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Clinical Toxicology of Cardiovascular Drugs
Toxicology of Selected Pesticides, Drugs, and Chemicals
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Clinical Toxicology of Cardiovascular Drugs Robert L. Hamlin, DVM, PhD*
Toxic manifestations of drugs used to treat the cardiovascular system may be more prominent than those of drugs used to treat diseases of any other organ system. There are many reasons for this: 1. Drugs used to treat heart disease have lower therapeutic indices; i.e. the doses used to achieve therapeutic effects are very close to doses known to produce toxic, often lethal, consequences. It is estimated, for example, that even in normal animals the therapeutic dose of digitalis is greater than 80% of the toxic dose. 19 2. When treating animals with heart failure, it is common to use a constellation of drugs for specific reasons. A given patient, for example, may be given a combination of drugs from among the following: digitalis to slow and to strengthen the heart, furosemide to promote diuresis and to reduce preload, spironolactone to prevent potassium loss, captopril to reduce afterload and to promote diuresis, procainamide to extinguish or to prevent ventricular arrhythmias, propranolol to extinguish arrhythmias and to slow heart rate, aminophylline to strengthen muscles of ventilation and to bronchodilate, dihydrocodeinone to suppress cough, and antibiotics to treat infection, not to mention drugs that might be used to treat diseases of other organ systems. Although this practice may constitute the phenomenon called "megapharmacy" or "polypharmacy," simultaneous use of all of those drugs can be justified on good pharmacologic grounds, and their use may result in amelioration of signs and symptoms and in prolongation of life. Nevertheless, the potential for toxic drug interactions probably increases exponentially as the number of drugs employed simultaneously increases. 8 It has been said that if one uses more than two or three drugs, the additional drugs probably are being used to treat the toxic effects of the first two or *Diplomate, American College of Veterinary Internal Medicine (Cardiology, Internal Medicine); Stanton Youngberg Professor of Veterinary Physiology and Pharmacology, Department of Veterinary Physiology and Pharmacology, The Ohio State University College of Veterinary Medicine, Columbus, Ohio; Consultant in Cardiology, Berwyn Veterinary Group, Berwyn, Illinois and Vienna Animal Hospital, Vienna, Virginia Veterinary Clinics of North America: Srooll Anirool Practice-Vol. 20, No.2, March 1990
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three. Such an assertion is not supportable if the clinician can justifY on sound pharmacologic basis the use of each drug and if the clinician understands what is known of the pharmacology and clinical pharmacology (including drug interactions) of each of the drugs. 3. Most animals treated for heart disease are old; therefore, they commonly have diseases of other organs (e.g., renal, hepatic, gastrointestinal) that not only require their own specific therapies, but change rates of absorption, excretion, and degree of protein binding of drugs used for the cardiovascular system. When this occurs, it is much more difficult to maintain desired tissue concentrations of cardiovascular drugs, and toxicosis is more likely. Furthermore, aged animals often have poor eating habits, and therefore may not take oral medicaments as reliably as a young, voracious eater. Lastly, older animals are commonly owned by older people who may have greater problems in complying with therapeutic instructions. 4. Drugs, such as digitalis and class I antiarrhythmics used to treat cardiovascular diseases, often produce 26 or aggravate the very clinical signs for which they are indicated; it is difficult to know whether the disease or the drug is producing the problem. Digitalis is probably the most common cause of junctional tachycardia; however, the tachycardia is also caused by disease of the perinodal tissue, and digitalis is useful for controlling it. Similarly, quinidine, procainamide, and tocainide may produce or exaggerate ventricular ectopia in up to 30% of the dogs in which they are used; however, the same three agents are useful in abolishing it. Digitalis may be life-saving in strengthening the failing ventricle; but, in so doing, it may cause an increase in myocardial oxygen demand and provoke ischemic necrosis or arrhythmia. 21 • 23 · 34 5. Drugs given to animals in heart failure with reduced cardiac output and, possibly, congested and edematous tissues have vastly altered pharmacokinetics; achieving and maintaining therapeutic (nontoxic) tissue levels therefore may become more difficult. When cardiac output falls, a greater proportion of drug goes to the heart and brain; in healthy animals, a greater proportion goes to the skeletal muscle and abdominal viscera. 5 • 6 In low cardiac output states, therefore, volume of distribution may be decreased, more drug may build up, and that build-up may be more rapid in the heart and brain. This may lead to toxicosis. It is thought that cardiotoxicity of digitalis, for example, is caused by a build up of the glycoside in the area postrema (see Digitalis Toxicosis section); if a greater percentage of digitalis goes to that organ, therefore, toxic effects might be anticipated at a relatively low dose. Absorption from an edematous gastrointestinal (GI) tract may be slower than normal, delaying the rate of onset and/or the time from dosing to peak effect. Because of the enormity of the area for absorption from the GI tract, however, the total amount absorbed may be unchanged even with severe edema. If the clinician awaits an immediate response but it is delayed due to delayed absorption, he or she may administer additional drug and promote toxicity. With edema, the volume of distribution for compounds that have access to the extracellular fluid will be increased. This decreases clearance and prolongs half-life, which in turn necessitates decreasing the frequency
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of administration. Furthermore, in heart failure, blood albumin may be diminished because of inanition and/or hepatocellular dysfunction, and tlie percentage of compound bound to protein may be diminished, thus making more available for potential toxic effects. Many agents (e. g., digitoxin, diazepam, phenytoin, class I antiarrhythmics, or many acidic compounds) used for heart failure are more than 80% protein bound; if plasma proteins decrease by 30%, plasma levels of unbound drug may. increase to highly toxic concentrations. Under other circumstances, a-acid glycoprotein may be elevated in response to the disease, and more compound (e. g., quinidine, propranolol, lidocaine) therefore will be bound to that protein and less will be available for a therapeutic effect. 46 Also complicating drug response irt patients with heart failure are reductions in Pa0 2 , which may decrease activity of cytochrome P450 enzymes, thereby decreasing the rate of metabolism of compounds (e.g., digitoxin) normally degraded and metabolized by the liver. This, of course, could predispose to toxicosis. What makes the situation even worse is that, when a patient responds favorably to many of the drugs, the very determinants of their kinetics change (e.g., decreased volume of distribution, increased renal and hepatic blood flow, shunting away from the heart and brain, increase in Pa0 2). This, then, necessitates reexamining dosing parameters to sustain optimal tissue levels and reduce potential for toxicosis. 15 It was hoped that therapeutic drug monitoring16• 42 would lessen the likelihood of toxicity; however, that has probably not proven to be the case. 7 • 41 Many dogs will exhibit definitive signs of cardiac toxicity from digitalis with plasma concentrations approximating the upper limits of the normal therapeutic range, and some will be affected within the middle of normal. Other dogs will not manifest clinical signs of digitalis toxicosis at plasma concentrations two or three times above the so-called toxic value. 17• 44 Therapeutic effects for milrinone are manifested for hours after blood concentrations fall to very low levels. Bretylium tosylate and propranolol29 provide beneficial therapeutic effects at times when plasma concentrations are undetectable. Furthermore, monitoring of blood levels is often expensive, and the turn-around time is long enough that clinical impression of toxicity may be of greater immediate value for a particular patient. The cardiovascular system may also be adversely affected by drugs used for diseases of other organ systems. Monensin (feed additive and coccidiostat), furazolidone (coccidiostat), 20 fenthion (an organophosphorus insecticide and ovicide), phosphodiesterase-inhibiting bronchodilators, aminoglycoside antibiotics, 1• 19 and most anesthetics, 35 for example, have profound, potentially lethal cardiovascular effects. Finally, the cardiovascular system may be affected by poisons found ubiquitously in otir environment (e.g., certain types of snail bait and rodenticides), herbicides, plants [e.g., oleander (Nerium oleander), lily-ofthe-valley (Convallaria majalis), Japanese yew (Taxus cuspidata)] and the pet owners' medicine. 18• 45 It would be impossible to address all of the possible poisons to the cardiovascular system, so the remainder of this paper will .discuss either prototypes of poisons or those that are particularly prevalent. The reader
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is advised to consult three excellent sources for information on cardiovascular toxicity. 3 • 13• 45
TOXICITY WITH CLASS I ANTIARRHYTHMICS Class l antiarrhythmics are the agents used most commonly in veterinary medicine to terminate or reduce the severity of ventricular arrhythmias. Compounds within this class 36• 40 have in common the ability to slow the rate of entry of sodium jons through fast sodium channels. Subclasses within this major group are based on effects of these agents on action potential duration: class lA drugs (e.g., quinidine, procainamide, disopyramide) prolong it, and class IB drugs (e.g., lidocaine, tocainide, mexiletine) have no appreciable effect. Class lA antiarrhythmics also have parasympatholytic, negative inotropic, 38 neurostimulating, anorexigenic, emetic, and, of greatest importance, proarrhythmic effects. 26 Although class IB agents possess lesser parasympatholytic, anorexigenic, negative inotropic, and emetic effects, they have greater neurostimulating effects. Like digitalis, class I agents have low therapeutic indices. Toxicosis may be manifested at doses only 15 to 20% greater than optimal therapeutic doses. A major difficulty with class I antiarrhythmics is that they produce or may aggravate the very arrhythmias they are intended to treat. And the major problem is that there is no method of predicting, a priori, in which patient they will produce a proarrhythmic effect. 33 When using antiarrhythmics it therefore is extremely important to weigh the risk-benefit relationship. What is the risk of leaving the arrhythmia unabated, versus the risk of producing a potentially lethal arrhythmia? Unfortunately, there is no information about the dangers of leaving an arrhythmia unabated; of even greater consequence, there is no information supporting the contention that reducing the severity of or abolishing the arrhythmia with antiarrhythmics prolongs the patient's life even a single day. Toxicity of antiarrhythmics can be diminished by selecting the proper antiarrhythmic for the particular arrhythmia and using the smallest dose that will provide the desired clinical effect. This is optimized by making certain the conditions for optimal antiarrhythmic effect are in order. Unfortunately, there are no hard and fast rules for selecting antiarrhythmics except that :phenytoin is the best agent for digitalis-induced arrhythmias, and lidocaine is the best agent for emergency ventricular tachycardias. 32 The efficacy of lidocaine can be maximized by making certain the animal is not hypokalemic, and the dose of phenytoin can be minimized by making certain the animal is neither hypokalemic nor hypercalcemic. In both instances, optimal antiarrhythmic action can be expected if acid-base balance is achieved. With respect to rules for selecting antiarrhythmics, Lown32• 33 suggests that pragmatism is the rule; that is, try the agent and if it works, use it. He states further that it does not matter what the mechanism of the arrhythmia is (i.e., increased automaticity, triggered activity, reentry) or by what mechanism the antiarrhythmic works (i.e., membrane stabilization, calcium channel blockade, 13-blockade, prolongation of refractory period).
