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Antiarrhythmic drugs

[edit]

Below is a table with detailed descriptions of medications under the Vaughan Williams classification that are used in the treatment of cardiac dysrhythmias.

Vaughan Williams Classification Drug Name and Approval Date Indications for Drug Use Mechanism of Action (MOA) Animal Model
Class Ia Procainamide Hydrochloride (Procanbid extended-release tablets)

Approved January 1996 (Warner-Lambert)

  • Ventricular ectopy and tachycardia, atrial fibrillation, and re-entrant and automatic supraventricular tachycardia[1]
  • Drawbacks of the Drug:
    • Causes gastrointestinal disturbances, lupus syndrome, ventricular tachydysrhythmias, and aggravates pre-existing abnormalities in impulse initiation and propagation[1]
    • Initiates leukopenia and/or agranulocytosis, which are serious hematologic disorders
    • Prolongs QT interval of action potential and increases the risk of torsade de points[2]
  • Prolongs refractoriness of the atria, AV node, and the His-Purkinje fibers, and prolongs the HV intervals of the His-Purkinje System[1]
  • Increases concentration-depedent action potential duration, refractory period, and the diastolic threshold potential[3]
  • In addition to blocking the INa current (Na+ channel blocker), it inhibits the IKr rectifier K+ current[2]
  • Induces a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes[4]
  • Ventricular tachycardia induced through the left anterior descending coronary artery in dogs (proximal occlusion ligation)
  • Ectopic tachycardia induced by chloroform-adrenaline in cats[5]
  • Perfused hearts of guinea-pigs and rabbits[2]
Class Ib Ranolazine (Ranexa)

Initial U.S. Approval in 2006 for oral use as an antianginal agent

Antiarrhythmic properties are also observed, yet is not approved for atrial or ventricular fibrillation in the U.S.

  • Chronic angina and ventricular fibrillation (VFib has not been approved yet, but multiple research articles support its effects[6][7][8]
  • Prolongs action potential duration, with corresponding QT interval prolongation on electrocardiography
  • Blocks the INa current and prevents calcium overload caused by the hyperactive INa current, thus it stabilizes the membrane and reducing excitability[8]
  • Exhibits its effects on the delayed rectifier current (hERG/IKr Potassium channels), inhibits the late inward Na+ current (INa), moderate inhibitor for CYP3A and P-gp (cyclosporine), stimulates myogenesis, reduces a pro-oxidant inflammation/oxidative condition, and activates the calcium signaling pathway[9]
  • Ventricular fibrillation in an isolated rabbit heart under hypoxia and reoxygenation conditions and in the presence of pinacidil, which is an ATP-dependent potassium channel opener[6]
  • Ventricular and atrial fibrillation were studied in Yorkshire pigs preanesthetized with telaol and xylazine and anesthetized with alpha-chloralose - the catheter was placed in the right atrium through the femoral vein for AFib and in the left ventricle via the left carotid artery for VFib[7]
Class Ic Propafenone (Rythmol)

Approved January 1998 (Knoll Pharmaceutical)

  • Paroxysmal atrial fibrillation
  • Inhibits sodium channel protein type 5 subunit alpha and potassium voltage-gated channel subfamily H member 2
  • Propafenone inhibits RyR2 channels in the open state, suppresses Ca2+ waves and prevents CPVT[10]
  • In Purkinje fibers, and, to some extent, myocardial fibers, propafenone reduces the fast inward current sustained by sodium ions, leading to propafenone's antiarrhythmic actions[11]
  • Beagle dogs of either sex were anesthetized, then the left carotid artery was isolated and a guide catheter inserted and positioned at the left coronary ostium under fluoroscopic control and infarction was induced through catheter balloon. Five or six days after myocardial infarction, animals were re-anesthetized and propafenone was administered[12]
Class II Metoprolol Succinate (Toprol-XL)

Approved January 1995 (for atrial fibrillation) (AstraZeneca)

  • Hypertension, angina pectoris, congestive heart failure, and atrial fibrillation[13]
  • Blocks ß1 adrenergic receptors of cardiomyocytes, thus it decreases the slope of phase 4 in the nodal action potential (reduces Na+ uptake) and prolongs repolarization of phase 3 (slows down K+ release)[13]
  • Suppresses the norepinephrine-induced increase in the sarcoplasmic reticulum (SR) Ca2+ leak and the spontaneous SR Ca2+ release, which are the major triggers for atrial fibrillation[13]
  • Inhibits adrenergic ß1 receptors of the pacemaker cells of the sinoatrial and atrioventricular nodes[14]
  • Atrial fibrillation induced in Yorkshire pigs and Boer goats by rapid atrial pacing (RAP) through implanted pacemakers[15]
  • Atrial fibrillation induced by trans-esophageal atrial burst pacing[13]
Class III Amiodarone Hydrochloride (Marketed as Cordarone and Pacerone)

