NEUROPHARMACOLOGY: HOW DRUGS CAN LEAD TO CARDIOTOXICITY
Cardiotoxicity is one of the most adverse drug reactions given that it causes dysfunction of the heart muscles. It causes the heart to become weaker and therefore limiting its ability to pump blood. Cardiotoxicity is a life-threatening condition given that it leads to cardiomyopathy and consequent heart failure. This report looks into how drugs cause cardiotoxicity with an emphasis on the mechanisms of toxicity and pathology associated with this process.
Clinical advancement is subject to the development of pharmacological interventions that have optimal treatment outcomes. Therefore fostering patient safety is critical in drug administration given that it determines adherence to treatment and consequent patient satisfaction. One of the limitations facing the efforts to ensure that drugs serve their predetermined purpose is the fact they contain toxins that have adverse implications on people’s cardiovascular systems (Burcham, 2014). For example, chemotherapy has emerged as a critical cause of cardiotoxicity given that the toxins contained in these drugs weaken the heart. It is vital to note that it is not about the amount of the drugs administered to the patient; rather it is the composition of these drugs that cause cardiotoxicity. Drug-induced cardiotoxicity is, therefore, one of the most notable barriers when it comes to novel drug development. Anthracyclines, cyclophosphamide, and 5- fluorouracil which are common anti-cancer drugs have been known to damage the heart by releasing toxins (Dipiro et al., 2014). They cause arrhythmias, left ventricular failure, myocarditis, or hypertension depending on the drugs’ toxicity. These implications can cause changes in the heart rhythm, lead to fatigue, shortness of breath, and heart failure. Apart from anti-cancer medications prostaglandin, tricyclic antidepressants, ketoconazole, chloroquine, minoxidil, anagrelide, and cocaine have been known to aggravate cardiotoxicity (Dipiro et al., 2014). They are known to cause structural and functional cardiac alterations which give rise to damages to the heart muscles and their functions.
Anthracyclines are the most cited drug categories when it comes to understanding the mechanisms of toxicity caused by drugs. Experts indicate the mechanism of drug-induced cardiotoxicity is multifactorial and hence there are numerous perspectives of looking into the issue. One of the mechanisms associated with this drug is that it induces the formation of reactive oxygen species which are associated with molecular cell death. Levis, Binkley, and Shapiro (2017) posit that Anthracyclines leads to the formation of free radicals which react with other molecules causing damage to DNA and RNA. Additionally, the formation of superoxide anion, hydroperoxide, and hydroxyl radical leads to the damage of macromolecules including lipids, proteins, and nucleic acids. Redox cycling via the mitochondrial respiratory chain leads to oxidative stress causing cellular membrane damage, cytotoxicity, and impaired mitochondrial function (Murabito, Hirsch, and Ghigo, 2020). Nitric oxide further worsens nitrosative stress by producing nitrogen species that are also toxic to the cells. This mechanism, therefore, ties anti-cancer drugs to the toxic metabolism reaction that induces reactive oxygen and nitrogen species (Burcham, 2014). These toxins cause cell damage in the heart and therefore leading to cardiotoxicity.
Another notable mechanism is that entailing how Anthracyclines target topoisomerase II (Top 2) and binds it to the DNA. This Top 2- DNA complex is affected by doxorubicin to implicate the efficacy of GTPase Rac1 in regulating DNA damage (Levis, Binkley, and Shapiro, 2017). Studies on doxorubicin-induced cardiotoxicity indicate that Rac1 deletion lead to myocardial dysfunction and attenuated apoptosis. It is also vital to point out that Anthracyclines are associated with a reduction in the population of cardiac progenitor cells. It, therefore, leads to an impaired response to pathologic stress and injury repair which is a critical limitation to the efficacy of the heart muscles. According to Levis, Binkley, and Shapiro (2017) the impaired vitro proliferation and decrease in population of C- kit* cardiac progenitor cells, therefore, causes cardiotoxicity. Another mechanism shown by studies indicates that increased intracellular calcium brought about by impaired sequestration and calpain‐dependent titin proteolysis causes cardiotoxicity. These dysfunctions are associated with Anthracyclines and they lead to impaired diastolic relaxation (Murabito, Hirsch, and Ghigo, 2020). They are the primary causes of abnormalities in diastolic function given that titin proteolysis causes cardiomyocyte cell death and myofilament instability and degradation.
Evidence from animal studies shows that several fundamental mechanisms associate anthracyclines with cardiotoxicity. While it is not the only drug causing cardiotoxicity, it is the most reviewed and has therefore provided crucial insights into the issue at hand. One of these mechanisms is the formation of radical oxygen species which are toxic to the macromolecules and hence cause the death of cell membranes. Additionally, the formation of anthracycline– complexes causes myocardial dysfunction while titin proteolysis leads to abnormalities in diastolic function. It is, therefore, accurate to state that these mechanisms play a pivotal role in augmenting the role of drugs in causing cardiotoxicity. They are the foundation to the development of better drugs and ensuring that proposed pharmacotherapy approaches have minimal adverse implications on the patient’s treatment outcomes.
Burcham, P.C., 2014. Core Concepts in Toxicology. In An Introduction to Toxicology (pp. 29-51). Springer, London. https://doi.org/10.1007/978-1-4471-5553-9_2
Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G. and Posey, L.M., 2014. Pharmacotherapy: A Pathophysiologic Approach, ed. McGraw-Hill Medical, New York. https://hsag.com/contentassets/244f9443fb7f414ea92107de839d7138/preventadeswebinarfnl100317508.pdf
Levis, B.E., Binkley, P.F. and Shapiro, C.L., 2017. Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms?. The Lancet Oncology, 18(8), pp.e445-e456. https://doi.org/10.1016/S1470-2045(17)30535-1
Murabito, A., Hirsch, E. and Ghigo, A., 2020. Mechanisms of anthracycline-induced cardiotoxicity: is mitochondrial dysfunction the answer?. Frontiers in cardiovascular medicine, 7. https://dx.doi.org/10.3389%2Ffcvm.2020.00035