NCLEX: Antiarrhythmics

In contrast to skeletal muscle, which contracts only when it receives a stimulus, the heart contains specialized cells that exhibit automaticity. That is, they intrinsically generate rhythmic action potentials in the absence of external stimuli. These “pacemaker” cells differ from other myocardial cells in showing a slow, spontaneous depolarization during diastole, caused by an inward positive current carried by sodium and calcium ions.

This depolarization is fastest in the sinoatrial (SA) node (the normal initiation site of the action potential), and it decreases throughout the normal conduction pathway through the atrioventricular (AV) node to the bundle of His and the Purkinje system. Dysfunction of impulse generation or conduction at any of a number of sites in the heart can cause an abnormality in cardiac rhythm.

Antiarrhythmics

 

Antiarrhythmics: INTRODUCTION TO THE ARRHYTHMIAS

Focus topic: Antiarrhythmics

The arrhythmias are conceptually simple. Dysfunctions cause abnormalities in impulse formation and conduction in the myocardium. However, in the clinical setting, arrhythmias present as a complex family of disorders with a variety of symptoms. To make sense of this large group of disorders, it is useful to organize the arrhythmias into groups according to the anatomic site of the abnormality: the atria, the AV node, or the ventricles. Although not shown, each of these abnormalities can be further divided into subgroups depending on the electrocardiogram findings.

Antiarrhythmics

 

A. Causes of arrhythmias

Focus topic: Antiarrhythmics

Most arrhythmias arise either from aberrations in impulse generation (abnormal automaticity) or from a defect in impulse conduction.

  • Abnormal automaticity: The SA node shows the fastest rate of phase 4 depolarization and, therefore, exhibits a higher rate of discharge than that occurring in other pacemaker cells exhibiting automaticity. Thus, the SA node normally sets the pace of contraction for the myocardium. If cardiac sites other than the SA node show enhanced automaticity, they may generate competing stimuli, and arrhythmias may arise. Most of the antiarrhythmic agents suppress automaticity by blocking either Na+ or Ca2+ channels to reduce the ratio of these ions to K+. This decreases the slope of phase 4 (diastolic) depolarization and/or raises the threshold of discharge to a less negative voltage. Antiarrhythmic drugs cause the frequency of discharge to decrease. This effect is more pronounced in cells with ectopic pacemaker activity than in normal cells.
  • Abnormalities in impulse conduction: Impulses from higher pacemaker centers are normally conducted down pathways that bifurcate to activate the entire ventricular surface. A phenomenon called reentry can occur if a unidirectional block caused by myocardial injury or a prolonged refractory period results in an abnormal conduction pathway. Reentry is the most common cause of arrhythmias, and it can occur at any level of the cardiac conduction system. This short-circuit pathway results in reexcitation of the ventricular muscle, causing premature contraction or sustained ventricular arrhythmia. Antiarrhythmic agents prevent reentry by slowing conduction (class I drugs) and/or increasing the refractory period (class III drugs), thereby converting a unidirectional block into a bidirectional block.

 

Antiarrhythmics

 

B. Antiarrhythmic drugs

Focus topic: Antiarrhythmics

As noted above, antiarrhythmic drugs can modify impulse generation and conduction to prevent arrhythmias from occurring or to reduce symptoms associated with arrhythmias. Unfortunately, many of the antiarrhythmic agents are known to have dangerous proarrhythmic actions—that is, to cause arrhythmias. Inhibition of potassium (K+) channels (typically thought of as class III activity) widens the action potential and can, thus, prolong the QT interval. If prolongation is excessive, these drugs increase the risk of developing life-threatening ventricular tachyarrhythmias (torsades de pointes).

The most common cause of QT prolongation is drug-induced, although other conditions (for example, ischemia and hypokalemia) and genetic profiles may contribute. QT prolongation is not only seen with class III antiarrhythmics. Drugs such as cisapride and terfenadine were withdrawn from the market because of severe and fatal arrhythmias. Many drugs are known to prolong the QT interval, such as macrolide antibiotics and antipsychotics.

Caution should be employed when combining drugs with additive effects on the QT interval or when giving QT-prolonging antiarrhythmic drugs with drugs known to inhibit their metabolism. As such, the benefit of antiarrhythmic drugs must always be compared to the potential for serious adverse effects or drug interactions. [Note: Implantable cardioverter defibrillators are becoming more widely used to manage ventricular arrhythmias.]

