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Antipsychotic Agents and Lithium
Chapter 54
Antipsychotic Agents and Lithium Leslie S. Carroll
ANTIPSYCHOTIC AGENTS Clinical Features Antipsychotic agents can cause severe neurologic and cardiovascular toxicity. These agents include the phenothiazines (e.g., chlorpromazine, trifluoperazine, perphenazine, thioridazine), butyrophenones (e.g., haloperidol, droperidol), and other structural classes such as the thioxanthene and benzisoxazole derivatives. Newer agents include risperidone, olanzapine, quetiapine, and ziprasidone. Neurologically, the antipsychotic agents may produce sedation, coma, seizures, and extrapyramidal side effects. The antipsychotic agents may lead to serious cardiovascular toxicity, including hypotension and dysrhythmias. The electrocardiogram (ECG) is an essential diagnostic tool in assessment and management of antipsychotic poisoning. Antipsychotic agents possess diverse neurotransmitter receptor antagonism and ion channel blocking properties. They antagonize dopamine, histamine, alpha-adrenergic, serotonin, and muscarinic acetylcholine receptors. Dopamine antagonism may produce the undesirable extrapyramidal syndromes (EPS) including dystonias, parkinsonism, akathisia, and tardive dyskinesia. Serotonin antagonism decreases EPS by disinhibition of central dopaminergic neurons.1,2 Histamine antagonism leads to central nervous system depression. Anticholinergic poisoning manifestations include a change in mental status, mydriasis, tachycardia, decreased gastrointestinal motility, and urinary retention. Alphaadrenergic receptor antagonism produces miosis, priapism, orthostasis, hypotension, and reflex tachycardia. The cardiovascular toxicity of antipsychotic agents is attributed to blockade of both neurotransmitter receptors and cardiac ion channels, including (1) muscarinic acetylcholine receptor blockade, (2) alpha-adrenergic receptor blockade, (3) cardiac potassium channel blockade, (4) cardiac fast sodium channel blockade, and (5) cardiac L-type calcium channel blockade. Potassium channel blockade produces a prolonged 268
QT interval.3 Fast sodium channel blockade exerts a “quinidine-like” effect on the myocardium, which widens the QRS complex.4,5 L-type calcium channel blockade properties have been demonstrated in vitro and may produce in vivo effects of bradycardia, heart block, and negative inotropy.5,6
Electrocardiographic Manifestations Reflex sinus tachycardia results from peripheral alpha-adrenergic receptor blockade, as well as muscarinic acetylcholine receptor antagonism. Normally, acetylcholine released from the vagus nerve binds to postsynaptic muscarinic receptors linked to potassium channels, resulting in potassium efflux. This hyperpolarization makes depolarization more difficult and results in bradycardia. Antipsychotic agents antagonize these vagally mediated effects, producing tachycardia.7 QT Interval Prolongation. Antipsychotic agents can cause an acquired form of the long QT syndrome (Fig. 54-1) secondary to blockade of the delayed rectifier potassium current. Blocking the delayed rectifier current prolongs repolarization Sinus Tachycardia.
ELECTROCARDIOGRAPHIC HIGHLIGHTS Antipsychotics
• Sinus tachycardia common • QRS complex interval widening • QT interval prolongation occurs with some antipsychotics in therapeutic use as well as toxicity
• QT interval prolongation predisposes to torsades de pointes Lithium
• T wave flattening and inversions at both therapeutic and toxic levels
• U wave • Sinus node dysfunction (bradycardia, junctional escape rhythms)
CHAPTER 54: Antipsychotic Agents and Lithium
269
FIGURE 54-1 • Antipsychotic agent toxicity. Prolonged corrected QT interval greater than 0.60 sec associated with antipsychotic agent.
