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ANTIARRHYTHMIC AGENTS
15. ANTIARRHYTHMIC AGENTS Andrew W. Beardow, B.V.M.&S., MRCVS 1. What are the fundamental mechanisms of arrhythmogenesis? Three mechanisms are commonly described in the induction of arrhythmias: (I) reentry, (2) enhanced automaticity, and (3) triggered activity. Reentry. Loops of cells or tissues with differing conduction properties are established, and disparities of conduction within the loop allow perpetuation of an impulse that otherwise would be extinguished. If the timing is right, such impulses trigger ectopic depolarizations in nonrefractory tissue. The loops may occur at the microscopic, cellular level or the macroscopic level. The microscopic loop consists of Purkinje cells and myocytes and a region of diseased tissue that acts as a unidirectional block in one limb of the loop. As an impulse passes down the conduction pathway, it is blocked from antegrade conduction through the diseased pathway. The impulse continues past this region in other portions of the loop and is then conducted in a retrograde direction in the diseased portion because this limb of the loop was not depolarized and therefore is not refractory. If the timing is correct, the tissue beyond the block is ready to conduct another impulse, setting up a reentry loop.
Areaof unidirectional block. Macroreentry loops use larger circuits composed of existing conduction pathways, i.e., reentry loops within the the atrioventricular (AV) node or by an accessory pathway, as in WolffParkinson-White (WPW) syndrome. In humans up to 85% of supraventricular tachyarrhythmias (SVTs) may be due to macroreentry loops utilizing disparity of conduction velocities in the fast and slow pathways through the AV node. These pathways also exist in the canine AV node, but it is unclear how many SVTs in dogs are generated through this mechanism. Enhanced automaticity. In this mechanism of arrhythrnogcnesis, either normal pacemaker tissues show abnormal activity or cells that are not usually automatic become so. Automaticity is a property of phase 4 of the action potential. In automatic cells a leakage of ions allows the resting membrane potential to change, moving it toward threshold. When the threshold is reached, depolarization is triggered. The rate of change of this potential determines the rate at which it reaches threshold and hence how frequently the pacemaker will fire. Changes in the membrane or the prevailing autonomic tone may affect this mechanism and hence enhance automaticity. Diseased cells that normally do not show automaticity may start to do so. For example, the membranes of diseased myocardial cells may develop an abnormal permeability to calcium ions. This leak allows the membrane to depolarize spontaneously, reach threshold, and trigger a premature beat. Triggered activity. As the name indicates, triggered activity does not occur spontaneously but requires one wave of depolarization to trigger another. It is believed that oscillations in the membrane potential following an action potential are responsible for this activity. Disease states or, in some cases, drugs render the membrane unstable and likely to allow such oscillations.
79
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Antiarrhythmic Agents
Described as afterdepolarization, these oscillations are further classified, depending on their relationship to the action potential, as either early or late. Late afterdepolarizations are typically cited as causing the arrhythmias induced by digoxin intoxication.
Triggered activity. AP = actionpotential; LAD = late afterdepolarization.
2. Which steps should be taken to determine the focus of an arrhythmia? 1. Try to identify a normal PQRST, i.e., a complex that originated from the sinoatrial (SA) node, was conducted through the AV node, and depolarized the ventricle with a normal timing and conduction pattern. A normal PQRST may show some abnormalities because of underlying disease, such as abnormal AV nodal conduction, aberrant ventricular conduction, or an abnormally shaped P-wave due to atrial changes. If in doubt, try to identify several complexes that look the same; all of them may have the same abnormality, but in each a P-wave is followed after an appropriate interval by a QRS complex and aT-wave. 2. Compare the normal complex with others on the strip. If the abnormal complexes have only a QRS complex and a T-wave, do they look like the normal QRS-T complex? If so, the arrhythmia most likely arises at or above the AV node and is thus supraventricular in origin. If not, the arrhythmia is probably ventricular in origin. 3. Try to identify any P-waves on the strip. Do they have a temporal relationship to the abnormal QRS complexes? The answer may help to determine whether the source of a supraventricular arrhythmia is atrial or junctional.
3. What is the most important first step in examining the EKG of a patient with tachyarrhythmia? Try to establish whether the arrhythmia is supraventricular or ventricular in origin. Generally speaking, this distinction is the most useful first step in choosing the most appropriate therapy. Even if you cannot definitively categorize the arrhythmia, first-line therapy has a better chance of success if it is based on your best guess. It is not unusual to have to reassess the diagnosis frequently throughout the management of tachyarrhythmia because of the inappropriate therapeutic response or a change in the underlying arrhythmia.
