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Poisoning By Antidysrhythmic Drugs
Pediatric Toxicology
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Poisoning By Antidysrhythmic Drugs Howard C. Mofenson, M.D.,* Thomas R. Caraccio, Pharm.D., R.Ph.,t and Jay Schauben, Pharm.D., R.Ph.t
This article encompasses those antidysrhythmic agents that exert their primary therapeutic effect on the cardiovascular system and might be ingested accidentally by young children or taken orally in attempted suicide by older children and adolescents. Most of these agents have been studied in patients with cardiac disorders, which makes it difficult to anticipate the effects of overdose on the healthy hearts of children and teenagers. Although many dysrhythmias have serious consequences for children and adults with significant cardiac and metabolic disorders, they appear to be relatively benign in healthy pediatric patients. The incidence of this type of ingestion is unknown, but the scenario is apparent. The source of the accidental ingestion usually occurs during a visit to the home of a grandparent, who is unaccustomed to having exploring children around. Visits to relatives who have had myocardial infarctions by small children are particularly hazardous. Table 1 contains a breakdown of the number and types of pediatric exposures of digitalis preparations and antidysrhythmic agents reported to the FDA Poisoning Surveillance and Epidemiology Branch from 1978 to 1982. 1,52 All of the agents used to treat rhythm disorders have the potential to cause major adverse effects. In some instances, the drugs are more dangerous than the dysrhythmia. It has been hypothesized that by slowing conduction, antidysrhythmic agents may enhance susceptibility to reentry and precipitate ventricular tachydysrhythmias. 24, 57 It is assumed in each management that the vital functions are estab*Professor of Clinical Pediatrics, State University of New York at Stony Brook, Director, Nassau County Medical Center's Long Island Regional Poison Control Center, East Meadow, New York tClinical Coordinator, Nassau County Medical Center's Long Island Regional Poison Control Center, East Meadow, New York; Preceptor, St. John's University College of Pharmacy and Allied Health Sciences, Jamaica, New York :j:Supervisor, Emergency Pharmacy Services, University Hospital of Jacksonville; Clinical Assistant Professor of Pharmacy, University of Florida College of Pharmacy, Gainesville, Florida
Pediatric Clinics of North America-Vol. 33, No.3, June 1986
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Table 1. Number and Types of Exposures of Digitalis Preparations and Antidysrhythmic Agents Reported to FDA from 1978-1982
Digitalis < 5 years All ages Group I Agents < 5 years All ages Group II Agents < 5 years All ages Group III Agents < 5 years All ages
TOTAL CALLS
TOXIC CASES*
476
108 196
716 97
214
160 47
2 2
559 968
39 174
*Implies symptomatic toxicity. (From Poisoning event reporting system. Food and Drug Administration, Poisoning Surveillance and Epidemiology Branch, HFN-720, with permission.)
lished and supported as first priority. Gastrointestinal (GI) decontamination may be implemented in ingested overdoses after the patient is stabilized. The article detailing GI decontamination (Rogers and Matyunas, April 1986) will discuss the technique, although statements about GI decontamination of special interest will be mentioned.
CLASSIFICATION OF ANTIDYSRHYTHMIC DRUGS Antidysrhythmic agents act on the cardiac conduction tissues by: 1) affecting the properties of the membrane so that ionic exchanges, occurring during the transmission of the action potential, are altered, with automaticity or excitability being either increased or decreased; 2) interfere with the responsiveness of specialized tissues so that conduction of the impulse is altered resulting in circuit and/or reentry rhythms; 3) altering the duration of the action potential and refractoriness of the tissue, interfering with or causing cessation of the mechanism of the abnormal rhythm. Ideally, the classification should be linked to the key electrophysiological abnormalities that underlie the various dysrhythmias. Current knowledge does not permit classification on this basis, however. As a framework for toxicologic discussion, we have chosen the classification that defines five different groups (Table 2). 1.50 Group I Group 1 agents are local anesthetics that appear to act by depressing sodium conduction. They slow the action potential upstroke in phase 0, which prolongs the conduction velocity. Thus they cause a prolongation of the action potential duration and refractory period, as well as decreasing automaticity by decreasing the slope of phase 4 depolarization. 1 These
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POISONING BY ANTIDYSRIIYTH"lIC DRUGS
Table 2. Classification of Antiarrhythmic Drugs GROVP
AGEt-.'T
Quinidine Procainamide Disopyramide II
Lidocaine Phenytoin Mexiletine Tocainide
III
Propranolol Metoprolol
IV
Bretylium
V
Verapamil Nifedipine Diltiazem
(From Amsdorf, M. F.: Electrophysiologic properties of antidysrhythmic drugs as a rational basis for therapy. Med. Clin. North Am., 60:213-216, 1976, with permission.)
agents are most useful for treating supraventricular and ventricular dysrhythmias. In therapeutic doses, these drugs tend to prolong the PR interval, QRS duration, H-V interval, and Q-T interval. Complete heart block and suppression of lower pacemakers may result in asystole. The anticholinergic properties of these agents may counter the direct action and accelerate AV node conduction. Table 3 contains comparative data on the pharmacotoxicology. Major Adverse or Toxic Manifestations of Group I Antidysrhythmic Agents. All of these agents may cause depression of myocardial contractility, dysrhythmias, conduction defects, hypotension, and syncope due to vasodilation. Some hypotensive episodes are not accompanied by ECG evidence of toxicity. 10. 12. 16. 39. 61. 66. 6S Most of the reported cardiac manifestations in infants are similar to those reported in adults, with the exception of atrial tachycardia. Some authors have failed to report this type of dysrhythmia. 16 ECG changes may include widening QRS, increased Q-T intervals, ectopic activity, and varying degrees of heart block. The ECG takes 36 to 72 hours to revert to normal. Disopyramide may cause greater anticholinergic toxicity than the others, and cardiovascular collapse can occur without ECG warning, followed by dysrhythmias, apnea, and death.30. 49 Noncardiac toxicity also is seen. Respiratory depression and arrest have been reported following both quinidine and disopyramide. 29, 61 Convulsions and coma have been reported following quinidine overdose,39. 61 whereas CNS depression and obtundation may be seen after procainamide ingestion,58 Both quinidine and procainamide may produce nausea and vomiting,58 whereas disopyramide may produce dry mouth, decreased bowel sounds, and distention as a result of its anticholinergic activity, Both quinidine 61 and disopyramide 45 have produced systemic acidosis and hypoglycemia, Hemolysis has been reported in glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients receiving quinidine, 58 and renal failure has been observed in association with procainamide ingestion. 58
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Table 3. Group I Agents: Phannacotoxicokinetic Data AGENTS
Available Forms
Trade Name Routes Available Bioavailability Peak Levels
QUINIDINE
Sulfate, gluconate lactate, hydrochloride, polygalactoronate Various, Duraquin, QUinaglute PO and 1M/IV 70-90 per cent 1-4 hrs
Duration of Action
Sulfate = 2-3 hrs Gluconate = 3-6 hrs sus. release = 8 hrs Metabolism (Primary) Liver 2-3 L per kg Volume of Distribution Renal Excretion per 20-50 per cent cent Unchanged Half Life Tberap. =3-16 hrs (AV=7-8 hrs) Overdose = 10 hrs Tberapeutic Serum 2-7 fLg per ml Concentrations Toxic Dose Toxic Serum Levels
1 gm in child 2-8 gm in adult >7 fLg per ml
PROCAINAMIDE
DISOPYRAMIDE
Hydrochloride (PA)
Phosphate
Pronestyl, Procan Procan-SR Oral and 1M or IV 75-95 per cent PA= 1-2 hrs; Nacetylprocainamide (NAPA) = 1-8 hrs 3-6 hrs
Norpace Oral 50-80 per cent 1-1.5 hrs
6-12 hrs
Liver 2 L per kg NAPA
Liver 0.8 L per kg
PA = 40-60 per cent NAPA = 80 per cent 3-6 hrs
50 per cent
PA=4-15 fLg per ml NAPA = 15-24 fLg per ml 7 gm in adult
2-4 fLg per ml
4-8 hrs
Varies
PA=>15 fLg per ml 7 fLg per ml NAPA = >16 fLg per ml Dosage Range-Child PO Gluconate 2-10 PO: 50 mg per kg per mg per kg q3-6 hrs day Sulfanate 3-6 mg/kg IV: 100 mg over q3-6hrs. 1M or IV 5 min. to max. = 1 5-8 mg/kg gm Adult Dosage PO 200-600 mg q 6- PO (loading) 1 gm over 100-400 mg q6hr 8 hrs 2 hrs maintenance I9 g per day; IV (loading) 1-2.5 gm at .;;;20 mg per kg, maintenance 20-80 fLg per kg per min Activity Slows conduction Similar to quinidine; Similar to quinidine; velocity. Prolongs may lower blood has negative effective refractory pressure by inotropic action period, decreases peripheral ganglionic and greater automaticity, blockade. anticholinergic anticholinergic properties than properties. others in class. PA = Procainamide; NAPA = N-Acetylprocainamide.
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Chronic ingestion of quinidine is associated with the development of "cinchonism," which is characterized by tinnitus, deafness, blurred vision, headache, diplopia, photophobia, confusion, delirium, psychosis, nausea, vomiting, and diarrhea. The skin may be warm and flushed. 39 Procainamide has produced a systemic lupus erythematosislike reaction. Treatment of intoxication due to agents in this group is largely symptomatic. Both mild alkalemia and hypokalemia have been found to be somewhat protective. Hypotension should be treated with intravenous fluids. When they occur, arrhythmias should be treated with lidocaine or phenytoin, which will decrease the action potential duration and refractory period; use of other type I agents is contraindicated. Forced diuresis has been suggested for quinidine intoxication; however, because this involves maintaining the urine pH at 4.5 to 5.5, this technique has not been consistently effective. The overall increase in excretion is not significant, and this is no longer recommended.
