An arrhythmia may occur as a result of heart disease or from a disorder that affects cardiovascular function.Conditions such as emotional stress, hypoxia, and electrolyte imbalance also may trigger an arrhythmia. An electrocardiogram (ECG) provides a record of the elec-trical activity of the heart.Careful interpretation of the ECG along with a thorough physical assessment is nec-essary to determine the cause and type of arrhythmia.The goal of antiarrhythmic drug therapy is to restore normal cardiac function and to prevent life-threatening arrhythmias.
ACTIONS
The cardiac muscle (myocardium) has attributes of both nerve and muscle and therefore has the properties of both. Some cardiac arrhythmias are caused by the gen-eration of an abnormal number of electrical impulses (stimuli). These abnormal impulses may come from the sinoatrial node or may be generated in other areas of the myocardium. The antiarrhythmic drugs are classified according to their effects on the action potential of car-diac cells and their
presumed mechanism of action. As understanding of the pathophysiology of cardiac arrhyth-mias and the drugs used to treat these arrhythmias has increased, a method of classification has been developed that includes four basic classifications and several sub-classes. Drugs in each class have certain similarities, yet each drug has subtle differences that make it unique.
Class I Antiarrhythmic Drugs
Class I antiarrhythmic drugs, such as moricizine, have a membrane-stabilizing or anesthetic effect on the cells of the myocardium, making them valuable in treating car- diac arrhythmias. Class I antiarrhythmic drugs contain the largest number of drugs of the four classifications.Because the actions differ slightly, they are subdivided into classes I-A, I-B, and I-C.
Class I-A
The drugs disopyramide, procainamide, and quinidine are examples of class I-A drugs. Quinidine depresses myocardial excitability or the ability of the myocardium to respond to an electrical stimulus. By depressing the myocardium and its ability to respond to some, but not all, electrical stimuli, the pulse rate decreases and the arrhythmia is corrected. Quinidine also prolongs or lengthens the refractory (resting) period and decreases the height and rate of the action potential of the impulses traveling through the myocardium.All cells are electrically polarized, with the inside of the cell more negatively charged than the outside. The difference in electrical charge is called the resting mem-brane potential. Nerve and muscle cells are excitable and can change the resting membrane potential in response to electrochemical stimuli. The action poten-tial is an electrical impulse that passes from cell to cell in the myocardium, stimulating the fibers to shorten, causing muscular contraction (systole). After the action potential passes, the fibers relax and return to their resting length (diastole). An action potential generated in one part of the myocardium passes almost simultaneously through all of the fibers, causing rapid contraction. Only one impulse can pass along a nerve fiber at any given time. After the passage of an impulse, there is a brief pause, or interval, before the next impulse can pass along the nerve fiber. This pause is called the refractory period, which is the period between the transmission of nerve impulses along a nerve fiber. By lengthening the refractory period, the number of impulses traveling along a nerve fiber within a given time is decreased. For example, a patient has a pulse rate of 120 bpm. By lengthening the refractory period between each impulse and decreasing the height and rate of the rise of action potential, fewer impulses would be generated each minute, and the pulse rate would decrease. Procainamide is thought to act by decreasing the rate of diastolic depolarization in the ventricles, decreasing the rate and height of the action potential and increasing the fibrillation threshold.
Disopyramide (Norpace) decreases the rate of depolar-ization of myocardial fibers during the diastolic phase of the cardiac cycle, prolongs the refractory period, and decreases the rate of rise of the action potential.
Nerve cells have positive ions on the outside and neg-ative ions on the inside of the cell membrane when they are at rest. This is called polarization.
When a stimulus passes along the nerve, the positive ions move from outside the cell into the cell, and the negative ions move from inside the cell to outside the cell. This movement of ions is called depolarization.Unless positive ions move into and negative ions move out of a nerve cell, a stimulus (or impulse) cannot pass along the nerve fiber. Once the stimulus has passed along the nerve fiber, the positive and negative ions move back to their original place, that is, the positive ions on the outside and the negative ions on the inside of the nerve cell. This movement back to the original place is called repolarization. By decreasing the rate (or speed) of depolarization, the stimulus must literally wait for this process before it can pass along the nerve fiber. Thus, decreasing the rate of depolarization decreases the number of impulses that can pass along a nerve fiber during a specific time period.