4. Describe the Vaughan-Williams classification system for antiarrhythmic drugs. Which class(es) do lidocaine, procainamide, diltiazem, and propranolol belong to? The Vaughan-Williams classification of antiarrhythmic drugs is based on their effect on the action potential of the cardiac myocyte: Class I drugs, frequently described as membrane stabilizers, block the fast sodium channel. They are subdivided according to their effect on the action potential in terms of automaticity, conductivity, contractility, AV conduction, and fibrillation threshold: SVT Class IA Decreased automaticity Procainamide VT Decreased conductivity Quinidine WPW Decreased contractility Class IE Lidocaine VT Decreased automaticity Tocainide Decreased contractility Mexiletine Increased AV conduction Increased fibrillation threshold
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VT Decreased automaticity Flecainide WPW Decreased conductivity Encainide Decreased contractility Decreased AV conduction Class II drugs are the beta-blockers, which decrease automaticity and conductivity. They cause variable degrees of depression of both contractility and AV node conduction, depending on the drug in question. Beta-blockers are used to manage supraventricular tachycardia (SVT), ventricular tachycardia (VT), and Wolff-Parkinson-White syndrome (WPW). Class III drugs block the outward potassium current that is important in repolarization, and in doing so, they prolong repolarization and increase refractory periods. Recently they have received a great deal of attention in the management of arrhythmias refractory to class I drugs. Many have significant side effects that must be taken into consideration. The most commonly used class III drugs are bretylium, amiodarone, and sotalo!. Class IV drugs, which block the slow calcium channel, have the most profound effects on AV node conduction. They also decrease automaticity, conductivity, and contractility, although the magnitude of these effects varies widely across the group. The most commonly used class IV drugs are verapamil and diltiazem. Class IC
5. How is the Vaughan-Williams classification used to determine the choice of antiarrhythmic drug? The ion that carries the action potential differs according to the location of the myocyte. For example, the action potential in the pacemaker cells of the SA and AV nodes is carried principally by the calcium ion. To treat arrhythmias that arise from these tissues or require the AV node for maintenance of the tachycardia (SVTs), a class IV drug (calcium channel blocker) such as diltiazem is appropriate. Class I drugs act principally on the sodium channel and are useful in the management of ventricular tachycardias because the sodium channel carries the depolarization phase of the action potential in working myocytes. 6. What is proarrhythmia? Proarrhythmia represents a change in or development of arrhythmias during treatment with antiarrhythmic drugs. The clinical importance of this phenomenon first became apparent when a clinical trial demonstrated that class IC antiarrhythmic agents increase mortality relative to placebo in asymptomatic people with ventricular premature complexes. Proarrhythmia must be considered whenever antiarrhythmic drugs are used. All antiarrhythmic drugs affect the myocardial action potentia!. Although this effect is often beneficial, it may be unpredictable, especially in diseased tissue. Hence drugs that suppress conduction velocity may affect the timing of conduction through reentrant loops in such a way as to "fine-tune" the loop and exacerbate the arrhythmia. Clinicians must consider the risk vs. benefit ratio of such drugs before they are used. Asymptomatic patients with premature ventricular contractions (PVCs) do not invariably need antiarrhythmic therapy. 7. Which medications are often selected for management of acute SVTs in dogs? The short-acting beta-blocker esmolol, the unclassified agent adenosine, intravenous calcium channel blockers (diltiazem and verapamil), or intravenous digoxin is often selected. Intravenous digoxin is the most difficult to manage and tends to be used less frequently. An exception is the patient with an SVT and suspected dilated cardiomyopathy (DCM); beta-blockers and calcium channel blockers are negative inotropes and should be used with extreme caution in such patients. Digoxin is also appropriate when dobutamine is indicated for the acute management of DCM in patients suspected of atrial fibrillation. Dobutamine increases the rate of conduction through the AV node and the ventricular response rate, thereby exacerbating tachycardia. Of the calcium channel blockers, diltiazem may cause less myocardial depression than verapamil and may be the better choice. Adenosine is a purine nucleotide found in every cell in the body. When exogenous adenosine is administered, it is presumed to bind to an extracellular purine receptor. It then decreases intracellular levels of the universal second messenger, cyclic
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adenosine monophosphate (cAMP), by blocking adenylate cyclase. Adenosine has profound inhibitory effects on AV node conduction and depresses SA node and ventricular automaticity.
8. Which characteristics of an arrhythmia are most important in selecting the appropriate antiarrhythmic drug? Characterizing an arrhythmia is critical if the appropriate antiarrhythmic drug is to be selected. Two important distinctions are whether the arrhythmia is a bradyarrhythmia or a tachyarrhythmia, and whether the arrhythmia arises from the AV node or above (supraventricular) or from the ventricles themselves (ventricular). If an arrhythmia is classified in this way, drug selection can be made as described below: ARRHYTHMIA CLASSIFICATION
ARRHYTHMIA CHARACTERISTICS
Supraventricular tachycardia
Rate> 200 bpm; "normal" QRS; breaks with vagal maneuver
Supraventricular bradycardia
Rate < 50 bpm; "normal" QRS
Ventricular bradycardia
