Efficacy of Bisoprolol in Treating Heart Failure and Renal Impairment

Selection of The Drug

What Evidence Supports/Refutes The Use Of The Drug?

What Evidence Supports Or Refutes Its Drawbacks?

What Is The Quality Of This Evidence?

Briefly Explain What Drug You Are Looking At And In What Context.?

Identify The Drug Or Group Of Drugs ?

The paper aims to explore the efficacy of the drug named bisoprolol in treating heart failure and renal impairment in the patients.

The main component of the drug bisoprolol is bisoprolol fumarate. The drug is available in the market in the form of tablets. Bisoprolol is the generic name of this drug, and it is available under various brand names in the market, such as Zebeta, Monocor and various others (Pubchem.ncbi.nlm.nih.gov 2020).

The drug belongs to the group of drug known as the beta-blockers. The beta-blocker drugs or the beta-adrenergic receptor blocking agents mainly block the action of the hormone named adrenaline (Pubchem.ncbi.nlm.nih.gov 2020).

The principal action of this drug involves lowering the heart rate in an individual. Thus it is used for treating patients with high blood pressure. The drug lowers the heart rate in the patients by controlling the effect of the hormones and improving the blood circulation in an individual. The treatment of heart failure requires all these aspects to be adequately addressed. Heart failure also presents with a comorbid condition in case of hypertension. Thus the drug is also used in patients with renal impairment disease conditions (Hori, Nagai, Izumi and Matsuzaki 2014). The drug is easily available all around the world, and thus, it is an easy and effective choice of drug in the treatment of the above-mentioned conditions.

The following section will be focusing on discussing the pathophysiology of the disease first, for which the bisoprolol drug is used. After that, the pharmacology of the drug will be discussed in brief. That discussion will cover the areas like pharmacodynamics and pharmacokinetics of the selected drug. Finally, the pieces of evidence suggesting the use of the drug in various groups of patients will be discussed in detail.

Heart failure might result from the damage to the heart muscles and/or damage to the blood vessels. Increased workload on the heart muscles also presents a risk of heart failure in an individual. The damage to the heart muscles might be resulting from a wide variety of reasons. Damage to the heart muscles or an increased workload on the heart muscles results in the increase in the heart rate. The condition is also associated with a difficulty in the pumping of the blood by the heart muscles. Damage to the blood vessels or blockage in the blood vessels results in the decreased circulation of the blood, which again is associated with the increased workload of the heart muscles (Borlaug 2014). If the situation is not brought under control with time, it is more likely to result in heart failure (Refer to Appendix). Many factors are responsible for increasing the blood pressure and thus, in turn, increasing the heart rate in the individuals. One of those factors can be the beta-1 receptors that are present in the cardiac tissue. The receptors have a variety of effects on the body of an individual. Its effects can be categorised into three types mainly. The muscular effects include an increase in the atrial contractility in the cardiac muscles and an increase in the contractility and automaticity in the ventricular cardiac muscles. As a result of all these effects, there is an increased cardiac output can be observed in the cardiac muscles. There is also an increased heart rate can be observed due to the positive effect of the receptors on the SA node and the AV node. The receptor also stimulates the renin release (Kelley, Snyder and Johnson 2018). It is an enzyme that regulates the blood pressure in an individual and also known as angiotensinogenase. The enzyme is a part of the renin-angiotensin system (Refer to Appendix). The system is mainly responsible for increasing blood pressure. There are two mechanisms that are adapted by this system to increase blood pressure in the body. The renin enzyme circulates freely in the blood and hydrolyses the angiotensinogen molecules. The resulting product is the angiotensin I, which again gets converted to the angiotensin II by the ACE. The angiotensin II constricts the blood vessels, and as a result, the resistance in the arteries is increased, which in turn results in the increased workload on the heart. The angiotensin II is also responsible for the release of aldosterone, which initiates a signalling pathway that results in the increased blood pressure along with the increased blood volume. If a damage condition occurs in the heart muscles or the blood vessels, these normal phenomena will be contributing to the increased workload of the heart (Wu et al. 2018). If timely action is not taken addressing those matters, the heart failure might be resulting from this.

Identification of The Drug Group

In case of renal diseases, the ability of the kidneys to maintain the fluid and electrolyte balance in the body is impaired. As a result of the electrolyte imbalance, the blood pressure of the body is increased (Odutayo et al. 2016). This phenomenon contributes in increasing the workload of the heart, which might progress to the heart failure if the timely actions are not taken.

