Teaching cardiac arrhythmias: A focus on pathophysiology and pharmacology
Sprague, Jon E
PROLOGUE The following manuscript reviews a method of teaching the pathophysiology and pharmacology of cardiac arrhythmias. This manuscript is supplemented with a complimentary web site (http://www.onu.edu/user/fs/jsprague/AJPE.html). Those interested in obtaining further information can use this site for lecture notes, animations of cellular mechanisms, practice case reports, electrocardiograms (ECG) strips, and Powerpoint, lecture presentations. The author hopes that other find this information useful in developing strategies for teaching this subject area.
The teaching of the pathophysiology and pharmacological treatment of cardiac arrhythmias can be a challenging task. The integrated modular system (for description see reference 1) utilized at Ohio Northern University (ONU) allows for the pathophysiology and pharmacology to be followed by the medicinal chemistry and therapeutic principles involved in the management of cardiac arrhythmias. Background material necessary for the comprehension of cardiac arrhythmias is provided in the Biomedical Science Modules. Before entering the Cardiovascular Module, where cardiac arrhythmias are covered in detail, students have been instructed in ion-channel function in muscle contraction, action potential physiology and the basics of ECG. The following text is a summary of a fourhour lecture sequence presented in the Cardiovascular Module on the pathophysiology and pharmacological treatment of cardiac arrhythmias. These lectures are supplemented by a web site that contains primary literature references in a downloadable format, animations of cellular mechanisms and practice case reports, ECG strips, and Powerpoint(R), lecture presentations. This manuscript is written in a fashion to complement a web site created specifically for the readers of the American Journal of Pharmaceutical Education that contains all the above and can be accessed at (http://www.onu.edu/user/ fs/jsprague/AJPE.html). General references utilized in developing these lectures included references 2-4.
MECHANISMS UNDERLYING CARDIAC ARRHYTHMIAS
Most cardiac arrhythmias result from disorders of impulse formation, impulse conduction or a combination of both. Disturbances in impulse formation or automaticity can involve no pathological change in the pacemaker site generating sinus bradycardia ( 100 bpm) due to rapid firing of the SA node. The development of an ectopic focus can also lead to impulse formation abnormalities. An ectopic focus is an impulse originating outside the SA node and can develop as a result of electrolyte disturbances, ischemia, excessive myocardial fiber stretch, drugs, or toxins(5).
Disorders in impulse conduction involve heart blocks. which result in slowed or blocked conduction through the myocardium. The pathological process of reentry is also au impulse conduction abnormality. Figure 1 demonstrates the process of reentry. This figure is animated allowing student tc visually comprehend how impulse conduction circles through the reentry pathway; the animation also draws a corresponding action potential for correlation to heart rate (see web link). In order for a reentry pathway to develop, there must be a unidirectional block within the conduction pathway. This unidirectional block can be the result of ischemia (e.g. following E myocardial infarction). A unidirectional block alone is not suf ficient to generate the arrhythmia. At least one of the following characteristics must be present for the arrhythmia to develop; long reentry pathway, short refractory period, or slowed conduction velocity. All three of these conditions will allow the surrounding myocardial tissue to be out of its refractory period so when the circulating impulse reaches the myocardium a premature contraction is generated. Each of these events is explained in detail. Hand drawings of the reentry pathway illustrating all three pathological events are given to the class. Genetic abnormalities in voltage-gated ion channel function have also been linked to arrhythmia generation(6). For example, the inherited potassium channel disorder that results in the long-QT syndrome(6). These examples are discussed in the previous Biomedical Sciences Module.
TYPES OF CARDIAC ARRHYTHMIAS (5)
After review of a normal ECG and the definitions of some general terminology (Appendix A), the students are introduced to the types of cardiac arrhythmia. The expectation is that they will be able to identify the arrhythmia type on lead II and learn the standard Advanced Cardiac Life Support (ACLS) treatment guidelines for this form of arrhythmia (7,12). ACLS guidelines are also utilized in assisting the students in arrhythmia identification and can be accessed by the students on the courses webpage. After the following types of arrhythmias are discussed, the students are given a handout of twenty different forms of arrhythmias to identify. A sample of the handout strips is in Appendix B and a sample handout can be downloaded from the web link.
