Agents Used In Cardiac Arrhythmias

抗心律失常药 Agents used in cardiac arrhythmias 南开大学医学院 张京玲 王侃

Antiarrhythmias 目的 了解抗心律失常药的不良反 应与临床应用，掌握各类抗心 律失常药对心肌电生理活动的 影响及临床应用、不良反应。

Antiarrhythmias 内容 复习心肌电生理的有关基本知识： 包括动作电位各时相及离子运动。膜 反应性与传导速度的关系，不应期， 快反应，慢反应电活动，折返激动， 心律失常发生的原因。抗心律失常药 的分类：第Ⅰ类药（ A ， B ， C ）； 第Ⅱ类药；第Ⅲ类药；第Ⅳ类药。

Antiarrhythmias

内容  钠通 道阻滞 药（第Ⅰ类） 1 ）奎尼丁（ A ）：降低 膜对钠的通透性，也降低膜对钾，钙的通透性。表现 为降低自律性，减慢传导速度，延长有效不应期，减 弱心肌收缩力。这些作用在心电图上的反映。奎尼丁 用于治疗心房颤动，扑动，房性或室性心动过速等。 不良反应，奎尼丁晕厥及用药注意事项。 2 ）普鲁卡 因胺：与奎尼丁的比较 3 ）利多卡因（ B ）：促钾 外流，也抑钠内流，主要作用于希浦氏系统。降低自 律性，加速受损纤维的传导速度，缩短不应期和动作 电位时程。用于治疗室性心律失常，体内过程及不良 反应。 4 ）苯妥英钠：作用特点，与利多卡因的比较。 5. 心律平（普罗帕酮），氟卡胺等（ C ）的作用特 点。

Antiarrhythmias 受体阻 断药 （第Ⅱ类）普奈洛尔抗心律 失常作用与 受体阻滞及膜效应的关系。其 左旋体与右旋体的作用区别。临床应用。不 良反应及禁忌症。其它 受体阻断药的应用 。  延长动 作电位时 程的药物 （第Ⅲ类）胺碘 酮（乙胺碘呋酮），溴苄铵延长动作电位时 程和不应期。临床应用和不良反应。  钙通道 阻滞药 （第Ⅳ类）维拉帕米（戊脉 安）对心肌细胞膜，慢通道的选择性阻滞作 用。临床应用与不良反应。 

Antiarrhythmic agents I.

Electrophysiology of normal cardiac rhythm II. Mechanisms of arrhythmias III. Mechanisms of action of the antiarrhythmic agents IV. Classification of the antiarrhythmic agents

Antiarrhythmic agents I.

Sodium channel-blocking drugs (class Ⅰ) II. Beta adrenoceptor-blocking drugs (class Ⅱ) III. Drugs that prolong effective refractory period by prolonging action potential (class Ⅲ)

Antiarrhythmic agents • •

Calcium channel-blocking drugs (class Ⅳ) Principles in the clinical use of antiarrhythmic agents

Antiarrhythmic agents I.

Electrophysiology of normal cardiac rhythm 1. Ionic basis of membrane electrical activity 2. The active cell membrane 3. The effect of resting potential on action potentials

Antiarrhythmic agents 1. Ionic basis of membrane electrical activity The transmembrane potential of cardiac cells is determined by the concentrations of several ions— chiefly Na+, K+, and Ca2+—on either side of the membrane and the permeability of the membrane to each ion.

Antiarrhythmic agents These water-soluble ions are unable to freely diffuse across the lipid cell membrane in response to their electrical and concentration gradients; they require aqueous channels for such diffusion.

Antiarrhythmic agents Ions move across cell membranes in response to their gradients only at specific times during the cardiac cycle when these ion channels are open.

Antiarrhythmic agents The movements of these ions produce currents that form the basis of the cardiac action potential. Individual channels are relatively ion-specific, and the flux of ions through them is thought to be controlled by “gates” .

Antiarrhythmic agents Each type of channel has its own type of gate, and each type of gate is opened and closed by specific transmembrane voltage, ionic, or metabolic conditions.