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Thus, although digitalis may induce arrhythmias by producing oscillatory afterpotentials (triggered activity) caused by altered calcium ion fluxes, and diltiazem may aggravate abnormal calcium ion fluxes, diltiazem may still not be the best antiarrhythmic to reverse arrhythmia generated by digitalis. 35, 36 What is the incidence of toxicosis caused by digitalis or antiarrhythmics? What is the incidence of proarrhythmia in response to antiarrhythmics? The answers are not known. Too often, when a patient dies after receiving a therapeutic compound, the veterinarian will state how very ill that patient was; not that he possibly killed it with the medicine. In one pilot study, a proarrhythmic effect of class IA antiarrhythmics was estimated to be greater than 15% but, because dogs were only monitored for 1 day, it is not known whether the antiarrhythmics were proarrhythmic or antiarrhythmic the next day or any days thereafter (unpublished data; Abstract 70, in Proc 5th Annu Vet Med Forum, p 92'4). If a class I antiarrhythmic is indicated for dogs with rather severely compromised ventricular function, disopyramide 10 should probably be excluded because it possesses greater negative inotropism than either quinidine or procainamide. The question for which there is not yet an answer is: "Can one obtain equal antiarrhythmic efficacy with a combination of quinidine and procainamide, without getting toxicity equal to the sum of the two agents?" If a (3-blocker is indicated to be used alone or in combination with a class IA antiarrhythmic, and if the animal has a history of increased bronchomotor activity (that is, asthma), then propranolol should be preferred over atenolol. Although atenolol (a more specific f3cblocker) is more cardiospecific than propranolol (a f3c and (3 2 -blocker) and therefore is less likely to produce bronchoconstriction, if it does produce bronchoconstriction, the crisis will be longer lasting because the half-lives of elimination are 4 hours for propranolol and over 24 hours for atenolol. In any case, whenever (3-blockers are used, aminophylline should be readily available to reduce possible bronchospasm. Isoproterenol should also be handy for animals exposed to toxic doses of (3-blockers, in case the negative inotropic actions of (3-blockade precipitate a cardiovascular crisis. Finally, when attempting to suppress ventricular tachycardia with antiarrhythmics, the clinician should be alert to the possibility that the ventricular rhythm is the only rhythm driving the heart; if suppressed, cardiac arrest will result. This toxic effect of the antiarrhythmics can seldom be anticipated, and there is good reason to keep a transvenous pacemaker handy for treatment of the arrest. When using such potent agents as antiarrhythmics, adequate and sometimes elaborate equipment and chemicals for emergency treatment must be available and their use must have been mastered. Because class I antiarrhythmics may produce neuroexcitability to the point of convulsions and apnea, endotracheal tubes, specula and a positive pressure ventilator must be available. Because these agents may produce either cardiac arrest or ventricular fibrillation, it would be ideal if an external pacemaker with either transvenous or transcutaneous electrodes and a direct current (DC) defibrillator were available. Sodium bicarbonate, potassium chloride, cal-
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cium, and atropine must be available to correct electrolyte or acid-base imbalance and complete heart block. Sodium bicarbonate may be particularly useful in the rare instances of quinidine toxicosis. 4 An intravenous dose of 1 mEq/L will alkalinize the blood, and will increase the proportion of quinidine that is protein bound and therefore unavailable for diffusion into cells. Hyperkalemia may aggravate toxicity of quinidine or procainamide. Acidification of urine will hasten excretion. In patients that develop severe bradyarrhythmia, either external pacing or isoproterenol infusion is indicated; experimentally, however, an infusion of glucagon has been shown useful. 36 DIGITALIS TOXICOSIS It is estimated that over 20% of human beings taking digoxin who are admitted to a hospital emergency room are intoxicated with that compound. 14 Furthermore, mortality among patients intoxicated with digitalis is strikingly higher than for patients receiving digitalis but who are not intoxicated. Equivalent data in canine medicine are not available; however, of 63 dogs receiving digoxin that the author examined in referral practices over 2 years, 17 of them (27%) were considered to be intoxicated with digoxin based either on their having blood concentrations of greater than 4.5 nG/ml (in eight), 44 or their clinical signs (e. g., depression, anorexia, vomiting, arrhythmia) of intoxication, which improved after withdrawal of the digoxin. Digitalis is probably the most common cause of junctional tachycardia; dogs receiving digitalis that manifest ventricular premature depolarizations and are depressed and anorectic must be considered intoxicated with the drug until proven otherwise. When given orally, absorption of digoxin tablets varies between 40 and 80%; the half-life of elimination varies, depending on renal function, from 18 hours (for dogs with normal renal function) to 96 hours (for dogs with azotemia). 11 · 15· 17· 3 t Because degree of absorption and rate of elimination are major determinants of the ease and reliability of achieving and maintaining satisfactory blood concentrations, it is not surprising that so many dogs receiving digoxin are either intoxicated or have subtherapeutic blood levels. A useful rule of thumb is to decrease the dose of digoxin by 50% for every increase in serum creatinine of 1 mg%. No glycoside (e. g., digoxin, digitoxin, ouabain) is any more therapeutic or more toxic than any other glycoside, if proper blood concentrations are maintained. The problem lies in sustaining proper blood levels when absorption, elimination, and volumes of distribution are variable and/or difficult to measure. During the course of digitalis therapy, renal function may vary because renal plasma flow varies as a function of change in cardiac output. Because digitalis is both filtered by the glomerulus and reabsorbed from the tubule into the peritubular capillary, a parameter of renal function that encompasses both of those renal functions (i.e., filtration and reabsorption) should be used to predict the handling of digitalis. Creatinine clearance measures only filtration; levels of serum creatinine therefore may not predict renal handling of digoxin. Plasma urea nitrogen may be a better
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descriptor of handling of digoxin; however, that substance may be low, even with renal failure, if the animal is not eating properly and/or hepatic function is abnormal. Thus, there may be no good predictor of impending digoxin toxicosis other than clinical signs (e. g., anorexia, depression, emesis) or monitoring serum concentrations of the glycoside. Volumes of distribution, absorption, and/or renal plasma flow may vary because of use of concomitant drugs (e. g., quinidine, verapamil, cimetidine, furosemide, fluid therapy). In this regard, digitoxin, although no less toxic or no more therapeutic, is superior21 to digoxin for the following reasons: (1) It is absorbed nearly 100% from the gastrointestinal tract. (2) It is eliminated predominantly by the liver and is therefore independent of renal function. Even with severe liver necrosis produced by carbon tetrachloride, the rate of elimination of digitoxin is not reduced. (3) Digitoxin has access to total body mass, whereas digoxin has access only to lean body mass. Digoxin dose therefore should be per kg of lean mass (a difficult value to obtain) while digitoxin can be dosed according to total body mass (a very easy measurement to make). (4) Dogs receiving digoxin and quinidine, a rather common occurrence, must have their digoxin input reduced by 50%, given that quinidine decreases the volume of distribution and renal clearance of digoxin, but not of digitoxin. Lastly, digitoxin is superior in dogs for the very reason that digoxin is superior in humans. The half-life of elimination of digitoxin in humans is 4 days, that for digoxin is 1 day. Physicians prefer digoxin over digitoxin so that if their patients become intoxicated, they will be ill for a much shorter time if they are receiving digoxin than if they receive digitoxin. For dogs, however, just the opposite is true. The half-life of elimination for digitoxin is 8 hours, that for digoxin is 1 day. If the veterinarian treating a dog with a glycoside happens to intoxicate the patient, therefore, it will remain intoxicated for a much longer time with digoxin than with digitoxin. The disparity in duration of intoxication with these two glycosides becomes even greater if the dog has poor renal function, in which case the half-life of elimination of digoxin may be 4 days. Thus, the veterinarian is much less likely to intoxicate a dog with digitoxin; and, if it happens, the intoxication will remain for a much shorter time. Digitalis intoxication may be prevented by selecting the correct glycoside 37 and adjusting dosage depending on renal function, level of cachexia or obesity, use of concomitant drugs, or the individual dog's tolerance. When intoxication occurs, digitalis should be stopped. If ventricular arrhythmias are occurring, the dog should be given, orally, 15 mg of phenytoin/kg body weight four times a day for two estimated half-lives of the digitalis. Phenytoin appears to abolish the ventricular arrhythmia by its effect on the area postrema; therefore, it is presumed that digitalis exerts this potentially lethal effect via this region in the brain. Neither first- nor second-degree atrioventricular (AV) block, nor junctional tachycardia require emergency treatment; merely stopping the digitalis and waiting is usually sufficient. If the junctional tachycardia persists, the calcium channel blocker diltiazem may be given at 1.25 mg/kg body weight. This will terminate the junctional tachycardia in all instances, usually after a single