The discussion begins with supraventricular arrhythmias. The students are informed that when they see these types of arrhythmias to think “protect the ventricles.” They are asked to recall some previously covered agents (e.g. 13-blockers, verapamil, diltiazem, digoxin) that slow atrioventricular (AV) nodal conduction that may be used to “protect the ventricles.” “Protect the ventricles” basically becomes the theme of this section and is reinforced over the entire week that arrhythmias are covered. The ECG strip in Figure 2 depicts an atrial premature beat. This form of arrhythmia is similar to a normal beat except for timing, and possible distortion of the P wave. The square heart diagram (left side of Figure 2) suggests that this premature beat may be the result of an ectopic focus. Note that the P wave often has contours slightly different from sinus beats and the PR interval is often long and the QRS complex is narrow (
With atrial tachycardias the heart rate is rapid (approximately 150 beats per minute) with atrial impulse generation. Ventricular rate is also correspondingly increased and is driven by the atrial impulses (“protect the ventricles”). Sinus tachycardia (Figure 3) has complexes that appear normal and are evenly spaced. The only apparent abnormality on the ECG is that the rate is greater than 100 beats per minute (bpm).
Multifocal atrial tachycardia (Figure 4) may be the result of several ectopic foci firing at different rates. P waves can be contoured resulting if varying lengths of the PR, PP and RR intervals. Inverted P waves suggest that the impulse generation occurs in a retrograde fashion.
Paroxysmal Supraventricular Tachcardia (PSVT, Figure 5) are rapid heart rates that result from a regular succession of ectopic beats in the atria or from a reentry pathway within the AV node. A PSVT can last anywhere from a few seconds to as long as several days. Two impulse pathways exist within the AV node. The alpha and beta pathways typically allow for directed impulse conduction through the AV node. Figure 5 shows that if a unidirectional block develops a recycling of the impulse can occur. A PSVT may result in atrial rates of 160 to 220 bpm, with normal or inverted P waves. The QRS complex can be normal, narrow or widened. The shapes of the QRS complex assist in making therapeutic drug selection. Therapeutic drug selection is discussed in the subsequent therapeutic lectures.
Atrial flutters and fibrillations can be differentiated from each other by looking for a rhythmic pattern on the ECG, which indicates a flutter or a “wavy” non-cyclic pattern to the baseline between QRS complexes, suggesting a fibrillation. Atrial flutter (Figure 6) can induce rapid atrial rates in excess of 300 bpm with only every second or third atrial impulse being conducted to the ventricles, giving rise to a ventricular rate of 100-150 bpm (“protect the ventricles”). Rapid flutter (F) waves may be seen between each of the QRS complexes. A flutter is defined as a rhythmic cycling of an electrical impulse and a fibrillation is defined as uncoordinated and “out-of-control” impulse conduction.
Atrial fibrillation (Figure 7) results from quivering, uncoordinated atrial activity, which produces an irregular ventricular rhythm. There are two types of atrial fibrillation: course and fine fibrillation. A course atrial fibrillation is characterized by a “saw-tooth” like baseline before each QRS complex. Whereas a fine atrial fibrillation is a smooth wavy almost flat line before each QRS complex. P waves may be absent and the ventricular response is irregular and again can be narrow or wide.
Junctional rhythm (nodal rhythm, Figure 8) results from the cells at the junction of the atrium and the AV node depolarizing spontaneously and may even become the “pacemaker” site determining overall cardiac rhythm (“Escape beat”). Normal anterograde conduction into the ventricles results in a typical QRS complex, whereas retrograde conduction into the atria produces a P wave that is often inverted and may actually occur after the QRS complex or not at all.
Ventricular premature beats (Figure 9) are characterized as ventricular contractions not coupled to an atrial impulse and occur prior to the next expected normal SA-initiated QRS response. A series of premature ventricular contractions can be suggestive of ventricular tachycardia may soon follow. Subsequently, the therapeutic lectures examine the rate of premature ventricular contractions (PVC) and when and how aggressively they need to be treated. The QRS complex is typically abnormal and distorted in shape.