Group II Agents
Lidocaine. Lidocaine hydrochloride is an aminoacyl amide that, although used as a parenteral cardiac antiarrhythmic agent, is also widely available for both topical and local injection anesthetic. A variety of topical preparations exist, including a popular 2 per cent solution (Xylocaine, viscous). Serious adverse systemic reactions to lidocaine have been reported after ingestion of the topical dosage form. 9, 22, 50 We have encountered an infant who experienced seizures after having lidocaine 2 per cent solution applied topically on the gums for teething,42 Pediatricians should be aware that when lidocaine is applied to the mucous membranes, a concentration similar to that of intravenous administration may occur. Table 4 contains pharmacotoxicokinetic data on lidocaine. Dose-related neurologic effects include dizziness, drowsiness, speech disturbances, perioral numbness, muscle twitching, confusion, vertigo, or tinnitus. These occur at plasma concentrations greater than 5 f,Lg per ml. Serious toxicities occurring at concentrations over 9 f,Lg per ml include psychosis, seizures, and respiratory depression, Severe bradycardia, sinus arrest, and arteriovenous (AV) block may also be associated with toxic blood levels; concomitant therapy with other antidysrythmic agents, or preexisting heart block or myocardial infarction. Methemoglobinemia also has been reported. 48 Therapy for lidocaine overdose should focus on the treatment of seizures and methemoglobinemia. Seizures may be relatively refractory to therapy, but phenytoin should be administered. Because both lidocaine and its metabolite, monoethylglycine xylidide (MEGX), may cause convulsions, the potential for seizures may remain even after the lidocaine serum concentration falls below 5 f,Lg per ml. Methylene blue and oxygen should be administered if the methemoglobin level is ~30 per cent and is accompanied by dyspnea, metabolic acidosis or altered mental status, Hemodialysis is ineffective. Phenytoin. Phenytoin has been found to be useful in the management of dysrhythmias, especially those resulting from intoxication with digitalis preparations, tricyclic antidepressants, and other drugs. 35 Phenytoin also is acknowledged as a valuable antiepileptic agent, particularly for grand mal
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Table 4. Pharmacotoxicokinetic Data: Croup II Agents AGENT
LIDOCAINE
PHENYTOIN
Trade Name
Xylocaine
Dilantin
Routes Available
Bioavailable Absorption (Oral) Peak Blood Levels Duration Metabolism Per cent Protein Bound Volume of Distribution Renal Excretion Per cent Unchange Half-life
Therapeutic Serum Level Toxic Serum Levels Dosage Range
Adult Dosage
Activity/Use
Topical PO IV ~35 per cent PO ~1 hr IV <1 min 10-20 min Liver to two active metabolites Not known 1.6 L per kg 30
PO: tablets and liqUids
90 per cent PO 6-12 hrs IV 1 hr Variably according to levels Liver 95 per cent 87-93 per cent 0.6-1.0 L per kg
5
2 hrs
20-30 hrs Varies in toxic doses; zero order kinetics 1.5-6 ,...g per ml 10-20 ,...g per ml >6,...g per ml >20,...g per ml IV loading 0.5-1.5 mg per PO 5-7 mg per kg per day in 1-2 doses; PO loading kg qlO min up to 300 mg IV (maintenance) 20-50 ,...g 500-600 mg followed in 24 hr by 200 mg per per kg per min, topical 4.5 mg per kg per dose, daily IV maximum 300 mg IV loading 1-1. 5 mg per PO 4-6 mg per kg per day; kg q5-1O min up to PO loading dose up to 1 300 mg IV (maintenance) gm in divided doses 400 2-4 mg per min. Topical mg, 300 mg, 300 mg same as child over 4 hr followed by maintenance dose of 300-400 mg daily IV loading dose = 1 gm at ~50 mg per min Local anesthetic amide Organic acid inhibits spread of ectopic activity type, most antidysrhythmic activity in brain and heart. due to blockade offast Useful for ventricular dysrhythmias; used sodium channel in Purkinje fibers primarily as anticonvulsant
seizures. It has little sedative effect at therapeutic levels. Although it is widely prescribed, fewer than ten deaths have been reported from overdose. 36 Deaths usually have been the result of idiosyncratic reactions or rapid intravenous injection. There are few accidental childhood poisonings reported, and they are generally mild intoxications (see Table 1). Table 4 contains pharmacotoxicokinetic data on phenytoin. 7, 36, 55 Adverse reactions to phenytoin may affect a large number of body systems. These include 1. Neurologic: Nystagmus is associated with serum phenytoin concentrations greater than 20 f,Lg per ml, ataxia with concentrations within the range of 30 to 40
POISONING BY ANTIDYSRHYTHMIC DRUGS
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ILg per ml, and coma and seizures occur at concentrations greater than 40 ILg per ml. 2. Cardiac: Toxicity is unlikely following oral overdose; however, rapid IV administration may result in dysrhythmias and asystole. 3. Gastrointestinal: Nausea and vomiting may occur. 4. Metabolic: Hyperglycemia may occur. S. Hypersensitivity: Hypersensitivity reactions are manifested by skin rashes and fever. 6. Dermatitis, hepatitis, gingival hyperplasia, lymphoid hyperplasia, and hematologic abnormalities are unlikely following acute overdose. 7. A few patients have a hereditary defect in parahydroxylation and may develop toxicity on therapeutic doses. 8. Fetal hydantoin embryopathy syndrome and coagulopathies have been reported in neonates.
Treatment of phenytoin overdose should focus on symptomatic and supportive care. 7 • 36. 55 Diuresis, charcoal hemoperfusion, and hemodialysis are generally ineffective. Exchange transfusion remains controversial. Group ill Agents Beta-adrenergic blocking agents are widely used in medicine in the treatment of hypertension, dysrhythmias, angina pectoris, open angle glaucoma, migraine, and as prophylaxis against sudden death after myocardial infarction. 5 In addition to beta-adrenergic blockade, group III drugs share many group p4 and group 1164 effects. Table 5 shows the beta blockers presently available in the United States and the pharmacologic and toxicokinetic data of these agents. Propranolol, the prototype for this group, is metabolized primarily in the liver to 4-hydroxypropanolol, an active metabolite. Differences in pharmacologic activity, such as cardioselectivity, membrane-stabilizing activity, lipid solubility, and intrinsic sympathomimetic activity within this group influence their clinical toxicity. The more lipid soluble the drug, the greater its potential to cause serious central nervous system toxicity. 36 The actions of beta blockers can be understood best by considering the distribution and function of beta-adrenergic receptors in the body. Receptors have been classified as beta-lor beta-2 on the basis of the relatively selective effects of particular agonists and antagonists for groups of organ systems. Cardioselectivity is a dose-related phenomenon, and the effect on beta-l receptors becomes less important with increasing plasma concentrations. Negative inotropic and chronotropic effects result in profound bradycardia and hypotension. Atenolo! and metoprolol may cause less pronounced bradycardia and hypotension. Oxyprenolol and pindolol with partial beta-agonist activity may cause tachycardia and hypertension. Prolongation and alterations of the QRS complex, T waves and ST segment may occur in addition to dysrhythmia. These agents may precipitate congestive heart failure. CNS effects of beta-receptor blocking agents may include hallucinations, delirium, coma, and seizures. The degree of membrane stabilization and lipid solubility will determine the potential to cause serious central nervous system manifestations. Metoprolol and oxyprenolol are moderately
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Table 5. Characteristics of Currently Available Beta Blockers
DRUG
Atcnolol (Tenormin) Dose: 50--200 mg MDD=200 mg Metoprolol (Lopressor) Dose: 50--400 mg MDD=450 mg Nadolol (Corgard) Dose: 40--320 mg MDD=320 mg Oxyprenolol:j: (Trasicor) Pindolol:l: (Visken) Dose: 20-60 mg MDD=60 mg Propranolol * (Inderal) Dose: 40--160 mg MDD=480 mg Timololt (Blocadren) Dose: 20 mg MDD=60 mg Ophthalmologic 0.25-5 per cent (Timoptic)
SULl'BILITY
RELATIVE
AND
POTESCY
PROTEIN BOUND
ABSORPTIO)"l;
ME~1BRANE
(PROPRA-
PLASMA
ELIMINA-
(PER
(PER CENT)
STABILIZER
NOLOL)
Tl/2 hrs
TION
CENT)
no
1.0
6-9
Water 4662 per
95 per
3-10
BETA-
VD UKG SPECIFICITY
0.7
renal
cent
Fat over 95 per cent
No
Water 1525 per
±
1.0
3-4
Hepatic
10
5.6
+ Low dose
1.0
17-23 70 per
25
2.1
Hepatic
80
1.5
cent
renal
cent
Fat 70--95 per cent Fat over 90 per cent
No
1.0
1.5-3
No
6.0
3-4
Hepatic (40 per cent renal)
57
2.0
Fat 100 per cent
++
1.0
2-3
Hepatic «1 per cent renal)
90--95
3.6
Fat over 90
No
6.0
3
<10
1.5
per cent
+ Low dose
cent
Hepatic 20 per cent renal
*Substantial first pass. tMitochondrial calcium protection during ischemia. :j:Partial agonist (intrinsic sympathetic activity). MDD = maximum daily dose. Toxic dose varies considerably. Toxicokinetics: Peak action 1 to 2 hours orally and lasts 24 to 48 hours. In drugs with long half-lives, the duration of toxicity may be prolonged.
fat soluble, whereas propranolol is highly fat soluble and may induce more eNS effects. Other manifestations of overdose with beta-blocking agents include hypoglycemia and bronchospasm. Hypoglycemia may occur in children and in patients with diabetes. These agents also may block the catecholamineinduced "warning signs" of hypoglycemia. Bronchospasm may occur in patients with or predisposed to asthma. This is less likely to occur with agents that are relatively more beta-l selective such as atenolol and metoprolol. Management of beta-blocking agent intoxication should follow the same principles outlined for other types of nonvolatile and noncaustic compounds. Because the heart appears to be a critical target organ for this type of agent,
POISONING BY ANTIDYSRHYTHMIC DRUGS
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specific therapy should be directed toward re-establishment of hemodynamic homeostasis. Bradycardia may be one of the earliest manifestations. If the patient is hemodynamically stable and asymptomatic, no therapy is required. If the patient shows associated hypotension or AV block, atropine, isoproterenol, glucagon, or a pacemaker may be required. Ventricular tachycardia or serious premature ventricular contractions (multifocal, greater than 5 per min, R on T phenomena) may be treated with lidocaine, phenytoin, overdrive pacing, or DC cardioversion. For myocardial depression and hypotension correction of dysrhythmias, Trendelenburg positioning and fluid support may be required. Invasive hemodynamic monitoring should be implemented. Glucagon may be the treatment of choice for patients with low cardiac output and normal pulmonary capillary wedge pressure. It works by means of the adenyl cyclase mechanism, which apparently is unaffected by beta blockers. It usually is given as a bolus and may be continued as an infusion. The dose of glucagon is 50 to 150 fA-g per kg over 1 minute intravenously followed by a continuous infusion of 1-5 mg per hr in 5 per cent dextrose, which then is tapered over a period of 5 to 12 hours. (Do not dissolve the lyophilized glucagon in the solvent packaged with it, which contains phenol, when preparing an intravenous infusion because of possible phenol toxicity. Use 5 per cent dextrose as the diluent.) The effects of a single dose may be observed in 5 to 10 minutes with a duration of 15 to 30 minutes. In addition to the recommendations above, quinidine, procainamide, and disopyramide (Norpace) should be avoided because of their negative inotropic effects. Charcoal hemoperfusion may be useful for water-soluble drugs with low volumes of distribution and low protein-binding (nadolol and atenolol). Hemodialysis may be used if there is evidence of renal failure. Group IV Bretylium is the only agent in this fourth group. It has not been approved for use in children under 12 years and is available for intravenous use only, so that toxicity in this age group should be extremely rare. Bretylium's actions are believed to be related to an initial catecholamine release and subsequent catecholamine depletion. It is postulated that this direct effect is independent of the adrenergic nervous system. 31 Administration of this agent causes an initial elevation of blood pressure, heart rate, and myocardial contractility owing to catecholamine release. This apparently is followed by hypotension resulting from neural blockade. The drug appears most effective in the control of severe ventricular tachyarrhythmias resistant to other antidysrhythmics. Hypotension is common, and nausea and vomiting may occur after rapid IV administration. 34 This drug is a quaternary ammonium compound. The onset of action may be delayed 20 to 60 minutes after IV administration, and the duration of action is usually 6 to 12 hours after a single dose. Bretylium is eliminated by the kidneys with 70 to 85 per cent excreted in urine unchanged. The volume of distribution is 8.2 L per kg, and it is apparently not bound to plasma protein. The half-life is approximately 6 to 7 hours in adults.