The drug bisoprolol drug is a beta-blocker drug. The drug blocks the action of the beta-1 adrenergic receptors. Those receptors are responsible for increasing the heart rate in the SA node and the AV node along with increasing the atrial contractility in the cardiac muscles and automaticity in the ventricular cardiac muscles. The beta-1 receptors are also responsible for the renin release, and thus, those receptors are hugely responsible for the increase in the blood pressure of an individual (Kelley, Snyder and Johnson 2018). The beta-blocker drugs including the bisoprolol act by blocking those receptors. The resulting events from the effect of the beta-1 receptors are also ceased. This results in the decreased work pressure on the heart muscles, lower cardiac output and the lowered blood pressure in the body. The effect of bisoprolol also involves the decreased release of renin or angiotensinogen. As already discussed before, the renin is hugely responsible for increased blood pressure in the body. Thus these events resulting from the action of bisoprolol ultimately result in the decrease of the blood pressure and workload of the heart muscles. The drug is a competitive agent that reacts antagonistically to the original ligands of the beta one receptors. The original activators of the beta one receptors are the adrenergic neurotransmitters, such as the epinephrine. The drug bisoprolol competes with epinephrine and binds with the beta one receptors. As a result, the receptors are not activated, and the effect of the pathway in increasing the blood pressure gets nullified (Bazroon and Alrashidi 2019).

There are various side effects of this drug. The most common ones among them are the feeling of headache, fatigue or tiredness, nausea, anxiety and excessively slower heart rate. The patients also experience the symptoms of flu, swelling at the parts of the body and feeling of weakness along with dry eyes or some burning sensation in the eyes and sweating. The severe side effects of this drug bisoprolol include the tingling and cold sensation in the hands or feet, tremors, confusion, fainting and trouble in breathing (Bazroon and Alrashidi 2019).

Use, Indication and The Patient Group for The Drug

The drug actually interferes with a normal physical phenomenon, which is responsible for maintaining the homeostatic blood pressure and the heart rate in the patient. When the drug blocks the whole pathway, the pressure on the heart muscles is decreased indeed. However, the process also affects the normal rate of blood flow in the body of an individual. The situation results from the fact that the heart is unable to pump enough blood to maintain the rate of normal blood flow. The severe symptoms mentioned in the previous paragraph result from the decreased blood flow in different organs. The tingling and the cold sensations in the feet and the hands of a person results from the less blood flow in the hands and feet of the individual. The confusion, dizziness and the fainting results from the less blood flow in the brain. The blood supplies the oxygen to the brain, which is necessary to carry out all the functions of the brain. In the case of its unavailability, the feeling of dizziness or the fainting occurs (Medow et al. 2017).

The route of administration of a drug can be described as the way of administering the medication in the body of a patient. The bisoprolol drug is mainly administered orally. This drug is available in the form of tablets mainly in the market, and thus the only way it can be administered in a patient is by choosing the oral route of administration (Bazroon and Alrashidi 2019). After administration, the drug is absorbed in the gastrointestinal tract. The absorption is not affected by the intake of the food, and the drug is completely available in the bloodstream within 2-4 hours of administration. The enzyme named CYP3A4 is responsible for maintaining the level of bisoprolol drug in the blood. The enzyme achieves this by metabolizing the drug and converting it to inactive compounds. The drug is eliminated from the body by using the renal route of elimination and also the hepatic pathways (Pubchem.ncbi.nlm.nih.gov 2020).

The half-life of a drug can be described as the time required for the body to eliminate the half amount of the drug out of the body (Smith, Beaumont, Maurer and Di 2017). Various studies have differ rent opinions on the half-life of this bisoprolol drug. Approximately the half-life of the drug bisoprolol ranges from about 9-12 hours (Khurana, Bin Jardan, Wilkie and Brocks 2014). The half-life of the drug might also increase in case of the renal impairment disease condition. In that scenario, the body is unable to eliminate the drugs effectively due to the inability of the kidney.

Discussion

After the oral administration of a specific dose of bisoprolol, most of the drug reaches the bloodstream. The first-pass metabolism of the drug is only 20%, and thus the 80% of the drug is completely available in the bloodstream. The first-pass metabolism is a metabolism activity of the body that metabolises a drug to some point, so when it ultimately reaches the bloodstream, it is slightly reduced. The 80% of the initial concentration of the bisoprolol drug becomes available in the serum in about 2-4 hours of the drug administration. After that, only 30% of the drug binds to the proteins present in the serum. The drug is then eliminated from the bloodstream of an individual by the use of the renal and hepatic pathway. The drug concentration gets reduced to half within 9-12 hours of the initial administration of the drug. 50% of the drug is excreted from the body via urine, which is a complete unchanged form of the drug. The metabolised and inactive version of the drug is excreted from the body by using the hepatic pathway via faeces (Pubchem.ncbi.nlm.nih.gov 2020).

