CLINICAL UPDATES ON DRUG – INDUCED CARDIOTOXICITY

CLINICAL UPDATES ON DRUG - INDUCED CARDIOTOXICITY

Ashif Iqubal ¹, Syed Ehtaishamul Haque^*2, Sumit Sharma ², Mohd. Asif Ansari ², Vasim Khan ² and Mohammad Kashif Iqubal ³

Translam Institute of Pharmaceutical Education and Research ¹, Mawana Road, Meerut - 250001, Uttar Pradesh, India.

Department of Pharmacology ², Department of Pharmaceutics ³, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi - 110062, Delhi, India.

ABSTRACT: Cardiotoxicity associated with the clinically used drugs is a global concern of safety for healthcare professionals. Various animal models have been used to study the drug-induced cardiotoxicity but the exact molecular involvement of toxicity is not much clear. Despite the recurrent occurrence of toxicities, drugs such as doxorubicin, calcium channel blockers, antiarrhythmics and immunomodulators are regularly used. Anticancer drugs mainly anthracyclines, 5- fluorouracil and cyclophosphamide exert prominent cardio-toxicity. Till date, there is only one drug approved for doxorubicin-related cardiotoxicity i.e. dexrazoxane. Few other drugs are used routinely  by clinicians to reduce the severity of toxicity which includes ACE inhibitors, L-carnitine, probucol, CoQ₁₀, N-acetylcysteine, Vitamin E and deferoxamine, whereas antidepressants drugs, specifically tricyclic antidepressants are potential candidates for cardiotoxicity. Calcium channel blockers, antiarrhythmic and beta receptor antagonist aggravate cardiac heart failure (CHF) and left ventricular arrhythmia. Interferons, mainly interferon-α is also associated with prominent and dose-dependant toxicity. Some other drugs like zidovudine, chloroquine, cocaine, minoxidil, ketoconazole, prostaglandin E2 and anagrelide are also reported to have cardiotoxic effects. A complication associated with the use of these drugs include hypoxia, coronary ischemia, calcium overload, oxidative stress, contractile dysfunction, left ventricular arrhythmia and cardiomyopathy

Anthracycline,

Interferon-α, Tricyclic

antidepressant, Arrhythmia,

Left ventricular dysfunction, Oxidative stress

INTRODUCTION: Cardiotoxicity is the common side effect of many drugs ¹ among which anticancer drugs, specifically anthracycline class of drugs exert severe cardiotoxicity ². Other drugs that cause cardiotoxicity are amphetamine, mitomycin, paclitaxel and zidovudine ^{3, 4}. The common mechanism leading to cardiotoxicity is oxidative stress, generation of free radicals and hypoxia ⁵.

Long-term exposure to cardiotoxic drugs further causes apoptosis and deregulation of myo-contractility. Cardiotoxic effect of drugs can be understood in two ways. (1) Drugs causing cardiac injury by affecting the performance of cardiac muscles. (2) By altering the ion channels and pump (voltage-gated sodium and potassium ion channel and Na⁺ - K⁺ ATPase pump) ⁴. Exposure to the cardiac-toxic drugs induces prolong cardiac repolarization (QT interval) and causes arrhythmia (Torsades de pointes) ⁴. Since these drugs causes cardiotoxicity as side effect, they can be used as cardiotoxicity inducing agents in preclinical experimental models ⁶. In this review we are going to focus on the Cardiotoxicity of drugs only and not the experimental models.

List of cardiotoxic drugs is shown in Table 1 and effect of cardiotoxic drug is displayed in Fig. 1 ⁷.

FIG. 1: EFFECT OF CARDIOTOXIC DRUGS ON HEART THROUGH DIFFERENT MECHANISMS

TABLE 1: LIST OF CLINICALLY USED DRUGS THAT EXERT CARDIOTOXIC EFFECT ⁸

MAO: Monoamine oxidase, AML: Acute myeloid leukemia, CML: Chronic myeloid leukemia, HAART: highly active antiretroviral therapy, UC: ulcerative colitis, PD: Parkinson’s disease, HRT: Hormonal replacement therapy, CHF: Congestive heart failure, COX: cycloxygenase

1. Anthracycline and Cardiotoxicity: Anthracycline class of drugs are the first line anticancer drugs but their usage are limited due to cardiotoxicity ⁹. Doxorubicin (adriamycin) and daunorubicin (daunomycin or rubidomycin) are two members of anthracycline group ¹⁰. These two drugs are obtained from actinobacteria ‘Streptomyces peucetius’ ¹¹. Anthracycline-induced cardiotoxicity can be acute which may cause arrhythmia, myocarditis, pericarditis or acute left ventricular failure. These symptoms subside just after withdrawal of treatment but restrict the further use of the drug ¹².

