or use text of its own.

Class I: Na+ channel antagonists

• Divided into three subclasses, Ia, Ib and Ic. Drugs named: lignocaine, flecainide.
• Mechanism: block fast Na+ channels in a use-dependent way. Lignocaine binds Na+ channels most strongly in the open state (the fast upstroke) and the inactivated state (the plateau), which is why it is useful for extinguishing re-entrant circuits.
• Effects: decrease the rate and magnitude of depolarisation during phase 0, giving decreased conduction velocity in non-nodal tissue, so adjacent cells depolarise more slowly.
• Indications (per current resuscitation guidelines, given for interest only): lignocaine may be used for polymorphic VT (torsades de pointes); flecainide is used for chemical cardioversion.
• Unwanted effects: can induce arrhythmias by slowing conduction.

Class II: beta-blockers (metoprolol, propranolol)

• Mechanism: block the effects of adrenaline and noradrenaline at cardiac β-receptors, diminishing nodal phase 4 depolarisation and so reducing cardiac automaticity.
• Effects:
  • Abolish β-receptor induced firing at the SA node, stopping sympathetic innervation from increasing SA node automaticity.
  • Slow conduction velocity, particularly at the AV node, which lengthens the refractory period.
  • May prevent re-entrant tachycardia at the AV site.
• Main uses: rate control, for example in AF; treatment of SVTs and VTs precipitated by sympathetic stimulation such as stress or exercise; prevention of recurrent tachycardias; decreased mortality post-MI.
• Adverse effects, mainly due to exaggerated doses: bronchospasm in asthmatics; negative inotropic effects (decreased contractility); bradycardia; severe AV node block (metoprolol prolongs the functional refractory period at the AV node); increased fatigue; uncompensated heart failure; metoprolol can cross the blood-brain barrier to produce insomnia and depression.
• Avoid in:
  • AV block (first, second or third degree).
  • Sinus node dysfunction (sinus bradycardia, tachy-brady).
  • Any wide complex tachycardia (>100 bpm with QRS width >120 ms), that is VTs, bundle branch blocks, WPW.
  • But they remain useful as first line for rate control in AF.

Beta-blocker withdrawal

• Abrupt withdrawal produces a rebound effect: worsening angina, MI and ventricular arrhythmia in patients with coronary artery disease; raised BP in patients with hypertension; malaise, headache, sweating and palpitations. Abrupt perioperative withdrawal is associated with increased postoperative mortality.
• Gradual withdrawal over a minimum of 2 weeks: generally halve the dose for a week, halve that again for another week, then stop. If the dose was high, reduce over 3 weeks.
• Occasionally the beta-blocker must be stopped acutely, for example if bradycardia arises.

Class III: amiodarone (prolongs the AP)

Amiodarone can fit into more than one class.

• Mechanism, a range of membrane effects:
  • Blocks K+ channels involved in membrane repolarisation.
  • Modulates lipid membrane properties and affects Na+ fluxes (decreasing nodal cell rate of firing) and Ca2+ channels (affecting both SA and AV nodes).
  • Plateau and AP duration are prolonged.
  • Substantially prolongs the effective refractory period (ERP), decreasing the chance of re-entry block. On the overlaid AP traces, the amiodarone trace sits to the right of baseline through phases 2 and 3, that is a lengthened plateau and later repolarisation, with the ERP bracket extended alongside.
• Effects: prolongs atrial and ventricular repolarisation; contractility is unchanged or increased; may prolong the QT interval, so torsades de pointes might result.
• Uses: rate control in AF; effective against a wide range of arrhythmias including supraventricular and ventricular; in current resuscitation guidelines (for interest) refractory VT/VF after adrenaline and shock.
• Cautions and interactions: amiodarone reduces warfarin and digoxin renal clearance (at p-glycoprotein); joint use with a beta-blocker has an additive AV effect, producing heart block.
• Adverse effects, a multitude, as an iodinated drug: photosensitive skin rashes and discolouration; thyroid abnormalities (iodine content may promote thyroid abnormalities and amiodarone resembles thyroxine structurally); pulmonary fibrosis; corneal deposits; neurological and GI disturbances. It is rarely associated with a pro-arrhythmic action.
• Features complicating use: gradual oral loading required (BP may drop); long elimination half-life of 10 to 100 days so it accumulates with repeated dosing; hepatic metabolites via CYP3A4 and CYP2C8 are also pharmacologically active; it damages veins if given undiluted by IV infusion. In the cardiac arrest setting, just give it.