 

Antiarrhythmics

 

Antiarrhythmics: CLASS I ANTIARRHYTHMIC DRUGS

Focus topic: Antiarrhythmics

Antiarrhythmic drugs can be classified according to their predominant effects on the action potential. Although this classification is convenient, it is not entirely clear-cut, because many drugs have actions relating to more than one class or may have active metabolites with a different class of action. Class I antiarrhythmic drugs act by blocking voltage-sensitive sodium (Na+) channels. The use of sodium channel blockers has declined due to their proarrhythmic effects, particularly in patients with reduced left ventricular function and ischemic heart disease.

 

Antiarrhythmics

 

A. Use dependence

Focus topic: Antiarrhythmics

Class I drugs bind more rapidly to open or inactivated sodium channels than to channels that are fully repolarized following recovery from the previous depolarization cycle. Therefore, these drugs show a greater degree of blockade in tissues that are frequently depolarizing. This property is called use dependence (or state dependence), and it enables these drugs to block cells that are discharging at an abnormally high frequency, without interfering with the normal, low-frequency beating of the heart. The class I drugs have been subdivided into three groups according to their effect on the duration of the ventricular action potential.

B. Class IA antiarrhythmic drugs: Quinidine, procainamide, and disopyramide

Quinidine [KWIN-i-deen] is the prototype class IA drug. Other agents in this class include procainamide [proe-KANE-a-mide] and disopyramide [dye-soe-PEER-a-mide]. Because of their concomitant class III activity, they can precipitate arrhythmias that can progress to ventricular fibrillation.

  • Mechanism of action: Quinidine binds to open and inactivated sodium channels and prevents sodium influx, thus slowing the rapid upstroke during phase 0 (Figure 20.5). It decreases the slope of phase 4 spontaneous depolarization, inhibits potassium channels, and blocks calcium channels. Because of these actions, it slows conduction velocity and increases refractoriness. Quinidine also has mild α-adrenergic blocking and anticholinergic actions. Procainamide and disopyramide have actions similar to those of quinidine. However, there is less anticholinergic activity associated with procainamide and more with disopyramide. Neither procainamide nor disopyramide has α-blocking activity. Disopyramide produces a negative inotropic effect that is greater than the weak effect exerted by quinidine and procainamide, and unlike the other drugs, it causes peripheral vasoconstriction. The drug may produce a clinically important decrease in myocardial contractility in patients with systolic heart failure.
  • Therapeutic uses: Quinidine is used in the treatment of a wide variety of arrhythmias, including atrial, AV junctional, and ventricular tachyarrhythmias. Procainamide is available in an intravenous formulation only and may be used to treat acute atrial and ventricular arrhythmias. However, electrical cardioversion or defibrillation and amiodarone have mostly replaced procainamide in clinical use. Disopyramide is used in the treatment of ventricular arrhythmias as an alternative to procainamide or quinidine and may also be used for maintenance of sinus rhythm in atrial fibrillation or flutter.
  • Pharmacokinetics: Quinidine sulfate or gluconate is rapidly and almost completely absorbed after oral administration. It undergoes extensive metabolism primarily by the hepatic cytochrome P450 3A4 (CYP3A4) isoenzyme, forming active metabolites. Procainamide has a relatively short duration of action of 2 to 3 hours. A portion of procainamide is acetylated in the liver to N-acetylprocainamide (NAPA), which prolongs the duration of the action potential. Thus, NAPA has properties and side effects of a class III drug. NAPA is eliminated via the kidney, and dosages of procainamide may need to be adjusted in patients with renal failure. Disopyramide is well absorbed after oral administration. It is metabolized in the liver to a less active metabolite and several inactive metabolites. Disopyramide is a substrate of CYP3A4. About half of the drug is excreted unchanged by the kidneys.
  • Adverse effects: Large doses of quinidine may induce the symptoms of cinchonism (for example, blurred vision, tinnitus, headache, disorientation, and psychosis). Drug interactions are common with quinidine since it is an inhibitor of both CYP2D6 and P-glycoprotein. Intravenous administration of procainamide may cause hypotension. Disopyramide has the most anticholinergic adverse effects of the class IA drugs (for example, dry mouth, urinary retention, blurred vision, and constipation). Both quinidine and disopyramide should be used with caution with potent inhibitors of CYP3A4.

Antiarrhythmics

 

C. Class IB antiarrhythmic drugs: Lidocaine and mexiletine

Focus topic: Antiarrhythmics

The class IB agents rapidly associate and dissociate from sodium channels. Thus, the actions of class IB agents are manifested when the cardiac cell is depolarized or firing rapidly. The class IB drugs lidocaine [LYE-doe-kane] and mexiletine [MEX-i-le-teen] are useful in treating ventricular arrhythmias.