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Table 6. Group V: Pharmacotoxicokinetics Data of Calcium Channel Blockers PROPERTY
I\IFEDIPII\E
VERAPAMIL
DILTIAZEM
Trade Name
Procardia
Calan, [soptin
Cardizem
Onset of Action
Peak Effect Half-life Route of Elimination Toxic Level
PO <20 min sublingual <3 min IV <1 min Oral 1-2 hrs 2 112-5 hrs Liver/kidney > 100 ng per ml
Oral <1 hr
Oral <15 min
IV <2" min 5 hrs 2-7 hrs Liver/kidney >300 ng per ml
30 mins 2-6 hrs Liver/kidney >200 ng per ml
(Modified from Mitchell, L. B., Schroeder, J. S., and Mason, J. W.: Comparative clinical electrophysiologic effects of diltiazem, verapamil, and nifedipine, and from Rosen, M. R., Wit, A. L., and Hoffman, B. F.: Electrophysiology and pharmacology of calcium antagonists: 6. Cardiac effects of verapamil. Am. Heart J., 89:665-673, 1975, with permission.)
Group V This fifth group acts by blocking the slow inward channel that allows influx of calcium ions. These drugs have been shown to be useful for the control of supraventricular and ventricular dysrhythmias. They also have been used to treat coronary artery spasm, heart failure, hypertension, and angina pectoris. Table 6 lists the calcium channel blockers available in the United States and a comparison of their pharmacotoxicokinetic data. Inhibition of the slow calcium channel current will result in 1. Myocardium depression-negative inotropic response. The order of potency of effect on cardiac muscle is nifedipine> verapamil> diltiazem. 2. Inhibition of nodal pacemaker tissue-bradycardia. The order of potency of effect on nodal conduction is verapamil> diltiazem> > nifedipine. 3. Inhibition of vasculature tone-peripheral vasodilation gives hypotension and coronary vasodilation produces oxygen sparing by decreasing oxygen utilization and increasing oxygen supply. The order of potency of effect on vasculature is nifedipine> verapamil> diltiazem. 4. Central nervous system depression 5. Nausea and vomiting 6. Hypoglycemia and mild acidosis
The bradycardia and hypotension occur within 1 to 5 hours of ingestion. The specific antagonist for the toxic manifestations of overdose with calcium channel blockers is calcium. Controversy exists regarding which calcium preparation to use. Some authors caution against the use of calcium chloride because of its potential vasodilating effect and suggest that the gluconate form be used. 43 Others suggest that the chloride preparation is more effective because of its predictable increase in extracellular ionized calcium. 2. 19. 70 Calcium chloride 10 per cent (27.9 mg or 1.36 mEq of calcium per ml) should be given under ECG monitoring to any patient not responding to supportive therapy alone. Calcium is given intravenously in doses of 10 to 20 mg per kg per dose (0.10-0.20 ml per kg per dose) in pediatric patients and up to 1 gm (10 ml per dose) in adults. 69 As an alternative, calcium gluconate 10 per cent (9 mg or 0.45 mEq of calcium per ml) can be used.
POISONING BY ANTIDYSRHYTHMIC DRUGS
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It can be given intravenously in doses of 2.7 mg per kg per dose (0.3 ml per kg per dose) in pediatric patients up to 1 gm (10 ml per dose) in adults over 5 to 10 minutes. Dopamine can be used if necessary (2 to 10 f.Lg per kg per min, IV infusion). Doses above 10 f.Lg per kg per min may cause systemic and renal vasoconstriction. Symptomatic bradycardia, heart block, and asystole have not responded consistently to calcium and atropine. The dose of atropine in children is 0.01 to 0.03 mg per kg (minimum 0.15 mg) and adults 0.5 to 1.0 mg. Isoproterenol can be used if necessary; a pacemaker may be needed as well. Severe rapid ventricular tachycardia in patients with Wolff-Parkinson-White's syndrome needs cardioversion. 11 Digitalis and Cardiac Glycosides. Digitalis preparations are among the top ten drugs prescribed in the United States. 26 Many digitalis preparations are available. We will discuss digoxin and digitoxin as prototypes of digitalis intoxication. Table 7 contains a summary of the pharmacotoxicokinetic data of these two agents. Digitalis glycosides exert positive inotropic effects by increasing availability of calcium ions to myocardial contractile elements, thereby increasing cardiac output in heart failure. The antidysrhythmic actions of digitalis glycosides are primarily due to an increase in AV nodal refractory period caused by increased vagal tone and sympathetic withdrawal. Additionally, digitalis exerts a direct vasoconstrictor effect on arterial and venous smooth muscle. In most cases, pediatric ingestions involving digitalis glycosides require only observation and general supportive care for the gastrointestinal symptoms and mild conduction and neurologic disturbances; nevertheless, one should remember that a significant ingestion may be lethal. 25, 47 Although there is reasonably good correlation between plasma digoxin concentration and manifestations of clinical toxicity in adults, this relationship has not been clearly established in children. It was thought for years that higher pllsma levels were needed in children for cardiac glycosides to be effective, Hut this has been refuted. 47 The clinical manifestations after an acute ingestion may differ from those of chronic toxicity. Acute ingestions in previously healthy adults and children do not differ appreciably. The manifestations of acute intoxication with digitalis include effects on a variety of organ systems: 1. Gastrointestinal: These are the first manifestations; persistent vomiting is a common one. IS, 53, 59, 65 2. Cardiac: Virtually any dysrhythmia may be produced, however, supraventricular tachyarrhythmias are characteristic of acute ingestions. 18 Bradycardia is also a common occurrence. A consistent lack of ventricular, dysrhythmia has been noted in acute versus chronic intoxications, especially in patients without pre-existing heart disease. Ventricular dysrhythmias are associated with a higher mortality. IS, 44, 53,59,65 The appearance of atrial tachycardia and AV block is considered fairly specific for digitalis toxicity. 3. Electrolyte Disturbances: Hypokalemia appears to be a consistent finding with chronic toxicity, 18 whereas acute ingestions are more likely to produce hyperkalemia. Hyperkalemia is an ominous sign in acute overdoses. 4. Neurologic: Blurred and altered color vision (usually green or yellow vision), headache, fatigue, depression, confusion, hallucinations and delirium have been reported to persist even after resolution of the cardiac toxicity. These manifestations have not been reported to be a consistent finding with acute ingestions. 59
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Table 7. Digitalis Preparations NAME
DIGOXIN
DIGOTOXIN
Trade Name
Lanoxin
Crystodigin
GI Absorption
Onset of Action (PO) Onset of Action (IV) Peak Effect Half-life Protein Binding Route(s) of Elimination Therapeutic Serum Concentration Toxic Serum Concentration Enterohepatic Recirculation Toxic Dose Dosage Range Children
Adult
55-75 per cent 1.5-6 hrs 15-30 mins 4-6 hrs 31-40 hrs 7-8 L per kg Renal 75 per cent Some GI excretion 1-2,5 >2.5 Small Acute ";2-3 mg Oral Initial Loading Dose Premature: 20-30 fLg per kg Full-term: 25-35 fLg per kg 1-24 mos: 35-60 fLg per kg 2-5 yrs: 30-40 fLg per kg 5-10 yrs: 20-35 fLg per kg > 10 yrs: 10-15 fLg per kg IV Loading Dose 80% of PO total daily dose (TDD) 112 TDD first, then 114 TDD q6-8 hrs for two doses Oral/IV Maintenance Dose Premature: 20-30 per cent POTDD All others: 25-35 per cent POTDD IV Laading Dose 8-10 fLg per kg For CHF; 13-15 fLg per kg for atrial fibrillation over 12-24 hrs Maintenance: 0.125-0.5 mg per day
90-100 per cent 3-6 hrs 25-120 mins 6-12 hrs 4-6 days 0.6 L per kg Liver 80 per cent
Renal excretion of metabolites 15-30 >3.5 Large
Oral/IV Loading Dose 25-35 fLg/kg over 12-24 hrs Maintenance Daily 10-25 per cent total loading dose
POIIV Laading Dose 0,8-1.4 mg over 12-24 hr or 10-15 fLg per kg Maintenance: 10 per cent of total loading dose
Management 1. Gastrointestinal decontamination can be effective up to 12 hours after ingestion. If persistent vomiting occurs, emesis or lavage may not be necessary. It is important to stabilize the cardiac rhythm before inducing emesis or lavage. If bradyc'ardia or block occurs, consider atropine 0.01 to 0.03 mg per kg (minimum 0.15 mg per dose) before lavage. Repeated doses of activated charcoal may interrupt enterohepatic recirculation. 53 Digitoxin elimination may also be enhanced by the administration of cholestyramine 4 gm PO every 6 hours. 25, 26 2. Treat ventricular premature contractions, including bigeminy, trigeminy, quadrigeminy, ventricular tachycardia, and atrial tachycardia with block, with phenytoin. The loading dose for children and adults is 15 mg per kg up to 1 gm
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IV, not to exceed 0.5 mg per kg per min. Following the loading dose, the maintenance dose for children is 2 mg per kg every 8 hours as needed; adults 300 mg daily. If this fails, consider a transvenous pacemaker or DC cardioversion. Monitor phenytoin concentrations. Lidocaine also may be administered for ventricular dysrhythmias. Loading dose (adult and children): administer 1 mg per kg per dose IV.2. 20. 23. 27. 44 A repeat dose of 0.5 to 1 mg per kg may be administered 20 minutes later if needed. Following the loading dose, begin a maintenance infusion of 10 to 40 flog per kg per min. If this fails, consider cardioversion. Recent reports indicate that magnesium sulfate has been effective in treating ventricular fibrillation that failed to respond to lidocaine or phenytoin. It may be administered to adults in doses of 2 to 3 gm in 1 minute IV, followed by 2 gm per hr for 4 to 5 hours?O 3. Treat bradycardia and second and third AV block with atropine. Doses may be repeated as needed. External pacing also may be required. 4. Treat hyperkalemia on the basis of potassium levels, ECG results, and clinical manifestations: If the potassium concentration is >8.0 mEq per L or the onset of cardiac dysrhythmias occurs, this indicates that urgent therapy is needed with glucose and bicarbonate while preparing for cation exchange resin or dialysis. Calcium, which usually is recommended in this situation, should be omitted in digitalis intoxications. 5. DC countershock should be used in life-threatening dysrhythmias that fail to respond to dysrhythmic agents. 6. Specific F AB antibody fragments have been used for intoxications with a) life-threatening cardiac dysrhythmias, b) hyperkalemia, and c) dysrhythmias refractory to conventional measures. Smith et al. have reported on the successful use, in both adults and children, of purified F AB fragments of digoxin specific antibodies in 21 patients with either digoxin or digitoxin overdose. 27. 71 Dramatic rapid reversal of cardiac toxicity was noted in most cases with a lack of obvious side effects. Other authors have also reported similar results. 4. 28. 44. 62. 71 7. Dialysis and forced diuresis are ineffective.
