Cardiac therapy: Therapy of Arrhythmias- Ettinger Flashcards
(28 cards)
Attempting to treat ventricular tachycardia (VT) with antiarrhythmic drugs when a patient is hypokalemic is counterproductive and probably dangerous. Why?
Hypokalemia can both make ventricular arrhythmias more likely to occur and, through effects on myocardial sodium channels, hypokalemia makes the arrhythmia refractory to the more commonly used intravenous antiarrhythmics including lidocaine
The V-W classification is based only on the electrophysiologic drug effects of isolated, normal cardiac tissue (except for class II agents), which is different from the diseased state. The classification excludes compounds such as digitalis, adenosine, and alpha-adrenergic blocking agents. The V-W classification system assumes that we know more than we really do. Not all drugs within a class have the same physiologic or clinical effects. The danger in using only the V-W scheme is that most drugs have more than one mode of action, and all the drugs within a category clearly are not always the same (Figure 245-4). crossover within the system among specific drugs, and its discussion principally of blocking mechanisms, whereas activation of ionic channels, receptors, or both are downplayed.
The V-W classification is based only on the electrophysiologic drug effects of isolated, normal cardiac tissue (except for class II agents), which is different from the diseased state. The classification excludes compounds such as digitalis, adenosine, and alpha-adrenergic blocking agents. The V-W classification system assumes that we know more than we really do. Not all drugs within a class have the same physiologic or clinical effects. The danger in using only the V-W scheme is that most drugs have more than one mode of action, and all the drugs within a category clearly are not always the same (Figure 245-4). crossover within the system among specific drugs, and its discussion principally of blocking mechanisms, whereas activation of ionic channels, receptors, or both are downplayed.
Figure 245-4 The classical four types of antiarrhythmic agents.
- Class I agents ………………phase …………. of the rapid depolarization of the action potential (rapid ……… channel).
- Class II agents, β-blocking drugs, have complex actions including inhibition of ……………….. depolarization (phase ……) and indirect closure of …………… channels, which are less likely to be in the “open” state when not phosphorylated by …………………………..
- Class III agents block the……………..potassium channels to prolong the ……………… duration and hence ………………………
- Class IV agents, verapamil and diltiazem, and the indirect calcium antagonist adenosine, all inhibit the ………………. calcium channel, which is most prominent in …………… tissue, particularly the ……………….. node.
Most antiarrhythmic drugs have more than one action. In the lower panel are shown the major currents on which antiarrhythmics act, according to the Sicilian gambit.[5] ICaL, Inward (L-type) calcium current; If, hyperpolarization-activated current; IKr, rapidly activating component of the delayed rectifier potassium current; IKs, slowly activating component of the delayed rectifier potassium current; INa sodium current; Ito, transient outward current.
Figure 245-4 The classical four types of antiarrhythmic agents.
- Class I agents decrease phase zero of the rapid depolarization of the action potential (rapid sodium channel).
- Class II agents, β-blocking drugs, have complex actions including inhibition of spontaneous depolarization (phase 4) and indirect closure of calcium channels, which are less likely to be in the “open” state when not phosphorylated by cyclic AMP.
- Class III agents block the outward potassium channels to prolong the action potential duration and hence refractoriness.
- Class IV agents, verapamil and diltiazem, and the indirect calcium antagonist adenosine, all inhibit the inward calcium channel, which is most prominent in nodal tissue, particularly the atrioventricular node.
Most antiarrhythmic drugs have more than one action. In the lower panel are shown the major currents on which antiarrhythmics act, according to the Sicilian gambit.[5] ICaL, Inward (L-type) calcium current; If, hyperpolarization-activated current; IKr, rapidly activating component of the delayed rectifier potassium current; IKs, slowly activating component of the delayed rectifier potassium current; INa sodium current; Ito, transient outward current.
CLASS I ANTIARRHYTHMICS
Class I drugs selectively block the ……. ………….. channels, decreasing ……….. …………. during phase ………. of depolarization. A reduced slope of phase ……. is the manifestation of decreased …………… velocity.
Slowed conduction velocity can interrupt a reentrant pattern. These drugs work best in cells dependent on the fast sodium channel for their action potential, such as normal and ischemic ……………….and …………..myocardial cells.
Within this class are three subgroups, distinguished by their electrophysiologic and antiarrhythmic differences. Most of the compounds within this class fail to perform adequately in the presence of hypokalemia.
CLASS I ANTIARRHYTHMICS
Class I drugs selectively block the fast sodium channels, decreasing sodium influx during phase zero of depolarization. A reduced slope of phase zero is the manifestation of decreased conduction velocity.
Slowed conduction velocity can interrupt a reentrant pattern. These drugs work best in cells dependent on the fast sodium channel for their action potential, such as normal and ischemic Purkinje cells and ventricular myocardial cells.
