Chlorpromazine: Cardiac arrhythmogenicity in the cat

Schraeder

2002

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Death may be the consequence of natural or unnatural causes, such as accidents, homicide, and suicide, which have no relationship to the disease of epilepsy. Direct causes of death include status epilepticus, and indirect causes may be head trauma or drowning subsequent to a seizure. When death occurs suddenly and without explanation, the term sudden unexpected unexplained death is used. Unexplained is a term that clinicians and research scientists are working to clarify. Numerous preclinical animal studies have been conducted as models for sudden death and have led to clinical studies in persons with epilepsy. These studies show that sympathetic nerve stimulation, ouabain, or coronary occlusion increased temporal dispersion of recovery of ventricular excitability and led to an underlying electrical instability that predisposed the ventricularmyocardium to arrhythmia. Cardiac arrhythmias in an animal model for ouabain-induced toxicity were associated with neural autonomic dysfunction. Neural discharges were characterized by increases, decreases, or no change in the discharge of postganglionic cardiac sympathetic nerves monitored simultaneously, predisposing to cardiac arrhythmia. Stimulation of the sympathetic ventrolateral cardiac nerve produced a shift in the origin of the pacemaker and tachyarrhythmias because the nerve is not uniformly distributed to the various regions of the heart but is localized to the atrioventricular junctional and ventricular regions. Such nonuniform distribution of sympathetic nerves would also contribute to initiation of arrhythmia as a nonuniform neural discharge occurred. Studies examining the physiology and pharmacology of this finding in multiple animal models found that subconvulsant, interictal discharge was associated with autonomic cardiac neural non-uniform discharge and cardiac arrhythmias. As a result of further investigations, Lathers and Schraeder edited a book in 1990 that summarized the clinical problem of sudden unexpected death and epilepsy (SUDEP). The contributors concluded that there was a paucity of clinical data addressing the mechanism of death. Regulatory response resulting from the consequent increased awareness of SUDEP occurred in 1993, when the FDA focused attention of practitioners and pharmaceutical manufacturers on the question of whether use of anticonvulsant drugs contributes to or prevents sudden unexpected death in epileptic persons. The FDA-convened panel of scientists considered the prevalence of sudden unexpected death in patients involved in studies associated with developing new anticonvulsant drugs and reviewed data on the risk of sudden unexpected death in patients taking lamotrigine. The risk of SUDEP was no different from thatfound in the young epilepsy population in general. Estimated SUDEP rates in patients receiving the new anticonvulsant drugs lamotrigine, gabapentin, topiramate, tigabine, and zonisamide were found to be similar to those in patients receiving standard anticonvulsant drugs, suggesting that SUDEP rates reflect population ...

Section: Figure 2 Postganglionic Cardiac Sympathetic Neural Dischargsupporting

confidence: 70%

Section: Figure 2 Postganglionic Cardiac Sympathetic Neural Dischargmentioning

confidence: 99%

Clinical Pharmacology: Drugs as a Benefit and/or Risk in Sudden Unexpected Death in Epilepsy?

Schraeder

2002

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The Effect of C1 Spinal Cord Transection or Bilateral Adrenal Vein Ligation on Thioridazine‐Induced Arrhythmia and Death in the Cat

Flax

Lipka

1986

The phenothiazine thioridazine 1 mg/kg/min was infused intravenously into three groups of cats: (1) thioridazine alone (N = 5), (2) after bilateral adrenal ligation (N = 4), and (3) after spinal cord section at the atlanto-occipital junction (C1; N = 6). The times to arrhythmia and death with thioridazine alone were 47.8 +/- 7.8 and 72.8 +/- 5.6 minutes respectively. After bilateral adrenal ligation, arrhythmia and death occurred at 41.1 +/- 5.2 and 53.1 +/- 5.8 minutes, respectively, which showed no increase (P greater than .05) from thioridazine alone. After spinal cord section, thioridazine-induced arrhythmia and death occurred at 74.0 +/- 13.7 and 85.7 +/- 13.8 minutes, respectively, which were not increased (P greater than .05) when compared with thioridazine alone. The results of this study suggest that neither adrenomedullary catecholamines nor the central sympathetic component above C1 plays a significant role in acute thioridazine-induced arrhythmia. The action of thioridazine to induce arrhythmia in spite of transection of the spinal cord or bilateral adrenal vein ligation suggests that its cardiotoxicity is a result of a direct myocardial effect. Thioridazine depressed blood pressure without producing the sustained reflex tachycardia normally seen with hypotension. This suggests that the agent may modify the baroreceptor reflex arc.

Psychoactive Agents, Seizure Production, and Sudden Death in Epilepsy

Lipka

1987

Major tranquilizers as well as antidepressant agents have been associated with clinical seizures in patients administered these agents. The incidence of such seizures is generally low when these drugs are administered in therapeutic doses. However, administration of large doses of these agents has been associated with many cases of convulsion production. The effects that these drugs have on animal models of epilepsy have been examined. It appears that the phenothiazines act as convulsant agents at lower doses, whereas, at higher doses, they act as anticonvulsant drugs. Antidepressants, on the other hand, appear to exert an anticonvulsant effect at low doses and convulsant effects at high doses. The mechanism by which these agents alter the seizure threshold is not yet known. Clinically, drugs of lower seizure production potential should be substituted for those drugs with greater potential in treating epileptic patients for psychiatric ailments. The problem of sudden death in epileptic patients is one that must be confronted. Sudden death has most frequently been attributed to autonomic dysfunction and cardiac arrhythmia in these patients. The contribution of stress in sudden death production also must be taken into account. In addition, some psychoactive agents have been associated with sudden death as well as cardiac arrhythmia and seizure production. Thus, in light of the possible additivity of the factors involved in the production of sudden death, the administration of a psychoactive agent to an epileptic patient should be approached with caution. Those agents that do not alter cardiac rhythm or seizure threshold should be administered if a psychoactive agent is deemed necessary for the management of psychiatric illness in the epileptic patient.