Initial FDA Approval in 1985 for ventricular tachycardia and fibrillation as an oral tablet and in 1995 for atrial arrhythmia as an injection for intravenous use (Herendael 2010) International Medication System, Ltd., Zydus Pharmaceuticals USA Inc., Teva, Mylan, etc. (Currently on the market as a tablet for oral uptake and as an injection)

  • Reccurent ventricular fibrillation and recurrent hemodynamically unstable ventricular tachycardia, congestive heart failure, and atrial fibrillation (due to its effect on blocking the AV node, thus slowing the ventricular response rate)[16]
  • Also, it is well known to treat high grade ventricular ectopic activity (VEA) and sick sinus syndrome[17]
  • Clinical need to suppress atrial fibrillation and an attempt to maintain the sinus rythm lead to patient trials of amiodarone administration[16]
  • Amiodarone's transition from an antianginal agent (1962–1985) to the treatment of ventricular and supraventricular tachycardias originated due to its observed antiarrhythmic properties in Europe and South America in the early 1970s[18]
  • Drawbacks of the drug: Pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis)
  • Slows conduction rate and prolongs the refractory period of the SA and AV nodes[19]
  • Prolongs the refractory periods of the ventricles, bundles of His, and the Purkinje fibres without exhibiting any effects on the conduction rate[19]
  • Prolongs the myocardial cell action potential duration and refractory period and is a non-competitive ß-adrenergic inhibitor[20]
  • Inhibits the voltage-dependent K+ and Na+ channels, and exhibits calcium channel blocking and beta-blocking effects[21]
  • In the animal models below, amiodarone was administered intravenously
  • Ventricular arrhythmias:
    • Chloroform-induced ventricular fibrillation (VFib) in mice
    • VFib induced in rats via an I.V. injection of CaCl2
    • Ventricular tachycardia (VTach) evoked in rats and dogs by aconitine hydrochloride
    • Experimental arrhythmias (known as multifocal ventricular ectopic beats) were induced by an IV injection of epinephrine in anesthetized dog, IV injection of barium chloride in anesthetized rabbit and dog, and IV injection of a large dose of strophanthin in the morphinized dog[19]
    • Experimental VTach in guinea pigs by an induction of either oubtain or isoproterenol[19]
    • VFib after coronary artery ligation in dogs and rats.
  • Supraventricular arrhythmias
    • Acetylcholine-induced atrial fibrillation (AFib) in dogs, aconite-induced AFib in cats, and electrically induced AFib in dogs[19]
    • Mongrel dogs were anaesthetized with sodium pentobarbital and atropinized. Adrenoceptor stimulation was achieved by IV administration of adrenaline and measurement of increased blood pressure via a catheter inserted into the femoral artery, Increase in heart rate was measured after an IV administration of isoprenaline[22]
Class III Dronedarone (Multaq) Approved July 2009 (for paroxysmal or persistent atrial fibrillation or atrial flutter)

(Sanofi-aventis)

  • Paroxysmal or persistent atrial fibrillation and atrial flutter
  • Advantage: Non-iodinated amiodarone derivative and is more potent than amiodarone in treating cardiac arrhythmias (atrial and ventricular)[23]
  • Illustrates antiadrenergic effects, and prolongs atrioventricular nodal conduction, atrial and ventricular refractory periods, and the duration of paced QRS interval[24]
  • Effectively blocks K+ channels, and exhibits Ca2+ and Na+ channel, and beta-blocking effects[25]
  • Ventricular fibrillation (VFib) in anesthetized pigs induced by occlusion to the left coronary descending artery[26]
  • Ventricular tachycardia (VTach) and atrial fibrillation (AFib) in Mongrel dogs anesthetized with chloralose[27]
  • Ventricular fibrillation induced by coronary artery ligation in anaesthetised rats[23]
Class III Sotalol (Betapace AF Tablet) Initial U.S. Approval in 1992 for atrial fibrillation, atrial flutter, and ventricular arrhythmias for intravenous use (FDA Drug Indications and Usage, 1)

Approved February 2000

(Berlex Laboratories)