Within this class are three subgroups, distinguished by their electrophysiologic and antiarrhythmic differences. Most of the compounds within this class fail to perform adequately in the presence of hypokalemia.
CLASS IA DRUGS
Class IA antiarrhythmic drugs are …………………… sodium channel blockers that markedly depress phase zero action potential, depress conduction of electrical impulses through the heart, and slow cardiac …………….. by lengthening the ………………refractory period.
By depressing the ……………. velocity and prolonging the …………………….. period, arrhythmias dependent on reentry may be interrupted.
Drugs in this class include ……………(prototype IA drug), ……….., and disopyramide.
CLASS IA DRUGS
Class IA antiarrhythmic drugs are intermediate sodium channel blockers that markedly depress phase zero action potential, depress conduction of electrical impulses through the heart, and slow cardiac repolarization by lengthening the effective refractory period.
By depressing the conduction velocity and prolonging the refractory period, arrhythmias dependent on reentry may be interrupted.
Drugs in this class include quinidine (prototype IA drug), procainamide, and disopyramide.
Quinidine decreases the rate of spontaneous depolarization in ……………. fibers, prolongs anterograde ……………….. accessory pathways, and can suppress or trigger delayed afterdepolarizations. Quinidine may prolong the ……. interval, widen the ………….. complex, and lengthen the ………….interval, and it was originally indicated for the control of supraventricular and ventricular arrhythmias. Today it and the other class IA drugs have very limited usefulness in clinical antiarrhythmic therapy of small animals. Proarrhythmic and other side effects make quinidine an agent that is now rarely used.
Procainamide has cardiac effects similar to those of quinidine. However, its propensity for inducing hypotension with intravenous use or increasing ventricular rates from enhanced atrioventricular (AV) conduction is less than that of quinidine. Procainamide specifically has been demonstrated to prolong the effective refractory period and slow conduction in the accessory pathway of dogs with orthodromic AV reciprocating tachycardia.[14]
Procainamide is metabolized by the liver and eliminated by the kidneys. The sustained release formulations may be poorly absorbed and even eliminated as intact tablets in the feces of dogs. Procainamide may be used in conjunction with other class I agents and beta-blockers for refractory arrhythmias. Oral administration of the drug at higher than usually recommended doses to achieve trough serum concentrations of 10 to 12 µg/mL were successful in controlling some supraventricular tachyarrhythmias.[14],[15] Side effects are infrequent and include anorexia, nausea, vomiting, fever, proarrhythmia, and agranulocytosis. In a four-way trial of antiarrhythmic drugs in boxer dogs with ventricular arrhythmias, procainamide (10 to 12 mg/lb orally, three times a day) successfully reduced the frequency of ventricular ectopy. However, the frequency of syncope was unaffected, and there were substantial side effects.[3]
Quinidine decreases the rate of spontaneous depolarization in pacemaker fibers, prolongs anterograde refractoriness accessory pathways, and can suppress or trigger delayed afterdepolarizations. Quinidine may prolong the PR interval, widen the QRS complex, and lengthen the QT interval, and it was originally indicated for the control of supraventricular and ventricular arrhythmias. Today it and the other class IA drugs have very limited usefulness in clinical antiarrhythmic therapy of small animals. Proarrhythmic and other side effects make quinidine an agent that is now rarely used.
Procainamide has cardiac effects similar to those of quinidine. However, its propensity for inducing hypotension with intravenous use or increasing ventricular rates from enhanced atrioventricular (AV) conduction is less than that of quinidine. Procainamide specifically has been demonstrated to prolong the effective refractory period and slow conduction in the accessory pathway of dogs with orthodromic AV reciprocating tachycardia.[14]
Procainamide is metabolized by the liver and eliminated by the kidneys. The sustained release formulations may be poorly absorbed and even eliminated as intact tablets in the feces of dogs. Procainamide may be used in conjunction with other class I agents and beta-blockers for refractory arrhythmias. Oral administration of the drug at higher than usually recommended doses to achieve trough serum concentrations of 10 to 12 µg/mL were successful in controlling some supraventricular tachyarrhythmias.[14],[15] Side effects are infrequent and include anorexia, nausea, vomiting, fever, proarrhythmia, and agranulocytosis. In a four-way trial of antiarrhythmic drugs in boxer dogs with ventricular arrhythmias, procainamide (10 to 12 mg/lb orally, three times a day) successfully reduced the frequency of ventricular ectopy. However, the frequency of syncope was unaffected, and there were substantial side effects.[3]
CLASS IB DRUGS
Class IB agents block fast sodium channels, which decreases the slope of phase ………………, depresses ………………, and increases the threshold for ……….
These drugs have an affinity for binding with inactivated sodium channels, thereby acting selectively on …………….. or ………………….. tissue. Minimal effects are seen on the ……………….,………………,……………….or…………….
……………….., phenytoin, tocainide, and …………….. are examples of drugs in this class (see Table 245-1).