Ventricular tachycardia (Figure 10) result in rapid ventricular rates not initiated by SA, atrial, or AV sources (recall these would be termed “supraventricular” tacycardia). This form of arrhythmia can result in heart rates in excess of 120 bpm and are commonly seen in association with ischemic tissue damage resulting in circulating or reentry of impulses within the ischemic zone. Students are told to think of ventricular tachycardia as the “flutter” of the ventricles. That is they typically have some form of consistent pattern associated with their development.
Ventricular fibrillation (Figure 11) results from chaotic ventricular activity depicted by bizarre and uncoordinated ECG traces. Circulatory arrest occurs within seconds and death within minutes if not corrected immediately. As with atrial fibrillation, two forms of ventricular fibrillation are seen: coarse and fine. The typical progression of these last three forms of ventricular arrhythmia is PVC, followed by ventricular tachycardia, followed by ventricular fibrillation. A discussion of how fine ventricular fibrillation may be mistaken for asystole then takes place.
Heart block is a delayed or interruption in the normal impulse conduction between the atria and the ventricles. Firstdegree heart block (Figure 12) is characterized by all impulses being conducted through the AV junction but the conduction time (PR interval) is abnormally prolonged (> 0.20 seconds).
Second degree heart block results from partial blockade to impulse conduction; some impulses are conducted to the ventricles but others are blocked. Mobitz I (Wenckebach, Figure 13) is characterized by repetitive cycles of progressively lengthening of AV conduction time, eventually leading to nonconduction of one beat (“dropped beat”). This form of arrhythmia typically has a pattern in that the PR interval gets longer, longer, longer and then drops out completely and then the pattern then repeats. Mobitz II (non-Wenckebach, Figure 14) involves conduction of some impulses with a constant AV conduction time, and nonconduction of other impulses resulting in the sudden and unpredictable dropping of QRS complexes.
Third degree heart block (Figure 15) results from the loss of communication between the atria and ventricles resulting in the atria and ventricles contracting in an unorganized fashion. The consequence of this can lead to inadequate ventricular filling and reduced cardiac output resulting in the patient becoming hemodynamically unstable. With most forms of bradycardia, treatment may not be necessary unless the patient is hemodynamically unstable (decreased blood pressure, shock, pulmonary congestion etc.). If the patient is hemodynamically unstable, start treatment with atropine(7). Students are then challenged to recall why and how atropine would increase heart rate.
Escape beats are ectopic beats resulting from sinus node failure. This serves a protective function by initiating a cardiac impulse in the absence of the normal pacemaker activity, and thereby prevents cardiac standstill. If arrest of the SA node occurs, a variable period of asystole will usually give way to an escape beat. Depending on the site of origin of the escape beat, the ECG reflects the resultant conduction abnormality (Figure 16). Time is spent explaining how the site of origin of the escape beat results in the various changes in the ECG depicted in Figure 16.
Some brief comments on some other forms of arrhythmia that the students may encounter are then discussed. WolfParkinson White Syndrome (WPW, Figure 17) is a form of cardiac arrhythmia that results from the AV node being by-passed via the Bundle of Kent. This form of arrhythmia is characterized by the presence of a delta wave prior to the QRS complex. The students are asked what is the rule for SVTs?…”protect the ventricles.” Examining the diagram in Figure 17, blocking AV nodal conduction would result in increased impulse conduction through the Bundle of Kent and ventricular rate could actually increase. Our “rule” doesn’t hold for this from of SVT.
Torsades de Pointes, meaning twisting of points, is typically drug induced. The twisting of points refers to the QRS complexes twisting along the isoelectric line. Typically, this is demonstrated by a hand drawing and a sample case report is then utilized in breakout groups for further discussion of Torsades. Breakout groups not only focus on Torsades but on at least four or five other forms of arrhythmia discussed in class.
The final form of arrhythmia discussed is Pulseless Electrical Activity (PEA), which is characterized by the absence of any detectable pulse in the presence of some electrical activity. PEA can be caused by hypovolemia, hypoxia, tension pneumothorax, hypothermia, and hyperkalemia.
