Pharmacologic Management for Ventricular Arrhythmias: Overview of Anti-Arrhythmic Drugs
Abstract
:1. Introduction
2. Drug Classification
3. Class I Medications: Sodium Channel Blockade
3.1. Class IA
3.1.1. Procainamide
3.1.2. Quinidine
3.1.3. Disopyramide
3.2. Class IB
3.2.1. Lidocaine
3.2.2. Mexiletine
3.3. Class IC
Flecainide and Propafenone
4. Class II Medications: Beta Blockade
5. Class III Medications: Potassium Channel Blockade
5.1. Amiodarone
5.2. Dronedarone
5.3. Dofetilide
5.4. Sotalol
6. Class IV Medications: Calcium Channel Blockade
7. Medications Outside of the Classification System
7.1. Ranolazine
7.2. Adenosine
7.3. Digoxin
7.4. Isoproterenol
7.5. Ivabradine
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drug | Mechanism of Action | Channels Effected | Dosing | Contraindications | Important Side Effects/Considerations |
---|---|---|---|---|---|
Class I—Sodium Channel Agents | |||||
Class IA | |||||
Quinidine | • Blockade of the rapid inward sodium depolarization current in a use dependent fashion and prolongation of repolarization via blockade of the delayed rectifier potassium channel in reverse use-dependence fashion. | INa, Ito, IKr, M, α | PO only: Sulfate 300 mg-max tolerated q6h–q12h, Gluconate 324–648 mg q8h–q12h | Severe AV node dysfunction, Thrombocytopenia or underlying platelet dysfunction. Prolonged QT. | • Negative Ionotropy, profound hypotension. |
• They slow phase 4 depolarization during spontaneous automaticity. | • Can be pro-arrhythmogenic at therapeutic doses | ||||
• The net effect is preferential prolongation of action potential duration at fast heart rates, prolonged effective refractory period (ERP), and decreased automaticity | • Can prolong QT | ||||
Procainamide | INa, IKr | IV: 10–17 mg/kg; PO: 500–1000 mg q6h | Severe AV node dysfunction, underlying Systemic Lupus Erythematosus. Prolonged QT. | • Can cause Drug-induced Systemic Lupus Erythematosus. | |
• Can cause agranulocytosis at therapeutic doses requrining CBC monitoring | |||||
• Breaks down into toxic metabolite ‘NAPA’ which requires monitoring, especially when on IV formulations. | |||||
• Can cause negative inotropy and profound hypotension. | |||||
• Can be pro-arrhythmogenic at therapeutic doses. | |||||
• Can prolong QT | |||||
Disopyramide | INa, Ito, IKr, IK(ATP), M | PO only: 150 mg q6h | Severe AV node dysfunction | • Negative Ionotropy, profound hypotension. | |
• Can be pro-arrhythmogenic at therapeutic doses | |||||
• Significant Anticholinergic side effects | |||||
• Can prolong QT | |||||
Class IB | |||||
Lidocaine | • Use dependent blockade of the inward sodium depolarization current thereby decreasing maximal velocity of depolarization. | INa | IV only: 1 mg/kg bolus followed by 1–3 mg/min | Severe AV node dysfunction | • CNS side effects including seizures, coma, or death requiring frequent blood level monitoring. |
Mexiletine | • Shortening of action potential and ERP duration thereby decreasing automaticity of phase 4 depolarization. | INa | PO only: 150 mg q8h | • Higher incidence of Drug-Induced Liver Injury. | |
• Can cause tremors and ataxia | |||||
• Has high rates of GI distress. | |||||
Class IC | |||||
Flecainide | • Most potent among the inward sodium blocking agents thereby markedly reducing the action potential conduction velocity in atrial, ventricular, and specialized conduction tissues. | INa, IKr, IKur | PO only: 50–200 mg q12h (can increase to q8h) | Structural Heart Disease or Reduced Ejection Fraction | • Can be pro-arrhythmogenic at therapeutic doses. |
• Blocking occurs in a use-dependent fashion with minimal effect on overall action potential duration or ERP. | • PR and QRS prolongation | ||||
Propafenone | INa, IKr, IKur, β, α | PO only: IR release 150–300 mg q8h; ER release: 225–425 mg q12h | • May cause the slowing of atrial arrhythmias leading to dangerous 1:1 conduction. | ||
Class II—Beta Blockers | |||||
Propranolol | • Blunting sympathetic activity on cardiac tissue, most notably through decreasing phase 4 depolarization thereby decreasing automaticity via decreased conduction velocity and increased ERP within the AV-node decreasing reentry | β1, β2, INa | IV: 1–3 mg boluses q5min, PO: 10–160 mg q6h–q12h | Severe AV node dysfunction, Sick Sinus Syndrome | • Can cause severe bradycardia and precipitate cardiogenic shock |
