Table 1.

List of drugs withdrawn from the market due to cardiovascular toxicity and their association with mitochondrial toxicity.

Medicinal Product	Class	Mechanism of Action	Launch Date	Year Withdrawn	Side Effects on Cardiac Function	Mitohondrial Toxicity
Amfepramone	Psychostimulant	Norepinephrine-releasing agent	1957	1975	-	Unknown
Benfluorex	Psychostimulant, anorectic, and hypolipidemic	Blocking of 5-HT2B	1976	2009	Valvular heart disease	Decrease in CPT I expression [46]
Emetine (ipecac syrup)	Emetic	Stimulation of the CTZ, local irritation	1912	1982	-	Unknown
Mephenesin	Muscle relaxant	Spinal reflex inhibition	1948	1976	-	Unknown
Rofecoxib	NSAID	COX-2 inhibitor	1999	2004	MI, cardiovascular thrombotic events, sudden death	Unknown
Adenosine phosphate	Antiarrhythmic	Direct nodal inhibition	1930	1973	-	Unknown
Alphacetylmethadol	Analgesic	OP1 receptor agonist	1993	2003	-	Unknown
Bepridil (Bepridil Hydrochlonde)	Antiarrhythmic, antianginal	Calcium channel blockers	1981	2004	Prolonged QT, TdP	Unknown
Budipine	Antiparkinsonian	Muscarinic and NMDA receptor antagonist	1979	2000	-	Unknown
Cliobutinol	Antitussive	Unclear	1961	2007	-	Unknown
Dofetilide	Antiarrhythmic	Inhibition of KCNH2, KCNK2, KCNJ12	1999	2004	QT prolongation, TdP	Unknown
Dolansetron	Propulsive	5-HT3 receptor antagonist	1997	2011	-	Unknown
Encainide	Antiarrhythmic	Na channel blocker	1985	1991	QT prolongation, TdP	Unknown
Grepafloxacin (Grepafloxacin Hydrochloride)	Antimicrobial	Inhibition of DNA gyrase	1997	1999	QT prolongation	Unknown
Indoramin	Vasodilator	Alpha-1 adrenoceptor antagonist	1981	2011	-	Unknown
Isoprenaline	Cardiac stimulant	Non-selective beta-adrenergic agonist	1949	1992	-	mPTP opening [47]
						Inhibition of OXPHOS [48]
Levacetylmethadol	Antidote	Mu-opioid receptor agonist, nicotinic acetylcholine receptor antagonist	1995	2001	-	Unknown
Nifedipine (10 mg)	Antihypertensive, antiemetic	Calcium channel blockers	1975	1996	Hypertension, angina, MI, CHF	Inhibition of ATP synthase [48]
Orciprenaline (metaprotenerol)	Bronchodilator	β2 adrenoceptor agonist	1961	2009	Tachycardia, palpitations	Unknown
Pergolide Mesylate	Anti-parkinsonian	Dopamine receptor agonist	2002	2007	Valvular heart disease	Unknown
Rosiglitazone	Hypoglycemic	Gluconeogenesis decrease	1999	2011	CHF, MI	Inhibition of ETC [48]
						Increase in mitochondrial oxidative stress, impairment of mitochondrial bioenergetics [13]
						Inhibition of complex I; uncoupling of OXPHOS [13]
Sibutramine (Sibutramine Hydrochlonde Hydrate)	Psychostimulant	Serotonin-norepinephrine reuptake inhibitor	2001	2002	Myocardial infarction	Increase in ROS formation [49]
Technetium (99mTc) fanolesomab	Radiography	Radioisotope	2004	2005	Cardiopulmonary arrest	Unknown
Tegaserod (Tegaserod Maleate)	Antispasmodic	5-HT4 receptor agonist	2002	2007	HF, ischemia	Unknown
Terodiline	Antispasmodic	Calcium channel blockade, blocks cholinergic receptor	1965	1991	Ventricular tachycardia, cardiac death	Unknown
Sertindole	Antipsychotic	5HT and D2 receptor antagonist/blocking of DRD2,HTR2A, HTR2C, HTR6	1996	1998	QT prolongation, TdP, sudden cardiac death	Unknown
Cloforex	Psychostimulant	Similar to amphetamine	1965	1967	-	Unknown
Astemizole	Antihistamine	H1-receptor antagonist, inhibition of KCNH2	1977	1987	long QT syndrome, TdP	Unknown
Cisapride monohydrate	Prokinetic agent	5-HT4 receptor agonist; inhibition of KCNH2	1993	2000	Ventricular arrhythmia, QT prolongation, TdP, cardiac arrest	Unknown
Tranylcypromine	Antidepressant	MAOI	1961	1964	-	Unknown
Bromocriptine mesylate	Anti-lactation	D2 and D3 agonist	1976	1989	-	Swollen mitochondria [50]
Domperidone (injectable)	Propulsive	Dopamine receptor antagonist	1979	1985	-	Unknown
Mepazine	Antiepileptic	Unclear	1955	1970	-	Unknown
Clozapine	Antipsychotic	Blocking of DRD2, HTR2A, DRD1, DRD3, DRD4, HTR1A, HTR1B, HTR1D, HTR1E, HTR2C, HTR3A, HTR6, HTR7, HRH1, HRH4, ADRA1A, ADRA1B, ADRA2A, ADRA2B, ADRA2C, CHRM1, CHRM2, CHRM3, CHRM4, CHRM5	1972	1975	Cardiomyopathy, MI, myocarditis, arrhythmia, Prolonged QT, TdP, cardiomyopathy	Inhibition of the ETC [51]
