CONTENTS

• Class 0: HCN channel modulators
  • • Ivabradine
• Class 1: Voltage-gated Na channel blockers
  • 1a: Intermediate dissociation kinetics
    • Procainamide
    • Quinidine
    • Disopyramide
  • 1b: Fast dissociation kinetics
    • Lidocaine
    • Mexiletine
  • 1c: Slow dissociation kinetics
    • Flecainide
    • Propafenone
  • 1d: Late Na channel (I-NaL) blocker
    • Ranolazine
• Class 2: Beta-blockers.
• Class 3: K-channel blockers
  • Selective I-Kr blockers
    • Ibutilide
    • Dofetilide
    • Sotalol
  • Nonselective blockers (I-Kr and I-Ks)
    • Amiodarone
    • Dronedarone
• Class 4: L-type calcium channel blockers
• Other:
  • • Digoxin
    • Magnesium
    • Adenosine
• Physiology
  • Normal action potential physiology
  • Mechanisms of arrhythmogenesis

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class 0: ivabradine

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[1/4] dosing & monitoring

• 2.5-7.5 mg PO BID.
• The dose should be adjusted for severe hepatic or renal impairment.

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[2/4] contraindications, interactions, toxicity 

contraindications

• Contraindicated with CYP3A4 inhibitors.
• Contraindicated for patients unable to tolerate bradycardia (e.g., acute decompensated heart failure, hypotension).
• Contraindicated in patients with sick sinus syndrome, sinus bradycardia, or first-degree AV block.

adverse effects

• Bradycardia.
• It may increase the risk of AF (5-8% incidence). (Opie 2021)
• It may increase the risk of torsade when combined with other torsadogenic medications due to reduced heart rate.

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[3/4] indications & use

• Ivabradine is a pure negative chronotropic agent (without negative inotropic effects). It inhibits the Na/K funny current, which causes the depolarization of pacemaker cells.
• Indications include:
  • Goal-directed medical therapy in systolic heart failure with persistent tachycardia (in patients unable to tolerate negative inotropy).
  • Inappropriate sinus tachycardia.

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[4/4] pharmacology

• Mostly hepatic metabolism (CYP3A4).

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class 1a: procainamide, quinidine, and disopyramide

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[1/4] dosing & monitoring

procainamide dosing

• Loading dose for cardioversion:
  • 15 mg/kg IV at a rate of 20-50 mg/min (reduced to 12 mg/kg in severe renal failure).
  • 1,000 mg infused over 30 minutes. (Brown 2023; AHA/ACC 2023)
  • Monitor carefully for hypotension or prolonged ECG intervals.
  • Stop infusion if:
    • The patient successfully cardioverts.
    • Hypotension occurs.
    • QRS is prolonged >150% of baseline.
• Maintenance dose:
  • An infusion of ~2 mg/minute (or ~1 mg/kg/hr) may be utilized after the loading dose. (Bojar 2021; Brown 2023; AHA/ACC 2023 recs 2 mg/min)
  • ⚠️ In the context of hepatic and/or renal dysfunction, procainamide and/or NAPA may accumulate, leading to proarrhythmia. Ideally, drug levels would be monitored, but most hospitals cannot check these levels.
  • Reduce by ~33% in moderate renal impairment (GFR<50 ml/min) or ~66% in severe renal impairment.
  • Reduce dose by 50% in hepatic impairment.

quinidine dosing

• A loading dose of 600-800 mg produces earlier effective concentrations. (Braunwald 12e)
• Different forms: 267 mg of quinidine gluconate is equivalent to 200 mg of quinidine sulfate
  • Quinidine gluconate: 324-648 mg q8hr.
  • Quinidine sulfate: 200-400 mg q6hr.
• No dose adjustment is needed in renal or heart failure.

disopyramide dosing

• 100-200 mg q6hr.
• 200-400 mg q12hr controlled release.
• The dose should be reduced for renal dysfunction.

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[2/4] contraindications, interactions, toxicity 

contraindications

• Infranodal conduction disease.
• Prolonged QT interval.
• History of torsade due to any class IA antiarrhythmic. (Murphy 2024)

complications: class effects

• [1] Torsade is the major adverse event. (Opie 2021)
  • Procainamide: Accumulation of active N-acetyl metabolite may promote torsades.
  • Quinidine: ~5% of patients develop marked QT prolongation and torsade. Unlike sotalol, procainamide, and other antiarrhythmic, torsade usually occurs at therapeutic or even subtherapeutic plasma concentrations. (Goodman & Gillman 14e) Torsade usually occurs within 2-4 days of initiating therapy. (Braunwald 12e)
• [2] Hypotension:
  • Procainamide may relate to ganglionic blockade or negative inotropic effects.
  • Quinidine: may relate to alpha-adrenergic blockade.
  • Disopyramide: may depress contractility and precipitate/aggravate heart failure.
• [3] 1:1 conduction of atrial flutter: In atrial flutter, the combination of slowing the flutter rate plus a vagolytic effect may cause dangerously rapid conduction to the ventricles. If procainamide or quinidine are utilized for atrial flutter, an agent that prevents accelerated AV conduction should be given first. (Bojar 2021)
• [4] Heart block at the sinus node or AV node level can occur. (Opie 2021)

complications of specific agents

• Procainamide:
  • Nausea, anorexia.
  • Delirium, insomnia.
  • (Prolonged use may cause drug fever, rash, and lupus-like syndrome).
• Quinidine:
  • The most common side effects are GI (nausea, vomiting, diarrhea, abdominal pain). Diarrhea and emesis may promote hypokalemia with subsequent torsade.
  • Cinchronism (headache and tinnitus related to elevated quinidine levels, which may improve with dose reduction).
  • Autoimmune side-effects (e.g., medication-induced lupus, hepatitis, bone marrow suppression).
• Disopyramide:
  • Anticholinergic effects.
  • Nausea.
  • Dizziness, insomnia.

drug interactions

• [1] Any drugs that may prolong QT interval.
• [2] Quinidine:
  • Potent inhibitor of CYP2D6, which may cause the accumulation of some other medications.
  • Quinidine metabolism is induced by CYP inducers such as phenobarbital and phenytoin.