  • Mechanism of action: In addition to sodium channel blockade, lidocaine and mexiletine shorten phase 3 repolarization and decrease the duration of the action potential.
  • Therapeutic uses: Although amiodarone has supplanted lidocaine for use in ventricular fibrillation or pulseless ventricular tachycardia (VT), lidocaine may be useful as an alternative. Lidocaine may also be used in polymorphic VT or in combination with amiodarone for VT storm. The drug does not markedly slow conduction and, thus, has little effect on atrial or AV junction arrhythmias. Mexiletine is used for chronic treatment of ventricular arrhythmias, often in combination with amiodarone.
  • Pharmacokinetics: Lidocaine is given intravenously because of extensive first-pass transformation by the liver, which precludes oral administration. The drug is dealkylated to two less active metabolites, primarily by CYP1A2 with a minor role by CYP3A4. Lidocaine should be monitored closely when given in combination with drugs affecting these CYP isoenzymes. As lidocaine is a high extraction drug, drugs that lower hepatic blood flow (β-blockers) may require lidocaine dose adjustment. Mexiletine is well absorbed after oral administration. It is metabolized in the liver primarily by CYP2D6 to inactive metabolites and excreted mainly via the biliary route.
  • Adverse effects: Lidocaine has a fairly wide therapeutic index. It shows little impairment of left ventricular function and has no negative inotropic effect. Central nervous system (CNS) effects include nystagmus (early indicator of toxicity), drowsiness, slurred speech, paresthesia, agitation, confusion, and convulsions, which often limit the duration of continuous infusions. Mexiletine has a narrow therapeutic index and caution should be used when administering the drug with inhibitors of CYP2D6. Nausea, vomiting, and dyspepsia are the most common adverse effects.

Antiarrhythmics

 

D. Class IC antiarrhythmic drugs: Flecainide and propafenone

Focus topic: Antiarrhythmics

These drugs slowly dissociate from resting sodium channels and show prominent effects even at normal heart rates. Several studies have cast serious doubts on the safety of the class IC drugs, particularly in patients with structural heart disease.

  • Mechanism of action: Flecainide [FLEK-a-nide] suppresses phase 0 upstroke in Purkinje and myocardial fibers. This causes marked slowing of conduction in all cardiac tissue, with a minor effect on the duration of the action potential and refractoriness. Automaticity is reduced by an increase in the threshold potential, rather than a decrease in slope of phase 4 depolarization. Flecainide also blocks potassium channels leading to increased action potential duration, even more so than propafenone. Propafenone [proe-PA-fen-one], like flecainide, slows conduction in all cardiac tissues but does not block potassium channels.
  • Therapeutic uses: Flecainide is useful in the maintenance of sinus rhythm in atrial flutter or fibrillation in patients without structural heart disease (left ventricular hypertrophy, heart failure, atherosclerotic heart disease) and in treating refractory ventricular arrhythmias. Flecainide has a negative inotropic effect and can aggravate chronic heart failure. Use of propafenone is restricted mostly to atrial arrhythmias: rhythm control of atrial fibrillation or flutter and paroxysmal supraventricular tachycardia prophylaxis in patients with AV reentrant tachycardias. The latter indication takes advantage of the β-blocking properties of propafenone.
  • Pharmacokinetics: Flecainide is absorbed orally and is metabolized by CYP2D6 to multiple metabolites. The parent drug and metabolites are mostly eliminated renally, and dosage adjustment may be required in renal disease. Propafenone is metabolized to active metabolites primarily via CYP2D6, and also by CYP1A2 and CYP3A4. The metabolites are excreted in the urine and the feces.
  • Adverse effects: Flecainide is generally well tolerated, with blurred vision, dizziness, and nausea occurring most frequently. Propafenone has a similar side effect profile, but it may also cause bronchospasm due to its β-blocking effects. It should be avoided in patients with asthma. Propafenone is also an inhibitor of P-glycoprotein. Both drugs should be used with caution with potent inhibitors of CYP2D6.

Antiarrhythmics

 

Antiarrhythmics: CLASS II ANTIARRHYTHMIC DRUGS

Focus topic: Antiarrhythmics

Class II agents are β-adrenergic antagonists, or β-blockers. These drugs diminish phase 4 depolarization and, thus, depress automaticity, prolong AV conduction, and decrease heart rate and contractility. Class II agents are useful in treating tachyarrhythmias caused by increased sympathetic activity. They are also used for atrial flutter and fibrillation and for AV nodal reentrant tachycardia. In addition, β-blockers prevent life-threatening ventricular arrhythmias following a myocardial infarction. [Note: In contrast to the sodium channel blockers, β-blockers and class III compounds, such as sotalol and amiodarone, are increasing in use.]