CONCLUSIONS This article reviews the electrophysiologic properties, mode of action, toxic dose, pharmacotoxicokinetics, toxic manifestations, management, and appropriate laboratory tests and monitoring parameters for overdose and poisonings by antidysrhythmic agents. We have tried to make reference to these types of poisonings and their management in children, pointing out any differences that might exist compared to the adult population. Most of these poisonings in children are benign and require supportive measures.
REFERENCES 1. Amsdord, M. F.: Electrophysiologic properties of antidysrhythmic drugs as a rational basis for therapy. Med. Clin. North. Am., 60:213-216, 1976. 2. Arison, J. K.: Digitalis intoxication. Clin. Sci., 674:253, 1983. 3. Atkinson, A. J., Krumlovsky, F. A., Huang, C. M., et al.: Hemodialysis for severe procainamide toxicity: Clinical and pharmacokinetic observations. Clin. Pharmacol. Therap., 20:585, 1976. 4. Baud, F., Bismuth, C. H., Ponta!, P. G., et al.: Time course of anti digoxin FAB fragments
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6. 7. 8. 9.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
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and plasma digitoxin concentrations in an acute digitalis intoxication. J. Toxico!. Clin. Toxico!. 19:857-860, 1982-1983. Benowitz, N. L.: Propranolol (Inderal) and beta-blocker toxicity. In Hadded, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Overdose, pp. 846--852. Philadelphia,W. B. Saunders, 1983. Beta blocker pOisoning. Lancet i, 1 :803, 1980. Booker, H. E., and Darcey, B.: Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication. Epilepsia, 14:177, 1973. Candell, J., Valley, V., Soler, M., et al.: Acute intoxication with verapamil. Chest, 75:200-201, 1979. Cohen, M. R., and Levinsky, W. J.: Topical anesthesia and swallowing. J.A.M.A., 236:562, 1976. Connolly, S. J., and Kates, R. E.: Clinical pharmacokinetics of n-acetylprocainamide. Clin. Pharmacokin., 7:206-220, 1982. Crump, B. J., Holt, D. W., and Vale, J. A.: Lack of response to intravenous calcium in severe verapamil poisoning. Lancet, ii:939, 1982. Czyz, J., Borkowska, K., Kuligowska, M., etal.: Quinidine poisoning in children. Pediatr. PoisOning, 49:1381-1386, 1974. DaSilva, D. A., DeMelo, R. A., and Filho, J. P. J.: Verapamil acute self-poisoning. Clin. Toxico!., 14:361-367, 1979. Davis, L. D., and Tente, J. V.: Effects of propranolol on the transmembrane potentials of ventricular muscle and Purkinje fibers of the dog. Circ. Res., 22:661-677, 1968. Del Negro, A. A.: Lidocaine and related compounds. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Overdose, pp. 863-886. Philadelphia, W. B. Saunders, 1983. Delocchi, T., Poilli, F., Testa, et al.: Accidental quinidine poisoning in two children. Pediatrics, 58:288, 1976. El-Sherif, N., and Lazzara, R.: Re-entrant ventricular arrhythmias in late myocardial infarction period. S. Mechanism of action of lidocaine. Circulation, 56:395-402, 1977. Ekins, B. R., and Watanabe, A. S.: Acute digoxin poisonings: Review of therapy. Am. J. Hosp. Pharm., 35:268-277, 1978. Enyeart, J. J., Price, W. A., Hoffman, D. A., et al.: Profound hyperglycemia and metabolic acidosis after verapamil overdose. 2:1228-1231, 1983. French, J. H., Thomas, R. G., Siskind, A. P., et al.: Magnesium therapy in massive digoxin intoxication. Ann. Emerg. Med., 13:562-566, 1984. Frishman, W., Jacob, H., Eisenberg, E., et al.: Clinical pharmacology of the new betaadrenergic drugs. Part 8: Self-poisoning with beta-adrenoceptor blocking agents: Recognition and management. Am. Heart J., 98:798-811, 1978. Fruncillo, R. J., Gibbons, W., and Bowman, S. M.: CNS toxicity after ingestion of topical lidocaine. N. Eng!. J. Med., 306:426-427, 1982. Gauthier, B., Edelmann, C. M., Jr., and Barnett, H. L.: Nephrology and Urology for the Pediatrician, p. 254. Boston, Little, Brown & Co., 1982. Gelband, H., and Rosen, M. R.: Pharmacologic basis for the treatment of cardiac arrhythmias. PediatriCS, 55:59, 1984. Goldfrank, L. R., and Kirstein, R.: Digoxin-The cardiac emergency. In Goldfrank, L. R. (ed.); Toxicologic Emergencies: A Comprehensive Handbook in Problem Solving. New York, Appleton-Century-Crofts, 1982. Goodman, L. S.: Digitalis. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Drug Overdose, pp. 813-829. Philadelphia, W. B. Saunders, 1983. Hansten, V., Jacobsen, D., Knudsen, K., et al.: Acute massive overdose poisoning with digitoxin-report of seven cases and discussion of treatment. Clin. Toxico!., 18:6789, 1981. Harenberg, J., Wahl, P., Steiger, C. H., et al.: Treatment of digitalis intoxication with digoxin-specific FAB antibody fragments. N. Eng!. J Med., 309:245-246, 1983. Hayler, A. M., Holt, D. W., and Volans, G. N.: Fatal overdosage with disopyramide. Lancet, i:968-969, 1978. Hayler, A. M., Holt, D. W., and O'Keefe, B.: Treatment of disopyramide overdosage. Med. J. Aust., 1 :234, 1978.
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31. Heissenbuttel R. H., and Bigger, J. T.: Bretylium tosyll\te: A newly available antiarrhythmic drug for ventricular arrhythmias. Ann. Intern. Med., 91:229-238, 1979. 32. Hong, C. Y., Yang, W. C., and Chiang, B. N.: Importance of membrane stabilizing effect in massive overdose of propranolol: Plasma level study in a fatal case. Human Toxico!., 3:511-517, 1983. 33. Jones, B.: Treatment of beta-blocker poisoning. Lancet, i:1031, 1980. 34. Koch Weser, J.: Bretylium. N. Eng!. J. Med., 300:473-477, 1979. 35. Kulling, P., Eleborg, L., and Persson, H.: Beta-adrenoceptor blocker intoxication: Epidemiological data; prenalteral as an alternative in the treatment of cardiac dysfunction. Human Toxico!., 2:175-181, 1983. 36. Laffey, S. H., and Luzzardi, L. J.: Phenytoin and other convulsants. In Haddad, L. M., and Winchester J. F. (eds.): Clinical Management of Poisoning and Overdose, pp. 557562. Philadelphia, W. B. Saunders, 1983. 37. Lewy, J. E.: Renal failure. Audio Digest., 30(5): Side B, 1984. 38. Lowery, C. M.: Crowth and Development of Children. 7th Edition, Chicago, Year Book Medical, 1978. 39. Lughi, R. J., Helwig, J. Jr., and Conn, H. L., Jr.: Quinidine toxicity and its treatment. Am. Heart J., 65:340-348, 1963. 40. Mitchel, L. B., Schroeder, J. S., and Mason, J. W.: Comparative clinical electrophysiologic effects of diltiazem, verapamil, and nifedipine. Am. J. Cardio!., 49:623-635, 1982. 41. Mitchell, B. C., Clements, J. A., Pottage, A., et al.: Mexiletin disposition: Individual variation in response to urine acidification and alkalinization. Br. J. Clin. Pharml\Co!., 16:281-284, 1983. 42. Mofenson, H. C., Caraccio, T. R., Miller, H., et al.: Lidocaine tOl(icity from topical mucosal application. Clin. Pediatr., 22:190-193, 1983. 43. Morris, D. L., and Coldschlager, N.: Calcium infusion for reversal of adverse effects of intravenous verapami!. J.A.M.A., 249:3212-3213, 1983. 44. Murphy, D. J., Bremer, W. F., and Haber, E.: Massive digoxin overdose treated with FAB: Fragment of digoxin-specific antibodies. Pediatrics, 70:472, 1982. 45. Nappi, J. M., Dhanani, S., Lovejoy, J. R., et al.: Severe hypoglycemia associated with disopyramide. West. J. Med., 138:95-97, 1983. 46. Nayler, W. C.: Calcium antagonists. Med. J. Aust., 2:506-511, 1983. 47. Nybert, L., and Wetrell, C.: Digoxin dosage schedules for neonates and infants based 011 pharmacokinetic considerations. Clin. Pharmacokinet., 3:453, 1978. 48. O'Donohue, W. J., Moss, L. M., and Angelillo, V. A.: Acute methemoglobinemia induced during topical benzocaine and lidocaine. Arch. Intern. Med., 140:1508, 1980. 49. O'Keefe, B., Haylev, A. M., Hold, D. W., et al.: Cardiac consequences and treatment of disopyramide intoxication: Experimental evaluation in dogs. Cardiovasc. Res., 13:630634,1979. 50. Opie, L. H.: Drugs and the heart. IV. Antil\rrhythmic agents. Lancet, i:861-867, 1980. 51. Orr, C. M., Bodansky, H. J., Oymond, D. S., et al.: Fatal verapamil overdose. Lancet, ii(8309):1218-1219, 1982. 52. Poisoning Event Reporting System. Food and Drug Administration, Poisoning Surveillance and Epidemiology Branch, HFN-720. 53. Pond, S., Jacobs, M., Marks, et al.: Treatment of digitalis overdose with oral-activated charcoa!' Lancet, ii:1177, 1982. 54. Reinold, E. W., Reynolds, W. J., Fixler, D. E., et al.: Use of hemodialysis in the treatment of quinidine poisoning. Pediatrics, 598:111, 1973. 55. Richens, A., Dunlop A., Ahmads, et al.: Monitoring serum phenytoin. Lancet, i:699, 1976. 56. Rosen, M. R., Wit, A. L., and Hoffman, B. F.: Electrophysiology and pharmacology of calcium antagonists: 6. Cardiac effects of verapamil. Am. Heart J., 89:665-673, 1975. 57. Rosen, M. R., and Horodof, A. J.: Mechanism of arrhythmias. In Roberts, N. K., and Celband H. (eds.): Cardiac Arrhythmias in Neonates, Infants and Children. p. 111. New York, Appleton-Century-Crofts, 1977. 58. Rumack, B. H. (ed.): Poisindex Management Monograph. Micromedex Inc., 1984. 59. Rumack, B. H., Wolfe, R. R., and Cilfrich, H.: Phenytoin treatment of massive digoxin overdose. Br. Heart J., 36:405-408, 1974. 60. Sakai, R. 1., and Lattin, J. E.: Lidocaine ingestion. Am. J. Dis. Child, 134:325, 1980.
