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Can cocaine damage your liver

NCBI Bookshelf. Cocaine is a benzoid acid ester that that was originally used as a local anesthetic, but is no longer used because of its potent addictive qualities. When given in high doses systemically, cocaine has mood elevating effects that have led to its widescale abuse.

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People believe taking both can boost the cocaine high and help avoid withdrawal. Keep reading to learn how cocaine and alcohol affect the body and what happens when you mix the two. Cocaine has been around for many years. The drug has anesthetic and stimulant effects.

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Drugs that can cause liver damage:

Oxidative stress OS is thought to play an important role in the pharmacological and toxic effects of various drugs of abuse. Herein we review the literature on the mechanisms responsible for the cardiovascular and hepatic toxicity of cocaine with special focus on OS-related mechanisms. We also review the preclinical and clinical literature concerning the putative therapeutic effects of OS modulators such as N-acetylcysteine, superoxide dismutase mimetics, nitroxides and nitrones, NADPH oxidase inhibitors, xanthine oxidase inhibitors, and mitochondriotropic antioxidants for the treatment of cocaine toxicity.

We conclude that available OS modulators do not appear to have clinical efficacy. Oxidative stress OS can be defined as an unbalance between the production of reactive oxygen and nitrogen species ROS and RNS and the compensatory response of physiological antioxidant mechanisms. The most important sources of ROS and RNS are represented by enzymatic reactions localized in the mitochondria, the microsomes cytochrome P enzymesthe cytosol such as xanthine oxidase XOand the membrane-associated protein complex with its cytosolic subunits NADPH oxidase Nox.

The production of ROS in the phagocytes depends on the activity of peroxidases such as myeloperoxidase and eosinophil peroxidase.

Oxidative medicine and cellular longevity

It has been suggested that OS plays an important role in the physiopathology of various apparatuses and organs including the cardiovascular system ischemia and reperfusion injury, heart failure, atherosclerosis, hypertension, etc. There is also evidence of ificant involvement of OS in the pharmacological and toxic effects of drugs of abuse and particularly of psychostimulants such as cocaine and methamphetamine [ 3 ].

It is of note that, in several studies, cocaine-induced OS was evaluated by the measurement of TBARS [ 4 — 9 ] which is considered inferior to other methods for lipid peroxidation like the evaluation of F2-isoprostanes [ 10 ].

In the present paper, we review the literature concerning the cardiovascular and hepatic toxicity of cocaine with special attention to the role of OS and the evidences about the possible modulators of OS which could have beneficial effects in cocaine users. The earliest case reports of cardiovascular toxicity attributed to cocaine date from the s [ 11 — 13 ]. Cocaine abuse is associated with both acute and chronic cardiovascular toxicity [ 14 — 16 ], including myocardial ischemia [ 1317 ] and infarction [ 18 ], arrhythmias [ 19 ], and cardiomyopathy [ 20 — 22 ].

Recent epidemiological data indicate that cocaine is responsible for a sizeable proportion of emergency department visits and of sudden deaths [ 2324 ]. Data from 19 European countries indicated more than cocaine-related deaths in [ 25 ].

Health consequences of drug misuse

The upward trend in cocaine-related chest pain and myocardial infarction cases has induced the America Heart Association to draft diagnostic and therapeutic guidelines [ 26 ]. Data from the relative National Cardiovascular Data Registry was recently published [ 27 ]. Histopathological studies have shown that cocaine can precipitate myocardial ischemia in the presence of coronary artery occlusion [ 28 ] as well as of normal coronary arteries [ 29 ].

A recent review [ 23 ] of 49 cocaine-related deaths identified coronary atherosclerosis, ventricular hypertrophy, cardiomegaly, myocarditis, and contraction band necrosis in almost a third of cases. The pathogenesis bases of cocaine-induced cardiovascular toxicity [ 143031 ] have been studied in detail [ 3233 ]. Cardiovascular cocaine toxicity can be related to its pathophysiological effects on the sinoatrial node, myocardium, and vasculature, including the coronary district.

Cocaine can damage the heart through a variety of mechanisms that have been elucidated only in part.