Rate < 50 bpm; abnormal QRS
Ventricular tachycardia
Rate> 180 bpm; abnormal QRS, hemodynamically unstable; breed predisposition to fatal ventricular arrhythmias (boxers)
APPROPRIATE MANAGEMENT
Digoxin; calcium channel blockers; beta-blockers; procainamide for WPW Atropine (oral propantheline bromide); nonspecific stimulants of HR (aminophylline, theophylline); pacemaker implantation. Atropine to stimulate SA node; nonspecific stimulantsof HR; pacemaker implantation Identify and correct under!ying cause; acute use parenteral class I drugs (lidocaine); chronic use class I, II, or III
9. If a single antiarrhythmic drug fails to control an arrhythmia, what alternative approaches can be considered? Combination therapy can be tried but only after the synergistic therapeutic effects and side effects have been considered. For example, a combination of a calcium channel blocker (class IV drug) and a beta-blocker (class II drug) may be necessary to manage a supraventricular tachycardia. While the different mechanisms of action may produce therapeutic synergy, they may also lead to compounding side effects, in this case a negative inotropic effect. Exacerbation of systolic dysfunction may therefore be the net effect of this combination of drugs. It is not uncommon for combinations of antiarrhythmic drugs to be used to control ventricular arrhythmias that are either causing clinical signs in a patient or when the arrhythmia is deemed to be life-threatening. Guidelines for the selection of drugs that can be combined include selecting drugs from different classes. For instance, class IA drugs may be combined with class IE drugs. If a patient with a life-threatening ventricular tachycardia does not respond to parenteral lidocaine, the addition of procainamide (class IA) into the protocol may be beneficial. Class I drugs (lidocaine, procainamide, mexiletine) are frequently combined with class II drugs (beta-blockers) to control the clinical signs associated with a ventricular arrhythmia. This combination may improve not only quality, but also quantity of life due to the beneficial effects of the beta-blocker. This is as yet unproven in veterinary patients, but suggested in humans. Class III drugs should be combined with extreme caution. Many of these drugs already combine the effects of several classes, and the results combining them with other drugs can thus prove unpredictable. 10. How is the efficacy of antiarrhythmic agents determined? Efficacy can be estimated in a number of ways: 1. Diminution or elimination of clinical signs that have been associated with the arrhythmia. One solid indication for the use of antiarrhythmic drugs is to control clinical signs that are
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recognized by the owner or clinician and associated with the arrhythmia. This association can be made by careful clinical observation or recording the arrhythmia while clinical signs are present. This can be challenging, but is facilitated by the use of patient/client-activated or arrhythmia-activated "event recorders." These devices are worn by the patient and constantly record the ECG. The ECG is not "memorized," however, until this unit is activated. Those most commonly used by veterinarians are activated by the client when the clinical sign is seen, but more sophisticated devices can be programmed to become activated when an arrhythmia is detected. The use of owner-activated devices makes sense when trying to correlate "events" that cause the owner concern with the concurrent ECG changes. Having correlated an arrhythmia to clinical signs allows us to use control of those signs as an indication of control of the arrhythmia and hence to judge the efficacy of our therapeutic protocol. 2. A decrease in the frequency of the arrhythmia. Ideally, this method should be used when no or limited clinical signs are seen, but when the clinician is concerned that the arrhythmia is likely to progress and become life-threatening. When no clinical signs are seen, one of the best ways to judge efficacy is an 85% decrease in the frequency of the arrhythmia when quantified by sequential 24-hour Holter monitoring. This is the standard used to judge the efficacy of arrhythmia management in human medicine. 3. A decrease in the frequency of the arrhythmia on a standard I, 6 or 10 lead ECG. This is the method most frequently used because of its simplicity. While conclusions can be drawn, one should bear in mind the limitations of this method. The likelihood of drawing inaccurate conclusions about the frequency of an arrhythmia increases as the length of the recording of the ECG decreases. Hence quantification of the arrhythmia is limited when only a 1- or 2-minute time frame is reviewed. Increasing the length of recording will help in assessing efficacy, but will never approach the accuracy of 24-hour Holter recordings. This should be borne in mind when making judgements in the asymptomatic patient, because support for your conclusions does not come from resolution of clinical signs. 4. An improvement in clinical signs when the arrhythmia is judged severe enough to have caused those signs but where direct correlation is not possible. Again, this is a technique frequently used in veterinary medicine when the clinician may be limited by the resources of the pet owner, or accessibility to more sophisticated testing. It is reasonable to suppose that if a patient has an arrhythmia deemed severe enough to cause clinical signs and is showing those signs, that resolution of those signs suggests efficacy of the drug. The Iimitations of this technique are, obviously, that arrhythmias will respond spontaneously, as will clinical signs. Therefore, the danger of this technique is that an animal will be kept on expensive and potentially dangerous drugs that are not contributing to control of clinical signs either because the arrhythmia has resolved spontaneously or because it was not causing these signs in the first place.