Class I-B Drugs
Lidocaine (Xylocaine), the representative class I-B drug, raises the threshold of the ventricular myocardium. Threshold is a term applied to any stimulus of the lowest intensity that will give rise to a response in a nerve fiber. A stimulus must be of a spe-cific intensity (strength, amplitude) to pass along a given nerve fiber To further illustrate the threshold phenomenon using plain figures instead of precise electrical values,a certain nerve fiber has a threshold of 10. If a stimu-lus rated as 9 reaches the fiber, it will not pass along the fiber because its intensity is lower than the fiber’s threshold of 10. If another stimulus reaches the fiber and is rated 14, it will pass along the fiber because its intensity is greater than the fiber’s threshold of 10. If the threshold of a fiber is raised from 10 to 15, only the stimuli greater than 15 can pass along the nerve fiber.
Some cardiac arrhythmias result from many stimuli present in the myocardium. Some of these are weak or of low intensity but are still able to excite myocardial tissue. Lidocaine, by raising the threshold of myocardial fibers, reduces the number of stimuli that will pass along these fibers and therefore decreases the pulse rate and corrects the arrhythmia. Mexiletine (Mexitil) and tocainide (Tonocard) are also antiarrhythmic drugs with actions similar to those of lidocaine.
Class I-C Drugs
Flecainide (Tambocor) and propafenone (Rythmol) are examples of class I-C drugs. These drugs have a direct stabilizing action on the myocardium, decreasing the height and rate of rise of cardiac action potentials, thus slowing conduction in all parts of the heart.
Class II Antiarrhythmic Drugs
Class II antiarrhythmic drugs include beta ()-adrener-gic blocking drugs, such as acebutolol (Sectral), esmolol (Brevibloc), and propranolol (Inderal). These drugs also decrease myocardial response to epinephrine and nor-epinephrine (adrenergic neurohormones) because of their ability to block stimulation of receptors of the
heart. Adrenergic neurohormones stimu- late the receptors of the myocardium and therefore increase the heart rate. Blocking the effect of these neurohormones decreases the heart rate. This is called a blockade effect.
Class III Antiarrhythmic Drugs
Bretylium (Bretylol) prolongs repolarization, prolongs refractory period, and increases the ventricular fibrilla-tion threshold. Amiodarone (Cordarone) appears to act directly on the cardiac cell membrane, prolonging the refractory period and repolarization and increasing the ventricular fibrillation threshold. Newer class III antiar-rhythmic drugs include ibutilide (Corvert) and dofetilide (Tikosyn). These two drugs are used to con-vert atrial fibrillation or flutter to a normal sinus rhythm. Ibutilide acts by prolonging the action potential, producing a mild slowing of the sinus rate and atri-oventricular conduction. Dofetilide selectively blocks potassium channels, widens the QRS complex, and prolongs the action potential. The drug has no effect on cal-cium channels or cardiac contraction.
Class IV Antiarrhythmic Drugs
Class IV antiarrhythmic drugs include verapamil (Calan) and the other calcium channel blockers.Calcium channel blockers produce their antiarrhythmic action by inhibiting the movement of calcium through channels across the myocardial cell membranes and vas-cular smooth muscle. Contraction of cardiac and vascular smooth muscle depends on the movement of calcium ions into these cells through specific ion channels. By reducing the calcium flow, conduction through the sinoatrial (SA) and atrioventricular (AV) nodes is slowed and the refractory period is prolonged, resulting in suppression of the arrhythmia. The calcium channel blockers are also called slow channel blockers or cal-cium antagonists. Two calcium channel blockers that have been approved as antiarrhythmics are verapamil and diltiazem.
USES
The uses of the antiarrhythmic drugs are given in Antiarrhythmic Drugs. In general these drugs are used to prevent and treat cardiac arrhythmias, such as premature ventricular contrac-tions (PVCs), ventricular tachycardia (VT), premature atrial contractions (PACs), paroxysmal atrial tachy-cardia (PAT), atrial fibrillation, and atrial flutter.Some of the antiarrhythmic drugs are used for other conditions. For example, propranolol, in addition to its use as an antiarrhythmic, may also be used for patients with myocardial infarction. This drug has reduced the risk of death and repeated myocardial infarctions in those surviving the acute phase of a myocardial infarction. Additional uses include control of tachycardia in those with pheochromocytoma (a tumor of the adrenal gland that secretes excessive amounts of norepinephrine), migraine headaches,angina pectoris caused by atherosclerosis, and hyper-trophic subaortic stenosis.