CLASS IB DRUGS
Class IB agents block fast sodium channels, which decreases the slope of phase zero, depresses automaticity, and increases the threshold for VF.
These drugs have an affinity for binding with inactivated sodium channels, thereby acting selectively on diseased or ischemic tissue. Minimal effects are seen on the sinus node, AV node, and atrial muscle or on isotropy.
Lidocaine, phenytoin, tocainide, and mexiletine are examples of drugs in this class (see Table 245-1).
Induced vagally associated atrial fibrillation was reverted rapidly with lidocaine in German Shepherd Dogs with inherited ventricular arrhythmias. The authors suggest that lidocaine decreased dominant frequency and increased organization as judged by the spectral entropy. Where AT and AF are induced by high vagal tone, lidocaine may be effective for conversion.[42]
Lidocaine is used for acute control of life-threatening ventricular arrhythmias. In usual doses it is not likely to affect myocardial contractility, systemic arterial blood pressure, the QRS complex, or AV conduction time,[1] although extremely high doses have been shown to decrease ventricular contractility. Lidocaine suppresses automaticity and conduction velocity and prolongs refractoriness in ischemic cardiac cells.
Induced vagally associated atrial fibrillation was reverted rapidly with lidocaine in German Shepherd Dogs with inherited ventricular arrhythmias. The authors suggest that lidocaine decreased dominant frequency and increased organization as judged by the spectral entropy. Where AT and AF are induced by high vagal tone, lidocaine may be effective for conversion.[42]
Lidocaine is used for acute control of life-threatening ventricular arrhythmias. In usual doses it is not likely to affect myocardial contractility, systemic arterial blood pressure, the QRS complex, or AV conduction time,[1] although extremely high doses have been shown to decrease ventricular contractility. Lidocaine suppresses automaticity and conduction velocity and prolongs refractoriness in ischemic cardiac cells.
Lidocaine is most effective when used intravenously, owing to first-pass hepatic metabolism. It is less than 10% protein bound. Hepatic disease, chloramphenicol, propranolol, halothane, cimetidine, and norepinephrine may all delay hepatic metabolism of lidocaine. Hepatic microenzyme inducers enhance degradation.
Lidocaine is most effective when used intravenously, owing to first-pass hepatic metabolism. It is less than 10% protein bound. Hepatic disease, chloramphenicol, propranolol, halothane, cimetidine, and norepinephrine may all delay hepatic metabolism of lidocaine. Hepatic microenzyme inducers enhance degradation.
Lidocaine intoxication results in ataxia, mental depression, and seizures. These signs usually subside within minutes after lidocaine infusion is discontinued. Diazepam or a short-acting barbiturate may be necessary to control seizures. Lidocaine may be administered by slow (2 to 5 minute) intravenous loading bolus (1 to 2 mg/lb) followed by a continuous rate infusion (CRI) of 10 to 30 µg/lb/min in dogs. Alternatively, after the initial bolus, an additional amount can be given at half the dose every 10 minutes to maintain the rhythm. Caution is recommended when using lidocaine in cats because of historical reports of bradyarrhythmias and sudden death. Lower bolus doses of 0.25 to 0.5 mg/lb slowly followed by 5 to 10 µg/lb/min CRI are recommended for cats. Intramuscular lidocaine is less efficacious and is rarely used.
Lidocaine intoxication results in ataxia, mental depression, and seizures. These signs usually subside within minutes after lidocaine infusion is discontinued. Diazepam or a short-acting barbiturate may be necessary to control seizures. Lidocaine may be administered by slow (2 to 5 minute) intravenous loading bolus (1 to 2 mg/lb) followed by a continuous rate infusion (CRI) of 10 to 30 µg/lb/min in dogs. Alternatively, after the initial bolus, an additional amount can be given at half the dose every 10 minutes to maintain the rhythm. Caution is recommended when using lidocaine in cats because of historical reports of bradyarrhythmias and sudden death. Lower bolus doses of 0.25 to 0.5 mg/lb slowly followed by 5 to 10 µg/lb/min CRI are recommended for cats. Intramuscular lidocaine is less efficacious and is rarely used.
Tocainide and mexiletine are structurally analogous to lidocaine but have …………………bioavailability. Response to lidocaine may not be a predictor of response to these oral agents, however.
Tocainide is orally absorbed and undergoes hepatic metabolism and renal excretion. It may be used after lidocaine or as initial treatment in a hemodynamically stable patient. At 6.8 to 11.4 mg/lb orally every 8 hours, peak levels were reached in cardiomyopathic Doberman Pinscher dogs after 2 hours and began to diminish by 8 hours. Fifteen of 23 (70%) dogs experienced a 90% diminution of VT, and there was a 70% reduction of all PVCs in 80% of the cardiomyopathic dogs. Although there was no relationship between dose and serum concentration, dogs without signs of toxicity had serum levels under 11 mg/L and all those with toxic signs exceeded 14 mg/L.[16] Side effects observed within 8 days are weakness, head tremor, ataxia, and head bobbing. Long-term side effects, including corneal dystrophy, corneal edema, and renal failure, were observed in more than 50% of dogs.