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oral dose. Signs of GI toxicity usually abate after termination of the glycoside; however, if the animal becomes dehydrated or there is a suspicion of electrolyte imbalance, fluid should be given. It is extremely important to make certain that serum potassium concentration is not depressed and that serum calcium is not elevated in animals receiving digitalis. The aforementioned electrolyte disturbances predispose to arrhythmias precipitated by digitalis. Because most dogs receiving digitalis are also receiving diuretics that may alter electrolyte imbalance, it is important to anticipate and/or correct electrolyte imbalance. CARDIAC TOXICITY OF ADRIAMYCIN Antineoplastic agents-in particular, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)-have great potential for producing serious adverse cardiac effects, leading to death either from arrhythmia or from heart failure. 24 • 25 • 27 · 28 The leading limitation in efficacy for Adriamycin probably is its cardiotoxicity, because greater antineoplastic activity could be achieved if larger doses of the drug could be tolerated. Dogs often manifest cardiotoxicity at total doses of Adriamycin greater than 300 mg/M 2 ; however, a rare dog may manifest toxicity at 200 or not until 500 mg/M 2 • 25 · 30 Of nearly 100 dogs treated in one institution, between 1 and 2% developed clear evidence of dilated cardiomyopathy, and probably 4-5% had echocardiologic evidence of impaired left ventricular function (Couto CG; personal communication, 1989). Electrocardiologic findings in dogs with Adriamycin toxicosis may include prolongation of PQ interval, manifesting impaired AV conduction; prolongation of QRS with development of slurs and notches in the R-waves, suggesting retarded intraventricular conduction; decreased voltage of the QRS, suggesting either pleural or pericardia! effusion or, possibly, altered resistivity of the myocardium; ectopic activity from supraventricular or ventricular foci, suggesting increased automaticity, triggered activity, or reentry from slowly conducting regions. Uni- or biventricular dilatation, reduction in ejection fraction (ratio of stroke volume to end-diastolic volume); reduction in cardiac output with oliguria, muscular weakness, and even syncope; and/or pulmonary edema may occur as manifestations of reduced myocardial function. The mechanisms by which Adriamycin produces these changes are only partially characterized. Toxicosis is thought to be mediated in part via histamine release, but antihistamines do not reduce the severity. Adriamycin may load myocytes with sodium and/or calcium ions, and it no doubt interferes with normal healing of injured myocytes, which leads to myofibrillar disarray and fibrosis. The main mechanism for cardiotoxicity, however, may be production of oxygen free radicals. Two routes for production of free radicals have been proposed. Adriamycin is reduced by flavindependent reductases to semiquinone radicals, which donate electrons to oxygen, which forms superoxide ions, hydrogen peroxide, and hydroxyl ions. The other route involves combination of Adriamycin and iron, which catalyzes the transfer of electrons from sulfhydril compounds to oxygen, creating the oxygen free radical. Such free-radical reactions tend to be self perpetuating.
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Some studies 25 suggest that Adriamycin cardiotoxicity can be minimized by treatment with scavengers (e.g., super oxide dismutase, glutathione, catalase) of free radicals of oxygen. Some studies 24 • 27• 28 suggest that exercise provokes, and others, that exercise protects against cardiotoxicity. Recent evidence indicates that the antineoplastic agent, ICRF 187, protects against cardiotoxicity when given between 30 and 15 minutes before Adriamycin. The mechanism of protection by ICRF is that it chelates iron, making it unavailable for the Adriamycin-iron combination. Dogs pretreated with ICRF 187 can tolerate up to four times the dose that would be lethal to unpretreated dogs. Even when the PQ interval is prolonged and ventricular premature depolarizations occur, normally two contraindications to the use of digitalis, many dogs developing heart failure from Adriamycin toxicosis improve dramatically when given digitalis.
CONSULTATION TO THE PHARMACEUTICAL INDUSTRY Toxicology of cardiovascular drugs or of drugs intended for diseases of other organ systems, but with potential to affect the cardiovascular system, is of prime importance to both the pharmaceutical industry and federal regulatory agencies and, therefore, to the many veterinarians who consult for those units. Although many compounds have the potential for altering mechanical properties (e.g., contractility, compliance) of the heart, more concern is placed on how compounds affect the electrophysiological properties (e.g., rhythmicity, conductivity, irritability) because alterations in the latter can lead to sudden death by either cardiac arrest or ventricular fibrillation. Electrocardiography is the best means of detecting these changes; 12 and we must acknowledge our debt to D. K. Detweiler for his pioneering efforts in the development of electrocardiography for both practice applications and toxicologic monitoring. Rhythmicity refers to the rate of discharge of the sinoatrial node; this can be studied through the frequency with which P waves are observed on an electrocardiogram (EKG). Conductivity must be evaluated on all of the cardiac structures that conduct, but more emphasis is placed on conduction through the AV transmission system (measured by the PQ interval of the EKG) and the ventricles (measured by duration of QRS-complex of the EKG). Irritability can be measured by frequency of premature depolarizations and from what foci they arise (e.g., atrial, AV junctional, His-Purkinje system). Likelihood for ventricular arrhythmia may relate to durations of QT and QRS. 43 When either is prolonged, likelihood of reentry and ventricular tachycardia or ventricular fibrillation increases. Provoking arrhythmias may be a useful means of identifying increased likelihood for their occurrence in the unprovoked state. Sensitivity to intravenous epinephrine 22 and exercise39 are two commonly used means for provocation. No testing of a pharmacologic agent is complete without a thorough electrocardiologic analysis. This usually includes screening one or up to 12 leads at conventional paper speed (25 mm/second) in target animals (i.e.,
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animals in which the compound is to be used) while those animals receive either the dose intended for clinical use or multiples of up to 10 times that dose. Multiples are used to identify a "worse-case" scenario of what cardiovascular effects the compound might produce. The minimal parameters to be measured are heart rate, PQ (PR) interval, QRS duration, QT interval, and, possibly, P wave duration. Configuration of ST-T is extremely important because that interval may well be the most sensitive (albeit less specific) to detect toxic effects of drugs. Two questions of importance when screening for cardiovascular toxicity are: What leads should be taken? And, for how long should EKGs be monitored? For detection of myocardial injury or ventricular hypertrophy, at least one unipolar thoracic lead (usually V3 ) should be monitored along with limb leads I and aVF. Because T waves are more consistent in leads rV2 and V10 , monitoring of those leads is recommended by some. It is highly unlikely that any greater number of leads will demonstrate electrocardiographic changes not visible on those three or four leads, and keeping the number of leads to a minimum will save both time and money for both recording and subsequent analysis. Deciding how long to monitor the animal is more difficult. If the compound has profound arrhythmogenic effects and produces more than 10,000 premature depolarizations a day (a normal dog has approximately 150,000 beats/day), a single 1-minute monitor has a reasonably likelihood of detecting ectopic activity, unless, of course, the ectopic activity occurs only within a short interval (i.e., at night, during excitement, during eating) when the tracing is not taken. If, on the other hand, the compound merely generates occasional premature depolarizations, then a 1-minute recording is unlikely to be fruitful in detecting the increased irritability or, if the agent is an antiarrhythmic, a reduction in irritability. 9 • 47 The best method would be to monitor the animal for 24 or 48 consecutive hours (Holter's monitoring), 2 and to compare frequency of ectopic activity before the compound with that after the compound. Fortunately, ectopic activity is extremely rare in normal dogs and cats, probably occurring in fewer than 1% of normal animals in those species; therefore, almost any ectopic depolarizations observed probably indicate that the compound increases irritability. The tendency for serious ventricular arrhythmias may be detected by prolongation of the QT interval; therefore this, too, must be considered a potentially toxic effect of a compound. Cardiovascular toxicity may be indicated by not only by ectopic depolarizations, but also by subtle changes in contour to ST-T. These subtle changes may be detected only if tracings of excellent quality are analyzed. This may require chemical restraint to reduce artifacts produced by motion or muscle fasciculation. Acepromazine, lnnovar-vet (fentanyl and droperidol; Pitman-Moore, Washington Crossing, NJ), ketamine, ketamine and xylazine, or ketamine and diazepam are all agents useful for improving the quality of EKGs and increasing the likelihood of identifYing subtle changes in ST-T, but these agents may also either extinguish or augment ectopic activity. The study director must decide whether he or she wishes to make an error because records of quality good enough to detect subtleties cannot