ADVERSE REACTIONS
General adverse reactions common to most antiarrhyth-mic drugs include light-headedness, weakness, hypoten-sion, bradycardia, and drowsiness. Adverse reactions associated with the administration of specific antiar-rhythmic drugs are given inAntiarrhythmic Drugs. All antiarrhythmic drugs may cause new arrhythmias or worsen existing arrhythmias,even though they are administered to resolve an existing arrhythmia. This phenomenon is called the proar-rhythmic effect. This effect ranges from an increase in frequency of premature ventricular contractions (PVCs), to the development of more severe ventricular tachycardia, to ventricular fibrillation, and may lead to death. Proarrhythmic effects may occur at any time but occur more often when excessive dosages are given,when the preexisting arrhythmia is life-threatening, or if the drug is given IV.
CONTRAINDICATIONS
The antiarrhythmic drugs are reserved for emergency situations and are contraindicated in patients with known hypersensitivity to the antiarrhythmic drugs and during pregnancy and lactation. Most antiar-rhythmic drugs are Pregnancy Category B or C drugs,indicating that safe use of these drugs during pregnancy, lactation, or in children has not been estab-lished. The antiarrhythmic drug amiodarone is a Pregnancy Category D drug, indicating that fetal harm can occur when the agent is administered to a preg-nant woman. It is used only if the potential benefits outweigh the potential hazards to the fetus.
Antiarrhythmic drugs are contraindicated in patients with second- or third-degree AV block (if the patient has no artificial pacemaker), severe congestive heart failure (CHF), aortic stenosis, hypotension, and car- diogenic shock. Quinidine and procainamide are con-traindicated in patients with myasthenia gravis
PRECAUTIONS
All antiarrhythmic drugs are used cautiously in patients with renal or hepatic disease. When renal or hepatic dysfunction is present, a dosage reduction may be necessary. All patients should be observed for renal and hepatic dysfunction. Quinidine and procainamide are used cautiously in patients with CHF. Disopyramide is used cautiously in patients with CHF, myasthenia gravis, or glaucoma, and in men with prostate enlarge-ment. Bretylium is used cautiously in patients with digitalis toxicity because the initial release of norepi-nephrine with digitalis toxicity may exacerbate arrhyth-mias and symptoms of toxicity. Verapamil is used cautiously in patients with a history of serious ventric-ular arrhythmias or CHF. Electrolyte disturbances such as hypokalemia, hyperkalemia, or hypomagnesemia may alter the effects of the antiarrhythmic drugs. Electrolytes are monitored frequently and imbalances corrected as soon as possible.
INTERACTIONS
When two antiarrhythmic drugs are administered con-currently the patient may experience additive effects and is at increased risk for drug toxicity. When quinidine and procainamide are administered with digitalis,the risk of digitalis toxicity is increased. Pharmacologic effects of procainamide may be increased when pro-cainamide is administered with quinidine. When quini-dine is administered with the barbiturates or cimetidine,quinidine serum levels may be increased. When quinidine is administered with verapamil, there is an increased risk of hypotensive effects. When quinidine is administered with disopyramide, there is an increased risk of increased disopyramide blood levels and/or decreased serum quinidine levels. Propranolol may increase procainamide plasma levels. Additive cholinergic effects may occur when procainamide is administered with other drugs with anticholinergic effects. There is the potential of additive cardiodepressant effects when procainamide is adminis-tered with lidocaine. When a beta blocker, such as Inderal, is administered with lidocaine, there is an increased risk of lidocaine toxicity.Propranolol may alter the effectiveness of insulin or oral hypoglycemic drugs. Dosage adjustments may be necessary.
Dofetilide is not administered with cimetidine because dofetilide plasma levels may be increased by as much as 50%. When treatment for gastric disor-ders is necessary, patients receiving dofetilide should take omeprazole, ranitidine, or antacids as an alterna-tive to cimetidine.Verapamil may cause an additive hypotensive effect when administered with other antihypertensives, alco-hol, or the nitrates. Verapamil increases plasma digoxin levels and may cause bradycardia or CHF.
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