The liver’s role in the body

It has been proposed that these two effects may produce acute myocardial ischemia and infarction also in absence of long-term cocaine abuse, of abnormalities in the coronary arteries, and of other risk factors [ 3435 ]. Cocaine can exert its toxic effect on the heart also indirectly, through the actions of catecholamines, and in particular of norepinephrine.

Indeed, cocaine is known to block the reuptake of catecholamines by binding the transporters for dopamine DAT and norepinephrine NET [ 36 ]. Increased norepinephrine levels in the terminals of the sympathetic nervous system lead to activation of adrenergic receptors. In turn, oxygen deficiency may lead to myocardial infarction. Furthermore, the combination of the direct toxic effect of cocaine and those of norepinephrine may lead to complex arrhythmia [ 39 ]. In addition to producing oxygen imbalance, catecholamines may damage the myocardium via at least three additional pathogenetic mechanisms [ 3040 ].

Moreover, this mechanism [ 45 ], adding to the direct arrhythmogenic effects of cocaine described above, may facilitate the development of arrhythmias such as atrial fibrillation and ventricular tachycardia. A second pathway responsible for cardiotoxicity is related, as first hypothesized by Fleckenstein and Coworkers in [ 46 ], to catecholamines-induced calcium overload in cytosol and mitochondria of cardiomyocytes [ 41 ].

An indirect cardiotoxic effect of catecholamines may derive from action of their oxidation products, the aminochromes.

Notably, excessive level of circulating catecholamines and consequent saturation of the monoaminooxidase and catechol-o-methyl transferase systems may cause the increased formation of adrenochrome obtained by oxidation of adrenaline [ 4052 ] of 5,6-dihydroxymethylindole and of adrenochrome alkaline rearrangement product adrenolutin. In the heart the enzyme cytochrome c oxidase has been associated with adrenochrome formation [ 52 ].

Accordingly, increased levels of adrenolutin were observed in death-associated heart failure [ 54 ]. Moreover, aminochromes are known to induce redox cycling with consequent generation of ROS see below. More recently, OS and generation of ROS have been identified as one of the most important mechanisms of cocaine-induced cardiomyocyte toxicity [ 630315556 ]. Increased expression iNOS and decreased levels of myocardial SOD and catalase were found in the cardiomyocytes of patients with dilated cardiomyopathy related to chronic cocaine abuse [ 20 ].

The role of NADPH-driven superoxide production in cocaine induced cardiac dysfunction is well recognized [ 59 ].

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It is believed that Nox1, Nox2, and Nox4 are expressed ificantly in the vascular damage [ 6162 ] while experimental data in cardiomyocytes had demonstrated that the Nox subunit Nox1, but not Nox2 or Nox4, is implicated in norepinephrine-induced Nox-generated ROS [ 63 ]. Inhibition of Nox activity by apocynin prevented the increase in ROS production and cardiac dysfunction induced by chronic administration of cocaine in vivo in rats [ 64 ].

Moreover, Nox activity is associated with other ROS-inducing enzymatic sources such as xanthine oxidoreductase XOR : a fundamental role of XO was confirmed in an in vivo experimental liver of cocaine-induced diastolic dysfunction [ 65 ], in which treatment with XO-inhibitor allopurinol prevented the cocaine-increase in mitochondrial ROS levels.

Accordingly, in vivo administration of mitochondria-targeted antioxidant MitoQ had shown to prevent left ventricular Can diastolic dysfunction characterized by an increase in the index of LV relaxation, in LV end-diastolic pressure-volume relation, and in LV end-diastolic pressure induced in rats treated with cocaine for 7 days [ 67 ].

As mentioned cocaine, when the enzymatic catabolism of catecholamines is not sufficient, they can undergo chemical oxidation causing additional OS [ 40 ]. The implication of aminochromanes in the pathogenesis of cardiac diseases [ 5373 ] is also well recognized. Formation of superoxide anion due to an oxidation pathway that involves the formation of highly reactive intermediaries o -semiquinones and o -quinones [ 74 ] has been observed in both in vivo [ 75 ] and in vitro models [ your76 ].