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be obtained from animals without chemical restraint, or because a rhythm disturbance was either provoked or extinguished by the chemical restraint. It occasionally is necessary to measure large numbers of EKG parameters from large numbers of animals, a task that is monotonous, timeconsuming, tedious, and prone to error. Digital computers are ideal for such analyses. There currently are two systems (Buxco, Detroit, MI; and Mortara, Milwaukee, WI) available for analyzing mass quantities of EKGs, these systems having been designed for toxicologic screening of beagles. Each system has the capability of recording up to 12 leads rapidly, and storing great numbers of EKGs (up to 60,000). Costs for these systems range between $5000 and $60,000, depending on individualized hardware and capabilities. In addition to digitizing and recording various conventional parameters (e.g., heart rate, P wave amplitudes and durations, QT and corrected QT duration), the systems analyze rhythm and detect arrhythmia; the Buxco system even makes quantitative measurements of subtle contours to ST-T. The systems are excellent for Good Laboratory Practice studies, given that all records are labeled, dated, and stored permanently, while permitting easy access. The veterinarian is called on more and more to assist the pharmaceutical industry and regulatory agencies in evaluating cardiovascular toxicity of compounds intended for humans or for infrahuman mammals. This is an extremely important task to maximize the chance of developing safe and effective drugs, and to minimize the chance of marketing drugs that have a poor risk-benefit ratio. Three excellent reviews on cardiovascular toxicity of various drugs are available. 3 · 12 · 45
REFERENCES 1. Adams HR, Parker JL, Durrett LR: Cardiac toxicities of antibiotics. Environ Health Perspect 26:217, 1978 2. Anderson G: Can Holter monitor findings predict the results of electrophysiologic studies? J Am Coli Cardiol 5:1094, 1985 3. Balazs T: Cardiac Toxicology, Vol. I, II, IIi. Boca Raton, CRC Press, 1981 4. Bellet S, Hamdan G, Somlyo A, et a!: The reversal of cardiotoxic effects of quinidine by molar sodium lactate: An experimental study. Am J Med Sci 237:165, 1959 5. Benowitz NL, Meister W: Pharmacokinetics in patients with cardiac failure. In Gibaldi M (ed): Handbook of Clinical Pharmacokinetics. New York, ADIS Health Sciences Press, 1983, pp 182-200 6. Benowitz NL, Meister W: Pharmacokinetics: Pathophysiologic considerations. In Benet LZ, et a! (eds): Pharmacokinetic Basis for Drug Treatment. New York, Raven Press, 1984, pp 89-103 7. Berry N, Bauman J, Gallastegui J, et a!: Analysis of antiarrhythmic drug concentrations determined during electrophysiologic drug testing in patients with inducible tachycardias. Am J Cardiol 61:922-924, 1988 8. Bigger JT, Strauss HC: Digitalis toxicity, drug interactions promoting toxicity, and management of toxicity. Semin Drug Treat 2:14, 1972 9. Bigger JT, Giardina E: Drug interactions in antiarrhythmic therapy. Ann New York Acad Sci 427:140-161, 1984 10. Crosby JJ, Hamlin RL, Strauch SM: Effects of disopyramide on the electrocardiogram and ventricular function in the unanesthetized dog. J Vet Pharmacal Therap 7:16, 1984 11. DeRick A, Belpaire FM, Bogaert MG, eta!: Plasma concentrations of digoxin and digitoxin during digitalization of healthy dogs and dogs with cardiac failure. Am J Vet Res 39:811, 1978
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12. Detweiler DK: The use of electrocardiography in toxicological studies with beagle dogs. In Balazs T (ed): Cardiac Toxicology. III. Boca Raton, CRC Press, 1981, pp 33-82 13. Detweiler DK: Electrocardiographic monitoring i!l toxicological studies: Principles and interpretations. New York, Plenum Press, 1983, p 579 14. Doherty JE: Suspicion of digitalis intoxication. JAMA 33:191, 1978 15. Doherty JE, Perkins WH, Wilson MD: Studies with tritiated digoxin in renal failure. Am J Med 37:536, 1964 . 16. Erichsen Df, Harris SG, Upson DW: Therapeutic and toxic plasma concentrations of digoxin in the cat. Am J Vet Res 41:2049, 1980 17. Fillmore GE, Detweiler DK: Maintenance of subacute digoxin toxicosis in normal beagles. Toxicol Appl Pharmacal 25:418, 1973 18. Fowler ME: Plant Poisoning in Small Companion Animals. St. Louis, Ralston Purina Company, 1980 19. Goodman A, Gillman L: The Pharmacologic Basis of Therapeutics, ed 7. New York, Macmillian Publishing, 1985 20. Gwathmey JD, Hamlin RL: Protection of turkeys against furazolidone-induced cardiomyopathy. Am J Cardia! 52:626, 1983 21. Hamlin RL: Basis for selection of l! cardiac glycoside for dogs. Baton Rouge, LA, Proc First Symp Vet Pharm and Therap, 1978 22. Hamlin RL, Bishop MA, Hadlock DJ, et a!: Effects of lidocaine, with or without epinephrine, on ventricular rhythm. JAm Anim Hasp Assoc 24:701-704, 1988 23. Hamlin RL, Pipers FS, Carter KL, et a!: Treatment of heart failure in dogs without use of digitalis glycosides. Vet Med Small Anim Clin 68:349-356, 1973 24. Hassler C, Thake D, Hamlin R, et a!: The effect of exercise on cardiotoxic potential of Adriamycin in rhesus monkeys. Toxicologist 2:9, 1982 25. Herman E, Ferr;ms V, Young R, et a!: Effect of pretreatment with ICRF-187 on total cumulative dose of qoxorubicin tolerated by beagle dogs. Cancer Res 48:6918, 1988 26. Horowitz L, Zipes D: A symposium: Perspectives on proarrhythima. Am J Cardiol59:1E, 1987 27. Kanter MM, Hamlin RL: Effect of exercise training on antioxidant enzymes and cardiatoxicity of doxorubicin. J Appl Physiol59(4):1298, 1985 28. Kanter M, Hamlin R, Unverferth D, et a!: Effect of exercise training on antioxidant enzymes and cardiotoxicity of doxorubicin. J Appl Physiol 59:1298, 1985 29. Kates RE, Keene BW, Hamlin RL: Pharmacokinetics of propranolol in the dog. J Vet Pharmacal Therap 2:21, 1979 30. Kehoe R, Stinger DH, Trapani A, eta!: Adriamycin-induced cardiac dysrrhythmias in an experimental dog model. Cancer Treat Rep 62:963-978, 1978 . 31. Lindenbaum J, Mellow MH, Blackstone MO, et a!: Variation in biologic availability of digoxin from four preparations. N Eng! J Med 285:1344, 1971 32. Lawn B, Verrier RL, Rabinowitz SH: Neuronal and psychological mechanisms and the problem of sudden death. Am J Cardia! 39:890, 1977 33. Lawn B, Graboys T: Evaluation and m;magement of the patient with ventricular arrhythmias. Cardiac Impulse 6(2):1-5, 1985 34. Lynch J, Simpson P, Gallagher K, eta!: Increase in experimental infarct size with digoxin in a canine model of myocardial ischemia-reperfusion injury. Am Heart J 115:1171, 1988 35. Muir WW, Werner LL, Hamlin RL: Effects ofxylazine and acetylpromazine upon induced ventricular fibrillation in dogs anesthetized with thiamylal and halothane. Am J Vet Res 36:1299, 1975 36. Opie LH: Drugs for the heart. Orlando, Grune & Stratton, 1980 37. Peters DN, Hamlin RL, Powers JD: Absence of pharmacokinetic interaction between digitoxin ;md quinidine in the dog. J Vet Pharmacal Therap 4:271, 1981 38. Podrid P, Lawn B: Congestive heart failure with disopyramide. N Eng! J Med 302:614, 1980 39. Saini V, Graboys T, Towne V, et a!: Reproducibility of exercise-induced ventricular arrhythmia in patients undergoing evaluation for malignant ventricular arrhythmia. Am J Cardiol63:697-707, 1989 40. Singh B, Hauswirth 0: Comparative mechanisms of action of antiarrhythmic drugs. Am Heart J 87:367, 1974
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41. Slater W, Lampert S, Podrid P, et a!: Clinical predictors of arrhythmic worsening by antiarrhythmic drJ.!gs. Am J Cardiol 61:349-353, 1988 42. Smith TW: Contribution of quantitative assay technics to the understanding of the clinical pharmacology of digitalis. Circulation 46:188, 1972 43. Surawicz B, Knoebel S: Lohg QT: Good, bad or indifferent? J Am Coli Cardiol 4:494516, 1985 44. Teske R, Bishop S, Rigter H, et a!: Subacute digoxin toxicosis in the beagle dog. Toxicol Appl Pharmacol 35:283, 1976 45. Van Stee E: Cardiovascular Toxicology. New York, Raven Press, 1982 46. Waserman F, et a!: Successful treatment of quinidine and procainamide intoxication. Report of three cases. N Eng! J Med 259:797-802, 1958 47. Winkle RA: Antiarrhythmic drug effect mimicked by spontaneous variabihty of ventricular ectopy. Circulation 57:1116-1121, 1978
Address requests for reprints to: Robert L. Hamlin, DVM, PhD Department of Physiology and Pharmacology College of Veterinary Medicine The Ohio State University 1935 Coffey Road Columbus, OH 43210
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Clinical Toxicology of Cardiovascular Drugs Robert L. Hamlin, DVM, PhD*