Bisoprolol is a cardio-selective beta-blocker drug. There are indeed some side effects of the drug. However, those effects can be considered as mild compared to the other beta-blockers. Those drugs have a similar mode of action and lower the heart rate and the rate of blood flow in an individual. Cardio-selective beta-blocker agents, like the bisoprolol drug, only targets a specific type of beta receptor, which is the beta-1 adrenoreceptor. The other non-selective beta-blocker drugs target all the beta-receptors to lower the pressure on the cardiac muscles (Bazroon and Alrashidi 2019). This involves serious side effects, which are often proved to be difficult to control.

There are many scholarly studies, which analysed the patient experiences and the efficacy of the drug in treating the patients with the above-mentioned disease conditions.

There is a study conducted on the patients with heart failure, and the renal impairment disease condition concluded that the use of this bisoprolol drug increased the survival in the patients. The study was a trial study that involved many individuals with heart failure and concomitant renal impairment disease condition. The study found that there were some beneficial effects on the mortality and the hospitalisation of the patients (Castagno et al. 2010). The strengths of the study included thorough research on the safety and tolerability of the drug and its large sample size. The main limitation of the study was the consideration of the estimated values for renal functions only in the research.

Pathophysiology of The Disease

Another study tried to determine whether or not the beta-blocker treatment is effective in patients with heart failure and renal impairment conditions. The study used a placebo-controlled trial on about 16,740 patients. Those patients had left ventricular ejection fraction of < 50%. The study described that moderate or moderately severe renal impairment condition is common in patients with heart failure. However, if those patients are provided with the beta-blocker treatment, the adverse conditions can be avoided (Kotecha et al. 2019). The main strength of this study was its double-blinded and placebo-controlled trial designs additional to the large sample size. The main limitation of this study is the risk of survivor bias in the findings.

There is another scholarly study that examined the efficacy of bisoprolol drug compared to carvedilol and metoprolol in treating the patients with heart failure. All those drugs are beta-blocker agents, and their mode of action involves blocking the beta-receptors to lower the workload on the cardiac muscles, which eventually result in a lowered heart rate and a lowered blood pressure in an individual. The bisoprolol and the metoprolol are selective beta-blocker drugs and have a similar mode of action. However, when this study examined the comparative efficacy of those drugs, the authors of this study found that the bisoprolol drug and the carvedilol drug are similarly effective on the patients with a low left ventricular ejection fraction. The study considered the mortality in the patients, who are receiving the treatment with those drugs. It was found that the mortality in the patients is almost the same for the patient, who were receiving bisoprolol and the ones who were receiving carvedilol. However, the mortality rate was higher in the patients, who were prescribed with metoprolol (Froehlich et al. 2017). The large sample size across a wide geographical area can be considered as the principal strength of the study. However, the limitations include the risk of bias due to the non-randomised study design and the lack of consideration for drug switching in the target group patients.

Another scholarly study examined the efficacy of the same drugs in improving the survival in the patients, who are receiving a long-term haemodialysis and heart failure condition. The study stated that it is a common phenomenon for patients with renal impairment conditions to develop a heart failure condition. The beta-blocker drugs that were considered for this study were bisoprolol, metoprolol and carvedilol. The study only involved the patients, who were aged >/= 35 years, were receiving long-term haemodialysis and were recently diagnosed with heart failure. The study again examined the mortality of the patients to determine the efficacy of the treatment method. The experimental group for this study were receiving beta-blocker treatment, and the control group consisted of the patients, who did not use the beta-blocker drugs. The study found that there was an improved survival rate among beta-blocker users compared to the non-users (Tang et al. 2016). The principal strength of this study was again the large sample size, and the main limitation was the observational study design.

Pharmacology of The Drug

There was another study conducted on the Japanese patients, which was focused on finding the comparative efficacy and safety between the carvedilol and the bisoprolol drug in treating the patients with chronic heart failure conditions. The study involved a randomized controlled study design. The study found the safety and the efficacy of the two drugs to be similar among patients with chronic heart failure disease condition (Hori, Nagai, Izumi and Matsuzaki 2014). The researchers utilised a double-blinded RCT design for this study, which can be considered as the main strength of the study. The limitations of the study included the use of smaller sample size and discontinuation of the research.

As already described in the previously, there are various side effects associated with the use of the bisoprolol drug or the similar beta-blockers. Various studies are supporting that statement.
There was a study that examined the possibility of impaired blood flow in the central retinal artery resulting from the beta-blocker treatment. The study was conducted on the patients suffering from systemic arterial hypertension. The patients were from the age group of 32-46 years. All the patients were receiving the beta-blocker drugs, such as bisoprolol. The study found that there might be a disturbance in the ocular blood flow, resulting from the side effects of the bisoprolol use in the patients (Madej et al. 2010). The researchers used a simple methodology for this study, which can be considered as the main strength of the study. However, the researchers did not consider the limitations of their study and the sample size of twenty patient cannot be considered to be large enough for ensuring the generalised applicability of the study.

