**6. Antipsychotic drug-induced cardiotoxicity**

Antipsychotic drugs have been used to treat psychosis caused by a variety of disorders such as bipolar disorder, delirium, paranoia, schizophrenia,

#### *Experimental Model of Cardiotoxicity DOI: http://dx.doi.org/10.5772/intechopen.101401*

substance-induced psychosis, Tourette's syndrome, dementia, Huntington's disease, multiple sclerosis, and parkinsonism. They come in a variety of forms and affect dopamine, serotonin, and other receptors as well as physiological systems. This can cause a wide range of negative effects, such as palpitations, akathisia, dystonia, tardive dyskinesia, orthostatic hypotension, tachycardia, arrhythmias, and heart failure [124]. Antipsychotics are grouped into two types: first-generation (typical, conventional or neuroleptics) antipsychotics (FGAs) such as butyrophenones, chlorpromazine, haloperidol, phenothiazines, thioridazine, and thiothixene, and second-generation (atypical) antipsychotics (SGAs) such as aripiprazole, asenapine, brexpiprazole, clozapine, iloperidone, lurasidone, olanzapine, paliperidon, quetiapine, risperidone, ziprasidone. They can have a variety of effects on cardiovascular function, including direct effects such as blocking cardiac muscarinic receptors, blocking 1-adrenoceptors, blocking sodium, potassium, and calcium channels, and blocking calmodulin, causing QT prolongation as well as indirect effects such as blocking 2-adrenoceptors in the central nervous system (CNS). Antipsychotic drug-induced toxic cardiomyopathy has also frequently been linked to myocardial infarction [125, 126].

Clozapine, the only drug approved for resistant schizophrenia, comes with a warning for an increased risk of fatal myocarditis [124, 127].

Cyclic antidepressants, such as tricyclic and tetracyclic forms, were among the first antidepressants to be developed. TCAs (tricyclic antidepressants) inhibit norepinephrine and serotonin reuptake, leading to an overproduction of these neurotransmitters in the presynaptic cleft [128]. They also inhibit postsynaptic histamine, alpha-1 adrenergic, and muscarinic-acetylcholine receptors [129]. These tricyclic antidepressants were approved by the FDA for the treatment of depression and anxiety disorders: amitriptyline, amoxapine, desipramine, doxepin, Imipramine, nortriptyline, protriptyline, and trimipramine [130].

Most mortality from arrhythmias, hypotension, QTc prolongation, myocardial depression, and ventricular fibrillation is caused by cardiac toxicity, which is the most common side effect of TCAs. TCAs lengthen the cardiac action potential by inhibiting cardiac sodium channels and slowing phase 0 depolarization [131].

Amitriptyline (AMT) intoxication is the third most prevalent cause of mortality among prescription medication-related toxicities, after sedative-hypnotic drugs and analgesic drugs [132].

Following are a few examples of *in vivo* models of antipsychotic drug-induced cardiotoxicity and protective agents based on the literature;

In a study conducted at the ERBAS Institute of Experimental Medicine, they investigated and compared the electrophysiological, immunohistochemical, and biochemical effects of metoprolol, lipid emulsion, and MgSO4 on AMT-induced cardiotoxicity. Thirty male Sprague-Dawley rats were used in the study. Five groups were given the following treatments: saline intraperitoneally (i.p.); AMT 100 mg/kg per os (p.o.) and saline i.p.; AMT 100 mg/kg p.o. and 5 mg/kg metoprolol i.p.; AMT 100 mg/kg p.o. and 20 ml/kg lipid emulsion. As a result of the study, the QT intervals were significantly prolonged in the AMT + saline group than in the other groups. The QT interval was significantly reduced in all the other groups when compared to the AMT + saline group. They reported that AMT has severe cardiotoxic effects and manifests with ECG abnormalities such as prolongation of QTc duration, which is crucial in cardiotoxicity. The study's findings also demonstrated that MgSO4 was more potent than other treatments in AMT-toxic rats in terms of shortness of QTc prolongation and immunohistochemical/biochemical effects [133].

In their research, Erbas and his colleague examined the impact of metoprolol and diltiazem on ziprasidone-induced QTc prolongation. For the experiment, 24 rats were divided equally into four groups: I, control, II, 3 mg/kg ziprasidone and saline, III, 3 mg/kg ziprasidone and 1 mg/kg metoprolol, IV, and 3 mg/kg ziprasidone and 2 mg/kg diltiazem. As a result, they observed that rats treated solely with antipsychotic drugs developed ECG abnormalities. When the QTc intervals of the four groups were compared, the QTc of the second group (ziprasidone + saline) was significantly prolonged than that of the control group. Moreover, in the study, metoprolol and diltiazem were found to have a beneficial effect on a prolonged QT interval [134].

A study on clozapine-induced cardiotoxicity was conducted using young male Wistar rats that were given clozapine (10, 15, and 25 mg/kg/day, i.p.) for 21 days. Clozapine, particularly at relatively high doses, was found to have a clear cardiotoxic effect after haemodynamic and echocardiographic studies were performed to assess cardiac functions. An increase in the serum activity of CK-MB (creatine kinasemyocardial band) and LDH (lactate dehydrogenase), two markers of cardiotoxicity, supported these findings [135].