and thereby lengthens the QT interval.8–10 This QT interval prolongation can exceed 0.50 sec and predisposes individuals to ventricular tachycardia, torsades de pointes, and cardiac arrest. QRS Complex Widening. Antipsychotic agents block cardiac fast sodium channels, leading to widening of the QRS complex. This effect has been demonstrated in guinea pig myocytes and case reports of overdose, and occurs especially with thioridazine.4,5 Similar to other agents that act by blocking sodium channels, the QRS complex interval prolongation is usually responsive to bicarbonate therapy. Torsades de Pointes. Prolongation of the QT interval predisposes patients to torsades de pointes (Fig. 54-2). Episodes of torsades de pointes may go unrecognized, recur in rapid succession, or degenerate into ventricular fibrillation, leading to syncope and death. The ECG features of torsades de pointes include a long QT interval followed by an early afterdepolarization, which triggers the dysrhythmia. Progressive twisting of the QRS complex occurs around an imaginary baseline, with amplitudes of the QRS complexes changing in a sinusoidal fashion. Heart rate is 150 to 300 bpm.11
LITHIUM TOXICITY Clinical Features Lithium is an extremely effective agent in the treatment of mania. Lithium can produce severe neurologic but rarely lifethreatening cardiac toxicity. Neurologic manifestations of toxicity include tremor, hyperreflexia, clonus, confusion, seizures, coma, extrapyramidal reactions, and cerebellar dysfunction.12 Severe cardiac manifestations of lithium toxicity are usually secondary to sinus node dysfunction.13
Electrocardiographic Manifestations T Wave Abnormalities and U Waves. T wave flattening or inversion on the ECG is reported to occur in 20% to 100% of patients therapeutically on lithium and is occasionally accompanied by U waves.14,15 Intracellular potassium displacement by lithium is thought to induce T wave changes and generate U waves.15,16 Severe toxicity can produce diffuse T wave inversion12 (Fig. 54-3). Sinus Node Dysfunction. Sinus node dysfunction is the most common conduction defect occurring with lithium.13 Sinus node dysfunction manifested as sinus bradycardia, sinus arrest, or asystole can occur with therapeutic and toxic
ELECTROCARDIOGRAPHIC PEARLS
• The ECG should be scrutinized for rate, QRS complex width,
•
• • •
and QT interval prolongation in the face of antipsychotic toxicity or cardiovascular symptoms in patients on these agents. QT interval prolongation can be exacerbated by concomitant electrolyte disorders, hereditary prolonged QT syndromes, and additional use of other agents that cause QT interval prolongation. Thioridazine is an older antipsychotic agent classically linked to “quinidine-like” effects and sodium channel blockade that can manifest with QRS complex interval prolongation. Newer antipsychotics can cause QT interval prolongation as well (risperidone and quetiapine in toxicity; ziprasidone in therapeutic dosing). The most significant cardiac effect of lithium is sinus node dysfunction. Ventricular dysrhythmias are rare with lithium.
270
SECTION III: ELECTROCARDIOGRAPHIC MANIFESTATIONS OF DISEASE
FIGURE 54-2 • Antipsychotic agent toxicity. Torsades de pointes in a patient after antipsychotic medication overdose.
A FIGURE 54-3 • Lithium toxicity. A, Sinus bradycardia with diffuse T wave inversion in a patient with a lithium level of 4.5 mmol/L. This ECG demonstrates both sinus node dysfunction and T wave changes.
CHAPTER 54: Antipsychotic Agents and Lithium
271
B FIGURE 54-3 • Lithium toxicity. B, Same patient after dialysis with a lithium level of 1.0 mmol/L. Patient is now in a normal sinus rhythm. The deep T wave inversions have resolved and now show flattening or minimal inversion, typical of a therapeutic lithium level.
concentrations of lithium.17 Occasionally a junctional escape rhythm arises.18,19 Sinus node dysfunction is usually reversible upon lithium withdrawal but may persist despite cessation of the drug.20 Permanent pacemaker placement has been used in patients with severe lithium-induced sinus node dysfunction.19,21,22 Ventricular Dysrhythmias. Lithium-associated ventricular dysrhythmias are rare. Three case reports of lithium-induced ventricular dysrhythmias have appeared in the literature.23–25 One case demonstrated torsades de pointes in a patient on lithium and thioridazine, a phenothiazine known to induce QT interval prolongation and subsequent torsades de pointes.23 The other cases report premature ventricular contractions (PVCs) and ventricular fibrillation in patients on lithium.24,25 Discontinuation of lithium abolished the PVCs, which returned with reintroduction of the drug. Tilkian et al. have noted increased PVCs in patients therapeutically on lithium.26 Myocarditis. Four cases of lithium-associated myocarditis have been reported in the literature.27 Although the etiology of the myocarditis could not definitively be attributed to lithium, the clinical scenario was consistent with a toxin-induced myocarditis. Three of these four cases demonstrated T wave changes, namely, flattening or inversion, which are consistent with either lithium therapy or myocarditis. Although lithium-induced myocarditis may exist, the condition is extremely rare.