Tocainide and mexiletine are structurally analogous to lidocaine but have oral bioavailability. Response to lidocaine may not be a predictor of response to these oral agents, however.
Tocainide is orally absorbed and undergoes hepatic metabolism and renal excretion. It may be used after lidocaine or as initial treatment in a hemodynamically stable patient. At 6.8 to 11.4 mg/lb orally every 8 hours, peak levels were reached in cardiomyopathic Doberman Pinscher dogs after 2 hours and began to diminish by 8 hours. Fifteen of 23 (70%) dogs experienced a 90% diminution of VT, and there was a 70% reduction of all PVCs in 80% of the cardiomyopathic dogs. Although there was no relationship between dose and serum concentration, dogs without signs of toxicity had serum levels under 11 mg/L and all those with toxic signs exceeded 14 mg/L.[16] Side effects observed within 8 days are weakness, head tremor, ataxia, and head bobbing. Long-term side effects, including corneal dystrophy, corneal edema, and renal failure, were observed in more than 50% of dogs.
Mexiletine is absorbed orally and undergoes less than 10% first-pass hepatic elimination. It is 70% protein bound. The drug is eliminated by renal excretion, and its half-life varies depending on urine pH. Side effects are infrequent in the dog but can include nausea, inappetence, and tremor.[18] Sinus bradycardia (SB), ataxia, dizziness, and thrombocytopenia are other potential problems. No data exist regarding its use in cats. In a group of Boxers with familial arrhythmia, mexiletine was given jointly with the beta-blocker atenolol as one of four forms of therapy being tested. This antiarrhythmic therapy reduced the frequency and “grade” of ventricular arrhythmia, and there was a reduction in peak heart rate. However, the frequency of syncope was not reduced with this form of treatment or with any other in the study.[3] Administered at a dosage of 4 to 5 mg/lb twice daily, a series of dogs with ventricular arrhythmias had cessation of the abnormal rhythm without observable changes in blood pressure, heart rate or biochemical side effects.[3],[38] There was no indication however that treatment in fact improved the dog’s clinical state.[38] Mexiletine is only available in the oral formulation in North America. Both mexiletine and tocainide appear to have synergistic properties when combined with class IA or class II agents.[3]
Mexiletine is absorbed orally and undergoes less than 10% first-pass hepatic elimination. It is 70% protein bound. The drug is eliminated by renal excretion, and its half-life varies depending on urine pH. Side effects are infrequent in the dog but can include nausea, inappetence, and tremor.[18] Sinus bradycardia (SB), ataxia, dizziness, and thrombocytopenia are other potential problems. No data exist regarding its use in cats. In a group of Boxers with familial arrhythmia, mexiletine was given jointly with the beta-blocker atenolol as one of four forms of therapy being tested. This antiarrhythmic therapy reduced the frequency and “grade” of ventricular arrhythmia, and there was a reduction in peak heart rate. However, the frequency of syncope was not reduced with this form of treatment or with any other in the study.[3] Administered at a dosage of 4 to 5 mg/lb twice daily, a series of dogs with ventricular arrhythmias had cessation of the abnormal rhythm without observable changes in blood pressure, heart rate or biochemical side effects.[3],[38] There was no indication however that treatment in fact improved the dog’s clinical state.[38] Mexiletine is only available in the oral formulation in North America. Both mexiletine and tocainide appear to have synergistic properties when combined with class IA or class II agents.[3]
CLASS IC DRUGS
Class IC drugs are blockers of ……..sodium channels and are strong depressants of phase ……. and …………… They exert a minimal effect on …………….or ……………..duration. They are indicated for supraventricular and some ventricular arrhythmias and arrhythmias involving accessory pathways. They are notorious in humans for their proarrhythmic tendencies when given in patients with coronary artery disease. They depress contractility, cardiac output, and systemic blood pressure. These drugs are contraindicated in the presence of AV block, BBB, and myocardial depression. Flecainide and propafenone are class IC agents.
CLASS IC DRUGS
Class IC drugs are blockers of slow sodium channels and are strong depressants of phase zero and conduction velocity. They exert a minimal effect on refractoriness or action potential duration. They are indicated for supraventricular and some ventricular arrhythmias and arrhythmias involving accessory pathways. They are notorious in humans for their proarrhythmic tendencies when given in patients with coronary artery disease. They depress contractility, cardiac output, and systemic blood pressure. These drugs are contraindicated in the presence of AV block, BBB, and myocardial depression. Flecainide and propafenone are class IC agents.
Flecainide is indicated for paroxysmal supraventricular tachycardia (SVT) and paroxysmal AFib but not for chronic AFib or in patients with ventricular dysfunction, ventricular hypertrophy, ischemic heart disease, or valvular heart disease. It has not been studied in clinical small animal medicine. This drug may induce or aggravate congestive heart failure (CHF).
