CARDIAC ARRHYTHMIA

ARRHYTHMIAS

It is defined as a loss of cardiac rhythm, especially irregular heartbeat. This is caused by an abnormality in the regularity, rate, or sequence of cardiac activation.

Pathophysiology of arrhythmias:

• 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, and latent pacemakers are depolarized by impulses coming from the SA node. However, if cardiac sites other than the SA node show enhanced automaticity, they may generate competing stimuli, and arrhythmias may arise. Abnormal automaticity may also occur if the myocardial cells are damaged (for example, by hypoxia or potassium imbalance). These cells may remain partially depolarized during diastole and, therefore, can reach the firing threshold earlier than normal cells. Abnormal automatic discharges may thus be induced.
• Effect of drugs on automaticity: 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. Such drugs cause the frequency of discharge to decrease an effect that 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. For example, consider a single Purkinje fiber with two conduction pathways to ventricular muscle. An impulse normally travels down both limbs of the conduction path. However, if myocardial injury results in a unidirectional block, the impulse may only be conducted down Pathway 1. If the block in Pathway 2 is in the forward direction only, the impulse may travel in a retrograde fashion through Pathway 2 and reenter the point of bifurcation. This short-circuits pathway results in reexcitation of the ventricular muscle, causing premature contraction or sustained ventricular arrhythmia.
• Effects of drugs on conduction abnormalities: Antiarrhythmic agents prevent reentry by slowing conduction and/or increasing the refractory period, thereby converting a unidirectional block into a bidirectional block.

Clinical manifestations:

• Dizziness or acute syncopal episodes, fatigue, palpitations and confusion.

Diagnosis:

• The surface electrocardiogram (ECG)
•  Specific maneuvers may be required to delineate the etiology of syncope associated with bradyarrhythmias.
• Diagnosis of carotid sinus hypersensitivity can be confirmed by performing carotid sinus massage with ECG and blood pressure monitoring.
• Vasovagal syncope can be diagnosed using the upright body-tilt test.

 On the basis of ECG findings, AV block is usually categorized into three different types (first-, second-, or third-degree AV block).

Desired outcome:

The desired outcome depends on the underlying arrhythmia. For example, the ultimate treatment goals of treating AF or atrial flutter are restoring sinus rhythm, preventing thromboembolic complications, and preventing further recurrences.

Treatment: The most widely used scheme for the classification of antiarrhythmic drug actions recognizes four classes:

1. Class 1: sodium channel blockade:
2. of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel blockade. Drugs with class 1A action prolong the APD and dissociate from the channel with intermediate kinetics; drugs with class 1B action shorten the APD in some tissues of the heart and dissociate from the channel with rapid kinetics; and drugs with class 1C action have minimal effects on the APD and dissociate from the channel with slow kinetics.
3.  

Subgroup 1A: Procainamide, Quinidine, Disopyramide

Subgroup 1B: lidocaine

Subgroup 1C: Flecainide, Moricizine, Propafenone

1. Class 2: Sympatholytic:

Drugs with this action reduce β-adrenergic activity in the heart.

Proparanolol, Esmolol, Satolol

1. Class 3:

Manifests as prolongation of the APD: Most drugs with this action block the rapid component of the delayed rectifier potassium current, I Kr.

Amiodarone, Dronedarone, Vernakalant, Dofetilide, Ibutilide

1. Class 4:

Blockade of the cardiac calcium current. This action slows conduction in regions where the action potential upstroke is calcium dependent, eg, the SA and AV nodes.

Verapamil, Diltiazem

PROCAINAMIDE (SUBGROUP 1A):

Cardiac Effects: By blocking sodium channels, procainamide slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG. The drug also prolongs the APD by nonspecific blockade of potassium channels. The drug may be somewhat less effective than quinidine in suppressing abnormal ectopic pacemaker activity but more effective in blocking sodium channels in depolarized cells. Procainamide has direct depressant actions on SA and AV nodes, and these actions are only slightly counterbalanced by drug induced vagal block.

Extra cardiac Effects: Procainamide has ganglion-blocking properties. This action reduces peripheral vascular resistance and can cause hypotension, particularly with intravenous use. However, in therapeutic concentrations, its peripheral vascular effects are less prominent than those of quinidine. Hypotension is usually associated with excessively rapid procainamide infusion or the presence of severe underlying left ventricular dysfunction.