References 1. Kapur S, Remington G: Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996;153:466. 2. Lieberman JA, Mailman RB, Duncan G, et al: Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry 1998;44:1099.
3. Welch R, Chue P: Antipsychotic agents and QT changes. J Psychiatry Neurosci 2000;25:154. 4. Ogata N, Narahashi T: Block of sodium channels by psychotropic drugs in single guinea-pig cardiac myocytes. Br J Pharmacol 1989;97:905. 5. Schmidt W, Lang K: Life-threatening dysrhythmias in severe thioridazine poisoning treated with physostigmine and transient atrial pacing. Crit Care Med 1997;25:1925. 6. Flaim SF, Brannan MD, Swigart SC, et al: Neuroleptic drugs attenuate calcium influx and tension development in rabbit thoracic aorta: Effects of pimozide, penfluridol, chlorpromazine, and haloperidol. Proc Natl Acad Sci USA 1985;82:1237. 7. Curry SC, Mills KC, Graeme KA: Neurotransmitters. In Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Goldfrank’s Toxicologic Emergencies, 6th ed. Stamford, Conn, Appleton and Lange, 1998, p 137. 8. Suessbrich H, Schonherr R, Heinemann SH, et al: The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. Br J Pharmacol 1997;120:968. 9. Rampe D, Murawsky MK, Grau J, Lewis EW: The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther 1998;286:788. 10. Kang J, Wang L, Cai F, Rampe D: High affinity blockade of the HERG cardiac K+ channel by the neuroleptic pimozide. Eur J Pharmacol 2000;392:137. 11. Tan LH, Hou CJY, Lauer MR, Sung RJ: Electrophysiologic mechanism of the long QT interval syndromes and torsades de pointes. Ann Intern Med 1995;122:701. 12. Timmer RT, Sands JM: Lithium intoxication. J Am Soc Nephrol 1999;10:666. 13. Riccioni N, Roni P, Bartolomei C: Lithium-induced sinus node dysfunction. Acta Cardiol 1983;2:133. 14. Mitchell JE, Mackenzie TB: Cardiac effects of lithium therapy in man: A review. J Clin Psychiatry 1982;43:47. 15. Kochar MS, Wang RIH, D’Cunha GF: Electrocardiographic changes simulating hypokalemia during treatment with lithium carbonate. J Electrocardiol 1971;4:371. 16. Tilkian AG, Schroeder JS, Kao JJ, Hultgren HN: The cardiovascular effects of lithium in man. Am J Med 1976;61:665.
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SECTION III: ELECTROCARDIOGRAPHIC MANIFESTATIONS OF DISEASE
17. Brady HR, Horgan JH: Lithium and the heart, unanswered questions. Chest 1988;93:166. 18. Ong ACM, Handler CE: Sinus arrest and asystole due to severe lithium intoxication. Int J Cardiol 1991;30:364. 19. Roose SP, Nurnberger JI, Dunner DL, et al: Cardiac sinus node dysfunction during lithium treatment. Am J Psychiatry 1979;136:804. 20. Terao T, Abe H, Abe K: Irreversible sinus node dysfunction induced by resumption of lithium therapy. Acta Psychiatr Scand 1996;93:407. 21. Hagman A, Arnman K, Rydén L: Syncope caused by lithium treatment. Acta Med Scand 1979;205:467. 22. Kast R: Reversal of lithium-related cardiac repolarization delay by potassium. J Clin Psychopharmacol 1990;10:304.
23. Rosenquist RJ, Brauer WW, Mork JN: Recurrent major ventricular arrhythmias. Minn Med 1971;54:877. 24. Tangedahl TN, Gau GT: Myocardial irritability associated with lithium carbonate therapy. N Engl J Med 1972;287:867. 25. Worthley LIG: Lithium toxicity and refractory cardiac arrhythmia treated with intravenous magnesium. Anaesth Intensive Care 1974;11:357. 26. Tilkian AG, Schroeder JS, Hultgren H: Effect of lithium on cardiovascular performance: Report on extended ambulatory monitoring and exercise testing before and during lithium therapy. Am J Cardiol 1976;38:701. 27. Arana GW, Dupont RM, Clawson LD: Is there clinical evidence that lithium toxicity can induce myocarditis? J Clin Psychopharmacol 1984; 4:364.