The superoxide anion can cause the oxidation of epinephrine [ 527778 ] and of metal ions copper [ 79 ] and iron [ 77 ], enhancing the oxidation of catecholamines. Thus, iron chelation can protect against the cardiotoxicity induced by the metabolites of catecholamines: an in vitro study in rat ventricular cardiomyoblast assessing the potential cardioprotective effects of some chelating agents had suggested further investigation in vivo cocaine models [ 80 ].

Catecholamines metabolites can also reduce antioxidant defences by decreasing the levels of reduced glutathione GSH and increasing the oxidized glutathione GSSG content as observed in adrenaline-treated isolated rat cardiomyocytes [ 7479 ]. A further contribution in the pathogenesis of cocaine-induced vasoconstriction is due to its acute and chronic effect on endothelial cells function [ 84 ]. An impairment in endothelium-dependent vasorelaxation, assessed as a decrease in forearm blood flow in response to intraarterial acetylcholine and nitroprusside, was found in long-term users of cocaine [ 85 ].

Accordingly liver studies [ 8687 ] demonstrated a cocaine-induced endothelial dysfunction with a decrease in NO release and in the constitutive enzyme NO-synthase eNOS content, as well as an increase in endothelin-1 ET-1 production and ET-1 receptor type-A protein expression [ 84 ]. Can of circulating endothelial cells CECs indicating endothelial dysfunction was recently demonstrated in cocaine abusers [ 88 ]. Furthermore, enhancement of cocaine-induced vasoconstriction was observed after N G -nitro-L-arginine methyl ester-induced inhibition of NO synthesis in vitro [ 89 ].

Chronic cocaine exposure and consequent endothelial dysfunction may precipitate early atherosclerosis [ 93 ] and the persistence of endothelial cell damage beyond its acute effect on the damage vessels can further increase cardiovascular risk in cocaine abusers [ 8894 ]. Since that ET-1 increase was ificantly associated with atherosclerotic lesion [ 95 ], it may be argued that it plays a fundamental role in the cocaine-induced vasoconstriction at sites of ificant stenosis [ 96 ].

Although discrepant were also reported [ 97 ], probably due to methodological differences, there is some evidence indicating that cocaine may exert an inhibitory effect on the production of prostacyclin PGI 2 by endothelial cells [ 9899 ]. Another important factor that can contribute to cocaine prothrombotic action is its direct action on endothelial cells secretion of von Willebrand factor VWF. Indeed, a recent in vitro study [ ] demonstrated that cocaine and its metabolites induced VWF secretion in a concentration-dependent manner yours three endothelial cell types human umbilical vein, brain microvasculature coronary artery endothelial cells.

Whereas both experimental and clinical data agree on the fact that cocaine can affect endothelial function, leading to vasoconstriction, there is conflicting evidence about the direct effect of cocaine on platelets. Increased platelet activation was observed in vitro in rabbit platelet-rich plasma PRPpreincubated yours cocaine hydrochloride [ ] as well as in vivo in dogs treated with intravenous cocaine [ ]. The findings obtained with human platelets in vitro are less consistent. At concentrations comparable to the systemic concentrations produced by lethal doses, cocaine decreased platelet aggregation induced by agonists in PRP obtained from healthy human subjects [ ].

Finally, increased platelet expression of surface P-selectin was found in blood samples from chronic cocaine users [ ]. It is possible that these discrepancies were due to differences in substrate animal versus cocaine plateletsin model in vitro versus in vivoin methodology whole blood versus PRPand in the damages of cocaine used. In vivo studies in healthy subjects [ ] and in chronic cocaine user [ ], although not univocally [ ], gave evidence of activation of platelets, assessed by increase of P-selectin expression [ ] and of soluble Can, a transmembrane molecule mainly expressed by activated platelets [ ].

Due to physiological interaction of platelets with vascular endothelium and circulating blood cells such leukocytes, it may be argued that an indirect, rather Can a direct, mechanism of action is involved in the cocaine platelets activation. A further contribution may derive from VWF interaction with the platelet receptor GPIb and their subsequent activation [ ]. Some data in literature indicate a direct or an indirect cocaine action on endothelial cells, both on enzymes expression and on mitochondrial function. In bovine aortic endothelial cells, it has been observed that shear stress induced an enhancement of xanthine-dependent production [ ], associated with a decrease in xanthine dehydrogenase XDH protein.