Flecainide is indicated for paroxysmal supraventricular tachycardia (SVT) and paroxysmal AFib but not for chronic AFib or in patients with ventricular dysfunction, ventricular hypertrophy, ischemic heart disease, or valvular heart disease. It has not been studied in clinical small animal medicine. This drug may induce or aggravate congestive heart failure (CHF).
Propafenone has local anesthetic effects and a direct stabilizing action on myocardial tissue, as well as weak beta-adrenergic-blocking activity. It prolongs AV nodal conduction (AH and HV) and has negative inotropic action. It is effective against many SVT and accessory pathway arrhythmias but has not performed as well as had been hoped in the context of treating ventricular arrhythmias.[19] In structurally normal hearts, proarrhythmia is unlikely in humans. Propafenone is only available in the oral form in North America.
Propafenone has local anesthetic effects and a direct stabilizing action on myocardial tissue, as well as weak beta-adrenergic-blocking activity. It prolongs AV nodal conduction (AH and HV) and has negative inotropic action. It is effective against many SVT and accessory pathway arrhythmias but has not performed as well as had been hoped in the context of treating ventricular arrhythmias.[19] In structurally normal hearts, proarrhythmia is unlikely in humans. Propafenone is only available in the oral form in North America.
CLASS II ANTIARRHYTHMICS
Class II antiarrhythmics (beta-blockers) decrease or nullify the electrophysiologic and arrhythmogenic effects of beta-adrenergic ………………… stimulation. The magnitude of the beta-blockade effect is dependent on the prevailing level of sympathetic tone.
……………..stimulation increases the likelihood of slow………………. channels opening and increases the rate of ……………………. discharge.
Overall, beta-blockers depress the slope of phase ……… depolarization and minimally raise the threshold for activation in ……….and ………. nodal cells, thereby suppressing ……………………
The effect of beta-blockers on normal cell refractoriness and conduction is modest, and it is unlikely that they influence cardiac ………………
As a result of the negative inotropic (………………….), chronotropic (……………), and dromotropic (AV node ……………….) effects, cardiac output is …………… and myocardial oxygen requirements and LV work are …………….. in normal tissue.
CLASS II ANTIARRHYTHMICS
Class II antiarrhythmics (beta-blockers) decrease or nullify the electrophysiologic and arrhythmogenic effects of beta-adrenergic sympathetic stimulation. The magnitude of the beta-blockade effect is dependent on the prevailing level of sympathetic tone.
Sympathetic stimulation increases the likelihood of slow calcium channels opening and increases the rate of pacemaker discharge.
Overall, beta-blockers depress the slope of phase 4 depolarization and minimally raise the threshold for activation in sinus and AV nodal cells, thereby suppressing automaticity.
The effect of beta-blockers on normal cell refractoriness and conduction is modest, and it is unlikely that they influence cardiac repolarization.
As a result of the negative inotropic (contractility), chronotropic (rate), and dromotropic (AV node clearance time) effects, cardiac output is reduced and myocardial oxygen requirements and LV work are decreased in normal tissue. I
n the past several years the beneficial effects of beta-blockers have become increasingly recognized in the setting of severe myocardial disease, where initiation of treatment at extremely low doses and careful up-titration appear to provide a long-term cardioprotective effect.
CLASS III ANTIARRHYTHMICS
Class III drugs specifically prolong the ……………… duration and the …………….. period, principally by inhibiting the ……………….. …………….. channel (IK).
This class of drugs reduces the myocardium’s ability to generate a ……………….potential before repolarizing. As a result these drugs …….. or ……………. tachycardia. These effects are most pronounced at …………..heart rates. These drugs lengthen the ……………… in a tachycardia, having few effects at normal heart rates.
Class III drugs specifically prolong the action potential duration and the refractory period, principally by inhibiting the repolarizing potassium channel (IK). This class of drugs reduces the myocardium’s ability to generate a new action potential before repolarizing. As a result these drugs slow or terminate tachycardia. These effects are most pronounced at higher heart rates. These drugs lengthen the action potential duration in a tachycardia,[24] having few effects at normal heart rates.
They are noted for increasing the threshold for ………. and …….. Each drug in this class also frequently displays properties of ……………….classes.
This drug group includes …………….., ……………, bretylium, ibutilide, and dofetilide (see Table 245-1). Only the first three are used in small animal medicine, and bretylium is expected soon to be unavailable because of the exhaustion of the world supply of bretylium.
They are noted for increasing the threshold for AFib and VF. Each drug in this class also frequently displays properties of other antiarrhythmic classes. This drug group includes amiodarone, sotalol, bretylium, ibutilide, and dofetilide (see Table 245-1). Only the first three are used in small animal medicine, and bretylium is expected soon to be unavailable because of the exhaustion of the world supply of bretylium.