THE PHARMACOLOGY OF ANTIARRHYTHMIC AGENTS(2.4.8)
After discussing the pathophysiology of cardiac arrhythmias and how to recognize them, the pharmacology of the agents used in arrhythmia therapy is discussed. One difficulty that must be overcome when explaining the methods for treating cardiac arrhythmias is the fact that drug therapy can result in the development of another arrhythmia (proarrhythmia) and other toxicities. Because of the lack of effective response and some studies showing that antiarrhythmic agents can actually increase mortality (Cardiac Arrhythmia Suppression Trial [CAST](9), several newer techniques are being developed for cardiac arrhythmias. The use of ablation therapy for conduction disorders such as WPW has been very successful(10). This method of treatment uses radiofrequency to destroy the Bundle of Kent and return conduction to normal(10). Ablation therapy is discussed in the subsequent therapeutic discussions. In the future, drug therapy may indeed become secondary to these other methods of regulating cardiac arrhythmias. Until this time arises the pharmacological agents are the main stay in treating arrhythmias and need to be discussed in detail.
For clarification, the Vaughan Williams Classification( 11) of antiarrhythmic agents is still used in the Cardiovascular Module. This classification method is beginning to lose favor for classifying antiarrhythmics because a few agents do not fit into this classification system. However, the Vaughan Williams Classification allows the anti-arrhythmic agents to be classified into four classes with just a few exceptions. The Class I agents (see Table I) are sodium channel blockers that are subdivided into subgroups based on their potency and differential effects on repolarization. The therapeutic selectivity is provided by the greater affinity these agents have for active (phase 0) and inactive (phase 1,2, and 3) sodium channels, but very low affinity for resting channels. A few minutes are spent reviewing the three phases of the sodium channel (see web link). The Class IA agents have moderate potency for sodium channel block and prolonging repolarization (potassium efflux block). Class IB agents have the lowest potency for the sodium channel and they actually shorten repolarization. The Class IB agents are considered the safest of the Class I agents and are most commonly used first line in the acute treatment of cardiac arrhythmias. The Class IC agents are the most potent sodium channel blockers and have limited effects on repolarization. The Class IC agents are associated with the greatest degree of adverse reactions (CAST trial) and are considered the least safe(9). The final class is the mixed agent with IA,B,C qualities that has moderate sodium channel blockade and only slight effects on repolarization.
Class II agents are the P-adrenergic blocking agents that depress phase 4 depolarization by blocking the beta^sub 1^ receptors. The depression of phase 4 depolarization can be a confusing concept and the students are taught to think of this terminology in the following way. Depression of phase 4 depolarization results in increased time between action potential generation. Correlating this response to the ECG would transpire to an increase in the PR interval. This is typically hand drawn with both an action potential and ECG trace.
Class III antiarrhythmic agents prolong phase 3 repolarization predominantly by blocking potassium efflux. Dofetilide and ibutilide prolong phase 3 repolarization by mechanisms other than potassium efflux blockade.
Class IV antiarrhythmic agents are the calcium channel blockers (CCB) that depress phase 4 depolarization and prolong phases 1 and 2. Only two CCBs, verapamil and diltiazem, are used for the treatment of arrhythmias (Table I). The students are asked questions as to why this would be the case…because of a reflex tachycardia seen with dihydropyridine CCBs like nifedipine.
Finally, the digitalis gylcosides and adenosine are discussed separately in the initial presentation of the classification of antiarrhythmic agents. The students are also presented with acronyms for remembering the different agents in each class. For example, for the Class IA agents, procainamide, disopyramide, and quinidine, they are given PDQ (Pretty Dam Quick).
Once a general overview of the different classes of antiarrhythmic agents is presented, the individual agents are discussed in detail. Structures of the agents are given at this point so as to compliment the subsequent medicinal chemistry lectures.