11. Lidocaine has a very short half-life when administered intravenously. What is the reason for this and how should I set up a lidocaine infusion? Lidocaine is often the antiarrhythmic drug of choice for controlling rapid ventricular tachycardias. It has to be administered parenterally because it undergoes extensive first-pass metabolism when administered orally. A single intravenous bolus has a half-life of 10-20 minutes and therefore its effects will not be sustained. In order to sustain therapeutic blood levels, it is necessary to administer lidocaine as a constant-rate infusion (CRI). However, it takes hours for a CRI alone to raise blood levels to therapeutic levels; therefore, a bolus/infusion combination is required. There should be minimal delay between the bolus and the initiation of the CRr. Starting the CRI before giving the bolus prevents inadequate blood levels leading to decreased efficacy. We typically use a dose of 50 ug/kg/rnin, The table on the next page provides a reference to assist in setting up these infusions. A formula for calculating the amount of a drug to be added to a bag of fluids for CRIs follows: Body weight (kg) x required dose (ug/kg/min) = amount of drug (mg) to be added to a 250-ml bag of fluids when the fluid/drug mix is administered at 15 ml/hr
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For example, for a 20-kg dog that requires 50 ug/kg/min of a drug, the calculation is: 20 x 50 = 1000 mg of drug that should be added to a 250-ml bag and administered at 15 ml/hr If you wish to administer the fluid more rapidly, simply divide the amount of drug by the ratio of the new infusion rate to the old infusion rate. For example, to administer the fluid at 30 ml/hr instead of 15 ml/hr: 30 (new) / 15 (old) = 2. Therefore, for an equivalent CRI dose we should divide the amount calculated for 15 ml/hr (1000 mg) by 2 to get 500 mg in 250 ml at 30 ml/hr. Side effects of long-term lidocaine administration include neurologic depression initially and ultimately seizures. The table below is a guide to the preparation of a 50 ug/kg/min constant-rate infusion (CRI) of lidocaine, when the infusion is administered at 15, 30, or 60 ml/hr. It is based on using a 250ml bag of fluids and should be used for dogs only. To use it, find the row that correlates to the dog's body weight and select the rate of infusion. The table gives both the number of mg of lidocaine to add to a 250-ml bag and the number of ml of 2% lidocaine that this represents. WEIGHT (KG)
15 MLlHR
MGT0250ML@ 30MLIHR
60MLlHR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 1550 1600 1650
25 50 75 100 125 150 175 200 225 250 275 300 325 350 375 400 425 450 475 500 525 550 575 600 625 650 675 700 725 750 775 800 825
12.5 25 37.5 50 62.5 75 87.5 100 112.5 125 137.5 150 162.5 175 187.5 200 212.5 225 237.5 250 262.5 275 287.5 300 312.5 325 337.5 350 362.5 375 387.5 400 412.5
ML OF 2% LIDOCAINE TO 250 ML 30MLIHR 60MLIHR 15 MLIHR
2.5 5 7.5 10 12.5 15 17.5 20 22.5 25 27.5 30 32.5 35 37.5 40 42.5 45 47.5 50 52.5 55 57.5 60 62.5 65 67.5 70 72.5 75 77.5 80 82.5
1.25 2.5 3.75 5 6.25 7.5 8.75 10 11.25 12.5 13.75 15 16.25 17.5 18.75 20 21.25 22.5 23.75 25 26.25 27.5 28.75 30 31.25 32.5 33.75 35 36.25 37.5 38.75 40 41.25
0.625 1.25 1.875 2.5 3.125 3.75 4.375 5 5.625 6.25 6.875 7.5 8.125 8.75 9.375 10 10.625 11.25 11.875 12.5 13.125 13.75 14.375 15 15.625 16.25 16.875 17.5 18.125 18.75 19.375 20 20.625
Table continued on next page
Antiarrhythmic Agents WEIGHT (KG)
I5MLIHR
34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1700 1750 1800 1850 1900 1950 2000 2050 2100 2150 2200 2250 2300 2350 2400 2450 2500 2550 2600 2650 2700 2750 2800 2850 2900 2950 3000
MGTO 250 ML 30MLIHR
850 875 900 925 950 975 1000 1025 1050 1075 1100 1125 1150 1175 1200 1225 1250 1275 1300 1325 1350 1375 1400 1425 1450 1475 1500
@
60MLIHR
425 437.5 450 462.5 475 487.5 500 512.5 525 537.5 550 562.5 575 587.5 600 612.5 625 637.5 650 662.5 675 687.5 700 712.5 725 737.5 750
85
ML OF 2% LIDOCAINE TO 250 ML I5MLIHR 30MLIHR 60MLIHR
85 87.5 90 92.5 95 97.5 100 102.5 105 107.5 110 112.5 115 117.5 120 122.5 125 127.5 130 132.5 135 137.5 140 142.5 145 147.5 150
42.5 43.75 45 46.25 47.5 48.75 50 51.25 52.5 53.75 55 56.25 57.5 58.75 60 61.25 62.5 63.75 65 66.25 67.5 68.75 70 71.25 72.5 73.75 75
21.25 21.875 22.5 23.125 23.75 24.375 25 25.625 26.25 26.875 27.5 28.125 28.75 29.375 30 30.625 31.25 31.875 32.5 33.125 33.75 34.375 35 35.625 36.25 36.875 37.5
12. What concurrent problems affect the required dose of lidocaine? Reduced blood flow to the liver decreases the required dose of lidocaine and may increase side effects, including mental depression. Low cardiac output and beta-blockade decrease hepatic blood flow. Liver failure and administration of cimetidine also decrease hepatic clearance of lidocaine. 13. Digoxin is often used in the management of heart failure. Which antiarrhythmic drugs affect the pharmacokinetics of digoxin and what are their effects? Certain class IA (quinidine and procainamide) and class IV (diltiazem) antiarrhythmics will elevate the blood levels of digoxin when these drugs are used concurrently. Careful attention should be paid to blood digoxin levels when these drugs are used concurrently and owners should be warned to be particularly vigilant in monitoring for signs of digoxin intoxication (primarily inappetance and vomiting). BIBLIOGRAPHY 1. Lunney J, Ettinger SJ: Cardiac arrhythmias. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, 4th ed. Philadelphia, W.B. Saunders, 1995. 2. Miller MS, Tilley LP: Treatment of cardiac arrhythmias and conduction disturbances. In Miller MS, Tilley LP: Manual of Canine and Feline Cardiology, 2nd ed. Philadelphia, W.B. Saunders, 1995. 3. Tilley LP: Essentials of Canine and Feline Electrocardiography, 3rd ed. Philadelphia, Lea & Febiger, 1992. 4. Wall RE, Rush JE: Cardiac emergencies. In Murtaugh RJ, Kaplan PM (eds): Veterinary Emergency and Critical Care Medicine. St. Louis, Mosby, 1992.