Chapter 55
Tricyclic Antidepressant Agents Richard A. Harrigan
Clinical Features Tricyclic antidepressant agents (TCAs) can cause serious neurologic and cardiovascular toxicity. Life-threatening manifestations include seizures, altered mental status, hypotension, and cardiac dysrhythmias. In the absence of a rapidly available laboratory test to predict toxicity, the electrocardiogram (ECG) has emerged as an indirect, easy, noninvasive screening tool for toxicity from these drugs. TCAs pose a quadruple threat to cardiovascular function: (1) peripheral and central nervous system inhibition of presynaptic neurotransmitter reuptake; (2) alpha-adrenergic receptor blockade; (3) anticholinergic effects at the muscarinic receptor; and (4) blockade of the fast sodium channels, causing a “quinidine-like” effect on the myocardium.1,2
ELECTROCARDIOGRAPHIC HIGHLIGHTS
• Sinus tachycardia • Widening of the QRS complex • Rightward deviation of the terminal 40-msec frontal plane QRS vector (prominent R wave in lead aVR)
• Prolongation of the corrected QT interval—although this is seen in both therapeutic and toxic scenarios7
Collectively, these four effects contribute in varying degrees to the cardiovascular changes seen with TCA toxicity.
Electrocardiographic Manifestations TCAs produce a number of ECG changes related to the four previously mentioned actions. Neurotransmitter reuptake inhibition, alpha-adrenergic blockade, and antimuscarinic effects can result in cardiac rhythm disturbances. “Quinidinelike” sodium channel blockade can decrease cardiac automaticity and impair conduction, resulting in cardiac rhythm and morphologic changes. Findings on ECG include sinus tachycardia, QRS complex widening, rightward deviation of the QRS axis, and QT interval prolongation. Sinus Tachycardia. Initially, the hyperadrenergic state produced from reuptake inhibition of biogenic amines (e.g., serotonin, dopamine, and norepinephrine) produces a tachycardia. Reflex tachycardia, due to the peripheral vasodilatation resulting from alpha-adrenergic antagonism, also contributes to increasing the heart rate. However, the principal cause of the sinus tachycardia frequently seen in TCA toxicity is the anticholinergic effects of these agents. This finding is extremely nonspecific.1,2 QRS Complex Widening. The sodium channel blocking effect of the drug causes progressive widening of the QRS complex. A number of studies suggest that QRS complex
Antipsychotic Agents and Lithium Leslie S. Carroll
ANTIPSYCHOTIC AGENTS Clinical Features Antipsychotic agents can cause severe neurologic and cardiovascular toxicity. These agents include the phenothiazines (e.g., chlorpromazine, trifluoperazine, perphenazine, thioridazine), butyrophenones (e.g., haloperidol, droperidol), and other structural classes such as the thioxanthene and benzisoxazole derivatives. Newer agents include risperidone, olanzapine, quetiapine, and ziprasidone. Neurologically, the antipsychotic agents may produce sedation, coma, seizures, and extrapyramidal side effects. The antipsychotic agents may lead to serious cardiovascular toxicity, including hypotension and dysrhythmias. The electrocardiogram (ECG) is an essential diagnostic tool in assessment and management of antipsychotic poisoning. Antipsychotic agents possess diverse neurotransmitter receptor antagonism and ion channel blocking properties. They antagonize dopamine, histamine, alpha-adrenergic, serotonin, and muscarinic acetylcholine receptors. Dopamine antagonism may produce the undesirable extrapyramidal syndromes (EPS) including dystonias, parkinsonism, akathisia, and tardive dyskinesia. Serotonin antagonism decreases EPS by disinhibition of central dopaminergic neurons.1,2 Histamine antagonism leads to central nervous system depression. Anticholinergic poisoning manifestations include a change in mental status, mydriasis, tachycardia, decreased gastrointestinal motility, and urinary retention. Alphaadrenergic receptor antagonism produces miosis, priapism, orthostasis, hypotension, and reflex tachycardia. The cardiovascular toxicity of antipsychotic agents is attributed to blockade of both neurotransmitter receptors and cardiac ion channels, including (1) muscarinic acetylcholine receptor blockade, (2) alpha-adrenergic receptor blockade, (3) cardiac potassium channel blockade, (4) cardiac fast sodium channel blockade, and (5) cardiac L-type calcium channel blockade. Potassium channel blockade produces a prolonged 268
QT interval.3 Fast sodium channel blockade exerts a “quinidine-like” effect on the myocardium, which widens the QRS complex.4,5 L-type calcium channel blockade properties have been demonstrated in vitro and may produce in vivo effects of bradycardia, heart block, and negative inotropy.5,6
Electrocardiographic Manifestations Reflex sinus tachycardia results from peripheral alpha-adrenergic receptor blockade, as well as muscarinic acetylcholine receptor antagonism. Normally, acetylcholine released from the vagus nerve binds to postsynaptic muscarinic receptors linked to potassium channels, resulting in potassium efflux. This hyperpolarization makes depolarization more difficult and results in bradycardia. Antipsychotic agents antagonize these vagally mediated effects, producing tachycardia.7 QT Interval Prolongation. Antipsychotic agents can cause an acquired form of the long QT syndrome (Fig. 54-1) secondary to blockade of the delayed rectifier potassium current. Blocking the delayed rectifier current prolongs repolarization Sinus Tachycardia.