Anthracycline can also cause cardiomyopathy on the chronic use and sometime late-onset of severe arrhythmia and ventricular dysfunction has been seen ¹². It has been observed that rate of survival with anthracycline is much lesser than those of ischemic or dilated cardiomyopathy ¹³. Doxorubicin induced cardio-toxicity is dose dependent and controlled monitoring of dose is the best possible way to prevent toxicity ¹³. Now-a-days echocardiography is used to monitor doxorubicin-induced cardiotoxicity and this is considered as gold standard test ¹⁴.

1.1 Mechanism of Anthracycline - Induced Cardiotoxicity: Generally, chemotherapeutic drugs induced cardiotoxicity is associated with the myocardial cell loss, apoptosis or necrosis which may be mediated by oxidative stress directly or indirectly ¹⁵. In practice, determination of exact mechanism of doxorubicin-induced cardiotoxicity is not possible because most of the time patient are on multiple therapies ^{16, 17}. There are four hypothesis proposed on the subject of anthracycline-induced cardiotoxicity ¹⁸.

(a) Iron and free radical theory in which occurrence of high oxidative stress and depletion of endogenous antioxidant is observed. Myocardium mitochondria are the central point of oxidative stress ¹⁸.

(b) Metabolic hypotheses in which C-13 alcoholic metabolite of anthracycline acts on the myocardium and hamper the myocardial energy pathway and intracellular calcium concentrations ¹⁸.

(c) Unifying hypothesis in which C-13 alcoholic metabolite is further acted by oxidative stress which results in increased calcium concentration at the interior of myocardial fiber and damages the cell. This may further enhance the lipid peroxidation and loss of selective membrane permeability ¹⁸.

(d) Apoptosis hypothesis in which there is upregulation of pro-apoptotic markers like Bax, caspase and cytochrome c, whereas downregulation of anti-apoptotic markers like Bcl-2, Akt, and PIKT3 pathway ¹⁸.

Keeping all these theories in view, the role of free radicals occupy the central position. It has been hypothesized that the oxidative stress not only causes myocardial death but directly affects excitation-contraction properties of cardiac muscles ^{9, 19}. Free radicals mainly nitrite free radicals are the major culprit of oxidative stress ²⁰.

1.2 Cardioprotective Agents Against Anthracycline - Induced Cardiotoxicity: Drugs used clinically for prevention of anthracycline (doxorubicin) induced toxicity are shown in Table 2.

TABLE 2: CLINICALLY USED DRUGS FOR PREVENTION OF ANTHRACYCLINE - INDUCED TOXICITY ^{21, 22}

Unfortunately, none of the drugs till date is clinically established as a cardioprotective agent against anthracycline (doxorubicin - induced toxicity) ²².

2. Cyclophosphamide and Cardiotoxicity: Cyclophosphamide is an alkylating agent that acts on 7 guanine residue ²³. The active metabolite of cyclophosphamide is responsible for anticancer activity ²⁴. However, cardiomyopathy which is likely to be diagnosed within 2 weeks of therapy is reported as a side effect ⁴. Cardiotoxicity of cyclophosphamide is due to the effect of toxic metabolite on endothelial cells that causes severe myopericarditis and myocardial necrosis ²⁵. If a patient suffers from congestive heart failure (CHF) and get exposed to cyclophosphamide, there is a high chance of death within two weeks ²⁶. In an in-clinic study, 19 women suffering from metastatic breast cancer were given cyclophosphamide at low dose with continuous infusion for 96 hours. It was observed that low dose for the longer duration of therapy increased the therapeutic response and chance of developing CHF ²⁶.
3. Paclitaxel and Cardiotoxicity: Paclitaxel belongs to taxane class of drugs that act by promoting the polymerization of tubulin ²⁷. Thus microtubule formed due to the activity of paclitaxel is unstable and interfere with the cell division at the interphase of the cell cycle. This interference finally leads to cell death ²⁷. Paclitaxel is the choice of drug in ovarian and breast cancer ^{28, 29}. Asymptomatic bradycardia is most common side effect ³⁰. 29% of patients undergoing paclitaxel therapy are likely to suffer from bradycardia ^{31, 32}. In a study, combined therapy of doxorubicin with paclitaxel induces CHF in six patients out of ³³. This occurrence of 18% CHF in patient raised a valid question for combined therapy of paclitaxel and doxorubicin ³³.
4. Mitoxantrone and Cardiotoxicity: Mitoxantrone is structurally similar to doxorubicin ³⁴. This drug is reported to be associated with left ventricular heart failure ³⁵. In a study when mitoxantrone was used in 805 patients, 1.5% of patient developed CHF, whereas another 1.5% of the patient showed decreased left ventricular ejection fraction ³⁶. In conclusion, mitoxantrone has potential to induce cardiotoxicity and caution must be taken while using it.
5. Antimetabolite [5 –fluorouracil (5-FU), cytarabine and Capecitabine] and Cardiotoxicity: Among all antimetabolites, 5-FU is most extensively studied drugs in term of cardiotoxicity ³⁷. It has a direct effect on myocardial cells and on endothelial cells ³⁸. Mononuclear inflammations and myocardial necrosis have been observed in a patient who died from myocardial infarction followed by 5-FU therapy ³⁹. 5-FU also induces myocardial hypoxia, CHF and dilated cardiomyopathy have been reported ³⁹. Capecitabine, on the other hand, causes ischemia ⁴⁰ and cytarabine has been reported for pericarditis ⁴¹.