Antiarrhythmic agents At rest, most cells are not significantly permeable to sodium, but at the start of each action potential, they become quite permeable. Similarly, calcium enters and potassium leaves the cell with each action potential.

Antiarrhythmic agents Therefore, the cell must have a mechanism to maintain stable transmembrane ionic conditions by establishing and maintaining ion gradients.

Antiarrhythmic agents The most important of these active mechanisms is the sodium pump— Na+/K+ ATPase. This pump and other active ion carriers contribute indirectly to the transmembrane potential by maintaining the gradients necessary for diffusion through channels.

Antiarrhythmic agents 1. The active cell membrane In normal atrial, Purkinje, and ventricular cells, the action potential upstroke (phase 0) is dependent on sodium current.

Antiarrhythmic agents Depolarization to the threshold voltage results in opening of the activation (m) gates of sodium channels. If the inactivation (h) gates of these channels have not already closed, the channels are now open or activated, and sodium permeability is markedly increased, greatly exceeding the permeability for any other ion.

Antiarrhythmic agents Most calcium channels become activated and inactivated in what appears to be the same way as sodium channels, but in the case of the most common type of cardiac calcium channel, the transitions occur more slowly and at more positive potentials.

Antiarrhythmic agents The action potential plateau (phases 1 and 2) reflects the turning off of most of the sodium current, the waxing and waning of calcium current, and the slow development of a repolarizing potassium current.

Antiarrhythmic agents Final repolarization (phase 3) of the action potential results from completion of sodium and calcium channel inactivation and the growth of potassium permeability, so that the membrane potential once again approaches the potassium equilibrium potential.

Antiarrhythmic agents 1. The effect of resting potential on action potentials A key factor in the pathophysiology of arrhythmias and the actions of antiarrhythmic drugs is the relationship between the resting potential of a cell and the action potentials that can be evoked in it.

Antiarrhythmic agents Because the inactivation gates of sodium channels in the resting membrane close over the potential range -75 to -55 mV, fewer sodium channels are “available” for diffusion of sodium ions when an action potential is evoked from a resting potential of -60 mV than when it is evoked from a resting potential of -80 mV.

Antiarrhythmic agents Important consequences of the reduction in peak sodium permeability include reduced upstroke velocity (called Vmax, for maximum rate of change of membrane voltage), reduced action potential amplitude, reduced excitability, and reduced conduction velocity.

Antiarrhythmic agents During the plateau of the action potential, most sodium channels are inactivated. Upon repolarization, recovery from inactivation takes place, making the channels again available for excitation.

Antiarrhythmic agents The time between phase 0 and sufficient recovery of sodium channels in phase 3 to permit a propagated response to external stimulus is the “refractory period.” Changes in refractoriness can be important in the genesis or suppression of certain arrhythmias.

Antiarrhythmic agents Another important effect of less negative resting potential is prolongation of this recovery time. The prolongation of recovery time is reflected in an increase in the effective refractory period.

Antiarrhythmic agents I.

Mechanisms of arrhythmias 1. Disturbances of impulse formation 2. Disturbances of impulse conduction 3. Both of above

Antiarrhythmic agents 1. Disturbances of impulse formation a. Increase of pacemaker rate b. Afterdepolarization and trigger action

Antiarrhythmic agents a. Increase of pacemaker rate The interval between depolarizations of a pacemaker cell is the sum of the duration of the action potential and the duration of the diastolic interval. Shortening of either duration results in an increase in pacemaker rate.

Antiarrhythmic agents The more important of the two, diastolic interval, is determined by three factors: b. Maximum diastolic potential, c. Slope of phase 4 depolarization, d. Threshold potential,

Antiarrhythmic agents Latent pacemakers are particularly prone to acceleration by the above mechanisms. All cardiac cells, may show repetitive pacemaker activity when depolarized under appropriate conditions, especially if hypokalemia is also present.

Antiarrhythmic agents a. Afterdepolarization and trigger action Afterdepolarizations are depolarizations that interrupt phase 3 (early afterdepolarizations, EADs) or phase 4 (delayed afterdepolarizations, DADs).

