B. Chandru1, D. Suryaprabha2,*

1 Pharm D-Internship, Kauvery Hospital, Cantonment, Trichy, India

2 Chief Clinical Pharmacist, Kauvery Hospitals, India

*Correspondence: Tel.: +91 98414 86267; email: [email protected]

Comprehensive review of Drug-Induced Cardiotoxicity

Abstract

Objective: The objective of the paper is to discuss drugs that induce cardiotoxicity, and their mechanisms.

Methods: Drugs that cause cardiotoxicity interrupt the key myocardial functions through various mechanisms some of which find mention in the paper.

Conclusion: Drugs causing cardiotoxicity may cause life-threatening complications. We can prevent this by safe dosage and continuous clinical monitoring of patients at risk.

Keywords: Cardiotoxicity, Mechanisms, Chemotherapeutic drugs, Myocarditis, QT prolongation, therapeutic management

Background

Cardiotoxicity refers to potential harm to the heart, and is a most common adverse drug effect. Numerous drugs have shown to have the potential to induce lethal arrhythmias by affecting cardiac electrophysiology. However, a substantial number of drugs can also affect cardiac function in other ways including heart failure.

The mechanisms are:

  • Causing cardiac injury by affecting the performance of cardiac muscles.
  • By altering the ion channels and pump (voltage-gated sodium and potassium channel and Na+ – K+ ATPase pump)
  • Byinducing prolonged cardiac repolarization (QT interval) and causing potentially fatal arrhythmias, eg- Torsades de pointes [1]

This paper lists some commonly used drugs which have the potential to cause cardiotoxicity.

The paper also mentions the possible mechanisms. Toxicity has previously led to the post-marketing withdrawal of numerous pharmacologically active drugs and limits the efficacy of other clinically useful ones. [2]

How does cardiotoxicity affect the body?

  • Left ventricular failure
  • Myocardial ischemia
  • Pericarditis
  • Myocarditis
  • Coronary artery disease
  • Hypertension
  • Thromboembolism
  • Asymptomatic diastolic dysfunction
  • Heart valve disease. [2]

Mechanism of cardiotoxicity

Drugs that cause cardiotoxicity interrupt key myocardial functions through disrupting electrophysiology, mitochondria, growth factors, contractility, cytokine regulation etc[3].

Mechanism-of-cardiotoxicity

Fig 1. Cardiotoxicity-Inducing mechanisms [4].

Table 1. Mechanisms and prescribing conditions of the drugs causing cardiotoxicity

DrugsIndicationsCardiotoxic Side EffectsMechanism Of Cardiotoxicity
Antineoplastic Agents
BevacizumabColorectal Cancer, Renal Cell CancerHeart FailureDisruption Of Cardiomyocyte Survival Via Vegf Signaling Inhibition
CisplatinBladder and Ovaries or Testicle CancerArrhythmias, Myocardial Ischemia, Heart FailureTxa2 Activation Leads To Cardiac Remodelling, Electrolyte Imbalance
DoxorubicinALL, AML, and Breast cancerArrhythmias, Heart FailureMyocardial Ischemia, Heart Failure
DaunorubicinALL and AMLArrhythmias, Heart FailureMitochondrial Toxicity, Oxidative Stress Leading To Apoptosis
VinblastineHodgkin's LymphomaMyocardial Ischemia, Heart FailureApoptosis of Cardiac Endothelial Cells[7]
Anti-Inflammatory Agents
DiclofenacNSAIDMyocardial InfarctionBlocking Prostacyclin Synthase
ibuprofenNSAIDMyocardial Infarction, HypertensionBlocking Prostacyclin Synthase
naproxenArthritismyocardial infarctionBlocking Prostacyclin Synthase [4]
Antiarrhythmic Agents
AmiodaroneAntiarrhythmicsQT prolongation , ArrhymiasisBlocking Sodium and Calcium channels [8]
Central Nervous System Agents
ClozapineAntipsychoticsMyocarditis, CardiomyopathyUnknown Mechanism
ErgotamineMigraineValvular Heart DiseaseInduction of Fibrosis via HTR2B-Induced Activation of TGF-β Signaling
FluoxetineDepression, OCD, and pain disorderBradycardiainhibition of ICaL, IKr; hERG Trafficking Inhibition
HaloperidolMood disorder and schizophreniaQT prolongation, TdP, Sudden cardiac deathInhibition of IKr, INa, ICaL
LignocaineLocal AnaestheticsBradycardia, Cardiac arrestInhibition of Voltage-Gated Sodium Channel, Mitochondrial Toxicity [4] [9]
Gastrointestinal Agents
CisaprideGERDVentricular Arrhythmia, Qt Prolongation, Tdp, Cardiac ArrestInhibition of IKr
LoperamideDiarrhea from Crohn's Disease, Ulcerative ColitisCardiac Arrest, Qt Prolongation, Ventricular Tachycardia, TdpInhibition Of Voltage-Gated Calcium Channels
OmeprazoleGERDAcute Myocardial Infarction, Heart FailureDisruption Of No Synthesis Via Adma Production
Antiallergic Agents
DiphenhydraminePruritus Of Dialysis Patients and InsomniaQT prolongationInhibition Of Ikr
Anti-Infective Agents
AzithromycinAntibioticsQt Prolongation, Tdp, Cardiac DeathMitochondrial Toxicity [10]
ClarithromycinAntibioticsQt Prolongation, Myocardial Infarction, Arrhythmias, Cardiac DeathMitochondrial Toxicity
ErythromycinAntibioticsQt Prolongation, Ventricular Tachycardia, Tdp, Ventricular FibrillationMitochondrial Toxicity
Anti-Diabetic Agents
SaxagliptinAnti-DiabeticsHeart FailureUnknown Mechanism[4]