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[3/4] indications & use

electrophysiology of 1a agents

• General properties of both agents:
  • Block Na channels with intermediate kinetics and use dependency (increased blocking at high heart rates).
  • Decrease the conduction speed of the action potential (but not as much as Ic drugs). (36686887) 
  • Class III activity: blocking multiple cardiac K+ currents causes prolongation of cardiac action potentials.
  • Decreases automaticity (sodium channel blockade increases the threshold for excitability).
  • Increases refractory periods (likely due to a combination of action potential prolongation and sodium channel blockade).
• Additional properties of each agent:
  • Procainamide also has ganglionic blockade properties, which may cause hypotension when administered in high doses.
  • Quinidine also has vagolytic properties (e.g., shortening PR interval) and alpha-adrenergic blocking activity.
  • Quinidine blocks the delayed rectifier (I-Kr) at lower concentrations, with expanded activity against other channels at higher concentrations (slow component of the delayed rectifier, inward rectifier, transient outward current, and L-type Ca current). Balanced action on the I-Kr and slow potassium channels might theoretically reduce the risk of torsade de pointes (analogous to amiodarone). (Goodman & Gillman 14e) Inhibition of the transient outward current may underlie its efficacy for ventricular arrhythmias in Brugada syndrome and idiopathic VF. (Braunwald 12e)
  • Disopyramide: anticholinergic effects.
• ECG effects:
  • Prolongation of QRS, PR, and QT may occur. QRS widening is greater at faster heart rates. 
  • Procainamide: QRS widening by >25% might suggest toxicity. (Brown 2023)
  • Quinidine: At therapeutic quinidine doses, the QRS is usually modestly elevated (10-20%), and the QT interval often prolongs by up to 25%. (Goodman & Gillman 143) The dose should be reduced if the QRS widens to >130% of its pretreatment duration, QTc widens to >130% of its pretreatment duration and is >500 ms, P-waves disappear, or significant tachycardia/bradycardia occurs. (Opie 2021)

indications for IV procainamide

• [1] Cardioversion of AF/AFlutter:
  • It may be utilized in AF + WPW.
• [2] Cardioversion of stable VT.
• (Oral procainamide isn't available in the United States).

indications for quinidine

• Maintain sinus rhythm in patients with AFlutter/AF.
• Quinidine is especially useful in specific arrhythmia syndromes:
  • Brugada syndrome.
  • Short QT syndrome.
  • Idiopathic VF.
• Refractory ventricular arrhythmias:
  • Recurrent VF in early repolarization syndrome. (19215837)
  • Polymorphic VT due to ischemia. (30696267)
  • Monomorphic VT in structural heart disease. (34586686)

indications for disopyramide

• Disopyramide isn't a very potent anti-arrhythmic. It could be used to maintain sinus rhythm in AF/Flutter or prevent the recurrence of VT/VF, but it doesn't seem to be utilized commonly for this. (Opie 2021)
• Due to negative inotropic effects, disopyramide is sometimes used in hypertrophic cardiomyopathy. (Goodman & Gillman 14e)

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[4/4] pharmacology

procainamide pharmacology

• Procainamide has a relatively short half-life of ~2-5 hours. (Opie 2021) 
• Procainamide is eliminated via renal (~50%; unchanged) and hepatic (conversion to an active metabolite, N-acetyl procainamide aka NAPA).
• NAPA lacks Na-channel blocking activity but does have Class III activity that prolongs action potentials.  NAPA is eliminated by renal excretion (half-life of 6-10 hours). Renal dysfunction may cause NAPA accumulation, with a risk of torsade.

quinidine pharmacology

• Well absorbed.
• 80% are bound to plasma proteins (albumin and acute-phase reactant alpha1-acid glycoprotein), so higher doses may be needed to achieve therapeutic effect in an acute phase response.
• The half-life is 4-10 hours. Quinidine is mostly metabolized by the liver (only 20% renal excretion). One metabolite (3-hydroxyquinidine) is nearly as potent as quinidine. (Goodman & Gillman 14e) 

disopyramide pharmacology

• Metabolism is hepatic (35%) and renal (65%).
• Half-life is 4-10 hours.
• Binding to plasma proteins may cause a small increase in the total concentration to correlate with a larger increase in free drug concentration. (Goodman & Gillman 14e)

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class 1b: lidocaine & mexiletine

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[1/4] dosing & monitoring

lidocaine dosing

• [#1/3] Loading regimen of ~3-4 mg/kg total (lower end for heart failure):
  • Start with 100 mg over two minutes.
  • Followed by 50 mg every 10 minutes for ~3 doses.
  • ⚠️ The initial half-life is as short as 7 minutes due to redistribution, so the effects of a single bolus can dissipate rapidly. (Goodman & Gillman 14e; Opie 2021) 
  • 💡 Hypokalemia impairs the efficacy of lidocaine, so this should be aggressively repleted. (Opie 2021)
• [#2/3] Initial infusion rate of 1-4 mg/min.
  • Consider starting at a rate of 2-4 mg/min.
  • Lower lidocaine doses are appropriate for:
    • Hepatic dysfunction.
    • Reduced hepatic blood flow (shock states, beta-blocker use). (Braunwald 12e; Opie 2021)
• [#3/3] Over time, the half-life of lidocaine extends (due to accumulation in various body compartments and the inhibition of lidocaine metabolism by some of its metabolites). Consequently, for infusions longer than ~12-24 hours, the rate should be decreased to avoid accumulation.

monitor for signs of lidocaine toxicity

• 🚩 Early signs of toxicity:
  • Paresthesias or numbness (especially perioral).
  • Metallic taste.
  • Tinnitus.
  • Visual or auditory disturbance, lightheadedness, dizziness.
  • Confusion, somnolence.
• Organ system manifestations:
  • Cardiac: Bradycardia, QRS widening, sinus node suppression.
  • Neurologic: Delirium, tremor, visual disturbances, numbness/tingling, metallic taste, tinnitus, seizure.
  • Gastrointestinal: Nausea and vomiting.
  • Hematologic: Methemoglobinemia (rare).
• Mild-moderate toxicity should resolve after discontinuing the infusion. Severe toxicity may be managed by the administration of intralipid.

mexiletine dosing

• 400 mg loading dose.
• Starting dose: 100-200 mg q8hr.
• It may be gradually up-titrated in 50-100 mg increments to a max dose of 300 mg q8hr.

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[2/4] contraindications, interactions, toxicity 

side effects

• Lidocaine:
  • At therapeutic levels, lidocaine is generally hemodynamically stable (no effect on AV conduction, myocardial contractility, or vascular tone). However, sinus node depression can occur if there is underlying sinus node disease.
  • The main adverse effects are CNS excitation (including seizure). (36686887)
  • At high doses, lidocaine may cause local anesthetic toxicity syndrome (LAST), discussed here: 📖
• Mexiletine:
  • Cardiovascular side effects are rare, but hypotension or bradycardia can occur. (Braunwald 14e)
  • The primary dose-limiting effects are GI intolerance (nausea, vomiting, diarrhea). Administration with food and/or PPI may help. (Opie 2021)
  • Neurological side effects include paresthesias, ataxia, tremor, dizziness, and blurred vision. (Opie 2021)
  • Less common side effects include DRESS syndrome or cytopenias.