Toxic manifestations of drugs used to treat the cardiovascular system may be more prominent than those of drugs used to treat diseases of any other organ system. There are many reasons for this: 1. Drugs used to treat heart disease have lower therapeutic indices; i.e. the doses used to achieve therapeutic effects are very close to doses known to produce toxic, often lethal, consequences. It is estimated, for example, that even in normal animals the therapeutic dose of digitalis is greater than 80% of the toxic dose. 19 2. When treating animals with heart failure, it is common to use a constellation of drugs for specific reasons. A given patient, for example, may be given a combination of drugs from among the following: digitalis to slow and to strengthen the heart, furosemide to promote diuresis and to reduce preload, spironolactone to prevent potassium loss, captopril to reduce afterload and to promote diuresis, procainamide to extinguish or to prevent ventricular arrhythmias, propranolol to extinguish arrhythmias and to slow heart rate, aminophylline to strengthen muscles of ventilation and to bronchodilate, dihydrocodeinone to suppress cough, and antibiotics to treat infection, not to mention drugs that might be used to treat diseases of other organ systems. Although this practice may constitute the phenomenon called "megapharmacy" or "polypharmacy," simultaneous use of all of those drugs can be justified on good pharmacologic grounds, and their use may result in amelioration of signs and symptoms and in prolongation of life. Nevertheless, the potential for toxic drug interactions probably increases exponentially as the number of drugs employed simultaneously increases. 8 It has been said that if one uses more than two or three drugs, the additional drugs probably are being used to treat the toxic effects of the first two or *Diplomate, American College of Veterinary Internal Medicine (Cardiology, Internal Medicine); Stanton Youngberg Professor of Veterinary Physiology and Pharmacology, Department of Veterinary Physiology and Pharmacology, The Ohio State University College of Veterinary Medicine, Columbus, Ohio; Consultant in Cardiology, Berwyn Veterinary Group, Berwyn, Illinois and Vienna Animal Hospital, Vienna, Virginia Veterinary Clinics of North America: Srooll Anirool Practice-Vol. 20, No.2, March 1990
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three. Such an assertion is not supportable if the clinician can justifY on sound pharmacologic basis the use of each drug and if the clinician understands what is known of the pharmacology and clinical pharmacology (including drug interactions) of each of the drugs. 3. Most animals treated for heart disease are old; therefore, they commonly have diseases of other organs (e.g., renal, hepatic, gastrointestinal) that not only require their own specific therapies, but change rates of absorption, excretion, and degree of protein binding of drugs used for the cardiovascular system. When this occurs, it is much more difficult to maintain desired tissue concentrations of cardiovascular drugs, and toxicosis is more likely. Furthermore, aged animals often have poor eating habits, and therefore may not take oral medicaments as reliably as a young, voracious eater. Lastly, older animals are commonly owned by older people who may have greater problems in complying with therapeutic instructions. 4. Drugs, such as digitalis and class I antiarrhythmics used to treat cardiovascular diseases, often produce 26 or aggravate the very clinical signs for which they are indicated; it is difficult to know whether the disease or the drug is producing the problem. Digitalis is probably the most common cause of junctional tachycardia; however, the tachycardia is also caused by disease of the perinodal tissue, and digitalis is useful for controlling it. Similarly, quinidine, procainamide, and tocainide may produce or exaggerate ventricular ectopia in up to 30% of the dogs in which they are used; however, the same three agents are useful in abolishing it. Digitalis may be life-saving in strengthening the failing ventricle; but, in so doing, it may cause an increase in myocardial oxygen demand and provoke ischemic necrosis or arrhythmia. 21 • 23 · 34 5. Drugs given to animals in heart failure with reduced cardiac output and, possibly, congested and edematous tissues have vastly altered pharmacokinetics; achieving and maintaining therapeutic (nontoxic) tissue levels therefore may become more difficult. When cardiac output falls, a greater proportion of drug goes to the heart and brain; in healthy animals, a greater proportion goes to the skeletal muscle and abdominal viscera. 5 • 6 In low cardiac output states, therefore, volume of distribution may be decreased, more drug may build up, and that build-up may be more rapid in the heart and brain. This may lead to toxicosis. It is thought that cardiotoxicity of digitalis, for example, is caused by a build up of the glycoside in the area postrema (see Digitalis Toxicosis section); if a greater percentage of digitalis goes to that organ, therefore, toxic effects might be anticipated at a relatively low dose. Absorption from an edematous gastrointestinal (GI) tract may be slower than normal, delaying the rate of onset and/or the time from dosing to peak effect. Because of the enormity of the area for absorption from the GI tract, however, the total amount absorbed may be unchanged even with severe edema. If the clinician awaits an immediate response but it is delayed due to delayed absorption, he or she may administer additional drug and promote toxicity. With edema, the volume of distribution for compounds that have access to the extracellular fluid will be increased. This decreases clearance and prolongs half-life, which in turn necessitates decreasing the frequency
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of administration. Furthermore, in heart failure, blood albumin may be diminished because of inanition and/or hepatocellular dysfunction, and tlie percentage of compound bound to protein may be diminished, thus making more available for potential toxic effects. Many agents (e. g., digitoxin, diazepam, phenytoin, class I antiarrhythmics, or many acidic compounds) used for heart failure are more than 80% protein bound; if plasma proteins decrease by 30%, plasma levels of unbound drug may. increase to highly toxic concentrations. Under other circumstances, a-acid glycoprotein may be elevated in response to the disease, and more compound (e. g., quinidine, propranolol, lidocaine) therefore will be bound to that protein and less will be available for a therapeutic effect. 46 Also complicating drug response irt patients with heart failure are reductions in Pa0 2 , which may decrease activity of cytochrome P450 enzymes, thereby decreasing the rate of metabolism of compounds (e.g., digitoxin) normally degraded and metabolized by the liver. This, of course, could predispose to toxicosis. What makes the situation even worse is that, when a patient responds favorably to many of the drugs, the very determinants of their kinetics change (e.g., decreased volume of distribution, increased renal and hepatic blood flow, shunting away from the heart and brain, increase in Pa0 2). This, then, necessitates reexamining dosing parameters to sustain optimal tissue levels and reduce potential for toxicosis. 15 It was hoped that therapeutic drug monitoring16• 42 would lessen the likelihood of toxicity; however, that has probably not proven to be the case. 7 • 41 Many dogs will exhibit definitive signs of cardiac toxicity from digitalis with plasma concentrations approximating the upper limits of the normal therapeutic range, and some will be affected within the middle of normal. Other dogs will not manifest clinical signs of digitalis toxicosis at plasma concentrations two or three times above the so-called toxic value. 17• 44 Therapeutic effects for milrinone are manifested for hours after blood concentrations fall to very low levels. Bretylium tosylate and propranolol29 provide beneficial therapeutic effects at times when plasma concentrations are undetectable. Furthermore, monitoring of blood levels is often expensive, and the turn-around time is long enough that clinical impression of toxicity may be of greater immediate value for a particular patient. The cardiovascular system may also be adversely affected by drugs used for diseases of other organ systems. Monensin (feed additive and coccidiostat), furazolidone (coccidiostat), 20 fenthion (an organophosphorus insecticide and ovicide), phosphodiesterase-inhibiting bronchodilators, aminoglycoside antibiotics, 1• 19 and most anesthetics, 35 for example, have profound, potentially lethal cardiovascular effects. Finally, the cardiovascular system may be affected by poisons found ubiquitously in otir environment (e.g., certain types of snail bait and rodenticides), herbicides, plants [e.g., oleander (Nerium oleander), lily-ofthe-valley (Convallaria majalis), Japanese yew (Taxus cuspidata)] and the pet owners' medicine. 18• 45 It would be impossible to address all of the possible poisons to the cardiovascular system, so the remainder of this paper will .discuss either prototypes of poisons or those that are particularly prevalent. The reader
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is advised to consult three excellent sources for information on cardiovascular toxicity. 3 • 13• 45