  • Atrial fibrillation, atrial flutter, and ventricular arrhythmia[28]
  • Blocks beta-adrenoreceptors and prolongs action potential duration
  • Decreases AV nodal conduction and increases the refractory periods of atrial and ventricular myocytes[28]
  • Actively inhibits the rapid component of the delayed rectifier potassium current, IKr[29]
  • Atrial fibrillation induced by an atrial electrical remodeling of rabbits by subjecting them to rapid atrial pacing of 600 beats/min for 2–4 weeks, which led to the atrial effective refractory period[30]
Class III Ibutilide Fumarate (Corvert IV Injection) Approved December 1995 Pharmacia & Upjohn
  • Irregular contractions of the heart and Atrial Fibrillation
  • Advantage:
    • No sedation necessary, alternative to electrical cardioversion.
    • Increased AERP and prevention of induced atrial flutter
  • Drawback:
    • Can cause Torsades de Pointes
  • Activates voltage-dependent L-type calcium channel subunit alpha-1C and voltage-dependent L-type calcium channel subunit beta-1. Inhibits potassium voltage-gated channel subfamily H member 2[31]
  • Activation of a late inward sodium current and possibly block of the rapidly activating component of the cardiac delayed rectifier potassium current that induces prolongation of the myocardial action potential duration[32]
  • In rabbit isolated papillary muscles, threshold, force of contraction, effective refractory period, and conduction time and rate were measured at varying pacing frequencies as ventricular muscle strips and right atria were exposed to ibutilide fumarate[33]
  • In conscious dogs, pacing-induced sustained atrial flutter over a 7-day post-surgical period was studied and the analysis of ibutilide (1.0 to 30.0 ug/kg) and d,l-sotalol (0.1 to 3.0 mg/kg) was measured. Ibutilide significantly increased atrial effective refractory period (AERP) and atrial flutter cycle length and terminated atrial flutter in all 12 cases[34]
Class IV Verapamil; IVAX; Generic equivalent of Knoll's Isoptin SR and Searle's Calan SR, Approved December 1997
  • Supraventricular tachycardia, angina, hypertension
  • Inhibits voltage-dependent L-type calcium channel subunits 1C (1D,1F, 1S and subunits beta-1-4)[35]
  • Verapamil is a calcium ion influx inhibitor and by inhibiting the L-type calcium channel it inhibits the transmembrane influx of ionic calcium into arterial smooth muscle as well as in conductile and contractile myocardial cells [36]
  • Verapamil was tested against electrically induced arrhythmias in conscious and anaesthetized rats. Stainless steel electrodes were permanently implanted into the left ventricle and fibrilloflutter was measured. As a result, verapamil showed dose dependent reduction in the arrhythmias induced by coronary occlusion as determined by reduction in arrhythmia score from control values that were measured[37]
Class IV Diltiazem Hydrochloride, Extended-Release Capsules; Biovail Laboratories; Approved January 2000
  • Angina pectoris, arrhythmia, hypertension
  • Inhibits voltage-dependent L-type calcium channel gamma-1 subunit[38]
  • By diltiazem being a calcium channel blocker, it inhibits the slow inward current, thus inhibiting the flow of calcium ions, causes excitation-contraction uncoupling in various myocardial tissues without changing action potential[39]
  • In halothane anesthetized guinea pigs, antiarrhythmic effects of diltiazem hydrochloride on adrenaline induced ventricular arrhythmias were examined. After infusion of diltiazem, arrhythmia was significantly reduced in comparison to the pre-drug control values[40]
  • Eight healthy horses were infused with diltiazem to determine the effects of diltiazem on cardiac rate and rhythm, left ventricular (LV) function, central hemodynamics, and peripheral blood flow. Cardiac effects of diltiazem were: intermittent depression of SA and AV nodes and slight impairment of systolic and diastolic LV function. Vascular effects of diltiazem were: arterial vasodilatation, increased blood flow of the limbs, and decreased systemic vascular resistance. Diltiazem may prove useful for heart rate control in horses with AF because of its shown inhibitory effects on AV nodal conduction[41]
First in Class Nesiritide (Natrecor); Scios; Approved August 2001
  • Acutely decompensated congestive heart failure
  • Particulate guanylate cyclase receptor agonist
  • Nesiritide is the recombinant form of the 32 amino acid human B-type natriuretic peptide. In vascular smooth muscle and endothelial cells, human BNP binds to the particulate guanylate cyclase receptor, thus, increases the concentrations of intracellular cGMP; leading to smooth muscle cell relaxation [42]
  • In 9 healthy, chronically instrumented, conscious dogs, hemodynamic and electrophysiologic parameters were assessed at baseline and during recombinant human BNP (hBNP), nesiritide, infusion. Infusion of recombinant hBNP increased hBNP and cyclic GMP plasma levels and reduced mean arterial pressure[43]
First in Class Ivabradine (Corlanor) Approved April 2015 Amgen S16257
  • Chronic heart failure
  • Advantage:
    • Does not affect resting epicardial coronary artery diameter and only attenuated its increase during exercise
  • Drawback:
    • Blurred vision, headaches, palpitations, vertigo, shortness of breath, bradycardia
  • In humans, ivabradine is an ‘open-channel’ blocker of hyperpolarization-activated cyclic nucleotide-gated channel isoform 4 (HCN4)[44] and I(f) current inhibitor
  • Twelve healthy aging Beagle dogs, regardless of sex, were anesthetized and a pacemaker was implantated through their external jugular vein. To induce age-related atrial fibrillation, all dogs underwent rapid right atrial pacing for 2 months. For those two months, Ivabradine was orally administered to six of the dogs during the pacing, while no drug was provided to the other six aging-AF dogs (to see how both compared—treated patients vs. untreated patients with AF). As a result, ivabradine effectively reduced the atrial fibrillation inducing rate,thus, making it a useful drug for the prevention of age-related AF[45]

References

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