Quinidine. Quinidine is the most commonly used oral antiarrhythmic agent. Quinidine’s therapeutic pharmacological effects are to depress the pacemaker rate and to reduce conduction and excitability. Cardiac toxicity due to the drug’s antimuscarinic activity may overcome myocardial depressant effects and lead to an increase in sinus rate and increased AV conduction. The concept of proarrhythmia is introduced here and explained as an antiarrhythmic drugs ability to cause or unmask another arrhythmia. Although an older method for administration, digoxin may be administered prior to quinidine in the presence of atrial fibrillation or flutter to prevent ventricular tachycardia. Digoxin will slow AV nodal conduction and protect the ventricles. This treatment strategy is only used acutely due to quinidine’s ability to decrease the renal clearance of digoxin. An early sign of serious toxicity with any Class IA agent is an increase in the QRS complex width by > 30 percent. Students are questioned as to why QRS complex may widen with toxicity. This allows for a review of the role of sodium channels in the development of the QRS complex. Hypotension may result from a reduced cardiac output as well as from a vasodilation caused by a-receptor antagonism. Quinidine is contraindicated in partial or complete AV block, severe renal disease resulting in azotemia, digitalis-induced arrhythmias, myasthenia gravis (students are asked why?… myasthenia gravis is covered in the previous quarter), and history of Torsades de Pointes. Torsades de Pointes may be seen with any of the agents that have the ability to inhibit potassium efflux such as quinidine. This fact is reiterated throughout the remaining discussion of agents used in the treatment of cardiac arrhythmias. Quinidine can be used to treat atrial arrhythmias such as PAC, Atrial Fibrillation, Atrial Flutter; SVTs such as WPW, AV nodal reciprocating tachycardia and ventricular arrhythmias such as PVC, ventricular tachycardia and for the prevention of ventricular fibrillation.
Procainamide. The direct effects of procainamide on the heart are very similar to quinidine, but has some indirect effects that are quite different from those of quinidine. Procainamide has much weaker anticholinergic activity on the heart and does not produce a-receptor antagonism. Additionally, procainamide has weak ganglionic blocking activity giving it greater negative inotropic effects than quinidine. Unlike quinidine, procainamide may produce a syndrome resembling lupus erythematosus, which is characterized by arthralgia and arthritis. An antinuclear antibody (ANA) test can be performed here to confirm a diagnosis similar to what we had already discussed with hydralazine during the hypertension lectures. Procainamide is also acetylated to an active metabolite acecainide or n-acetylprocainamide (NAPA). Finally, because of the drugs ability to induce proarrhythmias and bone marrow suppression, procainamide is typically reserved for arrhythmias deemed life-threatening.
Disopyramide. Pharmacologically, disopyramide is similar to quinidine but does not have alpha or beta receptor activity. Disopyramide is structurally related to the anticholinergic agent, isopropamide. Therefore, typical anticholinergic side effects can be seen. Students are asked to predict some examples of these anticholinergic side effects. Disopyramide can also reduce cardiac output and reduce left ventricular performance by a direct depressant effect and caution is warranted in heart failure patients. The fact that disopyramide is reserved for life-threatening arrhythmias is also stressed to the students.
Lidocaine. Because of the low incidence of toxicity associated with class lB agents, lidocaine is the most commonly used intravenous (IV) antiarrhythmic agent. Lidocaine has extraordinarily high degree of efficacy, especially in treating ventricular arrhythmias occurring after cardiac surgery or acute myocardial infarction. The IV route of administration is rapid, safe and coupled with a fast decline once the IV infusion is terminated. Lidocaine blocks both activated and inactivated sodium channels. A large fraction of unblocked sodium channels will become blocked during each action potential in the Purkinje fibers and the ventricular myocardial cells, which have long plateau phases. Lidocaine suppresses the electrical activity of the depolarized, arrhythmogenic tissue while minimally interfering with the electrical activity of normal tissue. Neurological side effects are the most common and are associated with the local anesthetic effects produced by central sodium channel blockade. The discussion is interrupted at this point and the students are questioned, “how many of you have dispensed lidocaine viscous?” A discussion then ensues on how blocking sodium channels can interfere with neurotransmission and how this can contribute to lidocaine’s adverse reaction profile. Lidocaine undergoes very extensive first-pass hepatic metabolism with only 30 percent of an orally administered dose appearing in the plasma. Lidocaine is typically considered the drug of choice in suppressing ventricular tachycardia and prevention of ventricular fibrillation following a MI. Lidocaine is rarely effective in treating supraventricular arrhythmias but is effective for those associated with digitalis toxicity.