Thus looking into features and shortcomings of these anticancer drugs, some newer drugs have been developed with the aim of targeted therapy ⁴². These drugs may offer an advantage in terms of selectivity for cancer cells and less systemic toxicity ⁴². Some of these drugs are trastuzumab, imatinib and bevacizumab ^{43 - 44}. Some of the targeting newer drugs also showed cardiotoxicity e.g., tyrosine kinase inhibitor (sunitinib and imatinib) have been reported with CHF and hypertension ⁴⁵.

6. Antidepressant Drugs and Cardiotoxicity: In today’s scenario, depression is getting common etiology in most of the chronic disorders ⁴⁶. More often antidepressant drugs are used by clinicians ⁴⁷, which are of 3 major classes (1) tricyclic antidepressant (TCA) (2) selective serotonin reuptake inhibitor (SSRIs) and (3) monoamine oxidase inhibitor (MAO inhibitors) ²⁶. Among these three classes of drugs, with TCA such as (amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline protriptyline and trimipramine), the related cardiotoxicity is more common ⁴⁸. Nearly 20% of the patient often suffers from postural hypotension ⁴⁹. This side effect becomes more severe when the patient has existing cardiac co-morbid complications ⁵⁰. There are reports of altering atrioventricular conduction ⁵¹. A possible mechanism was supposed to be a prolongation of the duration of QRS interval ⁵². Sudden death has also been reported with the use of antidepressant drugs ⁵³. TCA is extensively concentrated in the myocardium ⁵⁴ and it causes cardiotoxicity by interfering with reuptake of adrenergic amines ⁵⁵, altering myocardial membrane permeability ⁵⁵ and by direct action on myocardial ⁵⁵. Finally, TCA leads to altered cardiac rhythm and myocardium contractility ⁵⁵. There are published evidence of CHF with a number of TCA ⁵⁶. On the other hand, SSRIs are related with a lesser incidence of cardiac side effect ⁵⁷. Although few study has been performed on the cardio-toxicity of SSRIs ⁵⁸.
7. Calcium Channel Blockers and Cardiotoxicity: Calcium channel blockers (CCBs) are one of the extensively used drugs in cardiac complications, mainly in angina pectoris ⁵⁹. There is an area of debate on the use of CCBs in patients with existing left ventricular dysfunction ⁶⁰. Clinically used CCBs are classified into three groups ²⁶.

(1) Phenylethylamine viz. verapamil. (2) dihydropyridines viz. nifedipine, and (3) benzothiazepines viz. diltiazem ²⁶. There is a report of cardiotoxicity with the use of CCBs which include negative ionotropic effect, activation of rennin-angiotensin system and alteration in membrane calcium transport ⁶¹. There is always a high chance of marked hemodynamic alteration in patients of CHF taking CCBs ⁶². In a multicentre dilitiazem post-infarction trial (MDPIT), risk of CHF was found to be increased ⁶³. It has been seen clinically that the chronic use of nifedipine in a patient of existing CHF exert deleterious effects ⁶⁴.