TOXICITY WITH CLASS I ANTIARRHYTHMICS Class l antiarrhythmics are the agents used most commonly in veterinary medicine to terminate or reduce the severity of ventricular arrhythmias. Compounds within this class 36• 40 have in common the ability to slow the rate of entry of sodium jons through fast sodium channels. Subclasses within this major group are based on effects of these agents on action potential duration: class lA drugs (e.g., quinidine, procainamide, disopyramide) prolong it, and class IB drugs (e.g., lidocaine, tocainide, mexiletine) have no appreciable effect. Class lA antiarrhythmics also have parasympatholytic, negative inotropic, 38 neurostimulating, anorexigenic, emetic, and, of greatest importance, proarrhythmic effects. 26 Although class IB agents possess lesser parasympatholytic, anorexigenic, negative inotropic, and emetic effects, they have greater neurostimulating effects. Like digitalis, class I agents have low therapeutic indices. Toxicosis may be manifested at doses only 15 to 20% greater than optimal therapeutic doses. A major difficulty with class I antiarrhythmics is that they produce or may aggravate the very arrhythmias they are intended to treat. And the major problem is that there is no method of predicting, a priori, in which patient they will produce a proarrhythmic effect. 33 When using antiarrhythmics it therefore is extremely important to weigh the risk-benefit relationship. What is the risk of leaving the arrhythmia unabated, versus the risk of producing a potentially lethal arrhythmia? Unfortunately, there is no information about the dangers of leaving an arrhythmia unabated; of even greater consequence, there is no information supporting the contention that reducing the severity of or abolishing the arrhythmia with antiarrhythmics prolongs the patient's life even a single day. Toxicity of antiarrhythmics can be diminished by selecting the proper antiarrhythmic for the particular arrhythmia and using the smallest dose that will provide the desired clinical effect. This is optimized by making certain the conditions for optimal antiarrhythmic effect are in order. Unfortunately, there are no hard and fast rules for selecting antiarrhythmics except that :phenytoin is the best agent for digitalis-induced arrhythmias, and lidocaine is the best agent for emergency ventricular tachycardias. 32 The efficacy of lidocaine can be maximized by making certain the animal is not hypokalemic, and the dose of phenytoin can be minimized by making certain the animal is neither hypokalemic nor hypercalcemic. In both instances, optimal antiarrhythmic action can be expected if acid-base balance is achieved. With respect to rules for selecting antiarrhythmics, Lown32• 33 suggests that pragmatism is the rule; that is, try the agent and if it works, use it. He states further that it does not matter what the mechanism of the arrhythmia is (i.e., increased automaticity, triggered activity, reentry) or by what mechanism the antiarrhythmic works (i.e., membrane stabilization, calcium channel blockade, 13-blockade, prolongation of refractory period).
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Thus, although digitalis may induce arrhythmias by producing oscillatory afterpotentials (triggered activity) caused by altered calcium ion fluxes, and diltiazem may aggravate abnormal calcium ion fluxes, diltiazem may still not be the best antiarrhythmic to reverse arrhythmia generated by digitalis. 35, 36 What is the incidence of toxicosis caused by digitalis or antiarrhythmics? What is the incidence of proarrhythmia in response to antiarrhythmics? The answers are not known. Too often, when a patient dies after receiving a therapeutic compound, the veterinarian will state how very ill that patient was; not that he possibly killed it with the medicine. In one pilot study, a proarrhythmic effect of class IA antiarrhythmics was estimated to be greater than 15% but, because dogs were only monitored for 1 day, it is not known whether the antiarrhythmics were proarrhythmic or antiarrhythmic the next day or any days thereafter (unpublished data; Abstract 70, in Proc 5th Annu Vet Med Forum, p 92'4). If a class I antiarrhythmic is indicated for dogs with rather severely compromised ventricular function, disopyramide 10 should probably be excluded because it possesses greater negative inotropism than either quinidine or procainamide. The question for which there is not yet an answer is: "Can one obtain equal antiarrhythmic efficacy with a combination of quinidine and procainamide, without getting toxicity equal to the sum of the two agents?" If a (3-blocker is indicated to be used alone or in combination with a class IA antiarrhythmic, and if the animal has a history of increased bronchomotor activity (that is, asthma), then propranolol should be preferred over atenolol. Although atenolol (a more specific f3cblocker) is more cardiospecific than propranolol (a f3c and (3 2 -blocker) and therefore is less likely to produce bronchoconstriction, if it does produce bronchoconstriction, the crisis will be longer lasting because the half-lives of elimination are 4 hours for propranolol and over 24 hours for atenolol. In any case, whenever (3-blockers are used, aminophylline should be readily available to reduce possible bronchospasm. Isoproterenol should also be handy for animals exposed to toxic doses of (3-blockers, in case the negative inotropic actions of (3-blockade precipitate a cardiovascular crisis. Finally, when attempting to suppress ventricular tachycardia with antiarrhythmics, the clinician should be alert to the possibility that the ventricular rhythm is the only rhythm driving the heart; if suppressed, cardiac arrest will result. This toxic effect of the antiarrhythmics can seldom be anticipated, and there is good reason to keep a transvenous pacemaker handy for treatment of the arrest. When using such potent agents as antiarrhythmics, adequate and sometimes elaborate equipment and chemicals for emergency treatment must be available and their use must have been mastered. Because class I antiarrhythmics may produce neuroexcitability to the point of convulsions and apnea, endotracheal tubes, specula and a positive pressure ventilator must be available. Because these agents may produce either cardiac arrest or ventricular fibrillation, it would be ideal if an external pacemaker with either transvenous or transcutaneous electrodes and a direct current (DC) defibrillator were available. Sodium bicarbonate, potassium chloride, cal-
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cium, and atropine must be available to correct electrolyte or acid-base imbalance and complete heart block. Sodium bicarbonate may be particularly useful in the rare instances of quinidine toxicosis. 4 An intravenous dose of 1 mEq/L will alkalinize the blood, and will increase the proportion of quinidine that is protein bound and therefore unavailable for diffusion into cells. Hyperkalemia may aggravate toxicity of quinidine or procainamide. Acidification of urine will hasten excretion. In patients that develop severe bradyarrhythmia, either external pacing or isoproterenol infusion is indicated; experimentally, however, an infusion of glucagon has been shown useful. 36 DIGITALIS TOXICOSIS It is estimated that over 20% of human beings taking digoxin who are admitted to a hospital emergency room are intoxicated with that compound. 14 Furthermore, mortality among patients intoxicated with digitalis is strikingly higher than for patients receiving digitalis but who are not intoxicated. Equivalent data in canine medicine are not available; however, of 63 dogs receiving digoxin that the author examined in referral practices over 2 years, 17 of them (27%) were considered to be intoxicated with digoxin based either on their having blood concentrations of greater than 4.5 nG/ml (in eight), 44 or their clinical signs (e. g., depression, anorexia, vomiting, arrhythmia) of intoxication, which improved after withdrawal of the digoxin. Digitalis is probably the most common cause of junctional tachycardia; dogs receiving digitalis that manifest ventricular premature depolarizations and are depressed and anorectic must be considered intoxicated with the drug until proven otherwise. When given orally, absorption of digoxin tablets varies between 40 and 80%; the half-life of elimination varies, depending on renal function, from 18 hours (for dogs with normal renal function) to 96 hours (for dogs with azotemia). 11 · 15· 17· 3 t Because degree of absorption and rate of elimination are major determinants of the ease and reliability of achieving and maintaining satisfactory blood concentrations, it is not surprising that so many dogs receiving digoxin are either intoxicated or have subtherapeutic blood levels. A useful rule of thumb is to decrease the dose of digoxin by 50% for every increase in serum creatinine of 1 mg%. No glycoside (e. g., digoxin, digitoxin, ouabain) is any more therapeutic or more toxic than any other glycoside, if proper blood concentrations are maintained. The problem lies in sustaining proper blood levels when absorption, elimination, and volumes of distribution are variable and/or difficult to measure. During the course of digitalis therapy, renal function may vary because renal plasma flow varies as a function of change in cardiac output. Because digitalis is both filtered by the glomerulus and reabsorbed from the tubule into the peritubular capillary, a parameter of renal function that encompasses both of those renal functions (i.e., filtration and reabsorption) should be used to predict the handling of digitalis. Creatinine clearance measures only filtration; levels of serum creatinine therefore may not predict renal handling of digoxin. Plasma urea nitrogen may be a better