Class IV: Ca2+ channel antagonists

• Cardioselective (non-dihydropyridine) CCBs: diltiazem or verapamil. Avoid dihydropyridines.
• They reduce Ca2+ entry into nodal cells and cardiomyocytes by blocking the sarcolemmal voltage-gated Ca2+ channel that carries $I_{Ca}$. In the excitation-contraction coupling diagram, that Ca2+ entry normally triggers release from the sarcoplasmic reticulum via the ryanodine receptor, and the released Ca2+ acts on the myofilaments to produce contraction; Ca2+ is removed by SR re-uptake (ATP-dependent pump regulated by phospholamban), the sarcolemmal ATP-dependent Ca2+ pump, and the Na+/Ca2+ exchanger (3 Na+ in for 1 Ca2+ out).
• Act on L-type and T-type Ca2+ channels.
• In pacemaker/nodal cells: decrease the rate of discharge at the SA node; slow conduction and lengthen the refractory period at the AV node, because nodal cells require the slow inward Ca2+ current in phase 4 to discharge spontaneously.
• In ventricular cardiomyocytes: depress myocardial contraction (verapamil mainly) by inhibiting L-type Ca2+ channels. Therefore CCBs have negative inotropic and negative chronotropic actions.
• Uses: rate control in AF, only suitable for supraventricular arrhythmias. Avoid combined use with beta-blockers.
• Adverse effects (from the earlier CCB lecture): nausea, headache, fatigue, constipation; hypotension; bradycardia and heart block.

Digoxin

Digoxin, digitalis and digitonin are derived from the foxglove plant (Digitalis purpurea) and have been used since 1785. Digoxin does two things: it increases the force of contraction (cardiac glycoside action) and it slows rate (vagal effect).

MOA 1: positive inotrope

Cardiac glycosides are potent inhibitors of cellular Na+/K+-ATPase. Steps in order:

1. Glycoside inhibition of Na+/K+-ATPase.
2. Increased intracellular [Na+].
3. Decreased Na+/Ca2+ exchange, because the exchanger can move Ca2+ and Na+ in either direction depending on membrane potential and the chemical gradients, and raised intracellular Na+ reduces Ca2+ extrusion.
4. Increased intracellular [Ca2+], and increased Ca2+ binding to troponin C.
5. Increased force of contraction.

Beneficial effects of increased force of contraction: increased cardiac output, with decreased sympathetic tone, increased urine production, and decreased renin release.

Caution in heart failure: clinical trials indicate digoxin provides a definite but limited benefit in heart failure caused by systolic dysfunction (HFrEF), but not in diastolic dysfunction (HFpEF). On the Frank-Starling curves, digoxin shifts the depressed failing-heart curve upward towards, but not up to, the normal relationship, that is it raises contractile force and stroke volume for a given fibre length.

MOA 2: antiarrhythmic

• Digoxin increases vagal activity (ACh release). The mechanism of the vagal increase is not fully understood.
• Digoxin-induced ACh release onto M2 receptors reduces SA firing rate (heart rate drops) and reduces AV conduction velocity, which decreases the ventricular response rate.
• Expressed in ionic terms: prominent vagal stimulation decreases the Ca2+ current and increases the K+ current in the AV node and atrial tissue, increasing AV node refractoriness.
• Pathway conveyed by the diagram: re-entrant atrial excitation in AF → cardiac glycoside acts at the AV node → decreased ventricular rate.
• Main indications: heart failure with AF; rate control in AF. Digoxin is advocated in AF associated with impaired cardiac function.