Areaof unidirectional block. Macroreentry loops use larger circuits composed of existing conduction pathways, i.e., reentry loops within the the atrioventricular (AV) node or by an accessory pathway, as in WolffParkinson-White (WPW) syndrome. In humans up to 85% of supraventricular tachyarrhythmias (SVTs) may be due to macroreentry loops utilizing disparity of conduction velocities in the fast and slow pathways through the AV node. These pathways also exist in the canine AV node, but it is unclear how many SVTs in dogs are generated through this mechanism. Enhanced automaticity. In this mechanism of arrhythrnogcnesis, either normal pacemaker tissues show abnormal activity or cells that are not usually automatic become so. Automaticity is a property of phase 4 of the action potential. In automatic cells a leakage of ions allows the resting membrane potential to change, moving it toward threshold. When the threshold is reached, depolarization is triggered. The rate of change of this potential determines the rate at which it reaches threshold and hence how frequently the pacemaker will fire. Changes in the membrane or the prevailing autonomic tone may affect this mechanism and hence enhance automaticity. Diseased cells that normally do not show automaticity may start to do so. For example, the membranes of diseased myocardial cells may develop an abnormal permeability to calcium ions. This leak allows the membrane to depolarize spontaneously, reach threshold, and trigger a premature beat. Triggered activity. As the name indicates, triggered activity does not occur spontaneously but requires one wave of depolarization to trigger another. It is believed that oscillations in the membrane potential following an action potential are responsible for this activity. Disease states or, in some cases, drugs render the membrane unstable and likely to allow such oscillations.
79
80
Antiarrhythmic Agents
Described as afterdepolarization, these oscillations are further classified, depending on their relationship to the action potential, as either early or late. Late afterdepolarizations are typically cited as causing the arrhythmias induced by digoxin intoxication.
Triggered activity. AP = actionpotential; LAD = late afterdepolarization.
2. Which steps should be taken to determine the focus of an arrhythmia? 1. Try to identify a normal PQRST, i.e., a complex that originated from the sinoatrial (SA) node, was conducted through the AV node, and depolarized the ventricle with a normal timing and conduction pattern. A normal PQRST may show some abnormalities because of underlying disease, such as abnormal AV nodal conduction, aberrant ventricular conduction, or an abnormally shaped P-wave due to atrial changes. If in doubt, try to identify several complexes that look the same; all of them may have the same abnormality, but in each a P-wave is followed after an appropriate interval by a QRS complex and aT-wave. 2. Compare the normal complex with others on the strip. If the abnormal complexes have only a QRS complex and a T-wave, do they look like the normal QRS-T complex? If so, the arrhythmia most likely arises at or above the AV node and is thus supraventricular in origin. If not, the arrhythmia is probably ventricular in origin. 3. Try to identify any P-waves on the strip. Do they have a temporal relationship to the abnormal QRS complexes? The answer may help to determine whether the source of a supraventricular arrhythmia is atrial or junctional.
3. What is the most important first step in examining the EKG of a patient with tachyarrhythmia? Try to establish whether the arrhythmia is supraventricular or ventricular in origin. Generally speaking, this distinction is the most useful first step in choosing the most appropriate therapy. Even if you cannot definitively categorize the arrhythmia, first-line therapy has a better chance of success if it is based on your best guess. It is not unusual to have to reassess the diagnosis frequently throughout the management of tachyarrhythmia because of the inappropriate therapeutic response or a change in the underlying arrhythmia.
