Antiarrhythmic agent
Encyclopedia
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
(cardiac arrhythmias), such as atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
, atrial flutter
Atrial flutter
Atrial flutter is an abnormal heart rhythm that occurs in the atria of the heart. When it first occurs, it is usually associated with a fast heart rate or tachycardia , and falls into the category of supra-ventricular tachycardias. While this rhythm occurs most often in individuals with...
, ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
, and ventricular fibrillation
Ventricular fibrillation
Ventricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...
.
Many attempts have been made to classify antiarrhythmic agents. The problem arises from the fact that many of the antiarrhythmic agents have multiple modes of action, making any classification imprecise.
Singh Vaughan Williams classification
The Singh Vaughan Williams classification, introduced in 1970 based on the seminal work of Bramah N. Singh in his doctoral thesis at Oxford where Vaughan Williams was his advisor and on subsequent work by Singh and his colleagues in the United States, is one of the most widely used classification schemes for antiarrhythmic agents. This scheme classifies a drug based on the primary mechanism of its antiarrhythmic effect. However, its dependence on primary mechanism is one of the limitations of the Singh-VW classification, since many antiarrhythmic agents have multiple action mechanisms. AmiodaroneAmiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
, for example, has effects consistent with all of the first four classes. Another limitation is the lack of consideration within the Singh-VW classification system for the effects of drug metabolites. Procainamide
Procainamide
Procainamide INN is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, classified by the Vaughan Williams classification system as class Ia.-History:...
—a class Ia agent whose metabolite N-acetyl procainamide
N-Acetyl procainamide
N-Acetylprocainamide is the N-acetylated metabolite of procainamide. It is a Class III antiarrhythmic agent, whereas procainamide is a Class Ia antiarrhythmic drug...
(NAPA) has a class III action—is one such example. A historical limitation was that drugs such as digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
and adenosine – important antiarrhythmic agents – had no place at all in the VW classification system. This has since been rectified by the inclusion of class V.
There are five main classes in the Singh Vaughan Williams classification of antiarrhythmic agents:
- Class I agents interfere with the sodiumSodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
(Na+) channel. - Class II agents are anti-sympathetic nervous systemSympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
agents. Most agents in this class are beta blockers. - Class III agents affect potassiumPotassiumPotassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
(K+) efflux. - Class IV agents affect calciumCalciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
channels and the AV node. - Class V agents work by other or unknown mechanisms.
Overview table
| Class | Known as | Examples | Mechanism | Clinical uses |
|---|---|---|---|---|
| Ia | fast-channel blockers-Affect QRS complex |
|
(Na+) channel block (intermediate association/dissociation) |
Vagus nerve The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves... overactivity) Wolff-Parkinson-White syndrome Wolff–Parkinson–White syndrome is a disorder of the heart in which the ventricles of the heart contract prematurely due to an accessory pathway known as the bundle of Kent. This accessory pathway is an abnormal electrical communication from the atria to the ventricles... |
| Ib- Do not affect QRS complex |
Lidocaine Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino... Phenytoin Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels... Mexiletine Mexiletine belongs to the Class IB anti-arrhythmic group of medicines. It is used to treat arrhythmias within the heart, or seriously irregular heartbeats. It slows conduction in the heart and makes the heart tissue less sensitive. Dizziness, heartburn, nausea, nervousness, trembling, unsteadiness... Tocainide Tocainide is a class Ib antiarrhythmic agent. It is no longer sold in the United States.Quick look at the PharmacokineticsTocainide is a lidocaine analog, that does not have significant 1st pass metabolism. It is found in two enantiomers. The R isomer is 4x as potent as the S. Oral... |
(Na+) channel block (fast association/dissociation) |
Myocardial infarction Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die... , though this practice is now discouraged given the increased risk of asystole Asystole In medicine, asystole is a state of no cardiac electrical activity, hence no contractions of the myocardium and no cardiac output or blood flow... Ventricular tachycardia Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart... Atrial fibrillation Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction... |
|
| Ic |
Flecainide Flecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias . It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation , paroxysmal supraventricular tachycardia Flecainide acetate is a class Ic antiarrhythmic agent used to... Propafenone Propafenone is a class Ic anti-arrhythmic medication, which treats illnesses associated with rapid heart beats such as atrial and ventricular arrhythmias.-Mechanism of action:... Moricizine Moricizine is a phenothiazine derivative with Vaughan Williams class Ic antiarrhythmic properties. It undergoes extensive first-pass metabolism, has a bioavailability of 34-38 percent, and is 95 percent bound to plasma proteins. Moricizine is extensively metabolized and may have pharmacologically... |
(Na+) channel block (slow association/dissociation) |
Electrical conduction system of the heart The normal intrinsic electrical conduction of the heart allows electrical propagation to be transmitted from the Sinoatrial Node through both atria and forward to the Atrioventricular Node. Normal/baseline physiology allows further propagation from the AV node to the ventricle or Purkinje Fibers... . |
|
| II | Beta-blockers |
Esmolol Esmolol is a cardioselective beta1 receptor blocker with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages.... Timolol Timolol maleate is a non-selective beta-adrenergic receptor blocker.-Uses:In its oral form , it is used:* to treat high blood pressure* to prevent heart attacks* to prevent migraine headaches... Metoprolol Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate... Bisoprolol Bisoprolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. More specifically, it is a selective type β1 adrenergic receptor blocker. The FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets as a new molecular... |
beta blocking Beta blocker Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,... Propranolol also shows some class I action |
Myocardial infarction Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die... mortality |
| III |
Amiodarone Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985... Sotalol Sotalol is a drug used in individuals with rhythm disturbances of the heart, and to treat hypertension in some individuals. It is a non-selective competitive β-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels... Ibutilide Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory... Dofetilide Dofetilide is a class III antiarrhythmic agent.It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide.... Dronedarone Dronedarone is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages... E-4031 E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type.- Chemistry :E-4031 is a synthetized toxin that is a methanesulfonanilide class III antiarrhythmic drug.- Target :... |