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61. Shub, C., Gari, G. T., Sidell, P. M., et al.: The management of acute quinidine intoxication. Chest, 73:178, 1978. 62. Smith, T. W., Butler, V. P, Haber, E., et al.: Treatment of life-threatening digitalis intoxication with digoxin specific FAB antibody fragments. N. Engl. J. Med., 307:13571362, 1982. 63. Smith, T. W., and Willerson, J. T.: Suicidal and accidental digoxin ingestion. Circulation, 44:29-36, 1971. 64. Staff, A. L., and Wallace, A. G.: The effect of propranolol on membrane conductance in canine cardiac Purkinje fibers. Circulation, 145(Suppl. 3):49-50, 1974. 65. Sunderland, C. 0.: Arrhythmias in children: Which drugs to use when? Drug Therapy (Hosp.): p. 18., 1983. 66. Villalba-Pimentel, L., Epstein, L. M., Sellers, E. M., et al.: Survival after massive procainamide ingestion. Am. J. Cardiol., 32:727-730, 1973. 67. Wasserman, F., Brodsky, L., Dick, M. M., et al.: Successful treatment of quinidine and procainamide intoxication. N. Engl. J. Med., 259:797, 1952. 68. Winek, C. L., Davis, E. R., Callom, W. D., et al.: Quinidine fatality: Case report. Clin. Toxicol., 7:129, 1974. 69. Worthley, L. 1. G.: Treating the adverse effects ofverapamil (Letter). J.A.M.A., 252:1129, 1984. 70. Young, G. P.: Calcium channel blockers in emergency medicine. Ann. Emerg. Med., 13:719, 1984. 71. Zucker, A. R., Lacina, S. J., DasGupta, D. S., et al.: FAB fragments of digoxin-specific antibodies used to reverse ventricular fibrillation induced by digoxin ingestion in a child. Pediatrics, 70:468-471, 1982. Nassau County Medical Center Long Island Regional Poison Control Center 2201 Hempstead Turnpike East Meadow, New York 11554
0031-3955 $0.00
+ .20
Poisoning By Antidysrhythmic Drugs Howard C. Mofenson, M.D.,* Thomas R. Caraccio, Pharm.D., R.Ph.,t and Jay Schauben, Pharm.D., R.Ph.t
This article encompasses those antidysrhythmic agents that exert their primary therapeutic effect on the cardiovascular system and might be ingested accidentally by young children or taken orally in attempted suicide by older children and adolescents. Most of these agents have been studied in patients with cardiac disorders, which makes it difficult to anticipate the effects of overdose on the healthy hearts of children and teenagers. Although many dysrhythmias have serious consequences for children and adults with significant cardiac and metabolic disorders, they appear to be relatively benign in healthy pediatric patients. The incidence of this type of ingestion is unknown, but the scenario is apparent. The source of the accidental ingestion usually occurs during a visit to the home of a grandparent, who is unaccustomed to having exploring children around. Visits to relatives who have had myocardial infarctions by small children are particularly hazardous. Table 1 contains a breakdown of the number and types of pediatric exposures of digitalis preparations and antidysrhythmic agents reported to the FDA Poisoning Surveillance and Epidemiology Branch from 1978 to 1982. 1,52 All of the agents used to treat rhythm disorders have the potential to cause major adverse effects. In some instances, the drugs are more dangerous than the dysrhythmia. It has been hypothesized that by slowing conduction, antidysrhythmic agents may enhance susceptibility to reentry and precipitate ventricular tachydysrhythmias. 24, 57 It is assumed in each management that the vital functions are estab*Professor of Clinical Pediatrics, State University of New York at Stony Brook, Director, Nassau County Medical Center's Long Island Regional Poison Control Center, East Meadow, New York tClinical Coordinator, Nassau County Medical Center's Long Island Regional Poison Control Center, East Meadow, New York; Preceptor, St. John's University College of Pharmacy and Allied Health Sciences, Jamaica, New York :j:Supervisor, Emergency Pharmacy Services, University Hospital of Jacksonville; Clinical Assistant Professor of Pharmacy, University of Florida College of Pharmacy, Gainesville, Florida
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Table 1. Number and Types of Exposures of Digitalis Preparations and Antidysrhythmic Agents Reported to FDA from 1978-1982
Digitalis < 5 years All ages Group I Agents < 5 years All ages Group II Agents < 5 years All ages Group III Agents < 5 years All ages
TOTAL CALLS
TOXIC CASES*
476
108 196
716 97
214
160 47
2 2
559 968
39 174
*Implies symptomatic toxicity. (From Poisoning event reporting system. Food and Drug Administration, Poisoning Surveillance and Epidemiology Branch, HFN-720, with permission.)
lished and supported as first priority. Gastrointestinal (GI) decontamination may be implemented in ingested overdoses after the patient is stabilized. The article detailing GI decontamination (Rogers and Matyunas, April 1986) will discuss the technique, although statements about GI decontamination of special interest will be mentioned.
CLASSIFICATION OF ANTIDYSRHYTHMIC DRUGS Antidysrhythmic agents act on the cardiac conduction tissues by: 1) affecting the properties of the membrane so that ionic exchanges, occurring during the transmission of the action potential, are altered, with automaticity or excitability being either increased or decreased; 2) interfere with the responsiveness of specialized tissues so that conduction of the impulse is altered resulting in circuit and/or reentry rhythms; 3) altering the duration of the action potential and refractoriness of the tissue, interfering with or causing cessation of the mechanism of the abnormal rhythm. Ideally, the classification should be linked to the key electrophysiological abnormalities that underlie the various dysrhythmias. Current knowledge does not permit classification on this basis, however. As a framework for toxicologic discussion, we have chosen the classification that defines five different groups (Table 2). 1.50 Group I Group 1 agents are local anesthetics that appear to act by depressing sodium conduction. They slow the action potential upstroke in phase 0, which prolongs the conduction velocity. Thus they cause a prolongation of the action potential duration and refractory period, as well as decreasing automaticity by decreasing the slope of phase 4 depolarization. 1 These
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Table 2. Classification of Antiarrhythmic Drugs GROVP
AGEt-.'T
Quinidine Procainamide Disopyramide II
Lidocaine Phenytoin Mexiletine Tocainide
III
Propranolol Metoprolol
IV
Bretylium
V
Verapamil Nifedipine Diltiazem
(From Amsdorf, M. F.: Electrophysiologic properties of antidysrhythmic drugs as a rational basis for therapy. Med. Clin. North Am., 60:213-216, 1976, with permission.)
agents are most useful for treating supraventricular and ventricular dysrhythmias. In therapeutic doses, these drugs tend to prolong the PR interval, QRS duration, H-V interval, and Q-T interval. Complete heart block and suppression of lower pacemakers may result in asystole. The anticholinergic properties of these agents may counter the direct action and accelerate AV node conduction. Table 3 contains comparative data on the pharmacotoxicology. Major Adverse or Toxic Manifestations of Group I Antidysrhythmic Agents. All of these agents may cause depression of myocardial contractility, dysrhythmias, conduction defects, hypotension, and syncope due to vasodilation. Some hypotensive episodes are not accompanied by ECG evidence of toxicity. 10. 12. 16. 39. 61. 66. 6S Most of the reported cardiac manifestations in infants are similar to those reported in adults, with the exception of atrial tachycardia. Some authors have failed to report this type of dysrhythmia. 16 ECG changes may include widening QRS, increased Q-T intervals, ectopic activity, and varying degrees of heart block. The ECG takes 36 to 72 hours to revert to normal. Disopyramide may cause greater anticholinergic toxicity than the others, and cardiovascular collapse can occur without ECG warning, followed by dysrhythmias, apnea, and death.30. 49 Noncardiac toxicity also is seen. Respiratory depression and arrest have been reported following both quinidine and disopyramide. 29, 61 Convulsions and coma have been reported following quinidine overdose,39. 61 whereas CNS depression and obtundation may be seen after procainamide ingestion,58 Both quinidine and procainamide may produce nausea and vomiting,58 whereas disopyramide may produce dry mouth, decreased bowel sounds, and distention as a result of its anticholinergic activity, Both quinidine 61 and disopyramide 45 have produced systemic acidosis and hypoglycemia, Hemolysis has been reported in glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients receiving quinidine, 58 and renal failure has been observed in association with procainamide ingestion. 58
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Table 3. Group I Agents: Phannacotoxicokinetic Data AGENTS
Available Forms
Trade Name Routes Available Bioavailability Peak Levels
QUINIDINE
Sulfate, gluconate lactate, hydrochloride, polygalactoronate Various, Duraquin, QUinaglute PO and 1M/IV 70-90 per cent 1-4 hrs
Duration of Action
Sulfate = 2-3 hrs Gluconate = 3-6 hrs sus. release = 8 hrs Metabolism (Primary) Liver 2-3 L per kg Volume of Distribution Renal Excretion per 20-50 per cent cent Unchanged Half Life Tberap. =3-16 hrs (AV=7-8 hrs) Overdose = 10 hrs Tberapeutic Serum 2-7 fLg per ml Concentrations Toxic Dose Toxic Serum Levels
1 gm in child 2-8 gm in adult >7 fLg per ml
PROCAINAMIDE
DISOPYRAMIDE
Hydrochloride (PA)
Phosphate
Pronestyl, Procan Procan-SR Oral and 1M or IV 75-95 per cent PA= 1-2 hrs; Nacetylprocainamide (NAPA) = 1-8 hrs 3-6 hrs
Norpace Oral 50-80 per cent 1-1.5 hrs
6-12 hrs
Liver 2 L per kg NAPA
Liver 0.8 L per kg
PA = 40-60 per cent NAPA = 80 per cent 3-6 hrs
50 per cent
PA=4-15 fLg per ml NAPA = 15-24 fLg per ml 7 gm in adult
2-4 fLg per ml
4-8 hrs
Varies
PA=>15 fLg per ml 7 fLg per ml NAPA = >16 fLg per ml Dosage Range-Child PO Gluconate 2-10 PO: 50 mg per kg per mg per kg q3-6 hrs day Sulfanate 3-6 mg/kg IV: 100 mg over q3-6hrs. 1M or IV 5 min. to max. = 1 5-8 mg/kg gm Adult Dosage PO 200-600 mg q 6- PO (loading) 1 gm over 100-400 mg q6hr 8 hrs 2 hrs maintenance I9 g per day; IV (loading) 1-2.5 gm at .;;;20 mg per kg, maintenance 20-80 fLg per kg per min Activity Slows conduction Similar to quinidine; Similar to quinidine; velocity. Prolongs may lower blood has negative effective refractory pressure by inotropic action period, decreases peripheral ganglionic and greater automaticity, blockade. anticholinergic anticholinergic properties than properties. others in class. PA = Procainamide; NAPA = N-Acetylprocainamide.
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Chronic ingestion of quinidine is associated with the development of "cinchonism," which is characterized by tinnitus, deafness, blurred vision, headache, diplopia, photophobia, confusion, delirium, psychosis, nausea, vomiting, and diarrhea. The skin may be warm and flushed. 39 Procainamide has produced a systemic lupus erythematosislike reaction. Treatment of intoxication due to agents in this group is largely symptomatic. Both mild alkalemia and hypokalemia have been found to be somewhat protective. Hypotension should be treated with intravenous fluids. When they occur, arrhythmias should be treated with lidocaine or phenytoin, which will decrease the action potential duration and refractory period; use of other type I agents is contraindicated. Forced diuresis has been suggested for quinidine intoxication; however, because this involves maintaining the urine pH at 4.5 to 5.5, this technique has not been consistently effective. The overall increase in excretion is not significant, and this is no longer recommended.