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[3/4] indications & use

electrophysiology of 1b agents

• Preferentially bind to partially depolarized cells (diseased or ischemic tissue) beating rapidly. Meanwhile, healthy myocytes are relatively unaffected.
• Lidocaine rapidly dissociates (leaving cells ready for subsequent depolarization).
• The action potential is shortened, producing accelerated conduction.
• Lidocaine binds to sodium channels in the inactivated state. Because action potentials are shorter in the atria, agents that bind to inactivated sodium channels are less effective.
• ECG effects: generally, no changes are seen. (Brown 2023) The QT interval may be shortened. (Murphy 2024)

indications for lidocaine

• Useful for re-entrant and automatic ventricular arrhythmias (especially in myocardial ischemia or following cardiac surgery). (Brown 2023, Opie 2021)
  • Ventricular tachycardia.
  • Frequent/incessant PVCs.
• Refractory VT/VF storm (especially after cardiac surgery or in ischemic cardiomyopathy). Lidocaine alone has low efficacy and rarely terminates monomorphic VT. (Braunwald 12e) However, lidocaine may be combined with other agents (e.g., amiodarone, beta-blockers). In lidocaine failure, consider hypokalemia, hypomagnesemia, ongoing ischemia, or other reversible etiologies. (Opie 2021)
• No efficacy for atrial arrhythmias.

indications for mexiletine

• Mexiletine is essentially an oral form of lidocaine.
• Mexiletine monotherapy alone is often not very effective, so it is rarely used as a single agent for the treatment of ventricular arrhythmias. (Braunwald 14e) Mexiletine may be combined with various agents, including beta-blockers, quinidine, disopyramide, propafenone, or amiodarone. Combinations of mexiletine plus either quinidine or sotalol may improve efficacy while reducing adverse effects. (Goodman & Gillman 14e)
• Strengths:
  • Mexiletine may be especially effective for LQTS 3 with a mutation in SCN5A, causing a gain of function and delays in repolarization. (Opie 2021)
  • Other patients with baseline QT prolongation.

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[4/4] pharmacology

lidocaine pharmacology

• Lidocaine is highly bound to alpha-acid glycoproteins, which are acute-phase reactants.
• Metabolism:
  • [1] Lidocaine undergoes hepatic metabolism into two active metabolites (monoethylglycinexylidide and glycinexylidide). Hepatic metabolism may be influenced by hepatic blood flow and enzyme inducers. (Opie 2021)
  • [2] The kidney subsequently eliminates these metabolites. In renal failure, active metabolites can accumulate.
• Lidocaine undergoes roughly biphasic distribution.
  • Initially, lidocaine has a half-life of 7-30 minutes, as the drug distributes into body tissues.
  • Eventually, the half-life increases to ~1.5-3 hours. This reflects the saturation of the tissues and the elimination of the drug by the liver and kidneys. The terminal half-life may be up to 8 hours in patients with hepatic failure. (26335213)

mexiletine pharmacology

• Hepatic metabolism via CYP1A2 and CYP2D6 (with active metabolites).
• Half-life of 9-15 hours.

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class 1c: flecainide & propafenone

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[1/4] dosing & monitoring of 1c agents

⚠️ In AF/Flutter, a beta-blocker or diltiazem is generally coadministered to avoid rapid transmission through the AV node.

flecainide dosing

• Loading dose: 200-300 mg PO. (Bojar 2021)
• 50-150 mg q12 hours.
• Dose-reduce by 50% if GFR <50 ml/min.  (Bojar 2021)

propafenone dosing

• Loading dose: 600 mg. (Bojar 2021)
• 150-300 mg q8hr for immediate release.
• 225-425 mg q12 hrs controlled release.
• Reduce the dose to ~25% of the usual dose in patients with moderate-to-severe liver disease with careful monitoring. (Goodman & Gillman 14e)

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[2/4] contraindications, interactions, toxicity 

contraindications

• Structural heart abnormalities, e.g.:
  • LV dysfunction (agents reduce LV function).
  • Status post-MI (proarrhythmia).
• QT prolongation.
• Sick sinus syndrome.
• AV block (e.g., 2nd degree).
• Infranodal conduction disease (e.g., RBBB or LAHB without a permanent pacemaker).
• Renal dysfunction (relative or absolute contraindication depending on severity).

side effects

• [1] Ventricular proarrhythmia (monomorphic, reentrant VT): In the CAST trial, flecainide caused increased mortality among patients recovering from MI.  This was likely due to proarrhythmia (transient ischemia or sinus tachycardia may cause re-entrant ventricular tachycardia).
  • Proarrhythmia occurs even without QT prolongation. (Bojar 2021)
• [2] May slow atrial flutter enough to conduct 1:1 across the AV node, leading to dangerously rapid ventricular rates.
  • ⚠️ Always coadministered with an AV-blocking drug (e.g., beta-blocker). (Opie 2021)
• [3] Negative inotropic effects (especially propafenone, which has beta-blockade activity).
• [4] Heart block in patients with underlying conduction disease.

interactions

• Both agents are subject to interactions due to metabolism via CYP2D6.

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[3/4] indications & use of 1c agents

electrophysiology

• [1] Bind to sodium channels and dissociate very slowly, leading to steady-state channel blockade (even in normal tissues with normal heart rates).
  • These agents profoundly slow depolarization and conduction in all cardiac fibers.
  • They display use dependence, with increased effect at higher heart rates.
• [2] Inhibition of delayed rectifier K current (I-Kr).
• [3] Blockade of RyR2 channels, which may help suppress DADs (delayed after-depolarizations).
• Propafenone also has beta-blocker effects.
• ECG findings: Increased PR and QRS. If the QRS is prolonged >25%, then the dose should be decreased. (Opie 2021)

indications for flecainide or propafenone

• Supraventricular arrhythmias:
  • Conversion of AF (“pill in the pocket”).
  • Maintenance of sinus rhythm after AF cardioversion.
  • Atrial tachycardia.
• Ventricular arrhythmias:
  • VT/VF in patients without structural heart disease.
  • LQTS type 3 due to mutations that cause late Na currents (SCN5A: DeltaKPQ mutation causing sodium channels to open repetitively).
  • CPVT (catecholaminergic polymorphic VT), especially in patients with a mutation causing leaky RyR2 sarcoplasmic reticulum Ca release channels. Flecainide may be considered first-line here, but propafenone may also be utilized.

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[4/4] pharmacology

flecainide pharmacology

• Metabolism is primarily renal (85%), with some hepatic metabolism by CYP2D6.
• Half-life is 10-18 hours.

propafenone pharmacology

• Metabolism is hepatic via CYP2D6 to 5-hydroxy propafenone (equipotent as a sodium channel blocker). There is individual variability, with some people being “poor metabolizers,” which increases the risk of high drug levels with subsequent toxicity.
• Half-life is 2-32 hours.

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class 1d: ranolazine

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[1/4] dosing & monitoring

• Cardiac surgery AF prophylaxis: 500-1000 mg preoperatively, then 1 gram PO bid for a week. (Bojar 2021)
• Dose-reduce when combined with drugs that inhibit CYP3A.
• Avoid in severe liver disease.