Antiarrhythmic agents Early afterdepolarizations (EADs) are usually exacerbated at slow heart rates and are thought to contribute to the development of long QT-related arrhythmias.

Antiarrhythmic agents Delayed afterdepolarizations (DADs) often occur when intracellular calcium is increased. They are exacerbated by fast heart rates and are thought to be responsible for some arrhythmias related to digitalis excess, to catecholamines, and to myocardial ischemia.

Antiarrhythmic agents 1. Disturbances of impulse conduction a. Simple conduction blockade b. Reentry

Antiarrhythmic agents a. Simple conduction blockade a. Atrioventricular nodal block b. Atrioventricular bundle branch block

Antiarrhythmic agents a. Reentry (circus movement) In which one impulse reenters and excites areas of the heart more than once. Some forms of reentry are strictly anatomically determined.

Antiarrhythmic agents In order for reentry to occur, three conditions must coexist: b. There must be an obstacle (anatomic or physiologic) to homogeneous conduction, thus establishing a circuit around which the reentrant wavefront can propagate;

Antiarrhythmic agents a. There must be unidirectional block at some point in the circuit, conduction must die out in one direction but continue in the opposite direction.

Antiarrhythmic agents a. Conduction time around the circuit must be long enough so that the retrograde impulse does not enter refractory tissue as it travels around the obstacle, the conduction time must exceed the effective refractory period.

Antiarrhythmic agents Importantly, reentry depends upon conduction that has been decreased by some critical amount, usually as a result of injury or ischemia.

Antiarrhythmic agents I.

Mechanisms of action of the antiarrhythmic agents 1. Reduce automaticity of ectopic pacemakers 2. Decrease afterdepolarization and tiggered activity

Antiarrhythmic agents 1. Modify conduction 2. Lengthening of the refractory period in reentry circuits to disable circus movement

Antiarrhythmic agents Antiarrhythmic drugs decrease the automaticity of ectopic pacemakers more than that of the sinoatrial node. They also reduce conduction and excitability and increase the refractory period to a greater extent in depolarized tissue than in normally polarized tissue.

Antiarrhythmic agents This is accomplished chiefly by selectively blocking the sodium or calcium channels of depolarized cells. Therapeutically useful channelblocking drugs have a high affinity for activated channels (during phase 0) or inactivated channels (during phase 2) but very low affinity for rested channels.

Antiarrhythmic agents These drugs block electrical activity when there is a fast tachycardia (many channel activations and inactivations per unit time) or when there is significant loss of resting potential (many inactivated channels during rest).

Antiarrhythmic agents This type of drug action is often described as use-dependent or state-dependent, ie, channels that are being used frequently, or in an inactivated state, are more susceptible to block.

Antiarrhythmic agents a. Sodium channel blockade b. Blockade of sympathetic autonomic effects in the heart c. Prolongation of the effective refractory period d. Calcium channel blockade

Antiarrhythmic agents I.

Classification of the antiarrhythmic agents The antiarrhythmic agents have traditionally been divided into four distinct classes on the basis of their dominant mechanism of action.

Antiarrhythmic agents Class Ⅰ action is sodium channel block They are frequently subdivided according to their effects on action potential duration or on the kinetics of their interactions with cardiac sodium channels:

Antiarrhythmic agents Class ⅠA drugs, such as quinidine, procainamide, disopyramide, lengthen the action potential duration; Class ⅠB drugs, such as lidocaine, mexiletine, tocainide, phenytoin, shorten the action potential duration; Class ⅠC drugs, such as flecainide, have no effect or may minimally increase action potential duration.

Antiarrhythmic agents Class Ⅱ action is sympathoplegic, drugs include those that reduce adrenergic activity in the heart, especially β-blockers. Class Ⅲ action is prolongation of the action potential duration—by block of outward or augmentation of inward currents.

Antiarrhythmic agents Class Ⅳ action is block of cardiac calcium currents, which may slow conduction and increase refractory period in calcium-dependent tissues such as the AV node.

Antiarrhythmic agents I.