Group II Agents
Lidocaine. Lidocaine hydrochloride is an aminoacyl amide that, although used as a parenteral cardiac antiarrhythmic agent, is also widely available for both topical and local injection anesthetic. A variety of topical preparations exist, including a popular 2 per cent solution (Xylocaine, viscous). Serious adverse systemic reactions to lidocaine have been reported after ingestion of the topical dosage form. 9, 22, 50 We have encountered an infant who experienced seizures after having lidocaine 2 per cent solution applied topically on the gums for teething,42 Pediatricians should be aware that when lidocaine is applied to the mucous membranes, a concentration similar to that of intravenous administration may occur. Table 4 contains pharmacotoxicokinetic data on lidocaine. Dose-related neurologic effects include dizziness, drowsiness, speech disturbances, perioral numbness, muscle twitching, confusion, vertigo, or tinnitus. These occur at plasma concentrations greater than 5 f,Lg per ml. Serious toxicities occurring at concentrations over 9 f,Lg per ml include psychosis, seizures, and respiratory depression, Severe bradycardia, sinus arrest, and arteriovenous (AV) block may also be associated with toxic blood levels; concomitant therapy with other antidysrythmic agents, or preexisting heart block or myocardial infarction. Methemoglobinemia also has been reported. 48 Therapy for lidocaine overdose should focus on the treatment of seizures and methemoglobinemia. Seizures may be relatively refractory to therapy, but phenytoin should be administered. Because both lidocaine and its metabolite, monoethylglycine xylidide (MEGX), may cause convulsions, the potential for seizures may remain even after the lidocaine serum concentration falls below 5 f,Lg per ml. Methylene blue and oxygen should be administered if the methemoglobin level is ~30 per cent and is accompanied by dyspnea, metabolic acidosis or altered mental status, Hemodialysis is ineffective. Phenytoin. Phenytoin has been found to be useful in the management of dysrhythmias, especially those resulting from intoxication with digitalis preparations, tricyclic antidepressants, and other drugs. 35 Phenytoin also is acknowledged as a valuable antiepileptic agent, particularly for grand mal
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Table 4. Pharmacotoxicokinetic Data: Croup II Agents AGENT
LIDOCAINE
PHENYTOIN
Trade Name
Xylocaine
Dilantin
Routes Available
Bioavailable Absorption (Oral) Peak Blood Levels Duration Metabolism Per cent Protein Bound Volume of Distribution Renal Excretion Per cent Unchange Half-life
Therapeutic Serum Level Toxic Serum Levels Dosage Range
Adult Dosage
Activity/Use
Topical PO IV ~35 per cent PO ~1 hr IV <1 min 10-20 min Liver to two active metabolites Not known 1.6 L per kg 30
PO: tablets and liqUids
90 per cent PO 6-12 hrs IV 1 hr Variably according to levels Liver 95 per cent 87-93 per cent 0.6-1.0 L per kg
5
2 hrs
20-30 hrs Varies in toxic doses; zero order kinetics 1.5-6 ,...g per ml 10-20 ,...g per ml >6,...g per ml >20,...g per ml IV loading 0.5-1.5 mg per PO 5-7 mg per kg per day in 1-2 doses; PO loading kg qlO min up to 300 mg IV (maintenance) 20-50 ,...g 500-600 mg followed in 24 hr by 200 mg per per kg per min, topical 4.5 mg per kg per dose, daily IV maximum 300 mg IV loading 1-1. 5 mg per PO 4-6 mg per kg per day; kg q5-1O min up to PO loading dose up to 1 300 mg IV (maintenance) gm in divided doses 400 2-4 mg per min. Topical mg, 300 mg, 300 mg same as child over 4 hr followed by maintenance dose of 300-400 mg daily IV loading dose = 1 gm at ~50 mg per min Local anesthetic amide Organic acid inhibits spread of ectopic activity type, most antidysrhythmic activity in brain and heart. due to blockade offast Useful for ventricular dysrhythmias; used sodium channel in Purkinje fibers primarily as anticonvulsant
seizures. It has little sedative effect at therapeutic levels. Although it is widely prescribed, fewer than ten deaths have been reported from overdose. 36 Deaths usually have been the result of idiosyncratic reactions or rapid intravenous injection. There are few accidental childhood poisonings reported, and they are generally mild intoxications (see Table 1). Table 4 contains pharmacotoxicokinetic data on phenytoin. 7, 36, 55 Adverse reactions to phenytoin may affect a large number of body systems. These include 1. Neurologic: Nystagmus is associated with serum phenytoin concentrations greater than 20 f,Lg per ml, ataxia with concentrations within the range of 30 to 40
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729
ILg per ml, and coma and seizures occur at concentrations greater than 40 ILg per ml. 2. Cardiac: Toxicity is unlikely following oral overdose; however, rapid IV administration may result in dysrhythmias and asystole. 3. Gastrointestinal: Nausea and vomiting may occur. 4. Metabolic: Hyperglycemia may occur. S. Hypersensitivity: Hypersensitivity reactions are manifested by skin rashes and fever. 6. Dermatitis, hepatitis, gingival hyperplasia, lymphoid hyperplasia, and hematologic abnormalities are unlikely following acute overdose. 7. A few patients have a hereditary defect in parahydroxylation and may develop toxicity on therapeutic doses. 8. Fetal hydantoin embryopathy syndrome and coagulopathies have been reported in neonates.
Treatment of phenytoin overdose should focus on symptomatic and supportive care. 7 • 36. 55 Diuresis, charcoal hemoperfusion, and hemodialysis are generally ineffective. Exchange transfusion remains controversial. Group ill Agents Beta-adrenergic blocking agents are widely used in medicine in the treatment of hypertension, dysrhythmias, angina pectoris, open angle glaucoma, migraine, and as prophylaxis against sudden death after myocardial infarction. 5 In addition to beta-adrenergic blockade, group III drugs share many group p4 and group 1164 effects. Table 5 shows the beta blockers presently available in the United States and the pharmacologic and toxicokinetic data of these agents. Propranolol, the prototype for this group, is metabolized primarily in the liver to 4-hydroxypropanolol, an active metabolite. Differences in pharmacologic activity, such as cardioselectivity, membrane-stabilizing activity, lipid solubility, and intrinsic sympathomimetic activity within this group influence their clinical toxicity. The more lipid soluble the drug, the greater its potential to cause serious central nervous system toxicity. 36 The actions of beta blockers can be understood best by considering the distribution and function of beta-adrenergic receptors in the body. Receptors have been classified as beta-lor beta-2 on the basis of the relatively selective effects of particular agonists and antagonists for groups of organ systems. Cardioselectivity is a dose-related phenomenon, and the effect on beta-l receptors becomes less important with increasing plasma concentrations. Negative inotropic and chronotropic effects result in profound bradycardia and hypotension. Atenolo! and metoprolol may cause less pronounced bradycardia and hypotension. Oxyprenolol and pindolol with partial beta-agonist activity may cause tachycardia and hypertension. Prolongation and alterations of the QRS complex, T waves and ST segment may occur in addition to dysrhythmia. These agents may precipitate congestive heart failure. CNS effects of beta-receptor blocking agents may include hallucinations, delirium, coma, and seizures. The degree of membrane stabilization and lipid solubility will determine the potential to cause serious central nervous system manifestations. Metoprolol and oxyprenolol are moderately
730
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Table 5. Characteristics of Currently Available Beta Blockers
DRUG
Atcnolol (Tenormin) Dose: 50--200 mg MDD=200 mg Metoprolol (Lopressor) Dose: 50--400 mg MDD=450 mg Nadolol (Corgard) Dose: 40--320 mg MDD=320 mg Oxyprenolol:j: (Trasicor) Pindolol:l: (Visken) Dose: 20-60 mg MDD=60 mg Propranolol * (Inderal) Dose: 40--160 mg MDD=480 mg Timololt (Blocadren) Dose: 20 mg MDD=60 mg Ophthalmologic 0.25-5 per cent (Timoptic)
SULl'BILITY
RELATIVE
AND
POTESCY
PROTEIN BOUND
ABSORPTIO)"l;
ME~1BRANE
(PROPRA-
PLASMA
ELIMINA-
(PER
(PER CENT)
STABILIZER
NOLOL)
Tl/2 hrs
TION
CENT)
no
1.0
6-9
Water 4662 per
95 per
3-10
BETA-
VD UKG SPECIFICITY
0.7
renal
cent
Fat over 95 per cent
No
Water 1525 per
±
1.0
3-4
Hepatic
10
5.6
+ Low dose
1.0
17-23 70 per
25
2.1
Hepatic
80
1.5
cent
renal
cent
Fat 70--95 per cent Fat over 90 per cent
No
1.0
1.5-3
No
6.0
3-4
Hepatic (40 per cent renal)
57
2.0
Fat 100 per cent
++
1.0
2-3
Hepatic «1 per cent renal)
90--95
3.6
Fat over 90
No
6.0
3
<10
1.5
per cent
+ Low dose
cent
Hepatic 20 per cent renal
*Substantial first pass. tMitochondrial calcium protection during ischemia. :j:Partial agonist (intrinsic sympathetic activity). MDD = maximum daily dose. Toxic dose varies considerably. Toxicokinetics: Peak action 1 to 2 hours orally and lasts 24 to 48 hours. In drugs with long half-lives, the duration of toxicity may be prolonged.
fat soluble, whereas propranolol is highly fat soluble and may induce more eNS effects. Other manifestations of overdose with beta-blocking agents include hypoglycemia and bronchospasm. Hypoglycemia may occur in children and in patients with diabetes. These agents also may block the catecholamineinduced "warning signs" of hypoglycemia. Bronchospasm may occur in patients with or predisposed to asthma. This is less likely to occur with agents that are relatively more beta-l selective such as atenolol and metoprolol. Management of beta-blocking agent intoxication should follow the same principles outlined for other types of nonvolatile and noncaustic compounds. Because the heart appears to be a critical target organ for this type of agent,
POISONING BY ANTIDYSRHYTHMIC DRUGS
731
specific therapy should be directed toward re-establishment of hemodynamic homeostasis. Bradycardia may be one of the earliest manifestations. If the patient is hemodynamically stable and asymptomatic, no therapy is required. If the patient shows associated hypotension or AV block, atropine, isoproterenol, glucagon, or a pacemaker may be required. Ventricular tachycardia or serious premature ventricular contractions (multifocal, greater than 5 per min, R on T phenomena) may be treated with lidocaine, phenytoin, overdrive pacing, or DC cardioversion. For myocardial depression and hypotension correction of dysrhythmias, Trendelenburg positioning and fluid support may be required. Invasive hemodynamic monitoring should be implemented. Glucagon may be the treatment of choice for patients with low cardiac output and normal pulmonary capillary wedge pressure. It works by means of the adenyl cyclase mechanism, which apparently is unaffected by beta blockers. It usually is given as a bolus and may be continued as an infusion. The dose of glucagon is 50 to 150 fA-g per kg over 1 minute intravenously followed by a continuous infusion of 1-5 mg per hr in 5 per cent dextrose, which then is tapered over a period of 5 to 12 hours. (Do not dissolve the lyophilized glucagon in the solvent packaged with it, which contains phenol, when preparing an intravenous infusion because of possible phenol toxicity. Use 5 per cent dextrose as the diluent.) The effects of a single dose may be observed in 5 to 10 minutes with a duration of 15 to 30 minutes. In addition to the recommendations above, quinidine, procainamide, and disopyramide (Norpace) should be avoided because of their negative inotropic effects. Charcoal hemoperfusion may be useful for water-soluble drugs with low volumes of distribution and low protein-binding (nadolol and atenolol). Hemodialysis may be used if there is evidence of renal failure. Group IV Bretylium is the only agent in this fourth group. It has not been approved for use in children under 12 years and is available for intravenous use only, so that toxicity in this age group should be extremely rare. Bretylium's actions are believed to be related to an initial catecholamine release and subsequent catecholamine depletion. It is postulated that this direct effect is independent of the adrenergic nervous system. 31 Administration of this agent causes an initial elevation of blood pressure, heart rate, and myocardial contractility owing to catecholamine release. This apparently is followed by hypotension resulting from neural blockade. The drug appears most effective in the control of severe ventricular tachyarrhythmias resistant to other antidysrhythmics. Hypotension is common, and nausea and vomiting may occur after rapid IV administration. 34 This drug is a quaternary ammonium compound. The onset of action may be delayed 20 to 60 minutes after IV administration, and the duration of action is usually 6 to 12 hours after a single dose. Bretylium is eliminated by the kidneys with 70 to 85 per cent excreted in urine unchanged. The volume of distribution is 8.2 L per kg, and it is apparently not bound to plasma protein. The half-life is approximately 6 to 7 hours in adults.