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[2/4] contraindications, interactions, toxicity 

contraindications

• Significant hepatic impairment.
• Strong CYP3A inhibitors.

toxicity

• Ranolazine may cause slight QTc prolongation (e.g., 6-15 ms) due to inhibition of I-Kr.  However, inhibition of late inward Na currents balances this out, so ranolazine doesn't seem torsadogenic.

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[3/4] indications & use

electrophysiology

• Ranolazine inhibits the late (I-NaL) and delayed rectifier K (I-Kr) channels, causing a slight prolongation in action potential duration. This causes increased refractoriness and reduced intracellular calcium. (36686887)
• Reduced myocardial wall tension and reduced myocardial oxygen demand can decrease ischemia. (Bojar 2021)
• ECG effects: may cause QT prolongation.

use

• [1] Treating chronic stable angina.
• [2] Preventing and treating AF (including after surgery).

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[4/4] pharmacology

• ~75% bioavailable.
• Metabolized by hepatic CYP3A with a half-life of 7 hours.

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class 3: ibutilide, dofetilide, and sotalol

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[1/4] dosing & monitoring

ibutilide protocol for chemical cardioversion

• [#1/3] Replete potassium & pre-load with magnesium:
  • Replete potassium to target K >4 mM.
  • Preload with aggressive IV magnesium sulfate:
    • The main side effect of ibutilide is a prolongation of QTc, which causes torsade de pointes. Coadministration with a magnesium infusion will dramatically reduce the risk of Torsades. (20723644)
    • Administration of magnesium has been shown to substantially improve the efficacy of ibutilide (14652979, 32861384) If ibutilide is being utilized following initiation of a magnesium infusion, ibutilide's effectiveness may be maximized by delaying ibutilide administration until the magnesium level has risen over ~3.8 mg/dL. (32861384) For ICU patients, initiating a magnesium infusion protocol is a safe intervention to improve the safety and efficacy of ibutilide cardioversion.
• [#2/3] Chemical cardioversion:
  • The standard ibutilide dose is 1 mg infused over 10 minutes (or 0.01 mg/kg for patients <60 kg).
  • If AF persists for >10-20 minutes following the end of the infusion, the dose can be repeated once. Check the QT interval before administering the second dose. 
  • Most patients convert to sinus rhythm within 30-90 minutes. (38033089)
  • ⚠️ If cardioversion occurs while ibutilide is being infused, the infusion should be stopped immediately. 
  • ⚠️ An external defibrillator should be attached to the patient and prepared for cardioversion if necessary.
• [#3/3] Monitor for ~4 hours (although arrhythmias generally occur within the first hour after administration).

dofetilide dosing

• 0.25-0.5 mg q12 hours.
• Dose initiation must be performed in the hospital with careful monitoring of ECG 2-3 hours after each dose to monitor QT. (Bojar 2021) Dofetilide should be used continuously because cessation followed by reinitiation increases the risk of torsade. (Braunwald 12e)
• Dose reduction in renal failure; contraindicated if GFR <20 ml/min. (Opie 2021)

sotalol dosing

• ⚠️ Follow QTc on ECG with dose adjustment or changes in renal function.
• 80-160 mg PO BID.
• GFR <60 ml/min: given once daily. (Bojar 2021)
• GFR <40 ml/min: contraindicated. (Bojar 2021)

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[2/4] contraindications, interactions, toxicity 

toxicity: torsade de pointes

• Key variables in predicting the risk of torsade appear to be:
  • Resting/baseline bradycardia.
  • QT prolongation at baseline (>440 ms). (Opie 2021)
  • Hypokalemia.
  • Hypomagnesemia.
  • Higher drug levels (e.g., 2 mg ibutilide given to a more petite patient; sotalol in a patient with worsening kidney function).

contraindications/cautions with IV ibutilide

• Actual contraindications: (Braunwald 12e)
  • [1] QT prolongation (e.g., QTc >440 ms).
  • [2] Hypokalemia.
  • [3] Hypomagnesemia.
• (Reduced ejection fraction)
  • Patients with reduced ejection fraction might have an increased risk of torsade, based on the following studies:
    • Oral et al. noted two episodes of torsade among patients with EF<20%. These authors didn't administer magnesium, nor is there information about magnesium levels among these patients. (10369847)
    • Ellenborgen et al. noted six episodes of torsade among 157 patients with ibutilide, all of whom had reduced ejection fraction. However, half of the study population had a reduced ejection fraction, so it's unclear how significant this is. Notably, half of these patients had QTc >440 at baseline. (8752805)
  • Overall, there is very sparse evidence regarding the magnitude of risk and at which ejection fraction this risk might emerge.
  • Clinical judgment is required when deciding whether to use ibutilide in a patient with reduced ejection fraction. If ibutilide is utilized in this context, coadministration with a magnesium infusion could mitigate the risk of torsade.
• (Theoretical interaction with amiodarone)
  • Theoretically, since ibutilide and amiodarone can both prolong the QT interval, the combination of these drugs could promote torsade de pointes. However, although amiodarone prolongs the QTc interval, amiodarone isn't substantially torsadogenic.
  • Evidence review reveals several studies have demonstrated that amiodarone and ibutilide can be given together safely and effectively. (28584642, 16029392, 12122531, 11208685, 17284902, 16176535) Moderate doses of these drugs can likely be combined safely and effectively (especially with ICU-level monitoring and aggressive magnesium supplementation). This decision should be individualized based on the risks vs. benefits (incorporating patient specifics, such as the actual QTc value).

contraindications/cautions to dofetilide

• [1] Risk factors for torsade (prolonged QT, hypomagnesemia, hypokalemia).
• [2] All Class I and Class III antiarrhythmic should be stopped for three half-lives before dofetilide is given (in the case of amiodarone, it should be discontinued for three months). (Bojar 2021)
• (Structural heart disease doesn't appear to be a contraindication.)
  • In the DIAMOND studies, dofetilide didn't affect mortality among patients with advanced heart failure or recovering from MI. (Goodman & Gillman 14e)
  • Dofetilide can be utilized in structural heart disease. (Bojar 2021)