Digoxin toxicity and monitoring

• Narrow therapeutic index. Therapeutic levels 0.5 to 0.9 ng/mL (DIG trial and RADIANCE). Toxic level 2.5 ng/mL.
• Causes arrhythmias; needs careful loading (digitalizing); has PD and PK interactions with many drugs including calcium channel blockers, NSAIDs, amiodarone and beta-blockers. Can be unpleasant: nausea, vomiting, confusion.
• Why digoxin causes arrhythmias: decreased automaticity of the AV node; decreased conduction through the AV node; increased automaticity of Purkinje fibres; shortened refractory period in ventricular muscle. Toxicity may facilitate ectopic pacemaker activity in the His bundles and completely block conduction between atria and ventricles, producing AF.

Digoxin drug interactions

Interactions affect efficacy, retention and toxicity.

• Antacids and cholestyramine reduce digoxin absorption and decrease its therapeutic effect; separate administration by at least 2 hours.
• Diltiazem, quinidine and verapamil reduce digoxin clearance through p-glycoprotein transporters and increase serum digoxin levels; concurrent use requires the digoxin dose to be reduced by 50% of usual, with regular serum level monitoring.
• Diuretics should be used cautiously: diuretic-induced hypokalaemia can precipitate digitalis toxicity, because reduced serum K+ increases digitalis binding to the Na+ pump; hypokalaemia can also contribute directly to arrhythmias.

Managing a dysrhythmia in digoxin overdose

• Withhold the digoxin, and also K+-sparing diuretics.
• Keep track of serum [K+].
• Administer antidysrhythmic drugs: lidocaine, atropine.
• Neutralise digoxin: Fab antibody fragments, cholestyramine, activated charcoal.

Self-test

1. List the phases present in a nodal cell action potential and state which phases a ventricular cardiomyocyte has that a nodal cell lacks.
2. Describe, in order, the ionic events of the nodal action potential from phase 4 through to phase 3.
3. Explain which part of the ventricular action potential the ST segment represents, and what the PR interval measures.
4. Distinguish early after-depolarisations from delayed after-depolarisations by their timing and their underlying cause.
5. Describe the three requirements or steps that allow a re-entry circuit to form in Purkinje tissue.
6. List the causes of AF given in the lecture.
7. Distinguish paroxysmal, persistent and permanent AF, and state which one requires early rhythm control.
8. Explain the mechanism by which AF increases the risk of ischaemic stroke.
9. Explain what is meant by the statement that AF begets AF, naming the two myocyte-level processes that converge on AF.
10. State the CHA2DS2-VASc score contributed by age 75 or older, previous stroke, and female sex, and give the score thresholds at which oral anticoagulation is recommended for men and for women.
11. A patient with AF has moderate mitral stenosis. Which anticoagulant class should be used, and why is the usual preference not applied here?
12. Define use-dependency and predict in which tissue conditions antiarrhythmic effects will be most pronounced.
13. Distinguish the mortality signal associated with class I agents from that associated with class II and class III agents.
14. State the ionic target and the effect on the action potential for each of Vaughan Williams classes I to IV.
15. Explain why lignocaine is particularly effective at extinguishing re-entrant circuits.
16. List four situations in which beta-blockers should be avoided in arrhythmia management.
17. Describe how a beta-blocker should be withdrawn, and predict what happens if it is stopped abruptly in a patient with coronary artery disease.
18. Explain how amiodarone reduces the chance of re-entry, and state the ECG change it can produce along with the arrhythmia that may follow.
19. List the pharmacokinetic features of amiodarone that complicate its use.
20. Explain why non-dihydropyridine CCBs slow the SA and AV nodes, referring to the current those nodal cells depend on.
21. Describe the five steps by which digoxin increases the force of contraction.
22. Explain the receptor and the two nodal effects through which digoxin controls ventricular rate in AF.
23. State the therapeutic and toxic serum digoxin concentrations, and explain why diuretic-induced hypokalaemia precipitates toxicity.
24. A patient on digoxin is started on diltiazem. Predict the interaction and state the dose adjustment required.
25. A patient presents in AF with an LVEF of 30% and signs of congestive heart failure. Describe the acute rate control approach, the target heart rate, and what is done once rate is controlled.
26. Integrative: for a patient with AF and preserved LVEF, explain how the choice between a beta-blocker, diltiazem and digoxin relates to each drug’s mechanism, and why combining a beta-blocker with a CCB requires caution.