Toxicity: Procainamide’s cardio toxic effects include excessive action potential prolongation, QT-interval prolongation, and induction of torsades de pointes arrhythmia and syncope. A troublesome adverse effect of long-term procainamide therapy is a syndrome resembling lupus erythematosus and usually consisting of arthralgia and arthritis. In some patients, pleuritis, pericarditis, or parenchymal pulmonary disease also occurs. Renal lupus is rarely induced by procainamide. During long-term therapy, serologic abnormalities (eg, increased antinuclear antibody titer) occur in nearly all patients, and in the absence of symptoms, these are not an indication to stop drug therapy. Other adverse effects include nausea and diarrhea (in about

10% of cases), rash, fever, hepatitis (< 5%), and agranulocytosis (approximately 0.2%).

Pharmacokinetics & Dosage: Procainamide can be administered safely by intravenous and intramuscular routes and is well absorbed orally. Procainamide is eliminated by hepatic metabolism to NAPA and by renal elimination. Its half-life is only 3–4 hours.

Therapeutic Uses: Procainamide is effective against most atrial and ventricular arrhythmias. However, many clinicians attempt to avoid long-term therapy because of the requirement for frequent dosing and the common occurrence of lupus-related effects. Procainamide is the drug of second or third choice (after lidocaine or amiodarone) in most coronary care units for the treatment of sustained ventricular arrhythmias associated with acute myocardial infarction.

QUINIDINE (SUBGROUP 1A):

Cardiac Effects: Quinidine has actions similar to those of procainamide: it slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT-interval prolongation and induction of torsades de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart.

Extra cardiac Effects: Adverse GI effects of diarrhea, nausea, and vomiting are observed in one third to one half of patients. A syndrome of headache, dizziness, and tinnitus (cinchonism) is observed at toxic drug concentrations. Idiosyncratic or immunologic reactions, including thrombocytopenia, hepatitis, edema, and fever, are observed rarely.

Pharmacokinetics & Therapeutic Use: Quinidine is readily absorbed from the GI tract and eliminated by hepatic metabolism. It is rarely used because of cardiac and extra cardiac adverse effects and the availability of better-tolerated antiarrhythmic drugs.

DISOPYRAMIDE (SUBGROUP 1A):

Cardiac Effects: Its cardiac antimuscarinic effects are even more marked than those of quinidine. Therefore, a drug that slows AV conduction should be administered with disopyramide when treating atrial flutter or fibrillation.

Toxicity: Negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. Because of this effect, disopyramide is not used as a first-line antiarrhythmic agent in the USA. It should not be used in patients with heart failure. Disopyramide’s atropine-like activity accounts for most of its symptomatic adverse effects: urinary retention (most often, but not exclusively, in male patients with prostatic hyperplasia), dry mouth, blurred vision, constipation, and worsening of preexisting glaucoma. These effects may require discontinuation of the drug.

Pharmacokinetics & Dosage: Disopyramide is only available for oral use. The typical oral dosage of disopyramide is 150 mg three times a day, but up to 1 g/d has been used. In patients with renal impairment, dosage must be reduced. Because of the danger of precipitating heart failure, loading doses are not recommended.

Therapeutic Use: Disopyramide has been shown to be effective in a variety of supraventricular arrhythmias.

LIDOCAINE (SUBGROUP 1B):

Cardiac effect: Lidocaine has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route.

Lidocaine blocks activated and inactivated sodium channels with rapid kinetics the inactivated state block ensures greater effects on cells with long action potentials such as Purkinje and ventricular cells, compared with atrial cells. The rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction. The increased inactivation and slower unbinding kinetics result in the selective depression of conduction in depolarized cells. Little effect is seen on the ECG in normal sinus rhythm.

Toxicity: Lidocaine is one of the least cardio toxic of the currently used sodium channel blockers. Proarrhythmic effects, including SA node arrest, worsening of impaired conduction, and ventricular arrhythmias, are uncommon with lidocaine use. In large doses, especially in patients with preexisting heart failure, lidocaine may cause hypotension— partly by depressing myocardial contractility. Lidocaine’s most common adverse effects—like those of other local anesthetics are neurologic: tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions. These occur most commonly in elderly or otherwise vulnerable patients or when a bolus of the drug is given too rapidly.