ELECTROCARDIOGRAPHIC HIGHLIGHTS Antipsychotics
• Sinus tachycardia common • QRS complex interval widening • QT interval prolongation occurs with some antipsychotics in therapeutic use as well as toxicity
• QT interval prolongation predisposes to torsades de pointes Lithium
• T wave flattening and inversions at both therapeutic and toxic levels
• U wave • Sinus node dysfunction (bradycardia, junctional escape rhythms)
CHAPTER 54: Antipsychotic Agents and Lithium
269
FIGURE 54-1 • Antipsychotic agent toxicity. Prolonged corrected QT interval greater than 0.60 sec associated with antipsychotic agent.
and thereby lengthens the QT interval.8–10 This QT interval prolongation can exceed 0.50 sec and predisposes individuals to ventricular tachycardia, torsades de pointes, and cardiac arrest. QRS Complex Widening. Antipsychotic agents block cardiac fast sodium channels, leading to widening of the QRS complex. This effect has been demonstrated in guinea pig myocytes and case reports of overdose, and occurs especially with thioridazine.4,5 Similar to other agents that act by blocking sodium channels, the QRS complex interval prolongation is usually responsive to bicarbonate therapy. Torsades de Pointes. Prolongation of the QT interval predisposes patients to torsades de pointes (Fig. 54-2). Episodes of torsades de pointes may go unrecognized, recur in rapid succession, or degenerate into ventricular fibrillation, leading to syncope and death. The ECG features of torsades de pointes include a long QT interval followed by an early afterdepolarization, which triggers the dysrhythmia. Progressive twisting of the QRS complex occurs around an imaginary baseline, with amplitudes of the QRS complexes changing in a sinusoidal fashion. Heart rate is 150 to 300 bpm.11
LITHIUM TOXICITY Clinical Features Lithium is an extremely effective agent in the treatment of mania. Lithium can produce severe neurologic but rarely lifethreatening cardiac toxicity. Neurologic manifestations of toxicity include tremor, hyperreflexia, clonus, confusion, seizures, coma, extrapyramidal reactions, and cerebellar dysfunction.12 Severe cardiac manifestations of lithium toxicity are usually secondary to sinus node dysfunction.13
Electrocardiographic Manifestations T Wave Abnormalities and U Waves. T wave flattening or inversion on the ECG is reported to occur in 20% to 100% of patients therapeutically on lithium and is occasionally accompanied by U waves.14,15 Intracellular potassium displacement by lithium is thought to induce T wave changes and generate U waves.15,16 Severe toxicity can produce diffuse T wave inversion12 (Fig. 54-3). Sinus Node Dysfunction. Sinus node dysfunction is the most common conduction defect occurring with lithium.13 Sinus node dysfunction manifested as sinus bradycardia, sinus arrest, or asystole can occur with therapeutic and toxic
ELECTROCARDIOGRAPHIC PEARLS
• The ECG should be scrutinized for rate, QRS complex width,
•
• • •
and QT interval prolongation in the face of antipsychotic toxicity or cardiovascular symptoms in patients on these agents. QT interval prolongation can be exacerbated by concomitant electrolyte disorders, hereditary prolonged QT syndromes, and additional use of other agents that cause QT interval prolongation. Thioridazine is an older antipsychotic agent classically linked to “quinidine-like” effects and sodium channel blockade that can manifest with QRS complex interval prolongation. Newer antipsychotics can cause QT interval prolongation as well (risperidone and quetiapine in toxicity; ziprasidone in therapeutic dosing). The most significant cardiac effect of lithium is sinus node dysfunction. Ventricular dysrhythmias are rare with lithium.