4. Describe the Vaughan-Williams classification system for antiarrhythmic drugs. Which class(es) do lidocaine, procainamide, diltiazem, and propranolol belong to? The Vaughan-Williams classification of antiarrhythmic drugs is based on their effect on the action potential of the cardiac myocyte: Class I drugs, frequently described as membrane stabilizers, block the fast sodium channel. They are subdivided according to their effect on the action potential in terms of automaticity, conductivity, contractility, AV conduction, and fibrillation threshold: SVT Class IA Decreased automaticity Procainamide VT Decreased conductivity Quinidine WPW Decreased contractility Class IE Lidocaine VT Decreased automaticity Tocainide Decreased contractility Mexiletine Increased AV conduction Increased fibrillation threshold
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VT Decreased automaticity Flecainide WPW Decreased conductivity Encainide Decreased contractility Decreased AV conduction Class II drugs are the beta-blockers, which decrease automaticity and conductivity. They cause variable degrees of depression of both contractility and AV node conduction, depending on the drug in question. Beta-blockers are used to manage supraventricular tachycardia (SVT), ventricular tachycardia (VT), and Wolff-Parkinson-White syndrome (WPW). Class III drugs block the outward potassium current that is important in repolarization, and in doing so, they prolong repolarization and increase refractory periods. Recently they have received a great deal of attention in the management of arrhythmias refractory to class I drugs. Many have significant side effects that must be taken into consideration. The most commonly used class III drugs are bretylium, amiodarone, and sotalo!. Class IV drugs, which block the slow calcium channel, have the most profound effects on AV node conduction. They also decrease automaticity, conductivity, and contractility, although the magnitude of these effects varies widely across the group. The most commonly used class IV drugs are verapamil and diltiazem. Class IC
5. How is the Vaughan-Williams classification used to determine the choice of antiarrhythmic drug? The ion that carries the action potential differs according to the location of the myocyte. For example, the action potential in the pacemaker cells of the SA and AV nodes is carried principally by the calcium ion. To treat arrhythmias that arise from these tissues or require the AV node for maintenance of the tachycardia (SVTs), a class IV drug (calcium channel blocker) such as diltiazem is appropriate. Class I drugs act principally on the sodium channel and are useful in the management of ventricular tachycardias because the sodium channel carries the depolarization phase of the action potential in working myocytes. 6. What is proarrhythmia? Proarrhythmia represents a change in or development of arrhythmias during treatment with antiarrhythmic drugs. The clinical importance of this phenomenon first became apparent when a clinical trial demonstrated that class IC antiarrhythmic agents increase mortality relative to placebo in asymptomatic people with ventricular premature complexes. Proarrhythmia must be considered whenever antiarrhythmic drugs are used. All antiarrhythmic drugs affect the myocardial action potentia!. Although this effect is often beneficial, it may be unpredictable, especially in diseased tissue. Hence drugs that suppress conduction velocity may affect the timing of conduction through reentrant loops in such a way as to "fine-tune" the loop and exacerbate the arrhythmia. Clinicians must consider the risk vs. benefit ratio of such drugs before they are used. Asymptomatic patients with premature ventricular contractions (PVCs) do not invariably need antiarrhythmic therapy. 7. Which medications are often selected for management of acute SVTs in dogs? The short-acting beta-blocker esmolol, the unclassified agent adenosine, intravenous calcium channel blockers (diltiazem and verapamil), or intravenous digoxin is often selected. Intravenous digoxin is the most difficult to manage and tends to be used less frequently. An exception is the patient with an SVT and suspected dilated cardiomyopathy (DCM); beta-blockers and calcium channel blockers are negative inotropes and should be used with extreme caution in such patients. Digoxin is also appropriate when dobutamine is indicated for the acute management of DCM in patients suspected of atrial fibrillation. Dobutamine increases the rate of conduction through the AV node and the ventricular response rate, thereby exacerbating tachycardia. Of the calcium channel blockers, diltiazem may cause less myocardial depression than verapamil and may be the better choice. Adenosine is a purine nucleotide found in every cell in the body. When exogenous adenosine is administered, it is presumed to bind to an extracellular purine receptor. It then decreases intracellular levels of the universal second messenger, cyclic
82
Antiarrhythmic Agents
adenosine monophosphate (cAMP), by blocking adenylate cyclase. Adenosine has profound inhibitory effects on AV node conduction and depresses SA node and ventricular automaticity.
8. Which characteristics of an arrhythmia are most important in selecting the appropriate antiarrhythmic drug? Characterizing an arrhythmia is critical if the appropriate antiarrhythmic drug is to be selected. Two important distinctions are whether the arrhythmia is a bradyarrhythmia or a tachyarrhythmia, and whether the arrhythmia arises from the AV node or above (supraventricular) or from the ventricles themselves (ventricular). If an arrhythmia is classified in this way, drug selection can be made as described below: ARRHYTHMIA CLASSIFICATION
ARRHYTHMIA CHARACTERISTICS
Supraventricular tachycardia
Rate> 200 bpm; "normal" QRS; breaks with vagal maneuver
Supraventricular bradycardia
Rate < 50 bpm; "normal" QRS
Ventricular bradycardia