8. Antiarrhythmic drugs and Cardiotoxicity: Adverse effect related to antiarrhythmic drugs is related to its cardio depressant and negative ionotropic effect ⁶⁵. If the patient is already suffering from left ventricular dysfunctions, antiarrhythmic drugs can further worsen the situation ⁶⁶. Negative ionotropy of drugs vary from class to class, as class III antiarrhythmic drugs are devoid of negative inotropy ⁶⁷. Antiarrhythmic drugs induced negative inotropy is regulated by an alteration in intracellular calcium concentration ⁶⁸. There are randomized double blinded placebo controlled trials which showed the increased risk of CHF in the patients who were taking antiarrhythmic drugs ⁶⁹. Thus it can be concluded that almost all antiarrhythmic drug have potential to exert a negative inotropic effect, therefore, utmost caution and monitoring is required while using antiarrhythmic drugs ⁶⁵.
9. Beta - Adrenoceptor Antagonist and Cardiotoxicity: Beta - Adrenoceptor antagonists are commonly known as beta blockers. These drugs cause negative chronotropic and inotropic effects and exacerbate CHF ⁷⁰. Interestingly when beta blocker was used topically for treatment of glaucoma, it additionally caused CHF ⁷¹. In an epidemiological study, no association between the use of topical beta blockers and CHF was found ⁷². Similarly, a trial with carvedilol revealed the reduced mortality in patients suffering from CHF ²⁶. Thus in order to control beta blocker induced cardiotoxicity (CHF), the initial dose should be low and can be gradually increased ²⁶.
10. Interferon and Cardiotoxicity: There are three types of interferon used clinically i.e. interferon alpha, beta and gamma ⁷³. Interferon-alpha has been reported with a cardiotoxic effect which includes hypertension and arrhythmia starting from 1^st day of treatment ⁷⁴. It has been reported that almost 5 - 15% of patients suffer from interferon-mediated cardiotoxicity ⁷⁵. Other cardio-toxicities of interferon include cardiomyopathy and cardiac ischemia ⁷⁶. The possible mechanism proposed for the interferon alpha - induced cardiotoxicity is hypoxia, interference with energy metabolism and increased oxygen demand ⁷⁷.
11. Interleukin-2 (IL-2) and Cardiotoxicity: IL-2 is an approved drug for the treatment of metastatic renal cell carcinoma. IL-2 is associated with deleterious cardiovascular side effects ⁷⁸. Reversible left ventricular dysfunction, tachycardia and hypotension are more often reported with the use of IL-2 ⁷⁸. Use of IL-2 initiates the production of cytokines which further affect myocardium contractility ⁷⁸.
12. Amphetamines / Methamphetamines and Cardiotoxicity: Amphetamine class of drugs are the common drugs used by athletes and often associated with doping ⁷⁹. These drugs act centrally and cause stimulation which includes euphoria, intensifies emotions and increases sexuality ⁸⁰. This drug enhances neuronal reuptake of norepinephrine, serotonin and dopamine ⁸¹. A clinical study has reported the incidence of acute coronary syndrome in 25% of patients taking these drugs ⁸². Methamphetamine is reported to be associated with 18% and 40% of incidence of cardiomyopathy ^{83, 84}. Similarly, in other clinical study methamphetamine is associated with the incidence of 40% cardiomyopathy ⁸⁴. There was an animal study which supported the fact that repeated administration of methamphetamine caused cardiac hypertrophy, necrosis, myocarditis, inflammation, left ventricular dysfunction and left ventricular dilatation ⁸⁵. Amphetamine and methamphetamine when administered metabolize into catechol that further causes oxidative stress and cardiomyopathy ⁸⁶.
13. Cocaine and Cardiotoxicity: Cocaine is an alkaloid obtained from Erythroxylon coca which is a native plant of South America ⁸⁷. Initially, it was used as a local anaesthetic but later its use as an ingredient in cola drink started ⁸⁸. Pharmacology of cocaine consists of inhibition of catecholamine uptake by dopamine and norepinephrine transporter at the pre-synaptic neurons. This results in the accumulation of catecholamines at the postsynaptic neuron ⁸⁹ which causes increased psychomotor and sympathetic activity ⁸⁹. Cocaine also causes the release of norepinephrine and epinephrine from the adrenal medulla that result in severe vasoconstriction ⁸⁹. Use of cocaine is associated with myocardial ischemia or myocardial infarction ⁹⁰. Cocaine also causes tachycardia and increases systolic - diastolic blood pressure ⁹¹. Chronic use of cocaine causes vasoconstriction of coronary artery and thrombosis which together decreases oxygen supply to the myocardium and induces myocardial ischemia ⁹¹. Acute administration of cocaine causes an increase in intracellular calcium concentration and stimulates arrhythmia ⁹². Literature supports four mechanisms for the cardiotoxicity of cocaine.