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descriptor of handling of digoxin; however, that substance may be low, even with renal failure, if the animal is not eating properly and/or hepatic function is abnormal. Thus, there may be no good predictor of impending digoxin toxicosis other than clinical signs (e. g., anorexia, depression, emesis) or monitoring serum concentrations of the glycoside. Volumes of distribution, absorption, and/or renal plasma flow may vary because of use of concomitant drugs (e. g., quinidine, verapamil, cimetidine, furosemide, fluid therapy). In this regard, digitoxin, although no less toxic or no more therapeutic, is superior21 to digoxin for the following reasons: (1) It is absorbed nearly 100% from the gastrointestinal tract. (2) It is eliminated predominantly by the liver and is therefore independent of renal function. Even with severe liver necrosis produced by carbon tetrachloride, the rate of elimination of digitoxin is not reduced. (3) Digitoxin has access to total body mass, whereas digoxin has access only to lean body mass. Digoxin dose therefore should be per kg of lean mass (a difficult value to obtain) while digitoxin can be dosed according to total body mass (a very easy measurement to make). (4) Dogs receiving digoxin and quinidine, a rather common occurrence, must have their digoxin input reduced by 50%, given that quinidine decreases the volume of distribution and renal clearance of digoxin, but not of digitoxin. Lastly, digitoxin is superior in dogs for the very reason that digoxin is superior in humans. The half-life of elimination of digitoxin in humans is 4 days, that for digoxin is 1 day. Physicians prefer digoxin over digitoxin so that if their patients become intoxicated, they will be ill for a much shorter time if they are receiving digoxin than if they receive digitoxin. For dogs, however, just the opposite is true. The half-life of elimination for digitoxin is 8 hours, that for digoxin is 1 day. If the veterinarian treating a dog with a glycoside happens to intoxicate the patient, therefore, it will remain intoxicated for a much longer time with digoxin than with digitoxin. The disparity in duration of intoxication with these two glycosides becomes even greater if the dog has poor renal function, in which case the half-life of elimination of digoxin may be 4 days. Thus, the veterinarian is much less likely to intoxicate a dog with digitoxin; and, if it happens, the intoxication will remain for a much shorter time. Digitalis intoxication may be prevented by selecting the correct glycoside 37 and adjusting dosage depending on renal function, level of cachexia or obesity, use of concomitant drugs, or the individual dog's tolerance. When intoxication occurs, digitalis should be stopped. If ventricular arrhythmias are occurring, the dog should be given, orally, 15 mg of phenytoin/kg body weight four times a day for two estimated half-lives of the digitalis. Phenytoin appears to abolish the ventricular arrhythmia by its effect on the area postrema; therefore, it is presumed that digitalis exerts this potentially lethal effect via this region in the brain. Neither first- nor second-degree atrioventricular (AV) block, nor junctional tachycardia require emergency treatment; merely stopping the digitalis and waiting is usually sufficient. If the junctional tachycardia persists, the calcium channel blocker diltiazem may be given at 1.25 mg/kg body weight. This will terminate the junctional tachycardia in all instances, usually after a single
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oral dose. Signs of GI toxicity usually abate after termination of the glycoside; however, if the animal becomes dehydrated or there is a suspicion of electrolyte imbalance, fluid should be given. It is extremely important to make certain that serum potassium concentration is not depressed and that serum calcium is not elevated in animals receiving digitalis. The aforementioned electrolyte disturbances predispose to arrhythmias precipitated by digitalis. Because most dogs receiving digitalis are also receiving diuretics that may alter electrolyte imbalance, it is important to anticipate and/or correct electrolyte imbalance. CARDIAC TOXICITY OF ADRIAMYCIN Antineoplastic agents-in particular, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)-have great potential for producing serious adverse cardiac effects, leading to death either from arrhythmia or from heart failure. 24 • 25 • 27 · 28 The leading limitation in efficacy for Adriamycin probably is its cardiotoxicity, because greater antineoplastic activity could be achieved if larger doses of the drug could be tolerated. Dogs often manifest cardiotoxicity at total doses of Adriamycin greater than 300 mg/M 2 ; however, a rare dog may manifest toxicity at 200 or not until 500 mg/M 2 • 25 · 30 Of nearly 100 dogs treated in one institution, between 1 and 2% developed clear evidence of dilated cardiomyopathy, and probably 4-5% had echocardiologic evidence of impaired left ventricular function (Couto CG; personal communication, 1989). Electrocardiologic findings in dogs with Adriamycin toxicosis may include prolongation of PQ interval, manifesting impaired AV conduction; prolongation of QRS with development of slurs and notches in the R-waves, suggesting retarded intraventricular conduction; decreased voltage of the QRS, suggesting either pleural or pericardia! effusion or, possibly, altered resistivity of the myocardium; ectopic activity from supraventricular or ventricular foci, suggesting increased automaticity, triggered activity, or reentry from slowly conducting regions. Uni- or biventricular dilatation, reduction in ejection fraction (ratio of stroke volume to end-diastolic volume); reduction in cardiac output with oliguria, muscular weakness, and even syncope; and/or pulmonary edema may occur as manifestations of reduced myocardial function. The mechanisms by which Adriamycin produces these changes are only partially characterized. Toxicosis is thought to be mediated in part via histamine release, but antihistamines do not reduce the severity. Adriamycin may load myocytes with sodium and/or calcium ions, and it no doubt interferes with normal healing of injured myocytes, which leads to myofibrillar disarray and fibrosis. The main mechanism for cardiotoxicity, however, may be production of oxygen free radicals. Two routes for production of free radicals have been proposed. Adriamycin is reduced by flavindependent reductases to semiquinone radicals, which donate electrons to oxygen, which forms superoxide ions, hydrogen peroxide, and hydroxyl ions. The other route involves combination of Adriamycin and iron, which catalyzes the transfer of electrons from sulfhydril compounds to oxygen, creating the oxygen free radical. Such free-radical reactions tend to be self perpetuating.
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Some studies 25 suggest that Adriamycin cardiotoxicity can be minimized by treatment with scavengers (e.g., super oxide dismutase, glutathione, catalase) of free radicals of oxygen. Some studies 24 • 27• 28 suggest that exercise provokes, and others, that exercise protects against cardiotoxicity. Recent evidence indicates that the antineoplastic agent, ICRF 187, protects against cardiotoxicity when given between 30 and 15 minutes before Adriamycin. The mechanism of protection by ICRF is that it chelates iron, making it unavailable for the Adriamycin-iron combination. Dogs pretreated with ICRF 187 can tolerate up to four times the dose that would be lethal to unpretreated dogs. Even when the PQ interval is prolonged and ventricular premature depolarizations occur, normally two contraindications to the use of digitalis, many dogs developing heart failure from Adriamycin toxicosis improve dramatically when given digitalis.
CONSULTATION TO THE PHARMACEUTICAL INDUSTRY Toxicology of cardiovascular drugs or of drugs intended for diseases of other organ systems, but with potential to affect the cardiovascular system, is of prime importance to both the pharmaceutical industry and federal regulatory agencies and, therefore, to the many veterinarians who consult for those units. Although many compounds have the potential for altering mechanical properties (e.g., contractility, compliance) of the heart, more concern is placed on how compounds affect the electrophysiological properties (e.g., rhythmicity, conductivity, irritability) because alterations in the latter can lead to sudden death by either cardiac arrest or ventricular fibrillation. Electrocardiography is the best means of detecting these changes; 12 and we must acknowledge our debt to D. K. Detweiler for his pioneering efforts in the development of electrocardiography for both practice applications and toxicologic monitoring. Rhythmicity refers to the rate of discharge of the sinoatrial node; this can be studied through the frequency with which P waves are observed on an electrocardiogram (EKG). Conductivity must be evaluated on all of the cardiac structures that conduct, but more emphasis is placed on conduction through the AV transmission system (measured by the PQ interval of the EKG) and the ventricles (measured by duration of QRS-complex of the EKG). Irritability can be measured by frequency of premature depolarizations and from what foci they arise (e.g., atrial, AV junctional, His-Purkinje system). Likelihood for ventricular arrhythmia may relate to durations of QT and QRS. 43 When either is prolonged, likelihood of reentry and ventricular tachycardia or ventricular fibrillation increases. Provoking arrhythmias may be a useful means of identifying increased likelihood for their occurrence in the unprovoked state. Sensitivity to intravenous epinephrine 22 and exercise39 are two commonly used means for provocation. No testing of a pharmacologic agent is complete without a thorough electrocardiologic analysis. This usually includes screening one or up to 12 leads at conventional paper speed (25 mm/second) in target animals (i.e.,