Who are at risk of cardiotoxicity?

Cardiotoxicity highly depends on exposure level (especially overdose) and duration of the treatment. Some drugs may cause cardiotoxicity only after prolonged use [11]

Prevention and Treatment

Cardiotoxicity is a life-threatening condition, so preventive measures should be taken to avoid complications.

Risk Factors

What puts patients at risk of Drug-Induced Cardiotoxicity
Patient's age at time of exposure (below 4 years and old age)Hypertension
Female genderObesity
Black ethnicityDiabetes
Class of chemotherapeutic agentDyslipidaemia
Total cumulative dosePhysical inactivity
Concomitant radiotherapy/cardiac irradiationSmoking
History of heart disease or left ventricular dysfunctionGenetic predisposition
Abnormal cardiac imaging or biomarkers levelsCVD

Patients who are undergoing chemotherapy, and are on cardiotoxic risk drugs for long term, should be on regular monitoring to prevent cardiac failures. Reducing the dosage of the drugs and avoiding inappropriate duration for certain drugs greatly help in prevention. [12]

Cardiotoxicity can be treated based on its clinical manifestation. Cardiotoxicity caused by common medications can be treated by following standard cardiac disease guidelines.

Conclusion

Cardiotoxicity is one of the serious complications of cancer treatments.

Many drugs have the potential for causing cardiotoxicity.

Rational use of every drug and awareness of cardiotoxicity precent adverse cardiac events.

We can prevent cardiotoxicity by safe dosage and continuous clinical monitoring patients at risk.

References

  • Ashif I, et al. Clinical updates on drug-induced cardiotoxicity. Int J Pharmaceut Sci Res. 2018;9(1):16-26.
  • Kelleni MT, et al. Drug Induced Cardiotoxicity: Mechanism, Prevention and Management. Cardiotox. 2018
  • Nne Zwartsen, et al. Cardiotoxicity screening of illicit drugs and new psychoactive substances (NPS) in human iPSC-derived cardiomyocytes using microelectrode array (MEA) recordings. J Mol Cel Cardiol 2019;136:102-112.
  • Polina Mamoshina, et al. Toward a broader view of mechanisms of drug cardiotoxicity. Cell Rep Med. 2021;2(3):100216.
  • Varga ZV, et al, Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol. 2015;309(9):H1453-67.
  • Braumann S, et al. Molecular mechanisms underlying cardiotoxicity of novel cancer therapeutics. J Thorac Dis. 2018;10(Suppl 35):S4335-S4343.
  • Perez IE, et al. Cancer Therapy-Related Cardiac Dysfunction: An Overview for the Clinician. Clin Med Insights Cardiol. 2019;13:1179546819866445.
  • MladÄ›nka P, et al. TOX-OER and CARDIOTOX Hradec Králové Researchers and Collaborators. Comprehensive review of cardiovascular toxicity of drugs and related agents. Med Res Rev. 2018;38(4):1332-1403.
  • Weill A, et al, Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus. Pharmacoepidemiol Drug Saf. 2010;19(12):1256-62.
  • Atli O, et al. Evaluation of azithromycin induced cardiotoxicity in rats. Int J Clin Exp Med. 2015;8(3):3681-90.
  • Kremer LC, et al. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: a systematic review. Ann Oncol. 2002;13(6):819-29.
  • Ian Osoro, et al, Prevention and management of anthracycline induced cardiotoxicity: A review. Health Sci Rev. 2022;5:100070.
  • Pai VB, et al. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000;22(4):263-302.
B.-Chandru

B. Chandru

Pharm D Internship

D.-Suryaprabha

D. Suryaprabha

Assitant Manager-Clinical Research

 

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