270
SECTION III: ELECTROCARDIOGRAPHIC MANIFESTATIONS OF DISEASE
FIGURE 54-2 • Antipsychotic agent toxicity. Torsades de pointes in a patient after antipsychotic medication overdose.
A FIGURE 54-3 • Lithium toxicity. A, Sinus bradycardia with diffuse T wave inversion in a patient with a lithium level of 4.5 mmol/L. This ECG demonstrates both sinus node dysfunction and T wave changes.
CHAPTER 54: Antipsychotic Agents and Lithium
271
B FIGURE 54-3 • Lithium toxicity. B, Same patient after dialysis with a lithium level of 1.0 mmol/L. Patient is now in a normal sinus rhythm. The deep T wave inversions have resolved and now show flattening or minimal inversion, typical of a therapeutic lithium level.
concentrations of lithium.17 Occasionally a junctional escape rhythm arises.18,19 Sinus node dysfunction is usually reversible upon lithium withdrawal but may persist despite cessation of the drug.20 Permanent pacemaker placement has been used in patients with severe lithium-induced sinus node dysfunction.19,21,22 Ventricular Dysrhythmias. Lithium-associated ventricular dysrhythmias are rare. Three case reports of lithium-induced ventricular dysrhythmias have appeared in the literature.23–25 One case demonstrated torsades de pointes in a patient on lithium and thioridazine, a phenothiazine known to induce QT interval prolongation and subsequent torsades de pointes.23 The other cases report premature ventricular contractions (PVCs) and ventricular fibrillation in patients on lithium.24,25 Discontinuation of lithium abolished the PVCs, which returned with reintroduction of the drug. Tilkian et al. have noted increased PVCs in patients therapeutically on lithium.26 Myocarditis. Four cases of lithium-associated myocarditis have been reported in the literature.27 Although the etiology of the myocarditis could not definitively be attributed to lithium, the clinical scenario was consistent with a toxin-induced myocarditis. Three of these four cases demonstrated T wave changes, namely, flattening or inversion, which are consistent with either lithium therapy or myocarditis. Although lithium-induced myocarditis may exist, the condition is extremely rare.
References 1. Kapur S, Remington G: Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996;153:466. 2. Lieberman JA, Mailman RB, Duncan G, et al: Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry 1998;44:1099.
3. Welch R, Chue P: Antipsychotic agents and QT changes. J Psychiatry Neurosci 2000;25:154. 4. Ogata N, Narahashi T: Block of sodium channels by psychotropic drugs in single guinea-pig cardiac myocytes. Br J Pharmacol 1989;97:905. 5. Schmidt W, Lang K: Life-threatening dysrhythmias in severe thioridazine poisoning treated with physostigmine and transient atrial pacing. Crit Care Med 1997;25:1925. 6. Flaim SF, Brannan MD, Swigart SC, et al: Neuroleptic drugs attenuate calcium influx and tension development in rabbit thoracic aorta: Effects of pimozide, penfluridol, chlorpromazine, and haloperidol. Proc Natl Acad Sci USA 1985;82:1237. 7. Curry SC, Mills KC, Graeme KA: Neurotransmitters. In Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Goldfrank’s Toxicologic Emergencies, 6th ed. Stamford, Conn, Appleton and Lange, 1998, p 137. 8. Suessbrich H, Schonherr R, Heinemann SH, et al: The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. Br J Pharmacol 1997;120:968. 9. Rampe D, Murawsky MK, Grau J, Lewis EW: The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther 1998;286:788. 10. Kang J, Wang L, Cai F, Rampe D: High affinity blockade of the HERG cardiac K+ channel by the neuroleptic pimozide. Eur J Pharmacol 2000;392:137. 11. Tan LH, Hou CJY, Lauer MR, Sung RJ: Electrophysiologic mechanism of the long QT interval syndromes and torsades de pointes. Ann Intern Med 1995;122:701. 12. Timmer RT, Sands JM: Lithium intoxication. J Am Soc Nephrol 1999;10:666. 13. Riccioni N, Roni P, Bartolomei C: Lithium-induced sinus node dysfunction. Acta Cardiol 1983;2:133. 14. Mitchell JE, Mackenzie TB: Cardiac effects of lithium therapy in man: A review. J Clin Psychiatry 1982;43:47. 15. Kochar MS, Wang RIH, D’Cunha GF: Electrocardiographic changes simulating hypokalemia during treatment with lithium carbonate. J Electrocardiol 1971;4:371. 16. Tilkian AG, Schroeder JS, Kao JJ, Hultgren HN: The cardiovascular effects of lithium in man. Am J Med 1976;61:665.