Pharmacokinetics & Dosage: Because of its extensive first-pass hepatic metabolism, only 3% of orally administered lidocaine appears in the plasma. Thus, lidocaine must be given parenterally. Lidocaine has a half-life of 1–2 hours. In adults, a loading dose of 150–200 mg administered over about 15 minutes (as a single infusion or as a series of slow boluses) should be followed by a maintenance infusion of 2–4 mg/min to achieve a therapeutic plasma level of 2–6 mcg/mL. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition.

Therapeutic Use: Lidocaine is the agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardio version in the setting of acute ischemia.

Most physicians administer IV lidocaine only to patients with arrhythmias.

FLECAINIDE (SUBGROUP 1C): It is a potent blocker of sodium and potassium channels with slow unblocking kinetics. It is currently used for patients with otherwise normal hearts who have supraventricular arrhythmias. It has no antimuscarinic effects.

Flecainide is very effective in suppressing premature ventricular contractions. However, it may cause severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmia’s and those with a previous myocardial infarction and ventricular ectopy. This was dramatically demonstrated in the Cardiac Arrhythmia Suppression Trial (CAST), which was terminated prematurely because of a two and one-half-fold increase in mortality rate in the patients receiving flecainide and similar group 1C drugs. Pharmacokinetics: Flecainide is well absorbed drug with a half-life of approximately 20 hours. Elimination is both by hepatic metabolism and by the kidney. The usual dosage of flecainide is 100–200 mg twice a day.

PROPAFENONE (SUBGROUP 1C): Propafenone has some structural similarities to propranolol and possesses weak β-blocking activity. Its spectrum of action is very similar to that of quinidine, but it does not prolong the action potential. Its sodium channel-blocking kinetics is similar to that of flecainide. Propafenone is metabolized in the liver, with an average half-life of 5–7 hours. The usual daily dosage of propafenone is 450–900 mg in three divided doses. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation; arrhythmia exacerbation can also occur.

MORICIZINE (SUBGROUP 1C): Moricizine is an antiarrhythmic phenothiazine derivative that was used for treatment of ventricular arrhythmias. It is a relatively potent sodium channel blocker that does not prolong action potential duration.

BETA-ADRENOCEPTOR–BLOCKING DRUGS (CLASS 2):

Cardiac Effects: Propranolol and similar drugs have antiarrhythmic properties by virtue of their β-receptor–blocking action and direct membrane effects. Some of these drugs have selectivity for cardiac β 1 receptors; some have intrinsic sympathomimetic activity, some have marked direct membrane effects, and some prolong the cardiac action potential. The relative contributions of the β-blocking and direct membrane effects to the antiarrhythmic effects of these drugs are not fully known. Although β blockers are fairly well tolerated, their efficacy for suppression of ventricular ectopic depolarization is lower than that of sodium channel blockers. However, there is good evidence that these agents can prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction.

 Pharmacokinetics and Dosage: Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol’s β-blocking effect, and changes in these parameters may be used as guides for regulating dosage. Propranolol can be administered twice daily, and slow-release preparations are available.

Toxicity: The most important of these predictable extensions of the β-blocking action occur in patients with bradycardia or cardiac conduction disease, asthma, peripheral vascular insufficiency, and diabetes. When propranolol is discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, an increase of blood pressure. Myocardial infarction has been reported in a few patients. Although the incidence of these complications is probably low, propranolol should not be discontinued abruptly. The withdrawal syndrome may involve up-regulation or supersensitivity of β adrenoceptors.

Esmolol is a short-acting β blocker used primarily as an antiarrhythmic drug for intraoperative and other acute arrhythmias. It has a short half-life (9–10 minutes) and is administered by constant intravenous infusion. Esmolol is generally administered as a loading dose (0.5–1 mg/kg), followed by a constant infusion.

Sotalol is a nonselective β-blocking drug that prolongs the action potential. Sotalol has both β-adrenergic receptor-blocking (class 2) and action potential-prolonging (class 3) actions. The drug is formulated as a racemic mixture of D- and L-sotalol. All the β-adrenergic– blocking activity resides in the L-isomer; the D- and L-isomers share action potential prolonging actions. Beta-adrenergic– blocking action is not cardio selective and is maximal at doses below those required for action potential prolongation.