K+ channel blocker Potassium channel blocker Potassium channel blockers are agents which interfere with conduction through potassium channels.-Arrhythmia:Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic agents.-Mechanism:... Sotalol Sotalol Sotalol is a drug used in individuals with rhythm disturbances of the heart, and to treat hypertension in some individuals. It is a non-selective competitive β-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels... is also a beta blocker Beta blocker Beta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,... Amiodarone Amiodarone Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985... has Class I, II, and III activity |
|
|
| IV | slow-channel blockers |
Verapamil Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine... Diltiazem Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia.... |
Ca2+ channel blocker Calcium channel blocker A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with... |
Atrial fibrillation Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction... |
| V |
Digoxin Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin... Magnesium sulfate Magnesium sulfate is a chemical compound containing magnesium, sulfur and oxygen, with the formula MgSO4. It is often encountered as the heptahydrate epsomite , commonly called Epsom salt, from the town of Epsom in Surrey, England, where the salt was distilled from the springs that arise where the... |
Work by other or unknown mechanisms (Direct nodal inhibition). | Used in supraventricular arrhythmias, especially in Heart Failure with Atrial Fibrillation, contraindicated in ventricular arrhythmias. Or in the case of Magnesium Sulfate, used in Torsade de Pointe. | |
Class I agents
The class I antiarrhythmic agents interfere with the sodium channelSodium channel blocker
Sodium channel blockers are agents that impair conduction of sodium ions through sodium channels.-Extracellular:The following naturally produced substances block sodium channels by binding to and occluding the extracellular pore opening of the channel:...
.
Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s.
Class I agents are called Membrane Stabilizing agents. The 'stabilizing' is the word used to describe the decrease of excitogenicity of the plasma membrane which is brought about by these agents. (Also noteworthy is that a few class II agents like propranolol also have a membrane stabilizing effect
Membrane stabilizing effect
Membrane stabilizing effects involve the inhibition or total abolishing of action potential from being propagated across the membrane. This phenomenon is common in nerve tissues as they are the carrier of impulses from the periphery to the central nervous system. Membrane stabilization is the...
.)
Class I agents are divided into three groups (Ia, Ib and Ic) based upon their effect on the length of the action potential.
- Ia lengthens the action potential (right shift)
- Ib shortens the action potential (left shift)
- Ic does not significantly affect the action potential (no shift)
Class II agents
Class II agents are conventional beta blockers. They act by blocking the effects of catecholamineCatecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart. These agents are particularly useful in the treatment of supraventricular tachycardia
Supraventricular tachycardia
Supraventricular tachycardia is a general term that refers to any rapid heart rhythm originating above the ventricular tissue. Supraventricular tachycardias can be contrasted to the potentially more dangerous ventricular tachycardias - rapid rhythms that originate within the ventricular...
s. They decrease conduction through the AV node.
Class II agents include atenolol, esmolol
Esmolol
Esmolol is a cardioselective beta1 receptor blocker with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages....
, propranolol, and metoprolol
Metoprolol
Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
.
Class III agents
Class III agents predominantly block the potassium channelsPotassium channel blocker
Potassium channel blockers are agents which interfere with conduction through potassium channels.-Arrhythmia:Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic agents.-Mechanism:...
, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory). Drugs include: amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
, ibutilide
Ibutilide
Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory...
, sotalol
Sotalol
Sotalol is a drug used in individuals with rhythm disturbances of the heart, and to treat hypertension in some individuals. It is a non-selective competitive β-adrenergic receptor blocker that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels...
, dofetilide
Dofetilide
Dofetilide is a class III antiarrhythmic agent.It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide....
, and dronedarone
Dronedarone
Dronedarone is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages...
.
Class IV agents
Class IV agents are slow calcium channel blockerCalcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...
s. They decrease conduction through the AV node, and shorten phase two (the plateau) of the cardiac action potential. They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility.
Class IV agents include verapamil
Verapamil
Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
and diltiazem
Diltiazem
Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia....
.
Other agents ("Class V")
Since the development of the original Vaughan-Williams classification system, additional agents have been used that don't fit cleanly into categories I through IV.Some sources use the term "Class V". However, they are more frequently identified by their precise mechanism.
Agents include:
- DigoxinDigoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
, which decreases conduction of electrical impulses through the AV node and increases vagal activity via its central action on the central nervous system. - Adenosine
- Magnesium sulfateMagnesium sulfateMagnesium sulfate is a chemical compound containing magnesium, sulfur and oxygen, with the formula MgSO4. It is often encountered as the heptahydrate epsomite , commonly called Epsom salt, from the town of Epsom in Surrey, England, where the salt was distilled from the springs that arise where the...
, which has been used for torsades de pointesTorsades de pointesTorsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
.
Sicilian Gambit classification
Another approach, known as the "Sicilian Gambit", placed a greater approach on the underlying mechanism.It presents the drugs on two axes, instead of one, and is presented in tabular form. On the Y axis, each drug is listed, in approximately the Vaughan Williams order. On the X axis, the channels, receptors, pumps, and clinical effects are listed for each drug, with the results listed in a grid. It is therefore not a true classification in that it does not aggregate drugs into categories.
See also
- Action potentialAction potentialIn physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
- Cardiac action potentialCardiac action potentialIn electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart....
- Cardiac action potential
- ElectrocardiogramElectrocardiogramElectrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
- Proarrhythmic agent