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[3/4] indications & use

electrophysiology

• All of these agents inhibit I-Kr inhibitors:
  • Reverse use dependency blockade of I-Kr (HERG gene) causes increased blockade at low heart rates. Reverse-use dependence may improve the efficacy of preventing arrhythmias but decrease the effectiveness of terminating an arrhythmia.  Reverse use dependence also increases the risk of torsade de pointes in a pause-dependent fashion.
  • Prolongation of the action potential may increase contractility.
• Ibutilide can also activate a late inward Na current, which delays repolarization. (Goodman & Gillman 14e)
• Sotalol has additional nonselective beta-blocking activity. At low doses (<160 mg/day), sotalol might function predominantly as a beta-blocker with little Class III activity. (Opie 2021)
• Effect on ECG: QT prolongation.
  • Sotalol: During dose titration, if the QTc isn't >500 ms, the dose may be titrated upwards until a therapeutic effect is reached. (Opie 2021)
  • Dofetilide: The dose should be reduced if the QTc increases by >15% or if the QTc is >500 ms. (Opie 2021)

indications for ibutilide: cardioversion of AF/flutter

• [1] Chemical cardioversion of AF/Flutter (including urgent cardioversion within 1-2 hours).  
  • Available studies suggest that ibutilide has a high success rate for cardioversion of AF/Flutter. (34916053, 21209348, 10763074) Success is higher with AFlutter than with AF (especially longstanding AF).
  • Coadministration with magnesium may improve efficacy.
  • One small RCT found that amiodarone and ibutilide were equally effective for cardioversion. The advantage of ibutilide was a reduced rate of hypotension, whereas the advantage of amiodarone was a reduced rate of recurrent AF. (12682468)
  • Ibutilide may be superior to procainamide among critically ill patients because it has greater efficacy and no adverse hemodynamic effects. (9581743, 9416896, 15773423) 
• [2] DCCV-resistant atrial fibrillation: Treatment with ibutilide before cardioversion increases the success rate.
• [3] AF with WPW (the two options for chemical cardioversion in this scenario are ibutilide or procainamide).

indications for dofetilide

• Primarily AF/Flutter (cardioversion & maintenance of sinus rhythm).

indications for sotalol

• Maintenance of sinus rhythm in AF/flutter.
  • Most common use.
  • It can be utilized in patients with structural heart disease.
• Ventricular tachyarrhythmia (sotalol is as effective as most sodium-channel blockers in ventricular arrhythmias). (Goodman & Gillman 14e)

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[4/4] pharmacology

ibutilide pharmacology

• Half-life is 2-12 hours (average 6 hours).
• Ibutilide is metabolized in the liver via oxidation to yield mostly inactive metabolites. Dose adjustment isn't required for renal or hepatic dysfunction because maintenance doses are not utilized.

dofetilide pharmacology

• Dofetilide has excellent bioavailability, with peak plasma concentrations ~2.5 hours after administration. (Opie 2021)
• Renal and hepatic clearance.
• Half-life of 7-10 hours.

sotalol pharmacology

• Bioavailability is 90-100%, with peak levels after 2.5-4 hours.
• Sotalol is hydrophilic, nonprotein bound, and excreted solely by the kidneys.
• Half-life of 8-12 hours.

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amiodarone & dronaderone

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[1/4] dosing & monitoring

IV amiodarone dosing for rate control of AF

• [1] The usual loading dose is 150-300 mg IV over an hour. (2023 AHA/ACC) If this is ineffective, additional loading doses may be given up to ~450 mg in boluses.  
• [2] Maintenance therapy is 0.5 mg/minute.

IV amiodarone dosing for rhythm control of AF

• [1] The loading dose is 5-7 mg/kg or 300 mg. (38033089) In practice, 300 mg is often utilized, with additional boluses up to ~450-600 mg total administered in boluses as needed.
• [2] The initial maintenance dose is 1,200-3,000 mg via continuous infusion over 24 hours. (2023 AHA/ACC guidelines) This is equivalent to an infusion at 1 mg/min (which provides 1440 mg/day).
• After cardioversion, amiodarone infusion is generally continued to prevent recrudescence of atrial fibrillation. An immediate transition to PO amiodarone is unwise in this context since it takes PO amiodarone several days to work (discussed below). Some data suggest continuing the amiodarone infusion while the patient is critically ill. (27038791) Intravenous infusions can be safely continued for 2-3 weeks. (Braunwald 14e) Alternatively, once the patient has received a load of >4-6 grams, IV amiodarone may be transitioned to PO amiodarone following an overlap of both PO plus IV amiodarone for at least two days. (Opie 2021)

PO amiodarone 

• Loading dose:
  • ⚠️ Oral amiodarone typically takes ~3-7 days to have a clinical effect, even with a loading dose (due to slow and variable absorption of the drug and gradual accumulation of its active metabolite, desethylamiodarone).
  • An oral load of 800 – 1600 mg/day is usually utilized for several weeks. (Goodman & Gillman 14e)
  • Transition to maintenance dosing once the patient has received a cumulative dose of 6-10 grams (lower end for atrial arrhythmias, higher for ventricular arrhythmias). (Opie 2021)
• Maintenance therapy:
  • For AF, ~200 mg daily is often utilized.
  • For VT/VF, higher maintenance doses may be used (e.g., ~400 mg/day).
• Dose adjustment isn't required for hepatic, renal, or cardiac dysfunction. (Goodman & Gillman 14e)

amiodarone IV → PO conversion

• Conversion from IV amiodarone to PO amiodarone may cause a transient interruption of amiodarone activity. If IV amiodarone is stopped early in the loading process, the amiodarone will rapidly distribute out of the plasma and into the tissues. Meanwhile, oral amiodarone takes 3-7 days to have a clinical effect.
• There is no high-quality data regarding this. Two retrospective studies found no correlation between overlapping oral and IV amiodarone and the recurrence of arrhythmia. However, this may represent confounding (i.e., overlapping was utilized in patients at greater risk of arrhythmia recurrence). Additionally, the duration of the overlapping was often short (hours rather than days). 
• The aggressiveness of dosing depends on how vital arrhythmia avoidance is.
• Strategies to avoid arrhythmia recurrence could include the following:
  • [1] Administering a greater dose of IV amiodarone before transitioning to oral, to allow for tissue amiodarone levels to accumulate. At least 24 hours of IV infusion amiodarone is desirable. If IV amiodarone is well tolerated, it might be reasonable to continue IV amiodarone infusions for several days or even 1-2 weeks (allowing administration of 5-10 grams of IV amiodarone).
  • [2] Initiating oral therapy at a relatively high dose (i.e., 1200-1600 mg/day in divided doses until a loading dose of 6-10 grams has been reached). 1600 mg/day may seem like a high dose, but this is equivalent to <1 mg/min infusion when considering a 30-50% bioavailability.
  • [3] A 1-2 day overlap may be considered (especially when treating ventricular arrhythmias and if the duration of IV therapy has been relatively short). (Buxton A, UpToDate)

dronedarone dosing

• 400 mg q12 hours.