Tocainde and Mexiletine. These agents are congeners of lidocaine that are more resistant to gastric acid and relatively resistant to first-pass metabolism. Electrophysiology and antiarrhythmic actions are similar to those of lidocaine. These agents also have similar indications and neurological side effect profiles.
Phenytoin. Phenytoin is currently not approved to treat cardiac arrhythmias. However, phenytoin is quite effective in treating life-threatening atrial and ventricular arrhythmias caused by digitalis overdose, which have failed to respond to potassium salts.
Flecainide and Encainide. The manufacturer voluntarily recalled encainide in 1991, but it can be obtained for compassionate use by contacting the manufacturer directly. Both of these agents have rather selective depressant effects on the fast sodium channels and reduce the velocity and amplitude of phase 0. They have also been shown to slow conduction in cardiac tissue especially the His-Purkinje system. These agents are only indicated for life-threatening ventricular arrhythmias.
This is mainly due to the results of the CAST study which showed that flecainide and encainide increases mortality 2.5 times over no treatment(9). Other adverse reactions that are discussed are proarrhythmia and negative inotropy.
Propafenone. Propafenone does a little bit of everything needed for the treatment of arrhythmia. Propafenone is structurally similar to propranolol and possess about 1/40th the beta-blocking activity of propranolol. Propafenone also has weak Class III properties, which results in prolongation of repolarization. To complete its “little bit of everything” activity propafenone also has some weak calcium channel blocking activity. The side effect profile of propafenone is also discussed in detail as to the cellular mechanisms involved in producing the adverse response (Table II). Finally, the discussion of propafenone ends with the discussion of some major drug interactions with digoxin and warfarin.
Class 1A. BR C (Mixed)
Moricizine. Moricizine is a phenothiazine derivative, without significant activity on the dopaminergic system. Moricizine reduces the rate of phase 0 depolarization without affecting maximum diastolic potential or action potential amplitude. Contradictory to what we have discussed to this point is the fact that the action potential duration (APD) and effective refractory period (ERP) are both decreased. This requires a hand drawing to explain how shortening the APD may actually “normalize” rate in some sick tissue. This can result in the normalization of heart rate in some tissue. Moricizine has minimal effects on the sinus node or atrial tissue. Thus, this agent is most extensively used for the suppression of ventricular arrhythmias. As with most anti-arrhythmic agents, moricizine may lead to a proarrhythmic response, which could result in sudden cardiac death.
Class II: beta-Adrenergic Blocking Agents
The beta-blocking agents are covered in much detail in the lectures on hypertension and the introductory autonomic lectures. Thus, for time utilization the beta-blocking agents are reviewed very rapidly. The discussion focuses on the following agents: propranolol, acebutolol, esmolol. Sotalol is mentioned at this point, but is predominantly a Class III anti-arrhythmic agent. Most antiarrhythmic effects of these agents are a direct result of the receptor antagonist activity at the cardiac (31receptor. These agents are used to treat supraventricular arrhythmias. By blocking the (31-receptor influences on the AV node, ERP increases and cardiac impulse conduction of rapid atrial depolarization into the ventricles is reduced (“protect the ventricles”).
Class III: Prolong Phase 3 Repolarization
Before the discussion on the Class III agents begin, the students are asked, “what form of arrhythmia may be induced by an agent that prolongs phase 3 repolarization or blocks potassium efflux? The answer that the class typically yells out is “Torsades.”
Bretylium. Bretylium is similar to the post-ganglionic blockers, quanadrel and quanethidine, that were discussed during the lectures on hypertension. Bretylium was used as an antihypertensive in the 1950s. Like the post-ganglionic blockers, bretylium interferes with catecholamine release from adrenergic neurons. It is taken up into the nerve terminal, releases norepinephrine initially (hypertensive response) and then prevents its release later (hypotensive response). The use of triclycic antidepressants can block these responses. Students are asked to recall the mechanism by which this would work. Bretylium’s anti-arrhythmic properties are independent of autonomic effects. Bretylium lengthens ventricular (but not atrial) APD and ERP especially in ischemic cells and raises the threshold for ventricular fibrillation. Upon initial administration, bretylium causes a release of catecholamines. This may produce an early positive inotropic effect and may increase the firing rate of Purkinje fibers. Bretylium is typically reserved for lifethreatening ventricular arrhythmias and for the prophylaxis and treatment of ventricular fibrillation.