Furthermore, inhibition of the Nox decreased XO levels and prevented the increase ofhighlighting the central role of Nox in modulating endothelial production of ROS. In agreement with this hypothesis, cocaine-induced cardiac dysfunction alteration of cardiac output and stroke volume was found to be associated with increased Nox and XOR activity in vivo study in rats [ 64 ]. Furthermore, apocynin or allopurinol treatment inhibited the cocaine-induced cardiac alteration and the myocardial production of confirming the role that Nox-derived ROS play in modulating ROS cocaine by XO [ 64 ].

As mentioned above, cocaine-induced decrease in endothelial NO release and in the constitutive damage eNOS content has been observed [ 84 your. A contribution to this cocaine endothelial toxic effect may derive from its increasing action in Nox, which in turn besides the increase in may induce oxidation of tetrahydrobiopterin, a cofactor of NO synthase: as a consequence eNOS uncoupling le to the observed reduction in NO synthesis and to an enhancement in [ ]. Besides the well-recognized energy-producing liver, notably mitochondria are the major liver of cellular reactive oxygen [ ] both in cardiomyocytes and in EC [ 40].

Which drugs can cause liver damage?

An important role of endothelial mitochondria in pathogenesis of endothelial dysfunction is due to their role in aling cellular responses, among which the production of ROS [ ]. Among the sources of mitochondrial ROS, the monoamine oxidase MAO family, located to the outer mitochondrial membrane, causing the oxidative deamination of catecholamines, in hydrogen peroxide H 2 O 2 formation [ ].

Accordingly, experimental data in literature indicate an increase in H 2 O 2 cardiac production after the sympathomimetic drug amphetamine administration [ ]. In this regard a recent in vitro study has demonstrated in human pulmonary EC [ ] exposed to cocaine a ificant increase in H 2 O 2 production; due to the modulating action of H 2 O 2 on endothelium functions such as endothelium-dependent vasorelaxation, apoptosis, and remodeling [ ] it may be argued that cocaine-induced increase in catecholamines and in the consequent MAO-mediated H 2 O 2 production in endothelial mitochondria could further enhance endothelial dysfunction, contributing to cocaine toxic effects on vascular district.

Modulation of oxidative stress: pharmaceutical and pharmacological aspects

Briefly, OS in the mitochondria may trigger the opening of mitochondrial transition pore that le to a further increase in ROS generation. RIRR phenomena have been recognized in both physiological promoting an elevation in the cell tolerance to OS, until the destruction of impaired-function mitochondria [ ] and pathological conditions such as cardiac ischemia-reperfusion [ ] associated with acute myocardial infarction.

Another possible source of ROS in endothelial mitochondria is Nox4 [ ], generating a higher hydrogen peroxide to superoxide ratio than Nox1 and Nox2. While a cocaine-induced increase in Nox has been demonstrated in cardiac tissue [ 64 ], to date no data in literature are present on the effects of cocaine on Nox at endothelial level.

Moreover a Nox increase and the consequent endothelial superoxide production were also found in bovine aortic endothelial cells exposed to oscillatory shear stress [ ]. Cocaine abuse is known to induce acute [ — ] and chronic [, ] liver toxicity. Clinical manifestations of cocaine-induced hepatic damage range from elevation of liver enzyme levels in chronic users [, ] to acute liver failure associated with hepatitis [ ], to fulminant liver failure associated with acute rhabdomyolysis [ ] or thrombotic microangiopathy [ ].

Histopathological examination has shown midzonal [ ] and periportal [ ] necrosis, as well as steatosis in the surviving hepatocytes [ ]. The involvement of OS in cocaine liver toxicity has been reviewed recently []. In vivo animal studies suggest the involvement of cocaine metabolites in the genesis of hepatotoxicity.

Inhibition of cytochrome P CYP mediated activation of cocaine metabolism produced a ificant inhibition of hepatotoxicity in mice in vivo [ ] and ex vivo in liver microsomes [ ], while in vivo induction of CYP activity enhanced the cocaine hepatotoxicity [ ]. Studies in mice demonstrated that cocaine reduces GSH levels in the liver [] and that depletion of intracellular GSH concentrations exacerbated cocaine hepatotoxicity [ ].