Sodium channel-blocking drugs (class Ⅰ) 1. Quinidine 2. Procainamide 3. Disopyramide 4. Lidocaine*

Antiarrhythmic agents 1. 2. 3. 4. 5.

Phenytoin sodium Mexiletine Propafenone* Flecainide Encainide and lorcainide

Antiarrhythmic agents 1. Quinidine a. Pharmacological effects a.Depresses pacemaker rate, especially that of ectopic pacemakers b.Depresses conduction

Antiarrhythmic agents a.

b.

Depresses excitability, especially in depolarized tissue, depresses excitability and conduction in depolarized tissue more than in normal tissue. Lengthens ERP & APD, slows repolarization, reduces the maximum reentry frequency and can slow tachycardias

Antiarrhythmic agents a. Anti-muscarinic actions in the heart that inhibit vagal effects This can overcome some of its direct effects, sinus rate↑, A-V conduction↑

Antiarrhythmic agents α. α-R blocking properties, cause vasodilation and a reflex increase in sinoatrial nodal rate. They are most prominent after intravenous injection.

Antiarrhythmic agents a. Mechanism of action Quinidine can bind to and block activated sodium channels. Block of potassium channels with a reduction in repolarizing outward current is responsible for the effect of slowing repolarization.

Antiarrhythmic agents a. Pharmacokinetics Administration orally, rapidly absorbed from GI, 80% bound to plasma proteins, metabolized in the liver, 20% excreted unchanged in the urine, urinary excretion is enhanced in acid urine.

Antiarrhythmic agents T1/2 =6 hrs, may be longer in congestive heart failure or hepatic or renal disease, therapeutic concentration in plasma is 3 ～ 5 μg/ml, if serum concentration is ＞ 5 μg/ml, toxic effects may occur.

Antiarrhythmic agents a. Therapeutic use It has been used in nearly every form of arrhythmia. Its most common indications are atrial fibrillation and flutter and, occasionally, ventricular tachycardia.

Antiarrhythmic agents a. Toxicity a. Cardiac toxicity  HR↑, atrioventricular conduction↑, in atrial fibrillation or flutter, this effects on the AV node may result in an excessively high ventricular rate. This can be prevented by prior given of a calcium-blocker, a βblocker, or digitalis.

Antiarrhythmic agents Quinidine syncope, characterized by recurrent lightheadedness and episodes of fainting, recur frequently or even be fatal by degenerating into ventricular fibrillation. Precipitating arrhythmias or asystole

Antiarrhythmic agents Widening of the QRS duration by 30% by quinidine administration is usually considered premonitory of serious toxicity. Depress contractility and lower blood pressure

Antiarrhythmic agents a. Extracardiac  The most common adverse effects are gastrointestinal, diarrhea, nausea, and vomiting.  Cinchonism, headache, dizziness, tinnitus, diplopia, delirium and psychataxia  Rashes, angioneurotic edema, fever, hepatitis, and thrombocytopenia.

Antiarrhythmic agents 1. Procainamide a. Similar to those of quinidine, the most important difference between quinidine and procainamide is the less prominent antimuscarinic action of procainamide.

Antiarrhythmic agents  Procainamide has ganglionblocking properties, reduces peripheral vascular resistance and hypotension.

Antiarrhythmic agents a. Therapeutic use Like quinidine, is effective against most atrial and ventricular arrhythmias. It’s the drug of second choice, after lidocaine, for the treatment of sustained ventricular arrhythmias associated with acute myocardial infarction.

Antiarrhythmic agents a. Toxicity of procainamide  Cardiotoxic effects are similar to those of quinidine, new arrhythmias.  The most troublesome adverse effect of long-term therapy is a syndrome resembling lupus erythematosus, usually consisting of arthralgia and arthritis.

Antiarrhythmic agents 1. Disopyramide Very similar to those of quinidine, cardiac antimuscarinic effects are even more marked than those of quinidine. Effective in treatment of supraventricular and ventricular arrhythmias.

Antiarrhythmic agents Toxic concentration of disopyramide can cause cardiotoxic effects like quinidine. Atropine-like adverse effects, urinary retention, dry mouth blurred vision, constipation, and worsening of preexisting glaucoma.