Amiodarone. Amiodarone has effects that overlap with Class I and II anti-arrhythmic agents. It shares some properties with bretylium in that amiodarone slows repolarization and increases ventricular fibrillation threshold. Like the Class I agents, amiodarone is an effective blocker of inactive sodium channels. It has weak calcium channel blocking activity and is a noncompetitive inhibitor of alpha- and beta-receptors. These effects result in prolongation of repolarization and the subsequent lengthening of the APD and ERP. Amiodarone will also slow sinus rate and AV nodal conduction. Extracardic effects include peripheral vascular dilation as a result of alpha-blockade and calcium channel blockade. Pulmonary toxicity includes pulmonary fibrosis, interstitial pneumonitis and alveolitis. Looking at the structure of amiodarone (Figure 18), the iodine grouping lend toward the thyroid toxicity seen with amiodarone. Patients on amiodarone should have thyroid function test performed periodically. Pharmacokinetically, amiodarone has an extremely long half-life of greater than a month in some patients. Despite all these potential problems, amiodarone has recently become very popular clinically for the suppression of life-threatening ventricular arrhythmias(12). A discussion on how clinical application of the drug seems to contradict the pharmacological and toxicological properties of the compound. Thus, if dose is adjusted correctly and the patient monitored closely aminodarone can be used safely.
Sotalol. Because sotalol prolongs repolarization it is classified as a class III antiarrhythmic agent. Sotalol is also a nonselective beta-blocking blocker, which possess no intrinsic sympathomimetic or local anesthetic activity. Its side effect profile is similar to those typically seen with beta-blockers. Sotalol has some proarrhythmic potential. Such drugs as antihistamines and tricyclic antidepressants likely exaggerate this proarrhythmic potential. Sotalol is indicated for the treatment of lifethreatening arrhythmias.
Ibutalide. Ibutalide delays repolarization by activation of a slow, inward current of sodium rather than blocking outward potassium currents. This makes ibutalide different from all other Class III agents. In order to explain this effect, an AP is drawn and the effects of a slow inward flux of sodium on prolonging the APD is explained. Ibutalide is indicated for the treatment of atrial fibrillation/flutter.
Dofetilide. Dofetilide is a fairly new Class III antiarrhythmic agent. The students are asked to recall the different forms of potassium channels. Dofetalide is different than the typical Class III agents in that it blocks the delayed inward-rectifier potassium current. Again, an AP is drawn to clarify the effects of this blockade on prolonging APD. Dofetilide is indicated for “highly symptomatic” atrial fibrillation and flutter. Dofetilide is reserved for this type of arrhythmia because of the high risk of developing Torsades de Pointes. In fact, dofetilide is marketed with a training program to ensure appropriate dosing(12).
Class IV. Calcium-Channel Blocking Agents
The calcium channel blocking (CCB) agents are covered in great detail in the hypertension lectures. Thus, for time utilization the CCB agents are reviewed very rapidly. The discussion here focuses on verapamil and diltiazem. These agents have their most marked effects on the SA and AV nodes, which depend upon the calcium current for activation. They result in depressed SA and AV nodal conduction and prolongation of the ERP of the AV node. They slow ventricular rate in the presence of atrial fibrillation and flutter and are therefore indicated for reentrant SVT, and PSVT.
The cardiac glycosides have indirect vagomimetic action that decrease ventricular rate and improve ventricular function by increasing the ERP of the AV node. These agents are indicated for the treatment of atrial fibrillation and flutter in order to protect the ventricles. The specific details of the mechanisms of digoxin are covered prior to this lecture in the discussion of congestive heart failure.