Rate < 50 bpm; abnormal QRS
Ventricular tachycardia
Rate> 180 bpm; abnormal QRS, hemodynamically unstable; breed predisposition to fatal ventricular arrhythmias (boxers)
APPROPRIATE MANAGEMENT
Digoxin; calcium channel blockers; beta-blockers; procainamide for WPW Atropine (oral propantheline bromide); nonspecific stimulants of HR (aminophylline, theophylline); pacemaker implantation. Atropine to stimulate SA node; nonspecific stimulantsof HR; pacemaker implantation Identify and correct under!ying cause; acute use parenteral class I drugs (lidocaine); chronic use class I, II, or III
9. If a single antiarrhythmic drug fails to control an arrhythmia, what alternative approaches can be considered? Combination therapy can be tried but only after the synergistic therapeutic effects and side effects have been considered. For example, a combination of a calcium channel blocker (class IV drug) and a beta-blocker (class II drug) may be necessary to manage a supraventricular tachycardia. While the different mechanisms of action may produce therapeutic synergy, they may also lead to compounding side effects, in this case a negative inotropic effect. Exacerbation of systolic dysfunction may therefore be the net effect of this combination of drugs. It is not uncommon for combinations of antiarrhythmic drugs to be used to control ventricular arrhythmias that are either causing clinical signs in a patient or when the arrhythmia is deemed to be life-threatening. Guidelines for the selection of drugs that can be combined include selecting drugs from different classes. For instance, class IA drugs may be combined with class IE drugs. If a patient with a life-threatening ventricular tachycardia does not respond to parenteral lidocaine, the addition of procainamide (class IA) into the protocol may be beneficial. Class I drugs (lidocaine, procainamide, mexiletine) are frequently combined with class II drugs (beta-blockers) to control the clinical signs associated with a ventricular arrhythmia. This combination may improve not only quality, but also quantity of life due to the beneficial effects of the beta-blocker. This is as yet unproven in veterinary patients, but suggested in humans. Class III drugs should be combined with extreme caution. Many of these drugs already combine the effects of several classes, and the results combining them with other drugs can thus prove unpredictable. 10. How is the efficacy of antiarrhythmic agents determined? Efficacy can be estimated in a number of ways: 1. Diminution or elimination of clinical signs that have been associated with the arrhythmia. One solid indication for the use of antiarrhythmic drugs is to control clinical signs that are
Antiarrhythmic Agents
83
recognized by the owner or clinician and associated with the arrhythmia. This association can be made by careful clinical observation or recording the arrhythmia while clinical signs are present. This can be challenging, but is facilitated by the use of patient/client-activated or arrhythmia-activated "event recorders." These devices are worn by the patient and constantly record the ECG. The ECG is not "memorized," however, until this unit is activated. Those most commonly used by veterinarians are activated by the client when the clinical sign is seen, but more sophisticated devices can be programmed to become activated when an arrhythmia is detected. The use of owner-activated devices makes sense when trying to correlate "events" that cause the owner concern with the concurrent ECG changes. Having correlated an arrhythmia to clinical signs allows us to use control of those signs as an indication of control of the arrhythmia and hence to judge the efficacy of our therapeutic protocol. 2. A decrease in the frequency of the arrhythmia. Ideally, this method should be used when no or limited clinical signs are seen, but when the clinician is concerned that the arrhythmia is likely to progress and become life-threatening. When no clinical signs are seen, one of the best ways to judge efficacy is an 85% decrease in the frequency of the arrhythmia when quantified by sequential 24-hour Holter monitoring. This is the standard used to judge the efficacy of arrhythmia management in human medicine. 3. A decrease in the frequency of the arrhythmia on a standard I, 6 or 10 lead ECG. This is the method most frequently used because of its simplicity. While conclusions can be drawn, one should bear in mind the limitations of this method. The likelihood of drawing inaccurate conclusions about the frequency of an arrhythmia increases as the length of the recording of the ECG decreases. Hence quantification of the arrhythmia is limited when only a 1- or 2-minute time frame is reviewed. Increasing the length of recording will help in assessing efficacy, but will never approach the accuracy of 24-hour Holter recordings. This should be borne in mind when making judgements in the asymptomatic patient, because support for your conclusions does not come from resolution of clinical signs. 4. An improvement in clinical signs when the arrhythmia is judged severe enough to have caused those signs but where direct correlation is not possible. Again, this is a technique frequently used in veterinary medicine when the clinician may be limited by the resources of the pet owner, or accessibility to more sophisticated testing. It is reasonable to suppose that if a patient has an arrhythmia deemed severe enough to cause clinical signs and is showing those signs, that resolution of those signs suggests efficacy of the drug. The Iimitations of this technique are, obviously, that arrhythmias will respond spontaneously, as will clinical signs. Therefore, the danger of this technique is that an animal will be kept on expensive and potentially dangerous drugs that are not contributing to control of clinical signs either because the arrhythmia has resolved spontaneously or because it was not causing these signs in the first place.