Antiarrhythmic agents 1. Lidocaine It is used only by iv. It has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction.

Antiarrhythmic agents a. Pharmacological effects Rapidly blocks both activated and inactivated sodium channels, as a result, a large fraction ( ＞ 50%) of the unblocked sodium channels become blocked during each action potential in purkinje fibers and ventricular cells,

Antiarrhythmic agents They have long plateaus and correspondingly long periods of inactivation. During diastloe, most of the sodium channels in normally polarized cells rapidly become drug-free.

Antiarrhythmic agents Since lidocaine may shorten the action potential duration, diastole may be prolonged, thereby extending the time available for recovery.

Antiarrhythmic agents a. Therapeutic use It is the agent of choice for suppression of recurrences of ventricular tachycardia and fibrillation after termination of the arrhythmia by cardioversion.

Antiarrhythmic agents a. Toxicity of lidocaine a. Cardiac It’s one of the least cardiotoxic of the currently used sodium channel blockers, in large doses, lidocaine may cause hypotension, partly by depressing myocardial contractility.

Antiarrhythmic agents a. Extracardiac The most common adverse effects are neurological, paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions.

Antiarrhythmic agents 1. Phenytoin sodium 2. Mexiletine

Antiarrhythmic agents 1. Propafenone Its spectrum of action is very similar to that of quinidine, its potency as a sodium channel blocker is similar to that of flecainide, used primarily for supraventricular arrhythmias, the most common adverse effects are a metallic taste and constipation, arrhythmia exacerbation.

Antiarrhythmic agents I.

Beta adrenoceptor-blocking drugs (class Ⅱ) 1. Propranolol 2. Metoprolol 3. Esmolol

Antiarrhythmic agents β-R antagonists are effective in treatment of both supraventricular and ventricular arrhythmias. By increasing the atrioventricular nodal refractory period, it slows ventricular response rates in atrial flutter and fibrillation.

Antiarrhythmic agents Reduce ventricular ectopic beats, particularly if the ectopic activity has been precipitated by catecholamines. They prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction.

Antiarrhythmic agents Sotalol is a nonselective β-R blocking drug that prolongs the action potential (class Ⅲ action). Esmolol is a short-acting β-R blocker used primarily as an antiarrhythmic drug for intraoperative and other acute arrhythmias.

Antiarrhythmic agents I.

Drugs that prolong effective refractory period by prolonging action potential (class Ⅲ) 1. Amiodarone 2. Bretylium 3. Sotalol

Antiarrhythmic agents 1. Amiodarone For use only in serious ventricular arrhythmias, it’s very effective against a wide variety of arrhythmias. It has prominent adverse effects and unusual pharmacokinetic properties that make it a difficult drug to use appropriately.

Antiarrhythmic agents a. Pharmacological effects a. Cardiac effects  a powerful inhibitor of abnormal automaticity,  slows the sinus rate and A-V conduction, markedly prolongs the QT interval, and prolongs QRS duration,

Antiarrhythmic agents Markedly lengthens APD, increases atrial, A-V nodal, and ventricular refractory periods. It sustains its lengthening of APD quite well at fast heart rate. It has antianginal effects.

Antiarrhythmic agents a. Extracardiac effects Amiodarone causes peripheral vascular dilation.

Antiarrhythmic agents a. Mechanism of action  a very effective blocker of sodium channels  blocking K+ channels  a weak calcium channel blocker  a noncompetitive inhibitor of α-R & β-R

Antiarrhythmic agents Unlike quinidine, it has a low affinity for activated channels, combining instead almost exclusively with channels in the inactivated state. The sodium-blocking action of amiodarone is most pronounced in tissues that have long action potentials, frequent action potentials, or less negative diastolic potentials.