Metoprolol | β1 | IV: 5mg q5min ×3, PO: Tartrate 12.5–200 mg q6h–q12h, Succinate 12.5–200 mg q12h–q24h | |||
Nadolol | β1, β2 | PO only: 40–320 mg qDay | |||
Carvedilol | β1, β2, α | PO only: 3.125–25 mg q12h | |||
Class III—Potassium Channel Agents | |||||
Amiodarone | • Primarily through blockade of the delayed rectifier potassium channel effectively prolonging repolarization and increasing the ERP to decrease the likelihood of reentry. | INa, ICa, IKr, IK1, IKs, Ito, β, α | IV: 150–300 mg bolus, 0.5–1 mg/min (1 mg/min for 6 h then 0.5 mg/min for 18 h), PO: initial 400 mg q12h then taper to as low as 100 mg q24h if needed | Pre-existing Thyroid, Liver, and Pulmonary Disease | • Requires biannual TSH and LFT monitoring for thyroid/liver toxicity. |
• Additionally, amiodarone has mechanistic overlap with all other classes of antiarrhythmics and has vasodilatory and negative inotropic effects. | • Requires annual PFT monitoring for pulmonary fibrosis. | ||||
• Can cause skin photosensitivity. | |||||
• Can cause corneal microdeposits effecting vision | |||||
Sotalol | • Sotalol is a racemic mixture of d- and l- sotalol with unique pharmacologic effects exhibiting class II (nonselective ß-blocker) properties. | IKr, β1, β2 | IV: 75 mg q12h, PO: 80–120 mg q12h | Prolonged QT | • Profound QT prolongation, must complete load under observation in hospital with EKG monitoring (although emerging data to support rapid IV loading) |
• Additionally, to class III inhibition of delayed potassium rectifier channel resulting in an increase in action potential duration and effective refractory period. | • In patients with advanced heart failure, Sotalol can precipitate cardiogenic shock. | ||||
Dofetilide | • Specific class III antiarrhythmic which blocks the delayed outward rectifying potassium current thereby increasing the effective refractory period (ERP) in a reverse use-dependence fashion without delaying intracardiac conduction. | IKr | PO only: 500 mcg q12h | ||
Class IV—Calcium Channel Blockers | |||||
Verapamil | • The non-dihydropyridine calcium channel antagonists, verapamil and diltiazem, exhibit antiarrhythmic effects predominately at the AV-node via blocking of slow inward Ca current. | ICa-L | IV: 2.5–5 mg q15–30 mins as tolerated, PO: IR release 120 mg q8h; ER release: 120–480 mg q12h–q24h | Severely Depressed EF (<35%), Severe AV node dysfunction | • Negative inotropy, can precipitate cardiogenic shock. |
• Blocking of inward Ca current thereby prolongs the effective refractory period (ERP) with minimal effects on atrial/ventricular myocytes or the his-purkinje system | |||||
Diltiazem | • Although less common, these agents can cause blockade of slow inward calcium channels on some sensitive fascicular tissues. | ICa-L | IV: 0.25 mg/kg bolus followed by 5–15 mg/h as tolerated, PO: IR release: 30–120 mg q6h–q12h, ER release: 30–240 mg q12h–q24h | Severely Depressed EF (<35%), Severe AV node dysfunction | • Negative inotropy, can precipitate cardiogenic shock. |
No Class in Vaughn-Williams | |||||
Ranolazine | • Ranolazine exhibits features most similar to amiodarone, blocking inward depolarizing and outward repolarizing currents affecting sodium, potassium, and calcium channels. | INa, IKr | PO only: 500–1000 mg q12h | Hepatic Cirrhosis | • Can prolong QT |
• The net effect is a concentration dependent prolongation of action potential duration and decreased in early after depolarizations. | |||||
Ivabradine | • Ivabradine functions in a use-dependent fashion at the SA node inhibiting the mixed sodium-potassium current (If) thereby slowing depolarization of the pacemaker potential and lowering the heart rate | If | PO: 2.5–5 mg q12h | Bradycardia, heart block, sick sinus syndrome | • Symptomatic bradycardia, increase risk of atrial fibrillation |