Metoprolol [me-TOE-pro-lol] is the β-blocker most widely used in the treatment of cardiac arrhythmias. Compared to nonselective β-blockers, such as propranolol [pro-PRAN-oh-lol], it reduces the risk of bronchospasm. It is extensively metabolized in the liver primarily by CYP2D6 and has CNS penetration (less than propranolol, but more than atenolol [a-TEN-oh-lol]).

Esmolol [ESS-moe-lol] is a very-short-acting β-blocker used for intravenous administration in acute arrhythmias that occur during surgery or emergency situations. It has a fast onset of action and a short half-life, making it ideal for acute situations and also limiting its adverse effect profile. Esmolol is rapidly metabolized by esterases in red blood cells. As such, there are no pharmacokinetic drug interactions.

CLASS III ANTIARRHYTHMIC DRUGS

Focus topic: Antiarrhythmics

Class III agents block potassium channels and, thus, diminish the outward potassium current during repolarization of cardiac cells. These agents prolong the duration of the action potential without altering phase 0 of depolarization or the resting membrane potential. Instead, they prolong the effective refractory period, increasing refractoriness. All class III drugs have the potential to induce arrhythmias.

A. Amiodarone

Focus topic: Antiarrhythmics

  • Mechanism of action: Amiodarone [a-MEE-oh-da-rone] contains iodine and is related structurally to thyroxine. It has complex effects, showing class I, II, III, and IV actions, as well as α-blocking activity. Its dominant effect is prolongation of the action potential duration and the refractory period by blocking K+ channels.
  • Therapeutic uses: Amiodarone is effective in the treatment of severe refractory supraventricular and ventricular tachyarrhythmias. Amiodarone has been a mainstay of therapy for the rhythm management of atrial fibrillation or flutter. Despite its adverse effect profile, amiodarone is the most commonly employed antiarrhythmic and thought to be the least proarrhythmic of the class I and III antiarrhythmic drugs.
  • Pharmacokinetics: Amiodarone is incompletely absorbed after oral administration. The drug is unusual in having a prolonged half-life of several weeks, and it distributes extensively in adipose tissue. Full clinical effects may not be achieved until months after initiation of treatment, unless loading doses are employed.
  • Adverse effects: Amiodarone shows a variety of toxic effects, including pulmonary fibrosis, neuropathy, hepatotoxicity, corneal deposits, optic neuritis, blue-gray skin discoloration, and hypo- or hyperthyroidism. However, use of low doses and close monitoring reduce toxicity, while retaining clinical efficacy. Amiodarone is subject to numerous drug interactions, since it is metabolized by CYP3A4 and serves as an inhibitor of CYP1A2, CYP2C9, CYP2D6, and P-glycoprotein.

B. Dronedarone

Focus topic: Antiarrhythmics

Dronedarone [droe-NE-da-rone] is a benzofuran amiodarone derivative, which is less lipophilic, has lower tissue accumulation, and has a shorter serum half-life than amiodarone. It does not have the iodine moieties that are responsible for thyroid dysfunction associated with amiodarone. Like amiodarone, it has class I, II, III, and IV actions. Dronedarone has a better adverse effect profile than amiodarone but may still cause liver failure.

The drug is contraindicated in those with symptomatic heart failure or permanent atrial fibrillation due to an increased risk of death. Currently, dronedarone is used to maintain sinus rhythm in atrial fibrillation or flutter, but it is less effective than amiodarone.

C. Sotalol

Focus topic: Antiarrhythmics

Sotalol [SOE-ta-lol], although a class III antiarrhythmic agent, also has potent nonselective β-blocker activity. The levorotatory isomer (l-sotalol) has β-blocking activity, and d-sotalol has class III antiarrhythmic action. Sotalol blocks a rapid outward potassium current, known as the delayed rectifier. This blockade prolongs both repolarization and duration of the action potential, thus lengthening the effective refractory period.

Sotalol is used for maintenance of normal sinus rhythm in patients with atrial fibrillation, atrial flutter, or refractory paroxysmal supraventricular tachycardia and in the treatment of ventricular arrhythmias. Since sotalol has β-blocking properties, it is commonly used for these indications in patients with left ventricular hypertrophy or atherosclerotic heart disease.