						Increase in ROS formation, GSH depletion, mitochondrial dysfunction, and swelling [52]
Vincamine	Nootropic	Unclear	1955	1980	-	Unknown
Lysine amidotriazoate	Radiography	-	1975	1995	-	Unknown
Terfenadine	Antihistamine	H1-receptor antagonist	1985	1997	QT prolongation, TdP	Increase in mtROS formation [53]
						MMP collapse [54]
Naftidrofuryl oxalate (IV)	Vasodilator	5HT2 receptor antagonist	1974	1992	-	Unknown
Cobalt	Hematinic	As cobalamin	1951	1967	-	Interruption of TCA and interference with the MRC enzymes [54]
						MMP collapse [55]
Chloroform (trichloromethane)	Anesthetic	Depression of the respiratory centres	1847	1976	-	MMP collapse [56]
						Megamitochondria [57]
Dithiazanine iodide	Antihelminth	Interruption of glucose uptake in cells	1959	1964	Prolonged QT, TdP	Unknown
Epinephrine (topical)	Anesthetic	Vasoconstriction	1899	2004	-	Unknown
Methylhexanamine (DMAA)	Nasal decongestant	Norepinephrine and dopamine transporter blockade	1948	1983	-	Unknown
Dexfenfluramine	Psychostimulant	Serotonin receptor agonist	1995	1997	Valvular heart disease, cardiac fibrosis	Unknown
Fenfluramine	Psychostimulant	Serotonin receptor antagonist	1973	1997	valvular heart disease	Mitochondrial fragmentation [58]
Parecoxib	Analgesic	COX-2 inhibitor	2002	2005	-	-
Prenylamine	Antianginal	Calcium channel blocker	1960	1989	QT prolongation, sudden cardiac death, ventricular tachycardia, TdP	Inhibition of FAO [59]
Probucol	Antioxidant	Inductor of LDL catabolism	1980	1989	QT prolongation, arrhythmias	Unknown
Droperidol	Antipsychotic	Dopamine 2 receptor antagonist	1970	2001	-	Unknown
Valdecoxib	NSAID	COX-2 inhibitor	2001	2005	Cardiomyopathy, CHF, hypertension, angina, arrhythmia	Inhibition of OXPHOS, mPTP opening [16]
Celecoxib (Onsenal)	NSAID	COX-2 inhibitor	2003	2011	-	Decrease in mitochondrial complex IV activity and induces oxidative stress [14]
						Increase in ROS formation, MMP collapse, mitochondrial swelling, ATP depletion [60]
						Suppression of mitochondrial function [61]
Bismuth salts	Antidyspepsia	Unclear. Forms insoluble complexes	1875	1978	-	Unknown
Levarterenol	Vasopressor	L-norepinephrine analogue	1904	1973	-	Unknown
Pipradrol	Psychostimulant	Norepinephrine-dopamine reuptake inhibitor	1953	1982	-	Unknown
Pseudoephedrine	Sympathomimetic	Direct action on adrenergic receptors	1959	2008	-	Unknown
Gallopamil	Antiarrhythmic	Calcium channel blockers	1983	2001	-	Decrease in mitochondrial biogenesis and mass [62]
Chlorphentermine	Psychostimulant	TAAR1 agonist, blocking of 5-HTs	1962	1969	Pulmonary heart disease	Inhibition of OXPHOS, uncoupling of OXPHOS [63]
Thioridazine	Antipsychotic	5HT2 receptor antagonist	1959	2000	QT prolongation, TdP, sudden cardiac death	mPTP opening [64]
						MMP collapse [65]
Buflomedil	Vasodilator	A-adrenergic blockade	1970	2006	QT prolongation, cardiac arrest	Unknown
Ponatinib Hydrochloride	Antineoplastic	Multi-target kinase inhibitor	2012	2013	-	Impairment of respiratory chain, increase in ROS formation, MMP collapse, mitochondrial fission [66]
Levomethadyl acetate	Analgesic (central nervous system agents)	Activation of OPRM1	1993	2002	QT prolongation, TdP	Unknown
Mesoridazine Besylate	Antipsychotic		1970	-	-	Unknown
Clobutinol Hydrochloride	Antitussive	Inhibition of GABA receptors	1961	2007	QT prolongation	Unknown
Phentermine	Central nervous system agents	Inhibition of SLC6A2, SLC6A3, SLC6A4; blockingof MAOA, MAOB	1959	1997	Valvular heart disease	Unknown
Mibefradil	Antihypertensive	Calcium channel blockers	1997	1998	QT prolongation	Unknown
Sparfloxacin	Antibiotics	Inhibits DNA gyrase	1997	2001	QT prolongation	MMP collapse [67]
Etoricoxib	Anti-inflammatory agents	Inhibition of COX-2	2002	2007	thrombotic events	Inhibition of OXPHOS [16]
Propoxyphene	Central nervous system agents	Activation of OP1, OP2, OP3	1957	2010	QT prolongation, TdP	Unknown
Lidoflazine	Cardiovascular agents	Blocking of calcium channels	1973	1989	QT prolongation	Unknown