272
SECTION III: ELECTROCARDIOGRAPHIC MANIFESTATIONS OF DISEASE
17. Brady HR, Horgan JH: Lithium and the heart, unanswered questions. Chest 1988;93:166. 18. Ong ACM, Handler CE: Sinus arrest and asystole due to severe lithium intoxication. Int J Cardiol 1991;30:364. 19. Roose SP, Nurnberger JI, Dunner DL, et al: Cardiac sinus node dysfunction during lithium treatment. Am J Psychiatry 1979;136:804. 20. Terao T, Abe H, Abe K: Irreversible sinus node dysfunction induced by resumption of lithium therapy. Acta Psychiatr Scand 1996;93:407. 21. Hagman A, Arnman K, Rydén L: Syncope caused by lithium treatment. Acta Med Scand 1979;205:467. 22. Kast R: Reversal of lithium-related cardiac repolarization delay by potassium. J Clin Psychopharmacol 1990;10:304.
23. Rosenquist RJ, Brauer WW, Mork JN: Recurrent major ventricular arrhythmias. Minn Med 1971;54:877. 24. Tangedahl TN, Gau GT: Myocardial irritability associated with lithium carbonate therapy. N Engl J Med 1972;287:867. 25. Worthley LIG: Lithium toxicity and refractory cardiac arrhythmia treated with intravenous magnesium. Anaesth Intensive Care 1974;11:357. 26. Tilkian AG, Schroeder JS, Hultgren H: Effect of lithium on cardiovascular performance: Report on extended ambulatory monitoring and exercise testing before and during lithium therapy. Am J Cardiol 1976;38:701. 27. Arana GW, Dupont RM, Clawson LD: Is there clinical evidence that lithium toxicity can induce myocarditis? J Clin Psychopharmacol 1984; 4:364.
Chapter 55
Tricyclic Antidepressant Agents Richard A. Harrigan
Clinical Features Tricyclic antidepressant agents (TCAs) can cause serious neurologic and cardiovascular toxicity. Life-threatening manifestations include seizures, altered mental status, hypotension, and cardiac dysrhythmias. In the absence of a rapidly available laboratory test to predict toxicity, the electrocardiogram (ECG) has emerged as an indirect, easy, noninvasive screening tool for toxicity from these drugs. TCAs pose a quadruple threat to cardiovascular function: (1) peripheral and central nervous system inhibition of presynaptic neurotransmitter reuptake; (2) alpha-adrenergic receptor blockade; (3) anticholinergic effects at the muscarinic receptor; and (4) blockade of the fast sodium channels, causing a “quinidine-like” effect on the myocardium.1,2
ELECTROCARDIOGRAPHIC HIGHLIGHTS
• Sinus tachycardia • Widening of the QRS complex • Rightward deviation of the terminal 40-msec frontal plane QRS vector (prominent R wave in lead aVR)
• Prolongation of the corrected QT interval—although this is seen in both therapeutic and toxic scenarios7
Collectively, these four effects contribute in varying degrees to the cardiovascular changes seen with TCA toxicity.
Electrocardiographic Manifestations TCAs produce a number of ECG changes related to the four previously mentioned actions. Neurotransmitter reuptake inhibition, alpha-adrenergic blockade, and antimuscarinic effects can result in cardiac rhythm disturbances. “Quinidinelike” sodium channel blockade can decrease cardiac automaticity and impair conduction, resulting in cardiac rhythm and morphologic changes. Findings on ECG include sinus tachycardia, QRS complex widening, rightward deviation of the QRS axis, and QT interval prolongation. Sinus Tachycardia. Initially, the hyperadrenergic state produced from reuptake inhibition of biogenic amines (e.g., serotonin, dopamine, and norepinephrine) produces a tachycardia. Reflex tachycardia, due to the peripheral vasodilatation resulting from alpha-adrenergic antagonism, also contributes to increasing the heart rate. However, the principal cause of the sinus tachycardia frequently seen in TCA toxicity is the anticholinergic effects of these agents. This finding is extremely nonspecific.1,2 QRS Complex Widening. The sodium channel blocking effect of the drug causes progressive widening of the QRS complex. A number of studies suggest that QRS complex