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animals in which the compound is to be used) while those animals receive either the dose intended for clinical use or multiples of up to 10 times that dose. Multiples are used to identify a "worse-case" scenario of what cardiovascular effects the compound might produce. The minimal parameters to be measured are heart rate, PQ (PR) interval, QRS duration, QT interval, and, possibly, P wave duration. Configuration of ST-T is extremely important because that interval may well be the most sensitive (albeit less specific) to detect toxic effects of drugs. Two questions of importance when screening for cardiovascular toxicity are: What leads should be taken? And, for how long should EKGs be monitored? For detection of myocardial injury or ventricular hypertrophy, at least one unipolar thoracic lead (usually V3 ) should be monitored along with limb leads I and aVF. Because T waves are more consistent in leads rV2 and V10 , monitoring of those leads is recommended by some. It is highly unlikely that any greater number of leads will demonstrate electrocardiographic changes not visible on those three or four leads, and keeping the number of leads to a minimum will save both time and money for both recording and subsequent analysis. Deciding how long to monitor the animal is more difficult. If the compound has profound arrhythmogenic effects and produces more than 10,000 premature depolarizations a day (a normal dog has approximately 150,000 beats/day), a single 1-minute monitor has a reasonably likelihood of detecting ectopic activity, unless, of course, the ectopic activity occurs only within a short interval (i.e., at night, during excitement, during eating) when the tracing is not taken. If, on the other hand, the compound merely generates occasional premature depolarizations, then a 1-minute recording is unlikely to be fruitful in detecting the increased irritability or, if the agent is an antiarrhythmic, a reduction in irritability. 9 • 47 The best method would be to monitor the animal for 24 or 48 consecutive hours (Holter's monitoring), 2 and to compare frequency of ectopic activity before the compound with that after the compound. Fortunately, ectopic activity is extremely rare in normal dogs and cats, probably occurring in fewer than 1% of normal animals in those species; therefore, almost any ectopic depolarizations observed probably indicate that the compound increases irritability. The tendency for serious ventricular arrhythmias may be detected by prolongation of the QT interval; therefore this, too, must be considered a potentially toxic effect of a compound. Cardiovascular toxicity may be indicated by not only by ectopic depolarizations, but also by subtle changes in contour to ST-T. These subtle changes may be detected only if tracings of excellent quality are analyzed. This may require chemical restraint to reduce artifacts produced by motion or muscle fasciculation. Acepromazine, lnnovar-vet (fentanyl and droperidol; Pitman-Moore, Washington Crossing, NJ), ketamine, ketamine and xylazine, or ketamine and diazepam are all agents useful for improving the quality of EKGs and increasing the likelihood of identifYing subtle changes in ST-T, but these agents may also either extinguish or augment ectopic activity. The study director must decide whether he or she wishes to make an error because records of quality good enough to detect subtleties cannot
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be obtained from animals without chemical restraint, or because a rhythm disturbance was either provoked or extinguished by the chemical restraint. It occasionally is necessary to measure large numbers of EKG parameters from large numbers of animals, a task that is monotonous, timeconsuming, tedious, and prone to error. Digital computers are ideal for such analyses. There currently are two systems (Buxco, Detroit, MI; and Mortara, Milwaukee, WI) available for analyzing mass quantities of EKGs, these systems having been designed for toxicologic screening of beagles. Each system has the capability of recording up to 12 leads rapidly, and storing great numbers of EKGs (up to 60,000). Costs for these systems range between $5000 and $60,000, depending on individualized hardware and capabilities. In addition to digitizing and recording various conventional parameters (e.g., heart rate, P wave amplitudes and durations, QT and corrected QT duration), the systems analyze rhythm and detect arrhythmia; the Buxco system even makes quantitative measurements of subtle contours to ST-T. The systems are excellent for Good Laboratory Practice studies, given that all records are labeled, dated, and stored permanently, while permitting easy access. The veterinarian is called on more and more to assist the pharmaceutical industry and regulatory agencies in evaluating cardiovascular toxicity of compounds intended for humans or for infrahuman mammals. This is an extremely important task to maximize the chance of developing safe and effective drugs, and to minimize the chance of marketing drugs that have a poor risk-benefit ratio. Three excellent reviews on cardiovascular toxicity of various drugs are available. 3 · 12 · 45
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12. Detweiler DK: The use of electrocardiography in toxicological studies with beagle dogs. In Balazs T (ed): Cardiac Toxicology. III. Boca Raton, CRC Press, 1981, pp 33-82 13. Detweiler DK: Electrocardiographic monitoring i!l toxicological studies: Principles and interpretations. New York, Plenum Press, 1983, p 579 14. Doherty JE: Suspicion of digitalis intoxication. JAMA 33:191, 1978 15. Doherty JE, Perkins WH, Wilson MD: Studies with tritiated digoxin in renal failure. Am J Med 37:536, 1964 . 16. Erichsen Df, Harris SG, Upson DW: Therapeutic and toxic plasma concentrations of digoxin in the cat. Am J Vet Res 41:2049, 1980 17. Fillmore GE, Detweiler DK: Maintenance of subacute digoxin toxicosis in normal beagles. Toxicol Appl Pharmacal 25:418, 1973 18. Fowler ME: Plant Poisoning in Small Companion Animals. St. Louis, Ralston Purina Company, 1980 19. Goodman A, Gillman L: The Pharmacologic Basis of Therapeutics, ed 7. New York, Macmillian Publishing, 1985 20. Gwathmey JD, Hamlin RL: Protection of turkeys against furazolidone-induced cardiomyopathy. Am J Cardia! 52:626, 1983 21. Hamlin RL: Basis for selection of l! cardiac glycoside for dogs. Baton Rouge, LA, Proc First Symp Vet Pharm and Therap, 1978 22. Hamlin RL, Bishop MA, Hadlock DJ, et a!: Effects of lidocaine, with or without epinephrine, on ventricular rhythm. JAm Anim Hasp Assoc 24:701-704, 1988 23. Hamlin RL, Pipers FS, Carter KL, et a!: Treatment of heart failure in dogs without use of digitalis glycosides. Vet Med Small Anim Clin 68:349-356, 1973 24. Hassler C, Thake D, Hamlin R, et a!: The effect of exercise on cardiotoxic potential of Adriamycin in rhesus monkeys. Toxicologist 2:9, 1982 25. Herman E, Ferr;ms V, Young R, et a!: Effect of pretreatment with ICRF-187 on total cumulative dose of qoxorubicin tolerated by beagle dogs. Cancer Res 48:6918, 1988 26. Horowitz L, Zipes D: A symposium: Perspectives on proarrhythima. Am J Cardiol59:1E, 1987 27. Kanter MM, Hamlin RL: Effect of exercise training on antioxidant enzymes and cardiatoxicity of doxorubicin. J Appl Physiol59(4):1298, 1985 28. Kanter M, Hamlin R, Unverferth D, et a!: Effect of exercise training on antioxidant enzymes and cardiotoxicity of doxorubicin. J Appl Physiol 59:1298, 1985 29. Kates RE, Keene BW, Hamlin RL: Pharmacokinetics of propranolol in the dog. J Vet Pharmacal Therap 2:21, 1979 30. Kehoe R, Stinger DH, Trapani A, eta!: Adriamycin-induced cardiac dysrrhythmias in an experimental dog model. Cancer Treat Rep 62:963-978, 1978 . 31. Lindenbaum J, Mellow MH, Blackstone MO, et a!: Variation in biologic availability of digoxin from four preparations. N Eng! J Med 285:1344, 1971 32. Lawn B, Verrier RL, Rabinowitz SH: Neuronal and psychological mechanisms and the problem of sudden death. Am J Cardia! 39:890, 1977 33. Lawn B, Graboys T: Evaluation and m;magement of the patient with ventricular arrhythmias. Cardiac Impulse 6(2):1-5, 1985 34. Lynch J, Simpson P, Gallagher K, eta!: Increase in experimental infarct size with digoxin in a canine model of myocardial ischemia-reperfusion injury. Am Heart J 115:1171, 1988 35. Muir WW, Werner LL, Hamlin RL: Effects ofxylazine and acetylpromazine upon induced ventricular fibrillation in dogs anesthetized with thiamylal and halothane. Am J Vet Res 36:1299, 1975 36. Opie LH: Drugs for the heart. Orlando, Grune & Stratton, 1980 37. Peters DN, Hamlin RL, Powers JD: Absence of pharmacokinetic interaction between digitoxin ;md quinidine in the dog. J Vet Pharmacal Therap 4:271, 1981 38. Podrid P, Lawn B: Congestive heart failure with disopyramide. N Eng! J Med 302:614, 1980 39. Saini V, Graboys T, Towne V, et a!: Reproducibility of exercise-induced ventricular arrhythmia in patients undergoing evaluation for malignant ventricular arrhythmia. Am J Cardiol63:697-707, 1989 40. Singh B, Hauswirth 0: Comparative mechanisms of action of antiarrhythmic drugs. Am Heart J 87:367, 1974
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41. Slater W, Lampert S, Podrid P, et a!: Clinical predictors of arrhythmic worsening by antiarrhythmic drJ.!gs. Am J Cardiol 61:349-353, 1988 42. Smith TW: Contribution of quantitative assay technics to the understanding of the clinical pharmacology of digitalis. Circulation 46:188, 1972 43. Surawicz B, Knoebel S: Lohg QT: Good, bad or indifferent? J Am Coli Cardiol 4:494516, 1985 44. Teske R, Bishop S, Rigter H, et a!: Subacute digoxin toxicosis in the beagle dog. Toxicol Appl Pharmacol 35:283, 1976 45. Van Stee E: Cardiovascular Toxicology. New York, Raven Press, 1982 46. Waserman F, et a!: Successful treatment of quinidine and procainamide intoxication. Report of three cases. N Eng! J Med 259:797-802, 1958 47. Winkle RA: Antiarrhythmic drug effect mimicked by spontaneous variabihty of ventricular ectopy. Circulation 57:1116-1121, 1978
Address requests for reprints to: Robert L. Hamlin, DVM, PhD Department of Physiology and Pharmacology College of Veterinary Medicine The Ohio State University 1935 Coffey Road Columbus, OH 43210