Does Chlorpromazine Produce Cardiac Arrhythmia Via the Central Nervous System?

Lipka, Leslie J.; Lathers, Claire M.; Roberts, Jay

doi:10.1002/j.1552-4604.1988.tb03117.x

Cited by 17 publications

(4 citation statements)

References 40 publications

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“…49 Animal studies exploring the contribution of the autonomic nervous system versus the direct drug action on the heart of phenothiazines and cocaine emphasized the latter as the important contributing factor. [50][51][52][53][54] Confirmation of findings using a second animal model strengthens conclusions made from data obtained in a given experimental animal model such as the cat model developed to study autonomic parameters associated with epileptogenic activity. [55][56][57][58][59] The similarity of the function of the pig heart to the human heart provided a particularly appropriate animal model to confirm in a second species the autonomic neural dysfunction associated with epileptogenic activity in the cat.…”

Section: Figure 2 Postganglionic Cardiac Sympathetic Neural Dischargsupporting

confidence: 68%

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

Lathers

Schraeder

2002

The Journal of Clinical Pharma

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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 ...

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Section: Figure 2 Postganglionic Cardiac Sympathetic Neural Dischargsupporting

confidence: 68%

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

Lathers

Schraeder

2002

The Journal of Clinical Pharma

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“…This hypothesis of the drug's direct action on myocardiac channels in sarcolemma can be supported by the study showing that phenothiazine-induced arrhythmia and death were not produced via the central nervous system (Lipka et al, 1988). Also, it can be speculated that many effects of trifluoperazine on channels are due to nonspecific membrane effects such as general perturbation of membrane proteins because trifluoperazine changes the membrane fluidity (Minetti and Di Stasi, 1987).…”

Section: ϫ6mentioning

confidence: 93%

Inhibition of Human ether-a-go-go-Related Gene K⁺ Channel and I_Kr of Guinea Pig Cardiomyocytes by Antipsychotic Drug Trifluoperazine

Choi

Koh²,

Jo³

2005

J Pharmacol Exp Ther

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Trifluoperazine, a commonly used antipsychotic drug, has been known to induce QT prolongation and torsades de pointes, which can cause sudden death. We studied the effects of trifluoperazine on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the delayed rectifier K ϩ current of guinea pig cardiomyocytes. The application of trifluoperazine showed a dose-dependent decrease in current amplitudes at the end of voltage steps and tail currents of HERG. The IC 50 for a trifluoperazine block of HERG current progressively decreased according to depolarization: IC 50 values at Ϫ40, 0, and ϩ40 mV were 21.6, 16.6, and 9.29 M, respectively. The voltage dependence of the block could be fitted with a monoexponential function, and the fractional electrical distance was estimated to be ␦ ϭ 0.65. The block of HERG by trifluoperazine was use-dependent, exhibiting more rapid onset and greater steady-state block at higher frequencies of activation; there was partial relief of the block with decreasing frequency. In guinea pig ventricular myocytes, bath applications of 0.5 and 2 M trifluoperazine at 36°C blocked the rapidly activating delayed rectifier K ϩ current by 32.4 and 72.9%, respectively; however, the same concentrations of trifluoperazine failed to significantly block the slowly activating delayed rectifier K ϩ current. Our findings suggest the arrhythmogenic side effect of trifluoperazine is caused by a blockade of HERG and the rapid component of the delayed rectifier K ϩ current rather than by the blockade of the slow component.

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“…Aumento nos níveis plasmáticos de colesterol, glicose, prolactina, bilirrubina, iodo, hormônio tireo-estimulante (TSH), cortisol e das enzimas cardíacas e hepáticas têm sido associados ao uso da CPZ nas doses normalmente recomendadas [33]. Em adição, ela costuma deprimir o segmento ST e aumentar os intervalos QT e PR no eletrocardiograma por estar associada a alterações na condução atrioventricular [34].…”

Section: Introductionunclassified

Dos distúrbios psiquiátricos à antibioticoterapia: reposicionamento da clorpromazina como agente antibacteriano

Lima

Ramos-Alves

Soares

2019

Rev. Colomb. Cienc. Quím. Farm.

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O alarmante aumento na taxa de resistência aos antibióticos põe em check à eficácia da terapia antibacteriana futura. Em contrapartida, as indústrias farmacêuticas negligenciam os investimentos em pesquisa e desenvolvimento de novos fármacos antimicrobianos em virtude de questões financeiras, legais e farmacológicas. Assim sendo, o reposicionamento de agentes disponíveis clinicamente torna-se uma promissora ferramenta para tentar driblar o desinteresse das indústrias. O fármaco antipsicótico clorpromazina (CPZ) destaca-se por possuir uma ampla faixa de atividade antibacteriana, a qual cobre desde patógenos Gram-positivos e Gram-negativos, até as micobactérias. A atividade antibacteriana é independente do perfil de susceptibilidade do microrganismo, sendo ela mantida mesmo em cepas altamente resistentes aos antibióticos. Alguns estudos mostram que mesmo nas concentrações clinicamente disponíveis no plasma (entre 0,1-0,5 μg/mL), a CPZ é capaz de matar Staphylococcus aureus e Mycobacterium tuberculosis dentro dos macrófagos. Em adição, estudos clínicos têm revelado os benefícios do uso da CPZ na terapia de suporte para pacientes com infecções em curso. Em conclusão, a CPZ pode eventualmente ser direcionada ao arsenal terapêutico antimicrobiano, especialmente no manejo das infecções causadas por microrganismos intracelulares com fenótipo multirresistente.

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Does Chlorpromazine Produce Cardiac Arrhythmia Via the Central Nervous System?

Cited by 17 publications

References 40 publications

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

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

Inhibition of Human ether-a-go-go-Related Gene K⁺ Channel and I_Kr of Guinea Pig Cardiomyocytes by Antipsychotic Drug Trifluoperazine

Dos distúrbios psiquiátricos à antibioticoterapia: reposicionamento da clorpromazina como agente antibacteriano

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Does Chlorpromazine Produce Cardiac Arrhythmia Via the Central Nervous System?

Cited by 17 publications

References 40 publications

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

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

Inhibition of Human ether-a-go-go-Related Gene K+ Channel and IKr of Guinea Pig Cardiomyocytes by Antipsychotic Drug Trifluoperazine

Dos distúrbios psiquiátricos à antibioticoterapia: reposicionamento da clorpromazina como agente antibacteriano

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Inhibition of Human ether-a-go-go-Related Gene K⁺ Channel and I_Kr of Guinea Pig Cardiomyocytes by Antipsychotic Drug Trifluoperazine