Pharmacokinetics: Sotalol is well absorbed orally with bioavailability of approximately 100%. It is not metabolized in the liver and is not bound to plasma proteins. Excretion is predominantly by the kidneys in the unchanged form with a half-life of approximately 12 hours. Because of its relatively simple pharmacokinetics, solatol exhibits few direct drug interactions. Its most significant cardiac adverse effect is an extension of its pharmacologic action: a dose-related incidence of torsades de pointes that approaches 6% at the highest recommended daily dose. Patients with overt heart failure may experience further depression of left ventricular function during treatment with sotalol.

Uses: Sotalol is approved for the treatment of life-threatening ventricular arrhythmias and the maintenance of sinus rhythm in patients with atrial fibrillation. It is also approved for treatment of supra ventricular and ventricular arrhythmias in the pediatric age group. Sotalol decreases the threshold for cardiac defibrillation.

DRUGS THAT PROLONG EFFECTIVE REFRACTORY PERIOD BY PROLONGING THE ACTION POTENTIAL (CLASS 3):

These drugs prolong action potentials, usually by blocking potassium channels in cardiac muscle or by enhancing inward current, eg, through sodium channels. Action potential prolongation by most of these drugs often exhibits the undesirable property of “reverse use-dependence”: action potential prolongation is least marked at fast rates (where it is desirable) and most marked at slow rates, where it can contribute to the risk of torsades de pointes.

AMIODARONE:

Cardiac Effects: Amiodarone markedly prolongs the action potential duration (and the QT interval on the ECG) by blockade of I Kr. During chronic administration, I Ks is also blocked. The action potential duration is prolonged uniformly over a wide range of heart rates; that is, the drug does not have reverse use-dependent action. In spite of its present classification as class 3 agents, amiodarone also significantly blocks inactivated sodium channels. Its action potential prolonging action reinforces this effect. Consequences of these actions include slowing of the heart rate and AV node conduction. The broad spectrum of actions may account for its relatively high efficacy and its low incidence of torsades de pointes despite significant QT-interval prolongation.

Extra cardiac Effects: Amiodarone causes peripheral vasodilation. This action is prominent after intravenous administration and may be related to the action of the vehicle.

Toxicity: Amiodarone may produce symptomatic bradycardia and heart block in patients with preexisting sinus or AV node disease. The drug accumulates in many tissues, including the heart (10–50 times more so than in plasma), lung, liver, and skin, and is concentrated in tears. Dose-related pulmonary toxicity is the most important adverse effect. Even on a low dose of 200 mg/d or less, fatal pulmonary fibrosis may be observed in 1% of patients. Abnormal liver function tests and hypersensitivity hepatitis may develop during amiodarone treatment and liver function tests should be monitored regularly. The skin deposits result in a photo dermatitis and a gray-blue skin discoloration in sun-exposed areas. After a few weeks of treatment, asymptomatic corneal micro deposits are present in virtually all patients treated with amiodarone.

Pharmacokinetics: Amiodarone is variably absorbed with a bioavailability of 35–65%. It undergoes hepatic metabolism, and the major metabolite, desethylamiodarone, is bioactive. The elimination half-life is complex, with a rapid component of 3–10 days (50% of the drug) and a slower component of several weeks. After discontinuation of the drug, effects are maintained for 1–3 months.

Therapeutic Use: Low doses (100–200 mg/d) of amiodarone are effective in maintaining normal sinus rhythm in patients with atrial fibrillation. The drug is effective in the prevention of recurrent ventricular tachycardia.  The drug increases the pacing and defibrillation threshold and these devices require retesting after a maintenance dose has been achieved.

DRONEDARONE: Dronedarone is a structural analog of amiodarone in which the iodine atoms have been removed from the phenyl ring and a methane sulfonyl group added to the benzofuran ring. The design was intended to eliminate action of the parent drug on thyroxin metabolism and to modify the half-life of the drug. No thyroid dysfunction or pulmonary toxicity has been reported in short-term studies. However, liver toxicity, including two severe cases requiring liver transplantation, has been reported. Like amiodarone, Dronedarone has multichannel actions, including blocking I Kr, I Ks , I Ca , and I Na . It also has β-adrenergic–blocking action.