Adenosine is an endogenous nucleoside that produces a bradycardia which is resistant to atropine. Adenosine depresses SA nodal automaticity and AV nodal conduction. The electrophysiological mechanisms involve an increase in potassium conductance, reduced calcium mediated slow channel conduction, and possible antagonism of catecholamine-mediated effects. Adenosine will produce a rapid flatline on the ECG monitor, which is shocking but expected. Adenosine could be considered the pharmacological shocking of the heart. Adenosine is rapidly cleared from the plasma in less than 30 seconds. Adenosine is the drug of choice in the treatment of PSVT (12). As with all the antiarrhythmic agents, adenosine is not devoid of potentially serious adverse reactions. The students are informed that as pharmacist they should be aware that the following adverse reactions my be seen following adenosine administration; dyspnea (12 percent), flushing, retrosternal chest pain, heart block, asystole, and a transient arrhythmia at the time of conversion. Potential drug interactions are also stressed, dipyridamole inhibits the cellular uptake of adenosine and will potentiate its effects. Methylxanthines such as caffeine and theophylline are receptor antagonist of adenosine and may interfere with its electrophysiologic effects.
PREDICTING DRUG-INDUCED ECG CHANGES
In order to ensure that the students have a thorough understanding of the pharmacological mechanisms of the antiarrhythmic agents, they are asked to predict what effects the agents would have on the ECG. Table III list some of the antiarrhythmic agents discussed in class and the standard ECG changes induced by the drug (4). For example, with amiodarone, the PR interval increases as a result of weak calcium channel blocking and beta-blocking activity. The QRS interval increases due to sodium channel blocking activity and the QT interval increases by potassium channel blockade induced by amiodarone. We focus on understanding the mechanism and not memorizing the table. This forces the student to apply their understanding of drug mechanisms to ECG changes. The class is then given several drugs to practice predicting ECG changes on and that are then discussed the following day. The exams list several drugs and ask for predicted ECG changes. This type of question test several concepts emphasized in class from drug mechanism to understanding an ECG. Furthermore, pharmacy students then can get a better feel for the importance of understanding drug mechanism when the pharmacological response can actual be coupled to an ECG change.
The teaching of cardiac arrhythmias to pharmacy students can be a difficult and challenging task. The lectures highlighted within this manuscript and corresponding web site (http://www.onu.edu/user/fs/jsprague/AJPE.html) are just one approach that is used in teaching this subject material in the Cardiovascular Module at ONU. These lectures are then reinforced in subsequent lectures on medicinal chemistry and therapeutics. The students also practice analyzing case reports involving these drugs and arrhythmias in the breakout groups. Finally, in a capstone course one-year later, the students work in groups of three and evaluate and give therapeutic recommendations for the treatment of randomly generated ECG strips. During this time, many of the concepts discussed in this manuscript are reinforced on a more one-on-one basis before the students enter into their clinical rotations.
Acknowledgments. The author would like to thank Dr. Donnie Sullivan and Mr. Jeffery Blake for their thorough critique and evaluation of several drafts of this manuscript.
1Associate Professor of Pharmacology.
2Pfizer U.S. Pharmaceuticals, Dofetalide package insert (2000).
Am. J Pharm. Educ., 65, 169-177(2001); received 12/12/00, accepted 3/1/01.
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(9) CAST investigators, Preliminary report: Effects of encainide, and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. (The Cardiac Arrhythmia Suppression Trail),” N. Engl. J Med, 321, 406-412(1989).
(10) Panescu, D., “Intraventricular electrogram mapping and radiofrequency cardiac ablation for ventricular tachycardia,” Physiol. Meas., 18, 138(1997).
(11) Vaughan Williams, E.M., “Classifying antiarrhythmic actions: by facts or speculation,” J Clin. Pharmacol., 32, 964-977(1992).
(12) International Liaison Committee on Resuscitation (ILCOR)., “713: The tachycardia algorithms,” Circulation, 2000; 102(suppl I), 1-158-I165(2000).
Jon E. Sprague1
The Raabe College of Pharmacy, Ohio Northern University, Ada OH 45810
Copyright American Association of Colleges of Pharmacy Summer 2001
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