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Table 6. Group V: Pharmacotoxicokinetics Data of Calcium Channel Blockers PROPERTY
I\IFEDIPII\E
VERAPAMIL
DILTIAZEM
Trade Name
Procardia
Calan, [soptin
Cardizem
Onset of Action
Peak Effect Half-life Route of Elimination Toxic Level
PO <20 min sublingual <3 min IV <1 min Oral 1-2 hrs 2 112-5 hrs Liver/kidney > 100 ng per ml
Oral <1 hr
Oral <15 min
IV <2" min 5 hrs 2-7 hrs Liver/kidney >300 ng per ml
30 mins 2-6 hrs Liver/kidney >200 ng per ml
(Modified from Mitchell, L. B., Schroeder, J. S., and Mason, J. W.: Comparative clinical electrophysiologic effects of diltiazem, verapamil, and nifedipine, and from Rosen, M. R., Wit, A. L., and Hoffman, B. F.: Electrophysiology and pharmacology of calcium antagonists: 6. Cardiac effects of verapamil. Am. Heart J., 89:665-673, 1975, with permission.)
Group V This fifth group acts by blocking the slow inward channel that allows influx of calcium ions. These drugs have been shown to be useful for the control of supraventricular and ventricular dysrhythmias. They also have been used to treat coronary artery spasm, heart failure, hypertension, and angina pectoris. Table 6 lists the calcium channel blockers available in the United States and a comparison of their pharmacotoxicokinetic data. Inhibition of the slow calcium channel current will result in 1. Myocardium depression-negative inotropic response. The order of potency of effect on cardiac muscle is nifedipine> verapamil> diltiazem. 2. Inhibition of nodal pacemaker tissue-bradycardia. The order of potency of effect on nodal conduction is verapamil> diltiazem> > nifedipine. 3. Inhibition of vasculature tone-peripheral vasodilation gives hypotension and coronary vasodilation produces oxygen sparing by decreasing oxygen utilization and increasing oxygen supply. The order of potency of effect on vasculature is nifedipine> verapamil> diltiazem. 4. Central nervous system depression 5. Nausea and vomiting 6. Hypoglycemia and mild acidosis
The bradycardia and hypotension occur within 1 to 5 hours of ingestion. The specific antagonist for the toxic manifestations of overdose with calcium channel blockers is calcium. Controversy exists regarding which calcium preparation to use. Some authors caution against the use of calcium chloride because of its potential vasodilating effect and suggest that the gluconate form be used. 43 Others suggest that the chloride preparation is more effective because of its predictable increase in extracellular ionized calcium. 2. 19. 70 Calcium chloride 10 per cent (27.9 mg or 1.36 mEq of calcium per ml) should be given under ECG monitoring to any patient not responding to supportive therapy alone. Calcium is given intravenously in doses of 10 to 20 mg per kg per dose (0.10-0.20 ml per kg per dose) in pediatric patients and up to 1 gm (10 ml per dose) in adults. 69 As an alternative, calcium gluconate 10 per cent (9 mg or 0.45 mEq of calcium per ml) can be used.
POISONING BY ANTIDYSRHYTHMIC DRUGS
733
It can be given intravenously in doses of 2.7 mg per kg per dose (0.3 ml per kg per dose) in pediatric patients up to 1 gm (10 ml per dose) in adults over 5 to 10 minutes. Dopamine can be used if necessary (2 to 10 f.Lg per kg per min, IV infusion). Doses above 10 f.Lg per kg per min may cause systemic and renal vasoconstriction. Symptomatic bradycardia, heart block, and asystole have not responded consistently to calcium and atropine. The dose of atropine in children is 0.01 to 0.03 mg per kg (minimum 0.15 mg) and adults 0.5 to 1.0 mg. Isoproterenol can be used if necessary; a pacemaker may be needed as well. Severe rapid ventricular tachycardia in patients with Wolff-Parkinson-White's syndrome needs cardioversion. 11 Digitalis and Cardiac Glycosides. Digitalis preparations are among the top ten drugs prescribed in the United States. 26 Many digitalis preparations are available. We will discuss digoxin and digitoxin as prototypes of digitalis intoxication. Table 7 contains a summary of the pharmacotoxicokinetic data of these two agents. Digitalis glycosides exert positive inotropic effects by increasing availability of calcium ions to myocardial contractile elements, thereby increasing cardiac output in heart failure. The antidysrhythmic actions of digitalis glycosides are primarily due to an increase in AV nodal refractory period caused by increased vagal tone and sympathetic withdrawal. Additionally, digitalis exerts a direct vasoconstrictor effect on arterial and venous smooth muscle. In most cases, pediatric ingestions involving digitalis glycosides require only observation and general supportive care for the gastrointestinal symptoms and mild conduction and neurologic disturbances; nevertheless, one should remember that a significant ingestion may be lethal. 25, 47 Although there is reasonably good correlation between plasma digoxin concentration and manifestations of clinical toxicity in adults, this relationship has not been clearly established in children. It was thought for years that higher pllsma levels were needed in children for cardiac glycosides to be effective, Hut this has been refuted. 47 The clinical manifestations after an acute ingestion may differ from those of chronic toxicity. Acute ingestions in previously healthy adults and children do not differ appreciably. The manifestations of acute intoxication with digitalis include effects on a variety of organ systems: 1. Gastrointestinal: These are the first manifestations; persistent vomiting is a common one. IS, 53, 59, 65 2. Cardiac: Virtually any dysrhythmia may be produced, however, supraventricular tachyarrhythmias are characteristic of acute ingestions. 18 Bradycardia is also a common occurrence. A consistent lack of ventricular, dysrhythmia has been noted in acute versus chronic intoxications, especially in patients without pre-existing heart disease. Ventricular dysrhythmias are associated with a higher mortality. IS, 44, 53,59,65 The appearance of atrial tachycardia and AV block is considered fairly specific for digitalis toxicity. 3. Electrolyte Disturbances: Hypokalemia appears to be a consistent finding with chronic toxicity, 18 whereas acute ingestions are more likely to produce hyperkalemia. Hyperkalemia is an ominous sign in acute overdoses. 4. Neurologic: Blurred and altered color vision (usually green or yellow vision), headache, fatigue, depression, confusion, hallucinations and delirium have been reported to persist even after resolution of the cardiac toxicity. These manifestations have not been reported to be a consistent finding with acute ingestions. 59
734
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Table 7. Digitalis Preparations NAME
DIGOXIN
DIGOTOXIN
Trade Name
Lanoxin
Crystodigin
GI Absorption
Onset of Action (PO) Onset of Action (IV) Peak Effect Half-life Protein Binding Route(s) of Elimination Therapeutic Serum Concentration Toxic Serum Concentration Enterohepatic Recirculation Toxic Dose Dosage Range Children
Adult
55-75 per cent 1.5-6 hrs 15-30 mins 4-6 hrs 31-40 hrs 7-8 L per kg Renal 75 per cent Some GI excretion 1-2,5 >2.5 Small Acute ";2-3 mg Oral Initial Loading Dose Premature: 20-30 fLg per kg Full-term: 25-35 fLg per kg 1-24 mos: 35-60 fLg per kg 2-5 yrs: 30-40 fLg per kg 5-10 yrs: 20-35 fLg per kg > 10 yrs: 10-15 fLg per kg IV Loading Dose 80% of PO total daily dose (TDD) 112 TDD first, then 114 TDD q6-8 hrs for two doses Oral/IV Maintenance Dose Premature: 20-30 per cent POTDD All others: 25-35 per cent POTDD IV Laading Dose 8-10 fLg per kg For CHF; 13-15 fLg per kg for atrial fibrillation over 12-24 hrs Maintenance: 0.125-0.5 mg per day
90-100 per cent 3-6 hrs 25-120 mins 6-12 hrs 4-6 days 0.6 L per kg Liver 80 per cent
Renal excretion of metabolites 15-30 >3.5 Large
Oral/IV Loading Dose 25-35 fLg/kg over 12-24 hrs Maintenance Daily 10-25 per cent total loading dose
POIIV Laading Dose 0,8-1.4 mg over 12-24 hr or 10-15 fLg per kg Maintenance: 10 per cent of total loading dose
Management 1. Gastrointestinal decontamination can be effective up to 12 hours after ingestion. If persistent vomiting occurs, emesis or lavage may not be necessary. It is important to stabilize the cardiac rhythm before inducing emesis or lavage. If bradyc'ardia or block occurs, consider atropine 0.01 to 0.03 mg per kg (minimum 0.15 mg per dose) before lavage. Repeated doses of activated charcoal may interrupt enterohepatic recirculation. 53 Digitoxin elimination may also be enhanced by the administration of cholestyramine 4 gm PO every 6 hours. 25, 26 2. Treat ventricular premature contractions, including bigeminy, trigeminy, quadrigeminy, ventricular tachycardia, and atrial tachycardia with block, with phenytoin. The loading dose for children and adults is 15 mg per kg up to 1 gm
POISONING BY ANTIDYSRHYTHMIC DRUGS
735
IV, not to exceed 0.5 mg per kg per min. Following the loading dose, the maintenance dose for children is 2 mg per kg every 8 hours as needed; adults 300 mg daily. If this fails, consider a transvenous pacemaker or DC cardioversion. Monitor phenytoin concentrations. Lidocaine also may be administered for ventricular dysrhythmias. Loading dose (adult and children): administer 1 mg per kg per dose IV.2. 20. 23. 27. 44 A repeat dose of 0.5 to 1 mg per kg may be administered 20 minutes later if needed. Following the loading dose, begin a maintenance infusion of 10 to 40 flog per kg per min. If this fails, consider cardioversion. Recent reports indicate that magnesium sulfate has been effective in treating ventricular fibrillation that failed to respond to lidocaine or phenytoin. It may be administered to adults in doses of 2 to 3 gm in 1 minute IV, followed by 2 gm per hr for 4 to 5 hours?O 3. Treat bradycardia and second and third AV block with atropine. Doses may be repeated as needed. External pacing also may be required. 4. Treat hyperkalemia on the basis of potassium levels, ECG results, and clinical manifestations: If the potassium concentration is >8.0 mEq per L or the onset of cardiac dysrhythmias occurs, this indicates that urgent therapy is needed with glucose and bicarbonate while preparing for cation exchange resin or dialysis. Calcium, which usually is recommended in this situation, should be omitted in digitalis intoxications. 5. DC countershock should be used in life-threatening dysrhythmias that fail to respond to dysrhythmic agents. 6. Specific F AB antibody fragments have been used for intoxications with a) life-threatening cardiac dysrhythmias, b) hyperkalemia, and c) dysrhythmias refractory to conventional measures. Smith et al. have reported on the successful use, in both adults and children, of purified F AB fragments of digoxin specific antibodies in 21 patients with either digoxin or digitoxin overdose. 27. 71 Dramatic rapid reversal of cardiac toxicity was noted in most cases with a lack of obvious side effects. Other authors have also reported similar results. 4. 28. 44. 62. 71 7. Dialysis and forced diuresis are ineffective.