Antiarrhythmic agents a. Therapeutic use a. Very effective against both supraventricular and ventricular arrhythmias b. Low maintenance dosages (100200 mg/d) can be used against paroxysmal atrial fibrillation

Antiarrhythmic agents a. Quite effective against supraventricular arrhythmias in children, ralatively safe b. Iv is used in patients with recurrent ventricular tachycardia or fibrillation, with initial doses of 150 mg over 30’ or 1g over the first day, arrhythmias are often promptly suppressed.

Antiarrhythmic agents a. Toxicity a. Cardiac toxicity In patients with sinus or A-V nodal disease, drug causes bradycardia or heart block.

Antiarrhythmic agents a. Extracardiac toxicity  Yellowish-brown microcrystals deposits appear in the cornea, a few weeks after initiation of therapy  Photodermatitis results from skin deposits, grayish-blue skin discoloration

Antiarrhythmic agents Neurologic effects are common, such as parestheisas, tremor, ataxia and headaches Thyroid dysfunction, both hypo- and hyperthyroidism GI, 20% constipation; hepatocellular necrosis;

Antiarrhythmic agents Pulmonary inflammation and fibrosis, the latter may be fatal in 5-15% of patients Hypotension and bradycardia are the common adverse effects

Antiarrhythmic agents 1. Bretylium It interferes with the neuronal release of catecholamines but also has direct antarrhythmic properties. a. Cardiac effects b. Therapeutic use c. Adverse effects

Antiarrhythmic agents a. Cardiac effects a. Lengthens the ventricular but not the atrial APD and ERP, most pronounced in ischemic cells which have shortened APD. Bretylium may reverse the shortening of APD caused by ischemia.

Antiarrhythmic agents a. Markedly increases the ventricular fibrillation threshold b. It causes an initial release of catecholamines, has some positive inotropic actions when first administered, this action may precipitate ventricular arrhythmias and must be watched for at the onset of therapy

Antiarrhythmic agents a. Therapeutic use Bretylium is usually used in an emergency setting, often during attempted resuscitation from ventricular fibrillation when lidocaine and cardioversion have failed.

Antiarrhythmic agents a. Adverse effects The major daverse effects is postural hypotension. Nausea and vomiting may occur after iv.

Antiarrhythmic agents 1. Sotalol It is a nonselective β-R blocker, also slows repolarization and prolongs APD; used in both supraventricular and ventricular arrhythmias. It is excreted unchanged by the kidneys. Only lower dosages are usually used in atrial fibrillation.

Antiarrhythmic agents I.

Calcium channel-blocking drugs (class Ⅳ) 1. Verapamil 2. Diltiazem

Antiarrhythmic agents 1. Verapamil a. Cardiac effects Blocks both activated and inactivated calcium channels, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the sinoatrial and A-V nodes.

Antiarrhythmic agents a. A-V nodal conduction and ERP are invariably prolonged by therapeutic concentration b. suppress both early and delayed afterdepolarizations, and may antagonize slow responses arising in severely depolarized tissue

Antiarrhythmic agents a. Slows the sinoatrial node rate by its direct action, increases the rate by its indirect action (reflex action of its hypotensive action) b. Extracardiac effects Peripheral vasodilation

Antiarrhythmic agents a. Therapeutic use Reentrant supraventricular tachycardia is the major arrhythmia indication for verapamil. Reduce the ventricular rate in atrial fibrillation and flutter.

Antiarrhythmic agents a. Toxicity a. Negative inotropic effects b. A-V block when large doses, can be treated by atropine, or calcium, or β-R agonist c. Constipation, lassitude, nervousness, peripheral edema

Antiarrhythmic agents I.

Principles in the clinical use of antiarrhythmic agents 1. Principles 2. Choice of antiarrhythmic agents

Antiarrhythmic agents I.

Principles in the clinical use of antiarrhythmic agents 1. Principles 2. Choice of antiarrhythmic agents

Antiarrhythmic agents Bradycardia

atropine isoprenaline supraventricular atrial flutter digitoxin Tachycardia atrial fibrillation quinidine paroxysmal Supraventricular verapamil tachycardia

Antiarrhythmic agents lidocaine Ventricular phenyltoin sodium Tachycardia mexiletine disopyramide propafenone Sinus tachycardia propranolol