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[2/4] contraindications, interactions, toxicity 

contraindications to amiodarone & dronaderone

• Contraindications to either amiodarone or dronaderone:
  • QT prolongation (relative contraindication).
  • Bradycardia, sinus node dysfunction.
  • Second or third-degree heart block.
• Additional contraindications with dronedarone:
  • Heart failure or EF <35-40%. Dronaderone has shown increased mortality in patients with permanent AF and patients with severe heart failure. (Goodman & Gillman 14e)

amiodarone toxicity

• Short-term toxicity:
  • [1] Hypotension can result from vasodilation and myocardial depression (albeit less notably than many other antiarrhythmics). This may be primarily due to the IV solvent (so it might not occur with PO administration). (Murphy 2024)
  • [2] Bradycardia can happen.
  • [3] Amiodarone does prolong the QT interval, but it isn't substantially torsadogenic.
• Longer-term use (several weeks): toxicities include pulmonary fibrosis, hepatic dysfunction, thyroid disease, and peripheral neuropathy. (36686887)

dronedarone toxicity

• Dronaderone can cause severe liver injury, so the FDA recommends monitoring liver function tests for six months of therapy.
• Pulmonary toxicity is reported, but the risk is unclear.

drug interactions

• Amiodarone inhibits CYP3A4, CYP2C9, and P-glycoprotein, leading to numerous drug-drug interactions. This may require ~50% dose-reduction of various medications, especially: (Bojar 2021)
  • Warfarin.
  • Digoxin.
  • Procainamide, quinidine.
  • Simvastatin (increased risk of rhabdomyolysis; limit dose to 20 mg). (Bojar 2021)
• Dronaderone is metabolized by CYP3A4. Dronaderone is a moderate inhibitor of CYP3A, CYP2D6, and P-glycoprotein.

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[3/4] indications & use

electrophysiology of amiodarone

• Amiodarone has activity across all classes.
  • Blocks inactivated sodium channels with rapid recovery (~1.6s time constant).
  • Decreases Ca current.
  • Decreases transient outward delayed rectifier and inward rectifier K currents.
  • Inhibition of both HERG channels (I-Kr, which show reverse user dependency) and I-Ks channels (which show normal use dependency, with greater efficacy at high heart rate).  Inhibition of I-Ks is a safety mechanism, explaining why amiodarone has less proarrhythmic effects than pure I-Kr blockers (e.g., sotalol, ibutilide). (36686887) Inhibition of the L-type calcium channel may also reduce torsade risk. (Braunwald 12e)
  • Potently inhibits abnormal automaticity. (Goodman & Gillman 14e)
• Amiodarone also decreases peripheral conversion of T4 to T3 and impairs T3 binding to myocytes, causing cellular hypothyroidism. (Brown 2023)
• ECG effects:
  • Sinus bradycardia and PR prolongation are common.
  • Mild QRS widening can occur.
  • Mild QT prolongation can happen, sometimes changing the contour of the T-wave and producing U-waves. (Braunwald 12e) However, amiodarone is rarely proarrhythmic. (Brown 2023)
  • Aside from effects on heart rate and PR prolongation, ECG changes are much less notable after IV administration than oral administration. (Braunwald 12e)

electrophysiological effects of intravenous vs. oral amiodarone

• IV amiodarone: IV amiodarone primarily has class I and nonselective class II effects. (Opie 2021)
• PO amiodarone:
  • Oral administration leads to extensive first-pass metabolism to desethylamiodarone (DEA), which accumulates and contributes substantially to the electrophysiological effects.
  • PO amiodarone may have a broader range of electrophysiological activities, including:
    • Class III effect (QT prolongation).
    • Increased refractoriness of the atria and ventricles.

indications for amiodarone

• Rhythm control in AF.
• Rate control in AF.
  • Amiodarone is often helpful for patients with potential hemodynamic instability.
  • There is a theoretical risk of causing stroke among patients who aren't anticoagulated and might cardiovert into sinus rhythm. However:
    • (1) This theoretical risk is often superseded by the need to achieve hemodynamic stability for hemodynamically tenuous patients.
    • (2) The risk of stroke relates more to the duration of atrial fibrillation than the act of cardioversion. Since most critically ill patients will eventually transition to sinus rhythm spontaneously, leaving patients in atrial fibrillation longer may increase stroke risk.
• VT/VF.

indications for dronaderone

• Dronaderone is amiodarone lite: it's safer but less effective. (Goodman & Gillman 14e) 
• Dronaderone is FDA-approved for AF/flutter. However, dronaderone has no role in treating ventricular arrhythmias. (Opie 2021)
• Thyroid disease:
  • Dronaderone lacks iodine, so it does not cause thyroid toxicity. (Opie 2021) This could theoretically make it more desirable for patients with thyroid disease.
  • However, amiodarone is not absolutely contraindicated for patients with thyroid disease (e.g., thyrotoxicosis, which often causes arrhythmias). As noted above, amiodarone decreases peripheral conversion of T4 to T3 and impairs T3 binding to myocytes, causing cellular hypothyroidism – desirable properties for patients with hyperthyroidism. (Brown 2023) Amiodarone's side effects on thyroid function are gradual and uncommon. Therefore, for a patient who is presenting with thyroid storm and tachyarrhythmias, amiodarone is often an excellent option for initial stabilization.  

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[4/4] pharmacology

amiodarone pharmacology

• IV amiodarone:
  • IV amiodarone takes effect faster than oral amiodarone.
  • IV amiodarone rapidly redistributes out of the plasma into the tissue, with a drop to 10% of peak values within 30-45 minutes after the end of the infusion. (35170491)
• Oral amiodarone:
  • Oral amiodarone typically takes ~3-7 days to have a clinical effect, even with a loading dose (due to slow and variable absorption of the drug and gradual accumulation of its active metabolite, desethylamiodarone).
  • Bioavailability is variable (~30-50%) and slow (levels peak after 3-6 hours). (35504449, Opie 2021) Bioavailability may vary depending on the status of CYP3A enzymes that perform first-pass metabolism.
• Amiodarone is converted via hepatic metabolism (CYP3A4) to DEA (desmethyl-amiodarone). DEA also has antiarrhythmic activity, albeit distinct from amiodarone (discussed above).
• The terminal elimination half-life may be perhaps ~1 month.
• Amiodarone is highly lipophilic and concentrated in many tissues.

dronedarone pharmacology

• Oral bioavailability is ~80%, with peak levels achieved after ~3-4 hours.
• Clearance occurs via the liver (85% excreted unchanged in the bile).  Some metabolism occurs via CYP3A4 and CYP2D6.
• Half-life of 13-19 hours (with active metabolite).

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digoxin

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[1/4] dosing & monitoring

IV digoxin loading (digitalization)

• Digoxin takes a little while to work, but if given intravenously, it may take effect within several hours. When initiated in the ICU, digoxin is nearly always started with intravenous loading doses.
• Total IV loading dose: (package insert, 23616674)
  • Normal renal function: 8-12 mcg/kg ideal body weight (usually ~600-1,000 mcg).
  • Renal insufficiency: 6-10 mcg/kg ideal body weight.
  • Err on the lower end in patients with renal dysfunction, hypothyroidism, and/or reduced muscle mass.
• Typically, 50% of the total loading dose is given initially, followed by 25% given twice, every six hours. The first IV dose (typically ~400-600 mcg) takes effect within roughly 1-4 hours. Monitor for effect. If an adequate heart rate is achieved, subsequent doses may be omitted. If bradycardia occurs, further administration should be held.