CONCLUSIONS This article reviews the electrophysiologic properties, mode of action, toxic dose, pharmacotoxicokinetics, toxic manifestations, management, and appropriate laboratory tests and monitoring parameters for overdose and poisonings by antidysrhythmic agents. We have tried to make reference to these types of poisonings and their management in children, pointing out any differences that might exist compared to the adult population. Most of these poisonings in children are benign and require supportive measures.
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736
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and plasma digitoxin concentrations in an acute digitalis intoxication. J. Toxico!. Clin. Toxico!. 19:857-860, 1982-1983. Benowitz, N. L.: Propranolol (Inderal) and beta-blocker toxicity. In Hadded, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Overdose, pp. 846--852. Philadelphia,W. B. Saunders, 1983. Beta blocker pOisoning. Lancet i, 1 :803, 1980. Booker, H. E., and Darcey, B.: Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication. Epilepsia, 14:177, 1973. Candell, J., Valley, V., Soler, M., et al.: Acute intoxication with verapamil. Chest, 75:200-201, 1979. Cohen, M. R., and Levinsky, W. J.: Topical anesthesia and swallowing. J.A.M.A., 236:562, 1976. Connolly, S. J., and Kates, R. E.: Clinical pharmacokinetics of n-acetylprocainamide. Clin. Pharmacokin., 7:206-220, 1982. Crump, B. J., Holt, D. W., and Vale, J. A.: Lack of response to intravenous calcium in severe verapamil poisoning. Lancet, ii:939, 1982. Czyz, J., Borkowska, K., Kuligowska, M., etal.: Quinidine poisoning in children. Pediatr. PoisOning, 49:1381-1386, 1974. DaSilva, D. A., DeMelo, R. A., and Filho, J. P. J.: Verapamil acute self-poisoning. Clin. Toxico!., 14:361-367, 1979. Davis, L. D., and Tente, J. V.: Effects of propranolol on the transmembrane potentials of ventricular muscle and Purkinje fibers of the dog. Circ. Res., 22:661-677, 1968. Del Negro, A. A.: Lidocaine and related compounds. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Overdose, pp. 863-886. Philadelphia, W. B. Saunders, 1983. Delocchi, T., Poilli, F., Testa, et al.: Accidental quinidine poisoning in two children. Pediatrics, 58:288, 1976. El-Sherif, N., and Lazzara, R.: Re-entrant ventricular arrhythmias in late myocardial infarction period. S. Mechanism of action of lidocaine. Circulation, 56:395-402, 1977. Ekins, B. R., and Watanabe, A. S.: Acute digoxin poisonings: Review of therapy. Am. J. Hosp. Pharm., 35:268-277, 1978. Enyeart, J. J., Price, W. A., Hoffman, D. A., et al.: Profound hyperglycemia and metabolic acidosis after verapamil overdose. 2:1228-1231, 1983. French, J. H., Thomas, R. G., Siskind, A. P., et al.: Magnesium therapy in massive digoxin intoxication. Ann. Emerg. Med., 13:562-566, 1984. Frishman, W., Jacob, H., Eisenberg, E., et al.: Clinical pharmacology of the new betaadrenergic drugs. Part 8: Self-poisoning with beta-adrenoceptor blocking agents: Recognition and management. Am. Heart J., 98:798-811, 1978. Fruncillo, R. J., Gibbons, W., and Bowman, S. M.: CNS toxicity after ingestion of topical lidocaine. N. Eng!. J. Med., 306:426-427, 1982. Gauthier, B., Edelmann, C. M., Jr., and Barnett, H. L.: Nephrology and Urology for the Pediatrician, p. 254. Boston, Little, Brown & Co., 1982. Gelband, H., and Rosen, M. R.: Pharmacologic basis for the treatment of cardiac arrhythmias. PediatriCS, 55:59, 1984. Goldfrank, L. R., and Kirstein, R.: Digoxin-The cardiac emergency. In Goldfrank, L. R. (ed.); Toxicologic Emergencies: A Comprehensive Handbook in Problem Solving. New York, Appleton-Century-Crofts, 1982. Goodman, L. S.: Digitalis. In Haddad, L. M., and Winchester, J. F. (eds.): Clinical Management of Poisoning and Drug Overdose, pp. 813-829. Philadelphia, W. B. Saunders, 1983. Hansten, V., Jacobsen, D., Knudsen, K., et al.: Acute massive overdose poisoning with digitoxin-report of seven cases and discussion of treatment. Clin. Toxico!., 18:6789, 1981. Harenberg, J., Wahl, P., Steiger, C. H., et al.: Treatment of digitalis intoxication with digoxin-specific FAB antibody fragments. N. Eng!. J Med., 309:245-246, 1983. Hayler, A. M., Holt, D. W., and Volans, G. N.: Fatal overdosage with disopyramide. Lancet, i:968-969, 1978. Hayler, A. M., Holt, D. W., and O'Keefe, B.: Treatment of disopyramide overdosage. Med. J. Aust., 1 :234, 1978.
r
POISONING BY ANTIDYSRHYTHMIC DRUGS
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31. Heissenbuttel R. H., and Bigger, J. T.: Bretylium tosyll\te: A newly available antiarrhythmic drug for ventricular arrhythmias. Ann. Intern. Med., 91:229-238, 1979. 32. Hong, C. Y., Yang, W. C., and Chiang, B. N.: Importance of membrane stabilizing effect in massive overdose of propranolol: Plasma level study in a fatal case. Human Toxico!., 3:511-517, 1983. 33. Jones, B.: Treatment of beta-blocker poisoning. Lancet, i:1031, 1980. 34. Koch Weser, J.: Bretylium. N. Eng!. J. Med., 300:473-477, 1979. 35. Kulling, P., Eleborg, L., and Persson, H.: Beta-adrenoceptor blocker intoxication: Epidemiological data; prenalteral as an alternative in the treatment of cardiac dysfunction. Human Toxico!., 2:175-181, 1983. 36. Laffey, S. H., and Luzzardi, L. J.: Phenytoin and other convulsants. In Haddad, L. M., and Winchester J. F. (eds.): Clinical Management of Poisoning and Overdose, pp. 557562. Philadelphia, W. B. Saunders, 1983. 37. Lewy, J. E.: Renal failure. Audio Digest., 30(5): Side B, 1984. 38. Lowery, C. M.: Crowth and Development of Children. 7th Edition, Chicago, Year Book Medical, 1978. 39. Lughi, R. J., Helwig, J. Jr., and Conn, H. L., Jr.: Quinidine toxicity and its treatment. Am. Heart J., 65:340-348, 1963. 40. Mitchel, L. B., Schroeder, J. S., and Mason, J. W.: Comparative clinical electrophysiologic effects of diltiazem, verapamil, and nifedipine. Am. J. Cardio!., 49:623-635, 1982. 41. Mitchell, B. C., Clements, J. A., Pottage, A., et al.: Mexiletin disposition: Individual variation in response to urine acidification and alkalinization. Br. J. Clin. Pharml\Co!., 16:281-284, 1983. 42. Mofenson, H. C., Caraccio, T. R., Miller, H., et al.: Lidocaine tOl(icity from topical mucosal application. Clin. Pediatr., 22:190-193, 1983. 43. Morris, D. L., and Coldschlager, N.: Calcium infusion for reversal of adverse effects of intravenous verapami!. J.A.M.A., 249:3212-3213, 1983. 44. Murphy, D. J., Bremer, W. F., and Haber, E.: Massive digoxin overdose treated with FAB: Fragment of digoxin-specific antibodies. Pediatrics, 70:472, 1982. 45. Nappi, J. M., Dhanani, S., Lovejoy, J. R., et al.: Severe hypoglycemia associated with disopyramide. West. J. Med., 138:95-97, 1983. 46. Nayler, W. C.: Calcium antagonists. Med. J. Aust., 2:506-511, 1983. 47. Nybert, L., and Wetrell, C.: Digoxin dosage schedules for neonates and infants based 011 pharmacokinetic considerations. Clin. Pharmacokinet., 3:453, 1978. 48. O'Donohue, W. J., Moss, L. M., and Angelillo, V. A.: Acute methemoglobinemia induced during topical benzocaine and lidocaine. Arch. Intern. Med., 140:1508, 1980. 49. O'Keefe, B., Haylev, A. M., Hold, D. W., et al.: Cardiac consequences and treatment of disopyramide intoxication: Experimental evaluation in dogs. Cardiovasc. Res., 13:630634,1979. 50. Opie, L. H.: Drugs and the heart. IV. Antil\rrhythmic agents. Lancet, i:861-867, 1980. 51. Orr, C. M., Bodansky, H. J., Oymond, D. S., et al.: Fatal verapamil overdose. Lancet, ii(8309):1218-1219, 1982. 52. Poisoning Event Reporting System. Food and Drug Administration, Poisoning Surveillance and Epidemiology Branch, HFN-720. 53. Pond, S., Jacobs, M., Marks, et al.: Treatment of digitalis overdose with oral-activated charcoa!' Lancet, ii:1177, 1982. 54. Reinold, E. W., Reynolds, W. J., Fixler, D. E., et al.: Use of hemodialysis in the treatment of quinidine poisoning. Pediatrics, 598:111, 1973. 55. Richens, A., Dunlop A., Ahmads, et al.: Monitoring serum phenytoin. Lancet, i:699, 1976. 56. Rosen, M. R., Wit, A. L., and Hoffman, B. F.: Electrophysiology and pharmacology of calcium antagonists: 6. Cardiac effects of verapamil. Am. Heart J., 89:665-673, 1975. 57. Rosen, M. R., and Horodof, A. J.: Mechanism of arrhythmias. In Roberts, N. K., and Celband H. (eds.): Cardiac Arrhythmias in Neonates, Infants and Children. p. 111. New York, Appleton-Century-Crofts, 1977. 58. Rumack, B. H. (ed.): Poisindex Management Monograph. Micromedex Inc., 1984. 59. Rumack, B. H., Wolfe, R. R., and Cilfrich, H.: Phenytoin treatment of massive digoxin overdose. Br. Heart J., 36:405-408, 1974. 60. Sakai, R. 1., and Lattin, J. E.: Lidocaine ingestion. Am. J. Dis. Child, 134:325, 1980.
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