Amiodarone is one of the drugs of choice for many supraventricular and malignant ventricular tachyarrhythmias in humans. It exhibits properties of …………….. classes of antiarrhythmic agents and thus is considered a “……………….” antiarrhythmic. Unlike many antiarrhythmics, amiodarone has not been linked to increased mortality in large clinical trials in human cardiology, and it is second only to automated internal defibrillators in terms of beneficial outcomes in human patients with severe ventricular arrhythmia.[19] It may be useful in dogs with LV systolic dysfunction and to offer rate control, as well as for converting acute…………………..to sinus rhythm.
Amiodarone relaxes vascular ………………………, resulting in a decreased ………………. that may be beneficial. Amiodarone increases serum digoxin levels so that the dose of digoxin should be ……………….. Quinidine and procainamide levels are also elevated. Side effects reported in humans include liver damage, photosensitization, thyroid derangements, ocular lesions, and irreversible pulmonary fibrosis.
In dogs, …………………and ………………have been reported with amiodarone treatment,[26] as have anorexia, gastrointestinal (GI) disturbances, …………………… and positive Coombs’ testing. These signs resolved with discontinuation of treatment. Anecdotal reports of acute hypersensitivity, hyper- or hypothyroidism, likewise have surfaced but are not conclusively attributable to the drug.
Amiodarone is one of the drugs of choice for many supraventricular and malignant ventricular tachyarrhythmias in humans. It exhibits properties of all four classes of antiarrhythmic agents and thus is considered a “broad-spectrum” antiarrhythmic. Unlike many antiarrhythmics, amiodarone has not been linked to increased mortality in large clinical trials in human cardiology, and it is second only to automated internal defibrillators in terms of beneficial outcomes in human patients with severe ventricular arrhythmia.[19] It may be useful in dogs with LV systolic dysfunction and to offer rate control, as well as for converting acute atrial fibrillation to sinus rhythm. Amiodarone relaxes vascular smooth muscle, resulting in a decreased afterload that may be beneficial. Amiodarone increases serum digoxin levels so that the dose of digoxin should be halved. Quinidine and procainamide levels are also elevated.[25] Side effects reported in humans include liver damage, photosensitization, thyroid derangements, ocular lesions, and irreversible pulmonary fibrosis. In dogs, neutropenia and hepatopathy have been reported with amiodarone treatment,[26] as have anorexia, gastrointestinal (GI) disturbances, hepatopathy, and positive Coombs’ testing. These signs resolved with discontinuation of treatment. Anecdotal reports of acute hypersensitivity, hyper- or hypothyroidism, likewise have surfaced but are not conclusively attributable to the drug.
In an experimental study, normal dogs given amiodarone 12 mg/lb orally, twice a day for 3.5 weeks, followed by 12 to 14 mg/lb orally, once a day as maintenance, had serum amiodarone concentrations considered to be therapeutic (1 to 2.5 µg/mL) within 4 days, but these levels only reached a steady state after 11 weeks of treatment.[2] In a study of 22 Doberman Pinscher dogs with arrhythmias and preclinical DCM, those dogs that did not become toxic had blood levels in this range as well and those that did develop toxicity exhibited higher serum concentrations.[41] However, several anecdotal reports have surfaced indicating that adverse effects occur at this dose and that a lower dose may be preferable, such as 4.5 mg/lb orally, twice a day for 1 week and 2.2 to 3.8 mg/lb orally, once a day subsequently for maintenance.[28] Clearly, disparity exists over effective and safe dosages of amiodarone in the dog. Amiodarone toxicity (increased liver enzymes and GI disturbances) was reported in 10 of 22 Doberman dogs with arrhythmias, LV dysfunction, and asymptomatic DCM. Most were on other drugs at the same time, many on mexilitene. Loading dosages and high dosage therapy was associated with clinical toxicity. Those dogs that did well on therapy were usually treated with 200 mg once daily.[41] In another case report, amiodarone converted atrial flutter successfully at 6 mg/kg daily but a reversible toxicity developed after nine months of therapy.[43] Apparently once or twice daily loading doses should be used for a week followed by once daily maintenance therapy. Safe therapeutic dosing will require ECG and possibly serum level management. No clinical reports exist in veterinary medicine that address hemodynamic or electrophysiologic effects that could indicate proarrhythmia, which is a major concern in humans with a long QT syndrome. Despite the clear benefits of amiodarone in human cardiology, acceptance in veterinary medicine is compromised by these descriptions of adverse effects and the lack of reports indicating a benefit of amiodarone therapy over other antiarrhythmic agents. Amiodarone use has not been described in cats.