maintenance doses

• Typical maintenance dose:
  • Patients <70 years old with normal renal function: 250 mcg daily.
  • Patients over 70 years old –or- with renal dysfunction: 125 mcg daily.
  • Patients who are both >70 YO –and- have renal dysfunction: 62.5 mcg daily.
• The table below provides typical maintenance doses based on the patient's renal function and body weight. (Package insert)
• Digoxin has a long half-life (~36-48 hours, or longer in renal insufficiency). Therefore, a steady state may not be reached until about a week after a dose adjustment.

monitoring digoxin levels

• Drug level must be checked several hours after the last digoxin dose to allow for distribution (e.g., >8 hours after an oral dose). Ideally, this should be a trough level.
• The safest approach to digoxin dosing in the ICU among tenuous or dynamic patients is to monitor the digoxin level closely:
  • Check a trough digoxin level daily with AM labs.
  • Adjust the daily dose as needed, depending on the trough level.
  • As the patient stabilizes, digoxin levels may be spaced out.
• A therapeutic level is ~0.5-2 ng/mL
  • 0.5-1.2 ng/mL might be the optimal concentration for outpatients. (38033089)
  • 1-2 ng/mL levels may improve contractility, so these aren't unreasonable levels for closely monitored ICU patients.

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[2/4] contraindications, interactions, toxicity 

interactions

• Inhibition of P-glycoprotein decreases digoxin concentration (e.g., due to using amiodarone, dronaderone, verapamil, diltiazem, or cyclosporine).

digoxin toxicity

• Discussed further here: 📖

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[3/4] indications & use

mechanism of action

• Inhibits Na/K-ATPase activity, leading to increased intracellular calcium levels.
• Elevated intracellular calcium levels may exert a positive inotropic effect.
• Vagotonic effects reduce transmission through the AV node.

optimal candidates for digoxin in AF have:

• [1] Chronic, permenant AF
  • Digoxin perpetuates AF rather than favoring cardioversion back to normal sinus rhythm.
  • Digoxin may be less effective in rate control of paroxysmal AF, so it shouldn't be used as a sole therapy for paroxysmal AF. (Griffin 2022)
• [2] Heart failure with reduced ejection fraction: Digoxin is the only agent that reduces heart rate while simultaneously functioning as a positive inotrope. As such, digoxin may be uniquely helpful for patients with heart failure and tenuous hemodynamics.
• [3] Mild or moderate tachycardia for which immediate control isn't necessary:
  • Digoxin takes several hours to work and is not tremendously potent.
  • Digoxin is less effective in hyperadrenergic states since it functions primarily as a vagotonic agent.
• [4] Adequate renal function:
  • The presence of preserved renal function makes dosing of digoxin easier and a bit safer.
  • This isn't an absolute requirement because careful dosing and monitoring within the ICU allow digoxin to be given safely, even in the presence of renal dysfunction.

if digoxin alone fails, consider digoxin plus a beta-blocker

• Digoxin is not an extremely powerful agent, so it may fail to achieve optimal heart rate control.
• If digoxin does fail, it may be combined with a beta-blocker or diltiazem.
• Digoxin may reduce the required dose of a beta-blocker, improving hemodynamic stability. (31700500) In particular, the combination of digoxin and a beta-blocker may work well for some patients with systolic heart failure.

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[4/4] pharmacology

digoxin pharmacology

• The oral bioavailability is 40-90%. The onset of action occurs 2-6 hours after ingestion.
• The volume of distribution is ~6 L/kg.
• Excretion occurs mainly via the kidneys. The half-life is ~40 hours (with variation depending on renal function).
• Digoxin is secreted into the urine by P-glycoprotein:
  • P-glycoprotein inhibitors will increase digoxin levels, for example:
    • Amiodarone, carvedilol, ranolazine, ticagrelor.
    • Verapamil, tacrolimus, cyclosporine.
    • Azithromycin, erythromycin, clarithromycin.
    • Azole antifungals.
  • P-glycoprotein inducers will decrease digoxin levels, for example:
    • Carbamazepine, fosphenytoin, phenobarbital.
    • Rifampin.

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magnesium as an antiarrhythmic agent

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[1/4] dosing & monitoring

protocolized magnesium infusion

• A protocolized magnesium infusion may be helpful in patients with adequate renal function who have a stronger indication for IV magnesium, such as:
  • Torsade de pointes (infusion is highly recommended).
  • Cardioversion of new AF in critical care.
  • Severe, proven hypomagnesemia.
• The protocol below may be utilized. Most of the administered magnesium will be excreted, so a continuous infusion may be required to effectively replete intracellular magnesium levels. (18320707)

PRN magnesium boluses

• Magnesium boluses may be helpful for patients who don't qualify for a magnesium infusion (in the absence of hypermagnesemia).
• Intermittent boluses may be used, targeting ~3-4 mg/dL.

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[2/4] contraindications, interactions, toxicity 

contraindications to magnesium

• [1] Myasthenia gravis.
• [2] Renal failure: magnesium may still be given, but the dose needs to be adjusted and monitored more carefully.

clinical effects of hypermagnesemia

• Discussed here: 📖

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[3/4] indications & use

electrophysiologic actions of magnesium

• [1] Block of L-type calcium currents involved in EADs (early after-depolarizations) – may explain efficacy in torsade de pointes.
• [2] Inhibitor of RyR2 calcium release channels – may explain efficacy in arrhythmias related to digitalis intoxication. (Goodman & Gillman 14e)

magnesium indications

• Based on more robust evidence:
  • Torsade de pointes.
  • Cardioversion of new-onset AF in critical illness.
  • Patients with documented magnesium deficiency (e.g., alcoholism).
• Other indications
  • Rate control in AF.
  • Refractory VF. (Opie 2021)

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adenosine

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[1/4] dosing & monitoring

• Getting started:
  • Adenosine is generally very safe, but there is a low risk of causing asystole or VT.  A defibrillator should be immediately available.
  • Start a continuous 12-lead ECG before pushing adenosine.
  • Warn the patient that adenosine will make them feel horrible for a minute.
• Dose:
  • Typically: 6 mg –> 12 mg –> 18 mg.
  • May start with 3 mg if:
    • Administration via upper body central venous line.
    • Cardiac transplantation.
    • Carbamazepine or dipyridamole.
    • The patient is on other agents that cause AV node depression.
• Administer in a single 20 ml syringe: 🌊
  • First, ten cc of normal saline is drawn into the syringe.
  • Next, draw adenosine into the syringe (so adenosine is closer to the needle).
  • Rapidly push the whole syringe.  Use a large, proximal vein if possible (e.g., an antecubital vein is preferred over a hand vein).