Answers

Reveal answers

1. Nodal cells have only phases 0, 3 and 4. Cardiomyocytes additionally have phase 1 (early rapid repolarisation notch) and phase 2 (plateau), and unlike nodal cells they have a stable resting membrane potential of about $-90$ mV.
2. Phase 4: funny Na+ channels ($I_f$) open, raising Na+ permeability, while K+ channels close, giving slow drift from about $-60$ mV. Phase 0a: T-type Ca2+ channels open, pushing the membrane to threshold at about $-40$ mV. Phase 0b: L-type Ca2+ channels open, producing the upstroke. Phase 3: K+ channels open (K+ efflux) and L-type Ca2+ channels close, hyperpolarising the cell.
3. The ST segment represents the plateau phase (phase 2) of the ventricular action potential, that is the time until ventricular repolarisation. The PR interval is the time for electrical activity to propagate from the SA node through the AV node.
4. Early after-depolarisations interrupt repolarisation (during the action potential) and are associated with an abnormally prolonged AP, with Na+ channels recovering from inactivation and K+ rectifier currents implicated in torsades de pointes. Delayed after-depolarisations occur after full repolarisation and are typically the result of cellular Ca2+ overload, with high intracellular Ca2+ triggering an inward Na+ current.
5. There must be unidirectional block, with the effective refractory period prolonged at one limb so antegrade conduction is blocked; the impulse passes down the unblocked limb into ventricle and conducts retrogradely up the blocked limb; a region of slow conduction delays it long enough that the tissue at the branch point has recovered, so the wave re-enters recently excited tissue and sustains itself.
6. IHD, hypertension, heart failure, hyperthyroidism, diabetes, old age, excess alcohol intake, pneumonia and pericarditis.
7. Paroxysmal is self-terminating; persistent means sinus rhythm is responsive to treatment; permanent is long standing where sinus rhythm cannot be maintained. Permanent AF requires early rhythm control.
8. AF produces hypokinetic atria, so blood stasis occurs, thrombus forms, and the risk of ischaemic stroke rises. Slide 21 adds an atrial cavity hypercoagulable state (reduced fibrinolysis, thrombocyte activation, raised fibrinogen) leading to stroke.
9. A feedback loop runs from AF back to the atrial myocardium and atrial tachycardia components, so the arrhythmia perpetuates the substrate that maintains it. The two myocyte-level processes are Ca2+-handling instability causing ectopy, and conduction heterogeneities plus ion channel remodelling causing re-entry; both converge on AF.
10. Age 75 or older scores 2, previous stroke/TIA/thromboembolism scores 2, and female sex scores 1. Oral anticoagulation is recommended at a score of 2 or more in men and 3 or more in women, and should be considered at 1 in men and 2 in women.
11. A VKA (warfarin) should be used. The algorithm routes mechanical heart valves or moderate to severe mitral stenosis directly to a VKA, and DOACs are preferred over warfarin except in these patients.
12. Use-dependency means the drug has greater efficacy in abnormal tissue at high heart rates. Effects are therefore most pronounced with tachycardia or where the normal resting membrane potential has been lost, such as in ischaemic cardiac tissue.
13. Class I agents are associated with increased mortality, greatest for class Ic (OR 1.79), with the class I total increased at P = 0.05. Class II beta-blockers reduce mortality (P = 0.00001) and class III amiodarone reduces it (about OR 0.7, P = 0.05). Class IV shows no significant difference.
14. Class I blocks fast Na+ channels, reducing the slope and peak of phase 0 and so conduction velocity. Class II blocks β-adrenoceptors, diminishing nodal phase 4 depolarisation and reducing rate, conduction and contraction. Class III reduces K+ efflux, delaying phase 3 repolarisation and increasing AP duration and refractory period. Class IV blocks L-type (and T-type) Ca2+ channels, acting mainly at the SA and AV nodes to reduce rate and conduction.