This drug can cause the typical adverse effects associated with β-blockers but has a low rate of adverse effects when compared to other antiarrhythmic agents. The dosing interval should be extended in patients with renal disease, since the drug is renally eliminated. To reduce the risk of proarrhythmic effects, sotalol is most often initiated in the hospital to monitor QT interval.

D. Dofetilide

Focus topic: Antiarrhythmics

Dofetilide [doh-FET-il-ide] is a pure potassium channel blocker. It can be used as a first-line antiarrhythmic agent in patients with persistent atrial fibrillation and heart failure or in those with coronary artery disease. Because of the risk of proarrhythmia, dofetilide initiation is limited to the inpatient setting. The half-life of this oral drug is 10 hours. The drug is mainly excreted unchanged in the urine. Drugs that inhibit active tubular secretion are contraindicated.

E. Ibutilide

Focus topic: Antiarrhythmics

Ibutilide [eye-BYOO-tih-lide] is a potassium channel blocker that also activates the inward sodium current (mixed class III and IA action). Ibutilide is the drug of choice for chemical conversion of atrial flutter, but electrical cardioversion has supplanted its use. Ibutilide undergoes extensive first-pass metabolism and is not used orally. Because of the risk of QT prolongation and proarrhythmia, ibutilide initiation is limited to the inpatient setting.

 

Antiarrhythmics

 

Antiarrhythmics: CLASS IV ANTIARRHYTHMIC DRUGS

Focus topic: Antiarrhythmics

Class IV drugs are the nondihydropyridine calcium channel blockers verapamil [ver-AP-a-mil] and diltiazem [dil-TYE-a-zem]. Although voltage-sensitive calcium channels occur in many different tissues, the major effect of calcium channel blockers is on vascular smooth muscle and the heart. Verapamil shows greater action on the heart than on vascular smooth muscle, and diltiazem is intermediate in its actions.

In the heart, verapamil and diltiazem bind only to open depolarized voltage-sensitive channels, thus decreasing the inward current carried by calcium. They prevent repolarization until the drug dissociates from the channel, resulting in a decreased rate of phase 4 spontaneous depolarization. These drugs are therefore use-dependent. They also slow conduction in tissues that are dependent on calcium currents, such as the AV and SA nodes.

These agents are more effective against atrial than against ventricular arrhythmias. They are useful in treating reentrant supraventricular tachycardia and in reducing the ventricular rate in atrial flutter and fibrillation. Both drugs are metabolized in the liver by CYP3A4. Dosage adjustments may be needed in patients with hepatic dysfunction. Both agents are also inhibitors of CYP3A4, as well as substrates and inhibitors of P-glycoprotein. As such, they are subject to many drug interactions.

Antiarrhythmics

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Antiarrhythmics: OTHER ANTIARRHYTHMIC DRUGS

Focus topic: Antiarrhythmics

A. Digoxin

Focus topic: Antiarrhythmics

Digoxin [di-JOX-in] inhibits the Na+/K+-ATPase pump, ultimately shortening the refractory period in atrial and ventricular myocardial cells while prolonging the effective refractory period and diminishing conduction velocity in the AV node. Digoxin is used to control ventricular response rate in atrial fibrillation and flutter; however, sympathetic stimulation easily overcomes the inhibitory effects of digoxin. At toxic concentrations, digoxin causes ectopic ventricular beats that may result in VT and fibrillation. [Note: Serum trough concentrations of 1.0 to 2.0 ng/mL are desirable for atrial fibrillation or flutter, whereas lower concentrations of 0.5 to 0.8 ng/mL are targeted for systolic heart failure.]

B. Adenosine

Focus topic: Antiarrhythmics

Adenosine [ah-DEN-oh-zeen] is a naturally occurring nucleoside, but at high doses, the drug decreases conduction velocity, prolongs the refractory period, and decreases automaticity in the AV node. Intravenous adenosine is the drug of choice for abolishing acute supraventricular tachycardia. It has low toxicity but causes flushing, chest pain, and hypotension. Adenosine has an extremely short duration of action (approximately 10 to 15 seconds) due to rapid uptake by erythrocytes and endothelial cells.

C. Magnesium sulfate

Focus topic: Antiarrhythmics

Magnesium is necessary for the transport of sodium, calcium, and potassium across cell membranes. It slows the rate of SA node impulse formation and prolongs conduction time along the myocardial tissue. Intravenous magnesium sulfate is the salt used to treat arrhythmias, as oral magnesium is not effective in the setting of arrhythmia. Most notably, magnesium is the drug of choice for treating the potentially fatal arrhythmia torsades de pointes and digoxin-induced arrhythmias.

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