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[2/4] contraindications, interactions, toxicity 

contraindications to adenosine

• Hemodynamically unstable (Stopping the patient's heart temporarily may cause an unstable patient to decompensate further).
• 2nd or 3rd-degree AV block.
• Sick sinus syndrome.
• Acute bronchospasm (IV adenosine has little effect on bronchospasm; avoid in patients with active asthma exacerbation). (31504425)
• Atrial flutter is strongly suspected (mild, relative contraindication): Adenosine may cause a rebound increase in AV conduction, leading to 1:1 conduction, or it may precipitate atrial fibrillation. (31504425) So, if atrial flutter is strongly suspected, using adenosine to confirm the diagnosis may be unwise.

drug interactions

• Dipyridamole: adenosine-uptake inhibitor.
• Methylxanthines (e.g., theophylline, caffeine): block adenosine receptors, to higher doses are required to achieve an antiarrhythmic effect.

toxicity

• Most toxicity will only last seconds:
  • Asystole for <5 seconds.
  • Dyspnea, impending doom.
  • Coronary artery steal may cause transient myocardial ischemia (adenosine is sometimes used for chemical myocardial stress testing). (Opie 2021)
• Longer lasting side effects:
  • Precipitation of AF.
  • Bronchoconstriction in asthmatic patients can last for 30 minutes. (Opie 2021)

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[3/4] indications & use

electrophysiological effects of adenosine

• Mechanistic effects:
  • [1] Adenosine activates adenosine receptors, leading to acetylcholine-sensitive K+ current in the atrium, sinus, and AV nodes (I-K1). This causes shortening of action potential duration, hyperpolarization, and slowing of normal automaticity. (Goodman & Gillman 14e)
  • [2] Adenosine inhibits the effects of elevated cAMP due to sympathetic stimulation. This inhibits DADs caused by sympathetic activity.
• Effects on the heart:
  • Slowing of the sinus rate.
  • Slowing of AV nodal conduction velocity and increased AV nodal refractoriness.

arrhythmias that may be terminated by adenosine

• Re-entrant arrhythmia using the AV node (e.g., AVNRT, AVRT).
• Rare cases of VT in structurally normal hearts (e.g., RVOT VT).
• Some atrial tachycardias (~10% may be adenosine-responsive).
• Sinus node reentry tachycardia.

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[4/4] pharmacology

• Adenosine is taken up by cells, with a half-life of seconds.

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normal action potential physiology

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myocardial action potential 

phase 4 (resting)

• K1 (inward rectifying) potassium channels are open.
• The resting membrane potential roughly equals Ek's (the Nerst equilibrium potential for K).
• Extracellular potassium concentration is the primary determinant of the resting membrane potential. (36601026)

phase 0 (depolarization)

• Voltage-gated Na channels open.
• The rate of depolarization determines the conduction velocity of the propagating action potential.

phase 1 (notch)

• Voltage-gated potassium channels create a repolarizing current (I-to).
• Atrial myocytes have a greater I-to current, limiting their action potential duration.

phase 2 (plateau)

• Balance of opposing currents:
  • Inward Ca current (I-CaL) which gradually diminishes.
  • Outwards K currents (I-Kr and I-Ks), which eventually dominate.

phase 3 (repolarization)

• Inward Ca current diminishes further (I-CaL).
• Outward K currents (I-Kr and I-Ks) repolarize the myocyte.
• K1 (inward rectifying) potassium channels re-open to maintain resting membrane potential.

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SA & AV node action potential

phase 4 (spontaneous diastolic depolarization)

• Gradual depolarization: Inward currents of Na and K (funny current, I-f) occur via hyperpolarization-activated cyclic nucleotide-gated channels (HCN).
  • Beta-1 stimulation leads to the opening of HCN channels and increased I-funny.
• Beyond -50 mV, voltage-gated T-type Ca channels allow inward Ca current (I-CaT), accelerating this process.
• The slope of phase 4 determines heart rate.

phase 0 (depolarization)

• L-type calcium channels open (I-CaL).
• These open slowly, resulting in a slow rate of depolarization and low conduction velocity. (36601026)

phase 3 (repolarization)

• Inactivation of Ca channels.
• Opening of delayed rectifier K channels (I-Kr via the HERG potassium channel).

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mechanisms of arrhythmogenesis

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enhanced automaticity

• Examples:
  • Sinus tachycardia (increased slope of phase 4 pacemaker cells).
  • Inappropriate sinus tachycardia (tx: beta-blockers).
  • Idiopathic ventricular tachycardia (some forms; tx with Na-channel blockers).
  • Focal atrial tachycardia.
  • Accelerated idioventricular rhythms.
• Potential treatment could include:
  • Beta-blockers indirectly reduce the funny current (If), decreasing the slope of phase 4 within pacemaker cells.
  • Na or Ca blockade increases the threshold for triggering an action potential.

EADs (early afterdepolarizations) causes TdP

• EAD occurs in phase 3 when the action potential is prolonged:
  • Reduced outward I-Kr, I-Ks, and I-K1
  • Increased inward I-NaL and I-CaL currents.
• Causes include:
  • Myocardial ischemia (causes reduced I-K).
  • Hypomagnesemia (decrease in Na/K-ATPase activity causes the resting membrane potential to be less negative, which slows the rate of depolarization).
  • Hypokalemia (severe hypokalemia inhibits delayed rectifier K channels, prolonging the action potential).
  • Hypocalcemia (prolongs the action potential).
  • Drugs that inhibit HERG K channels.
  • Sympathetic stimulation (increases I-CalL current).
• ECG findings:
  • QT prolongation.
  • Torsade de pointes.
• Treatment may include:
  • Shorting action potential duration (e.g., heart acceleration with isoproterenol or pacing).
  • Shorting action potential duration with Ib sodium channel blockers.
  • Mg2+ can inhibit triggered beats by blocking Ca2+ channels.
  • Increasing the depolarization threshold with sodium channel blockers.

DAD (delayed afterdepolarizations), one type of triggered activity

• This occurs during the early stage of phase 4, essentially representing a failure of phase 4 to establish a stable resting potential.
• DAD is due to intracellular calcium overload. This upregulates the electrogenic 3Na/Ca exchanger, bringing the membrane to threshold potential and ‘triggering' an action potential. (36601026)
• Causes of DAD include:
  • Adrenergic stimulation (increases I-CaL).
  • Myocardial ischemia (causes spontaneous Ca release).
  • Digoxin toxicity.
  • Hypokalemia (severe hypokalemia inhibits delayed rectifier K channels, prolonging the action potential).
• Clinical arrhythmia syndromes:
  • Catecholaminergic polymorphic VT.
  • Digoxin-induced arrhythmias.
  • RVOT tachycardia.
• Treatment may include:
  • Calcium channel blockers.
  • Beta-blockers or diltiazem (indirectly reduce intracellular calcium).
  • Sodium channel-blocking drugs (which elevate the threshold required to produce the abnormal upstroke). (Goodman & Gillman 14e)

re-entry

• It involves circular activity, which may include either a micro-reentrant or macro-reentrant circuit.
• Often responds to electrical cardioversion.
• Medical therapy may involve:
  • Prolonging the effective refractory period:
    • Blocking Na channels directly (class Ia and Ic activity).
    • Prolonging action potential duration (class III activity).
  • Accelerating conduction through slow conduction: Lidocaine (Ib).

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questions & discussion

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