15. Lignocaine binds Na+ channels most strongly in the open state (the fast upstroke) and the inactivated state (the plateau), which is the use-dependent behaviour that lets it act preferentially on the rapidly firing or abnormal tissue sustaining a re-entrant circuit.
16. AV block of any degree; sinus node dysfunction (sinus bradycardia, tachy-brady); any wide complex tachycardia, meaning >100 bpm with QRS width >120 ms, including VT, bundle branch block and WPW. They also carry cautions in asthma (bronchospasm) and uncompensated heart failure.
17. Withdraw gradually over a minimum of 2 weeks: halve the dose for a week, halve again for a second week, then stop; reduce over 3 weeks if the dose was high. Abrupt withdrawal in coronary artery disease causes rebound worsening angina, MI and ventricular arrhythmia; abrupt perioperative withdrawal is associated with increased postoperative mortality.
18. Amiodarone substantially prolongs the effective refractory period (alongside prolonging the plateau and AP duration), which decreases the chance of re-entry. It may prolong the QT interval, and torsades de pointes might result.
19. Gradual oral loading is required and BP may drop; the elimination half-life is 10 to 100 days so it accumulates with repeated dosing; hepatic metabolites via CYP3A4 and CYP2C8 are pharmacologically active; undiluted IV infusion damages veins.
20. Nodal cells depend on a slow inward Ca2+ current in phase 4 to discharge spontaneously, so blocking L-type and T-type Ca2+ channels decreases the rate of discharge at the SA node and slows conduction while lengthening the refractory period at the AV node.
21. Digoxin inhibits Na+/K+-ATPase; intracellular Na+ rises; Na+/Ca2+ exchange decreases so less Ca2+ is extruded; intracellular Ca2+ rises; increased Ca2+ binding to troponin C increases contractile force.
22. Digoxin increases vagal ACh release acting on M2 receptors, which reduces SA node firing rate (heart rate drops) and reduces AV conduction velocity, decreasing the ventricular response rate. In ionic terms it decreases the Ca2+ current and increases the K+ current in the AV node and atrial tissue, increasing AV node refractoriness.
23. Therapeutic 0.5 to 0.9 ng/mL, toxic 2.5 ng/mL. Diuretic-induced hypokalaemia precipitates toxicity because the reduced serum K+ concentration increases digitalis binding to the Na+ pump; hypokalaemia can also contribute directly to arrhythmias.
24. Diltiazem reduces digoxin clearance through p-glycoprotein transporters, raising serum digoxin levels. The digoxin dose should be reduced by 50% of usual and serum digoxin levels monitored regularly.
25. With LVEF <40% or signs of congestive heart failure, give the smallest dose of beta-blocker that achieves rate control, with amiodarone an option if there is haemodynamic instability or severely reduced LVEF; add digoxin if needed. The initial resting heart rate target is <110 bpm. Then avoid bradycardia, perform an echocardiogram to determine further management and choice of maintenance therapy, and consider the need for anticoagulation. Where hypotension or symptomatic heart failure is significant, IV digoxin, IV amiodarone or urgent cardioversion is a first approach.
26. With LVEF ≥40%, a beta-blocker, diltiazem or verapamil, or digoxin may all be used first line. A beta-blocker blocks sympathetic drive at the SA and AV nodes, slowing conduction and lengthening AV refractory period, and is first line for rate control while reducing mortality post-MI. Diltiazem blocks the L-type Ca2+ current the nodal cells depend on, giving the same nodal slowing but with negative inotropy, so it is avoided in AF with heart failure with systolic dysfunction. Digoxin works through vagal M2 stimulation on the AV node and adds positive inotropy, which is why it suits AF with impaired cardiac function and is often added to avoid high doses of the other two. Combining a beta-blocker and a CCB is hazardous because both are negatively inotropic and chronotropic and both slow AV conduction, risking bradycardia and heart block, so it must only be done with caution and in patients without heart failure symptoms or hypotension.