In an experimental study, normal dogs given amiodarone 12 mg/lb orally, twice a day for 3.5 weeks, followed by 12 to 14 mg/lb orally, once a day as maintenance, had serum amiodarone concentrations considered to be therapeutic (1 to 2.5 µg/mL) within 4 days, but these levels only reached a steady state after 11 weeks of treatment.[2] In a study of 22 Doberman Pinscher dogs with arrhythmias and preclinical DCM, those dogs that did not become toxic had blood levels in this range as well and those that did develop toxicity exhibited higher serum concentrations.[41] However, several anecdotal reports have surfaced indicating that adverse effects occur at this dose and that a lower dose may be preferable, such as 4.5 mg/lb orally, twice a day for 1 week and 2.2 to 3.8 mg/lb orally, once a day subsequently for maintenance.[28] Clearly, disparity exists over effective and safe dosages of amiodarone in the dog. Amiodarone toxicity (increased liver enzymes and GI disturbances) was reported in 10 of 22 Doberman dogs with arrhythmias, LV dysfunction, and asymptomatic DCM. Most were on other drugs at the same time, many on mexilitene. Loading dosages and high dosage therapy was associated with clinical toxicity. Those dogs that did well on therapy were usually treated with 200 mg once daily.[41] In another case report, amiodarone converted atrial flutter successfully at 6 mg/kg daily but a reversible toxicity developed after nine months of therapy.[43] Apparently once or twice daily loading doses should be used for a week followed by once daily maintenance therapy. Safe therapeutic dosing will require ECG and possibly serum level management. No clinical reports exist in veterinary medicine that address hemodynamic or electrophysiologic effects that could indicate proarrhythmia, which is a major concern in humans with a long QT syndrome. Despite the clear benefits of amiodarone in human cardiology, acceptance in veterinary medicine is compromised by these descriptions of adverse effects and the lack of reports indicating a benefit of amiodarone therapy over other antiarrhythmic agents. Amiodarone use has not been described in cats.
Sotalol provides both class……..higher dose) and class……… (l-isomer, lower dose) effects. It is not a ……… inotrope and thus …………………….. LV contractility.
It induces systolic and diastolic ……………………… and is considered to have ≈30% beta-blocking potency compared with propranolol. It is considered to be protective against ……………………., particularly life-threatening ventricular arrhythmias. Currently, only dl-sotalol, which combines the class III and class II effects, is used (d-sotalol caused increased mortality in human clinical trials and is not recommended).
Sotalol provides both class III (higher dose) and class II (l-isomer, lower dose) effects. It is not a negative inotrope and thus does not decrease LV contractility. It induces systolic and diastolic hypotension and is considered to have ≈30% beta-blocking potency compared with propranolol. It is considered to be protective against proarrhythmia, particularly life-threatening ventricular arrhythmias. Currently, only dl-sotalol, which combines the class III and class II effects, is used (d-sotalol caused increased mortality in human clinical trials and is not recommended).
In the first reported veterinary study using sotalol, three classes of Boxer dogs with familial ventricular arrhythmia were identified: asymptomatic, syncopal, and CHF. Slowing of the heart rate and first-degree AV block were the only side effects observed, although proarrhythmic effects have been suspected in other cardiomyopathic dogs given sotalol. The dose of sotalol administered to these dogs was 0.44 to 2.8 mg/lb/day twice a day orally, titrated to effect. The heart failure dogs received less medication, up to 104 mg/day average versus the syncopal group at 183 mg/day. Syncopal signs were diminished on sotalol therapy, and dogs with markedly diminished shortening fraction did not appear to exhibit untoward drug effects.[30] In a second study comparing four types of treatment for familial ventricular arrhythmia of Boxers, sotalol 0.68 mg/lb to 1.6 mg/lb orally twice a day significantly reduced the number of PVCs, arrhythmia grade, and maximum and minimum heart rates. However, there was no significant change in the occurrence of syncope for sotalol or for any of the other three treatments studied.[3] Sotalol has been effectively administered to cats with severe ventricular arrhythmias at 10 to 20 mg orally every 8 to 12 hours.[29] It is thought that class II effects are predominant at lower doses and class III effects are predominant only at higher doses (>160 mg in humans).
Sotalol’s good oral absorption is reduced when given with food. Steady state is reached within 2 to 3 days. It is indicated for life-threatening ventricular arrhythmias, may be used with caution in CHF, and should not be abruptly discontinued. Sotalol is used cautiously with other drugs that decrease blood pressure, as well as other antiarrhythmics, specifically those that prolong the QT interval. Prolongation of the P-R interval with sotalol treatment in dogs, as has been reported anecdotally has been observed by the author as well. No overt problems or progression occurred, and it was not necessary to discontinue the drug concurrent with this finding.