11. Lidocaine has a very short half-life when administered intravenously. What is the reason for this and how should I set up a lidocaine infusion? Lidocaine is often the antiarrhythmic drug of choice for controlling rapid ventricular tachycardias. It has to be administered parenterally because it undergoes extensive first-pass metabolism when administered orally. A single intravenous bolus has a half-life of 10-20 minutes and therefore its effects will not be sustained. In order to sustain therapeutic blood levels, it is necessary to administer lidocaine as a constant-rate infusion (CRI). However, it takes hours for a CRI alone to raise blood levels to therapeutic levels; therefore, a bolus/infusion combination is required. There should be minimal delay between the bolus and the initiation of the CRr. Starting the CRI before giving the bolus prevents inadequate blood levels leading to decreased efficacy. We typically use a dose of 50 ug/kg/rnin, The table on the next page provides a reference to assist in setting up these infusions. A formula for calculating the amount of a drug to be added to a bag of fluids for CRIs follows: Body weight (kg) x required dose (ug/kg/min) = amount of drug (mg) to be added to a 250-ml bag of fluids when the fluid/drug mix is administered at 15 ml/hr
84
Antiarrhythmic Agents
For example, for a 20-kg dog that requires 50 ug/kg/min of a drug, the calculation is: 20 x 50 = 1000 mg of drug that should be added to a 250-ml bag and administered at 15 ml/hr If you wish to administer the fluid more rapidly, simply divide the amount of drug by the ratio of the new infusion rate to the old infusion rate. For example, to administer the fluid at 30 ml/hr instead of 15 ml/hr: 30 (new) / 15 (old) = 2. Therefore, for an equivalent CRI dose we should divide the amount calculated for 15 ml/hr (1000 mg) by 2 to get 500 mg in 250 ml at 30 ml/hr. Side effects of long-term lidocaine administration include neurologic depression initially and ultimately seizures. The table below is a guide to the preparation of a 50 ug/kg/min constant-rate infusion (CRI) of lidocaine, when the infusion is administered at 15, 30, or 60 ml/hr. It is based on using a 250ml bag of fluids and should be used for dogs only. To use it, find the row that correlates to the dog's body weight and select the rate of infusion. The table gives both the number of mg of lidocaine to add to a 250-ml bag and the number of ml of 2% lidocaine that this represents. WEIGHT (KG)
15 MLlHR
MGT0250ML@ 30MLIHR
60MLlHR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 1550 1600 1650
25 50 75 100 125 150 175 200 225 250 275 300 325 350 375 400 425 450 475 500 525 550 575 600 625 650 675 700 725 750 775 800 825
12.5 25 37.5 50 62.5 75 87.5 100 112.5 125 137.5 150 162.5 175 187.5 200 212.5 225 237.5 250 262.5 275 287.5 300 312.5 325 337.5 350 362.5 375 387.5 400 412.5
ML OF 2% LIDOCAINE TO 250 ML 30MLIHR 60MLIHR 15 MLIHR
2.5 5 7.5 10 12.5 15 17.5 20 22.5 25 27.5 30 32.5 35 37.5 40 42.5 45 47.5 50 52.5 55 57.5 60 62.5 65 67.5 70 72.5 75 77.5 80 82.5
1.25 2.5 3.75 5 6.25 7.5 8.75 10 11.25 12.5 13.75 15 16.25 17.5 18.75 20 21.25 22.5 23.75 25 26.25 27.5 28.75 30 31.25 32.5 33.75 35 36.25 37.5 38.75 40 41.25
0.625 1.25 1.875 2.5 3.125 3.75 4.375 5 5.625 6.25 6.875 7.5 8.125 8.75 9.375 10 10.625 11.25 11.875 12.5 13.125 13.75 14.375 15 15.625 16.25 16.875 17.5 18.125 18.75 19.375 20 20.625
Table continued on next page
Antiarrhythmic Agents WEIGHT (KG)
I5MLIHR
34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1700 1750 1800 1850 1900 1950 2000 2050 2100 2150 2200 2250 2300 2350 2400 2450 2500 2550 2600 2650 2700 2750 2800 2850 2900 2950 3000
MGTO 250 ML 30MLIHR
850 875 900 925 950 975 1000 1025 1050 1075 1100 1125 1150 1175 1200 1225 1250 1275 1300 1325 1350 1375 1400 1425 1450 1475 1500
@
60MLIHR
425 437.5 450 462.5 475 487.5 500 512.5 525 537.5 550 562.5 575 587.5 600 612.5 625 637.5 650 662.5 675 687.5 700 712.5 725 737.5 750
85
ML OF 2% LIDOCAINE TO 250 ML I5MLIHR 30MLIHR 60MLIHR
85 87.5 90 92.5 95 97.5 100 102.5 105 107.5 110 112.5 115 117.5 120 122.5 125 127.5 130 132.5 135 137.5 140 142.5 145 147.5 150
42.5 43.75 45 46.25 47.5 48.75 50 51.25 52.5 53.75 55 56.25 57.5 58.75 60 61.25 62.5 63.75 65 66.25 67.5 68.75 70 71.25 72.5 73.75 75
21.25 21.875 22.5 23.125 23.75 24.375 25 25.625 26.25 26.875 27.5 28.125 28.75 29.375 30 30.625 31.25 31.875 32.5 33.125 33.75 34.375 35 35.625 36.25 36.875 37.5
12. What concurrent problems affect the required dose of lidocaine? Reduced blood flow to the liver decreases the required dose of lidocaine and may increase side effects, including mental depression. Low cardiac output and beta-blockade decrease hepatic blood flow. Liver failure and administration of cimetidine also decrease hepatic clearance of lidocaine. 13. Digoxin is often used in the management of heart failure. Which antiarrhythmic drugs affect the pharmacokinetics of digoxin and what are their effects? Certain class IA (quinidine and procainamide) and class IV (diltiazem) antiarrhythmics will elevate the blood levels of digoxin when these drugs are used concurrently. Careful attention should be paid to blood digoxin levels when these drugs are used concurrently and owners should be warned to be particularly vigilant in monitoring for signs of digoxin intoxication (primarily inappetance and vomiting). BIBLIOGRAPHY 1. Lunney J, Ettinger SJ: Cardiac arrhythmias. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, 4th ed. Philadelphia, W.B. Saunders, 1995. 2. Miller MS, Tilley LP: Treatment of cardiac arrhythmias and conduction disturbances. In Miller MS, Tilley LP: Manual of Canine and Feline Cardiology, 2nd ed. Philadelphia, W.B. Saunders, 1995. 3. Tilley LP: Essentials of Canine and Feline Electrocardiography, 3rd ed. Philadelphia, Lea & Febiger, 1992. 4. Wall RE, Rush JE: Cardiac emergencies. In Murtaugh RJ, Kaplan PM (eds): Veterinary Emergency and Critical Care Medicine. St. Louis, Mosby, 1992.