Pharmacokinetic: The drug has a half-life of 24 hours and can be administered twice daily at a fixed dose of 400 mg. Dronedarone absorption increases twofold to threefold when taken with food, and this information should be communicated to patients as a part of the dosing instructions. Dronedarone elimination is primarily non-renal. However, it inhibits tubular secretion of creatinine, resulting in a 10–20% increase in serum creatinine. However, because glomerular filtration rate is unchanged, no adjustments are required. Dronedarone is both a substrate and an inhibitor of CY3A4 and should not be co-administered with potent inhibitors of this enzyme, such as the azole and similar antifungal agents, and protease inhibitors.

VERNAKALANT: Vernakalant is a multi-ion channel blocker that was developed for the treatment of atrial fibrillation. Vernakalant prolongs the atrial effective refractory period and slows conduction over the AV node. Ventricular effective refractory period is unchanged. In the maximal clinical dose of 1800 mg/day, vernakalant does not change the QT interval on the ECG. Vernakalant blocks I Kur, I ACh, and I too . These currents play key roles in atrial repolarization and their block accounts for the prolongation of the atrial effective refractory period. The drug is a less potent blocker of I Kr and, as a result, produces less APD prolongation in the ventricle; that is, the APD-prolonging effect is relatively atrium specific. Vernakalant also produces use-dependent block of the sodium channel. Recovery from block is fast, such that significant blockade is observed only at fast rates or at low membrane potentials. In the therapeutic concentration range, vernakalant has no effect on heart rate.

Toxicity: Adverse effects of vernakalant include dysgeusia (disturbance of taste), sneezing, paresthesia, cough, and hypotension.

 Pharmacokinetics & Therapeutic Uses: Pharmacokinetic data for vernakalant are limited. After IV administration, the drug is metabolized in the liver by CYP2D6 with a half-life of 2 hours. However, on an oral regimen of 900 mg twice daily, a sustained blood concentration was observed over a 12-hour interval. Clinical trials with the oral drug have used a twice-daily dosing regimen. Intravenous vernakalant is effective in converting recent-onset atrial fibrillation to normal sinus rhythm in 50% of patients. Final approval for this purpose is pending. The drug is undergoing clinical trials for maintenance of normal sinus rhythm in patients with paroxysmal or persistent atrial fibrillation.

DOFETILIDE: Dofetilide has class 3 action potential prolonging action. This action is effected by a dose-dependent blockade of the rapid component of the delayed rectifier potassium current (I Kr ) and the blockade of I Kr increases in hypokalemia. Dofetilide produces no relevant blockade of the other potassium channels or the sodium channel. Because of the slow rate of recovery from blockade, the extent of blockade shows little dependence on stimulation frequency.

Dofetilide is approved for the maintenance of normal sinus rhythm in patients with atrial fibrillation. It is also effective in restoring normal sinus rhythm in patients with atrial fibrillation.

IBUTILIDE: It slows cardiac depolarization by blockade of the rapid component (I Kr) of the delayed rectifier potassium current. Activation of slow inward sodium current has also been suggested as an additional mechanism of action potential prolongation. After intravenous administration, ibutilide is rapidly cleared by hepatic metabolism. The metabolites are excreted by the kidney. The elimination half-life averages 6 hours. Intravenous ibutilide is used for the acute conversion of atrial flutter and atrial fibrillation to normal sinus rhythm. The drug is more effective in atrial flutter than atrial fibrillation, with a mean time to termination of 20 minutes. The most important adverse effect is excessive QT-interval prolongation and torsades de points. Patients require continuous ECG monitoring for 4 hours after ibutilide infusion or until QT c returns to baseline.

CALCIUM CHANNEL-BLOCKING DRUGS (CLASS 4):

VERAPAMIL:

Cardiac Effects: Verapamil blocks both activated and inactivated L-type calcium channels. Thus, 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 SA and AV nodes. AV nodal conduction time and effective refractory period are consistently prolonged by therapeutic concentrations. Verapamil usually slows the SA node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of SA rate. Verapamil can suppress both early and delayed after depolarization and may antagonize slow responses arising in severely depolarized tissue.