Sotalol (or a β-blocker) was demonstrated to aggravate or precipitate neurogenic bradycardia in some Boxers with VT. This suggests an unusual contraindication for such therapy in a limited number of dogs.[44]
In the first reported veterinary study using sotalol, three classes of Boxer dogs with familial ventricular arrhythmia were identified: asymptomatic, syncopal, and CHF. Slowing of the heart rate and first-degree AV block were the only side effects observed, although proarrhythmic effects have been suspected in other cardiomyopathic dogs given sotalol. The dose of sotalol administered to these dogs was 0.44 to 2.8 mg/lb/day twice a day orally, titrated to effect. The heart failure dogs received less medication, up to 104 mg/day average versus the syncopal group at 183 mg/day. Syncopal signs were diminished on sotalol therapy, and dogs with markedly diminished shortening fraction did not appear to exhibit untoward drug effects.[30] In a second study comparing four types of treatment for familial ventricular arrhythmia of Boxers, sotalol 0.68 mg/lb to 1.6 mg/lb orally twice a day significantly reduced the number of PVCs, arrhythmia grade, and maximum and minimum heart rates. However, there was no significant change in the occurrence of syncope for sotalol or for any of the other three treatments studied.[3] Sotalol has been effectively administered to cats with severe ventricular arrhythmias at 10 to 20 mg orally every 8 to 12 hours.[29] It is thought that class II effects are predominant at lower doses and class III effects are predominant only at higher doses (>160 mg in humans).
Sotalol’s good oral absorption is reduced when given with food. Steady state is reached within 2 to 3 days. It is indicated for life-threatening ventricular arrhythmias, may be used with caution in CHF, and should not be abruptly discontinued. Sotalol is used cautiously with other drugs that decrease blood pressure, as well as other antiarrhythmics, specifically those that prolong the QT interval. Prolongation of the P-R interval with sotalol treatment in dogs, as has been reported anecdotally has been observed by the author as well. No overt problems or progression occurred, and it was not necessary to discontinue the drug concurrent with this finding.
Sotalol (or a β-blocker) was demonstrated to aggravate or precipitate neurogenic bradycardia in some Boxers with VT. This suggests an unusual contraindication for such therapy in a limited number of dogs.[44]
CLASS IV ANTIARRHYTHMICS
Class IV drugs, known as the calcium channel blockers, selectively inhibit slow ……….. calcium current channels (….-type) during the action potential. Calcium channel blockers interrupt arrhythmias resulting from …………… and triggered mechanisms and inhibit ……………. They slow the ………. and, more profoundly, ………….. conduction by blocking the ………………calcium current carried by the ….-type (and probably …..-type) channels. By decreasing ………………. of Ca++, they also decrease the force ………………..
Decreasing the amount of calcium into the myocyte may help to decrease myocardial …………….. synthesis and thus attenuate the pathologic process of …………………… They have indications for the control of most SVTs. Contraindications include ……….,………,…………,…………..and……………… Calcium channel blockers are classified as either dihydropyridines, which do not affect conduction and act principally on the vasculature (e.g., nifedipine, amlodipine), or nondihydropyridines, which have SA and AV nodal (but minimum vascular) effects (e.g., verapamil, diltiazem).
CLASS IV ANTIARRHYTHMICS
Class IV drugs, known as the calcium channel blockers, selectively inhibit slow inward calcium current channels (L-type) during the action potential. Calcium channel blockers interrupt arrhythmias resulting from abnormal automaticity and triggered mechanisms and inhibit reentry. They slow the sinus rate and, more profoundly, AV conduction by blocking the inward calcium current carried by the L-type (and probably T-type) channels. By decreasing sarcoplasmic reticulum release of Ca++, they also decrease the force of contraction.
Decreasing the amount of calcium into the myocyte may help to decrease myocardial protein synthesis and thus attenuate the pathologic process of hypertrophy. They have indications for the control of most SVTs. Contraindications include SB, AV block, myocardial failure, sick sinus syndrome, and digoxin toxicity. Calcium channel blockers are classified as either dihydropyridines, which do not affect conduction and act principally on the vasculature (e.g., nifedipine, amlodipine), or nondihydropyridines, which have SA and AV nodal (but minimum vascular) effects (e.g., verapamil, diltiazem).
DIGITALIS GLYCOSIDES
Digitalis glycosides (digoxin) have multiple effects on cardiac muscle and conductive tissues. Their predominant ………………. effects and …………….. action on the …. and …..nodes and …………….muscle. AV nodal conduction is ……………., AV nodal refractoriness is ……………….., and vagal tone to the ………………………… muscle is increased. Digitalis glycosides are the only antiarrhythmic agents that produce a positive inotropic effect, although this effect may be limited in degree and real benefit.
Digitalis glycosides (digoxin) have multiple effects on cardiac muscle and conductive tissues. Their predominant antiarrhythmic properties result from neuroendocrine and baroreceptor effects and parasympathomimetic action on the SA and AV nodes and atrial muscle.[32] AV nodal conduction is slowed, AV nodal refractoriness is increased, and vagal tone to the ventricular muscle is increased. Digitalis glycosides are the only antiarrhythmic agents that produce a positive inotropic effect, although this effect may be limited in degree and real benefit.