Adenosine | • Adenosine is an endogenous nucleoside that acts on adenosine receptors primarily located on the specialized conduction tissues of the SA and AV nodes resulting in activation of potassium channels and hyperpolarization and decreased automaticity of these tissues. | Activation of A1, A2, and IKATP | IV only: initial 6mg dose followed by 12 mg × 2 q1 minutes if peripherally administered. | Use in pre-excitation syndromes (Wolff-Parkinson-White) can precipitate VA’s. | • Can cause temporary, but profound, chest discomfort. |
50% dose reduction if via central line |
Arrhythmia Type | Etiology | Medication | Evidence |
---|---|---|---|
Brugada Syndrome | Brugada syndrome is an autosomal dominant genetic disorder with variable expression characterized by abnormal findings on the surface electrocardiogram (ECG) with an increased risk of ventricular tachyarrhythmias and sudden cardiac death. Most commonly, Brugada is the result of defective sodium channels leading the reduction of sodium inflow current and a subsequent reduction in the duration of action potentials. | First Line: Quinidine | Belhassen et al. [32] |
Marquez et al. [31] | |||
Long QT Syndrome | Long QT syndromes may be congenital or acquired and represent a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG). These findings lead to an increased risk of polymorphic VT, which can be life-threatening. This review focuses on congenital LQT in the structural normal heart. | ||
Long QT1/Long QT2 | Both Long QT1 and Long QT2 are caused by mutations in genes encoding potassium channel leading to a defect in inward potassium current and QT prolongation. Their major difference is LQT1 effects KCNQ1 gene most commonly leading to a defect in slow potassium current (Iks) while LQT2 effects KCNH2 gene most commonly leading to a defect in rapid potassium current (Ikr). The overall effect and treatment remains the same for both types. | Beta Blockers (Propranolol/Nadolol preferred) | Bennett et al. [88] |
Schwartz et al. [87] | |||
Long QT3 | Unlike LQT1/LQT2, LQT3 is caused by a defect in SCN5A gene most commonly. This mutation leads to a defect in a cardiac sodium channel and subsequently increases the delayed Na+ inward current and, therefore, prolonging the action potential duration. As the primary effect is on sodium channels, it is amenable to treatments with mechanism of action on these channels. | First Line: Beta Blockers | Wilde et al. [89] |
Second Line: Mexiletine | Mazzanti et al. [56] | ||
Salvage Therapy: Flecainide/Propafenone | Moss et al. [63] | ||
Belardinelli et al. [62] | |||
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) | CVPT is an often familial syndrome leading to exercise-induced polymorphic VT in childhood/adolescents. CVPT most commonly arises due to mutations in one of two genes: the cardiac ryanodine receptor gene (an autosomal dominant form) and the calsequestrin 2 gene (autosomal recessive). Both mutations act by inducing intracellular calcium release and causing a intracellular calcium overload. This overload leads to delayed afterdepolarization, which can induce ventricular arrhythmias. | First Line Beta Blockers (Nadolol with strongest evidence) | Priori et al. [86] |
Second Line: Calcium Channel Blockers | Leenhardt et al. [85] | ||
Rosso et al. [126] | |||
Idiopathic Left Ventricular Tachycardia (ILVT) | ILVT is an idiopathic form a VT presenting in young adulthood of unclear etiology. Current studies indicate that this arrhythmia is caused by localized reentry circuit close to the posterior fascicle. | Calcium Channel Blockers | Belhassen et al. [121] |
Ohe et al. [123] |
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Larson, J.; Rich, L.; Deshmukh, A.; Judge, E.C.; Liang, J.J. Pharmacologic Management for Ventricular Arrhythmias: Overview of Anti-Arrhythmic Drugs. J. Clin. Med. 2022, 11, 3233. https://doi.org/10.3390/jcm11113233
Larson J, Rich L, Deshmukh A, Judge EC, Liang JJ. Pharmacologic Management for Ventricular Arrhythmias: Overview of Anti-Arrhythmic Drugs. Journal of Clinical Medicine. 2022; 11(11):3233. https://doi.org/10.3390/jcm11113233
Chicago/Turabian StyleLarson, John, Lucas Rich, Amrish Deshmukh, Erin C. Judge, and Jackson J. Liang. 2022. "Pharmacologic Management for Ventricular Arrhythmias: Overview of Anti-Arrhythmic Drugs" Journal of Clinical Medicine 11, no. 11: 3233. https://doi.org/10.3390/jcm11113233