13.1 Promotion of Intracoronary Thrombus Formation: Cocaine administration causes platelet aggregation and increases thromboxane - A2 production which together contributes to the development of cardiomyopathy and left ventricular dysfunction ⁹³.

13.2 Sympathomimetic Effect of Cocaine: Cocaine use results in activation of the beta-adrenergic receptor and increases myocardial contraction which finally leads to increased blood pressure and increased wall stress ⁹³.

13.3 Increased Calcium Flux: Increased myocardial calcium flux into the myocardial cell causes membrane instability and arrhythmia ⁹³.

13.4 Electrophysiological Effects: Use of cocaine causes prolongation of PR, QRS and QT duration that result into arterial fibrillation and tachycardia ⁹³.

14. Anabolic - Androgenic Steroids and Cardio-Toxicity: Inappropriate use of anabolic steroid is associated with left ventricular hypertrophy ⁹⁴. Anabolic steroid when administered, binds with androgenic receptors in the heart and in arteries ⁴. Anabolic steroid causes hypertension, dyslipidemia atherosclerosis and impaired contraction-relaxation ⁹⁵. Animal studies have shown the increased risk of cardiomyopathy and apoptosis in cardiac cells ⁹⁶. Further, use of anabolic steroid causes the discrete release of calcium from sarcoplasmic reticulum which additionally worsens the situation of arrhythmia and cardiomyopathy ⁹⁵. Some other complications associated with the use of steroid includes endocardial and myocardial fibrosis, cardiac steatosis, myocardial necrosis, coagulation and coronary atheroma ³.
15. Alcohol Abuse / Heavy Metals and Cardio-toxicity: Alcohol abuse primarily affects the central nervous system but it also exerts direct cardiotoxic effects ^{97, 98}. There are documented evidence for dose-related cardiotoxicity for ethanol that includes left ventricular dysfunction and cardiomyopathy ⁹⁹. Alcohol consumption affects the myocardial contractility, systolic-diastolic deregulations and abnormal rhythm ¹⁰⁰. There are also documented evidence for dose-related cardiac depression ¹⁰⁰. Ethanol when exceeds the limit of 75 mg/100 ml in plasma, the force of contraction reduces significantly ¹⁰¹. Some heavy metals such as cadmium, lead, and cobalt also causes cardiotoxicity ¹⁰². These heavy metal causes a structural change in cardiac cells, alter myocardial contraction and deregulation of some essential enzymes in heart muscles ¹⁰².

15.1 Trigger of Torsade de pointis and Cardiotoxicity: QT prolongation is a standard parameter to study cardiac abnormalities ¹⁰³. Further, prolongation of QT may be responsible for the sudden death and is called Torsade de Pointes ¹⁰⁴. This type of arrhythmia is defined as the polymorphic ventricular tachycardia ¹⁰⁵. Torsades de pointis are very complicated and serious situation which often shift to ventricular fibrillation ¹⁰⁶. Drugs associated with increased risk of Torsade de Pointes are shown in Table 3 ¹⁰⁷.

TABLE 3: DRUGS ASSOCIATED WITH INCREASED RISK OF TORSADE DE POINTES ¹⁰⁷

CONCLUSION: Now-a-days cardiac complication is increasing day by day. Polypharmacy approach, on the other hand is responsible for the occurrence of secondary disorders such as hypertension and arrhythmia. There are many drugs which are co-administered with existing therapy and further worsen the cardiac complications. Beta blockers, calcium channel blockers, antiarrhythmic drugs, anticancer drugs and immunomodulatory drugs are routinely used by the clinician, thus appropriate monitoring is a prerequisite for the use of these drugs. Particularly in patients with left ventricular dysfunction, utmost precaution should be taken for cardiac toxicity of prescribed medicine. Although, drug - induced cardiomyopathy doesn’t occur frequently, a regular monitoring is advised to prevent any such situation while using the discussed therapeutic agents.

ACKNOWLEDGEMENT: The authors would like to thank Department of Pharmacology, Jamia Hamdard for providing the facilities.

CONFLICT OF INTEREST: Nil

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     How to cite this article:

     Iqubal A, Haque SE, Sharma S, Ansari MA, Khan V and Iqubal MK: Clinical updates on drug-induced cardiotoxicity. Int J Pharm Sci Res 2018; 9(1): 16-26.doi: 10.13040/IJPSR.0975-8232.9(1).16-26.

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