Extra cardiac Effects: Verapamil causes peripheral vasodilation, which may be beneficial in hypertension and peripheral vasospastic disorders. Its effects on smooth muscle produce a number of extra cardiac effects.

Toxicity: Verapamil cardio toxic effects are dose-related and usually avoidable. A common error has been to administer intravenous Verapamil to a patient with ventricular tachycardia misdiagnosed as supra ventricular tachycardia. In this setting, hypotension and ventricular fibrillation can occur.  Verapamil can induce AV block when used in large doses or in patients with AV nodal disease. This block can be treated with atropine and β-receptor stimulants.

Extra cardiac effects: constipation, lassitude, nervousness, and peripheral edema.

Pharmacokinetics & Dosage: The half-life of verapamil is approximately 7 hours. It is extensively metabolized by the liver; after oral administration, its bioavailability is only about 20%. Therefore, verapamil must be administered with caution in patients with hepatic dysfunction or impaired hepatic perfusion. In adult patients without heart failure or SA or AV nodal disease, parenteral verapamil can be used to terminate supraventricular tachycardia, although adenosine is the agent of first choice.

Therapeutic Use: Supraventricular tachycardia is the major arrhythmia indication for verapamil. Adenosine or verapamil are preferred over older treatments (propranolol, digoxin, edrophonium, and vasoconstrictor agents) and cardio version for termination. Verapamil can also reduce the ventricular rate in atrial fibrillation and flutter. It only rarely converts atrial flutter and fibrillation to sinus rhythm. Verapamil is occasionally useful in ventricular arrhythmias.

DILTIAZEM: Diltiazem appears to be similar in efficacy to Verapamil in the management of supraventricular arrhythmias, including rate control in atrial fibrillation. An intravenous form of diltiazem is available for the latter indication and causes hypotension or bradyarrhythmias relatively infrequently.

MISCELLANEOUS ANTIARRHYTHMIC AGENTS:

ADENOSINE: Adenosine is a nucleoside that occurs naturally throughout the body. Its half-life in the blood is less than 10 seconds. Its mechanism of action involves activation of an inward rectifier K + current and inhibition of calcium current. The results of these actions are marked hyper polarization and suppression of calcium-dependent action potentials. When given as a bolus dose, adenosine directly inhibits AV nodal conduction and increases the AV nodal refractory period but has lesser effects on the SA node. The drug is less effective in the presence of adenosine receptor blockers such as theophylline or caffeine, and its effects are potentiated by adenosine uptake inhibitors such as dipyridamole.

Toxicity: Adenosine causes flushing in about 20% of patients and shortness of breath or chest burning (perhaps related to bronchospasm) in over 10%. Induction of high-grade AV block may occur but is very short-lived. Atrial fibrillation may occur. Less common toxicities include headache, hypotension, nausea, and paresthesias.

MAGNESIUM: Originally used for patients with digitalis-induced arrhythmias who were hypomagnesemic, magnesium infusion has been found to have antiarrhythmic effects in some patients with normal serum magnesium levels. The mechanisms of these effects are not known, but magnesium is recognized to influence Na + /K + -ATPase, sodium channels, certain potassium channels, and calcium channels. Magnesium therapy appears to be indicated in patients with digitalis-induced arrhythmias if hypomagnesaemia is present; it is also indicated in some patients with torsades de pointes even if serum magnesium is normal. The usual dosage is 1 g (as sulfate) given intravenously over 20 minutes and repeated once if necessary.

POTASSIUM: The significance of the potassium ion concentrations inside and outside the cardiac cell membrane was discussed earlier in this chapter. The effects of increasing serum K + can be summarized as (1) a resting potential depolarizing action and (2) a membrane potential stabilizing action, the latter caused by increased potassium permeability. Hypokalemia results in an increased risk of early and delayed after depolarization, and ectopic pacemaker activity, especially in the presence of digitalis. Hyperkalemia depresses ectopic pacemakers (severe hyperkalemia is required to suppress the SA node) and slows conduction. Because both insufficient and excess potassium is potentially arrhythmogenic, potassium therapy is directed toward normalizing potassium gradients and pools in the body.

Arrythmia, irregular heart beat