Another study examined the long term side effects of a selective beta-blocker drug on the patients, who are receiving the beta-blocker treatment for their hypertension condition. The study was focused on examining the factors such as the level of serum lipids, fasting blood sugar, the uric acid level in the serum, electrolytes level, HDL-cholesterol and blood pressure of the patient. The study found that there was a slight increase in the serum triglycerides in the patients. However, there were no significant effects of this treatment therapy on the LDL and the HDL level in the patients. There were no significant and long-term effects found on the blood pressure and the other factors in the patient either (Salve and Khanwelkar 2012). The main strength of this study was the prospective study design. However, the researchers did not utilise a large sample size, and there was no consideration of the possible limitation of this study.

Side Effects

There was another scholarly study that examined the possible effects of bisoprolol on the exercise capacity and the respiratory function in an individual. The study considered the statement that there are very little effects on the bisoprolol drug on the lungs of patients with chronic obstructive pulmonary disease (COPD). However, there are a few other factors like dynamic hyperinflation and exercise tolerance, which contributes to worsening the manifestations associated with COPD. The study examined the effect of bisoprolol treatment on these aspects. It was found that there was no significant effect on the exercise capacity in the patients, but there was a modest level worsening of the dynamic hyperinflation in the COPD patients as a result of the bisoprolol treatment (Mainguy et al. 2012). The research was based on a double-blinded placebo-controlled RCT design, which was the principal strength of the study. However, the research was a small-scale study, with lower generalised applicability.

The quality of the evidence can be considered high if further research on the same field has no chance of disagreeing with the findings of the study. The level of evidence can be considered as moderate quality if further studies on the same field have a low chance of disagreeing with the findings of the study. A study can be considered to be providing a low level of evidence if there an almost certain chance of disagreement with the findings of the study in further research on the same field (Balshem et al. 2011). The study by Kotecha et al. (2019), Hori, Nagai, Izumi and Matsuzaki (2014) and Mainguy et al. (2012) utililised RCT study design, which has only a slight chance of disagreement with the findings of the studies, if there are further studies conducted in the same field and thus can be considered as a high level of evidence. The other studies by Castagno et al. (2010), Froehlich et al. (2017), Tang et al. (2016), Madej et al. (2010), Salve and Khanwelkar (2012) are observational studies. They are not considered as very high-quality evidence due to the chances of bias and less generalised applicability of the findings. However, they had certain strengths that could be considered for suggesting higher reliability on the findings. The studies found that bisoprolol is significantly effective in lowering the adverse outcomes in cardiovascular patients. However, there is also evidence that the drug has some side effects, such as hyperinflation, impaired blood flow and a slight increase in the triglyceride levels. However, none of the studies suggested any long-term or potentially life-threatening adverse effects from the use of the drugs. Thus, it can be decided that the use of the bisoprolol drug in the patients with heart failure, hypertension and the patients with renal impairment conditions is significantly beneficial and it should be used in the patients for inviting an improved patient outcome. However, further investigation regarding the side effects of the drug in the target group patient should also be described in an attempt to ensure patient safety.

Conclusion

Hence it can be concluded from the above discussion that the bisoprolol is a drug that belongs to the family of beta-blockers. The mechanism of action of the beta-blockers involves the blocking of the beta receptors that are present in the cardiac tissues. The aim of the beta-blockers is to lower the heart rate and the blood pressure in the patients. The group of patients, who receive treatment with this drug involve the patients with heart failure, hypertension and patients with renal impairment conditions. The bisoprolol drug is a cardio-selective agent, which affects the beta-1 receptors only. Beta-1 receptors are involved in increasing the blood pressure and the heart rate of an individual normally. The bisoprolol drug is a competitive agent that binds with the beta-receptor and prevents its activation. In the individuals, who have damage in the cardiac muscles or in the blood vessels, already experience an increased workload on their hearts. The bisoprolol drug blocks the natural pathway of increasing the blood pressure in the body. This way, the additional workload on the heart of those individuals gets reduced. However, there are a few side effects associated with the use of the bisoprolol drug. Those side effects include the feeling of headache, fatigue or tiredness, nausea, anxiety and excessively slower heart rate. This drug is available in the form of tablets mainly in the market, and thus the only way it can be administered in a patient is by choosing the oral route of administration. Approximately the half-life of the drug bisoprolol ranges from about 10-12 hours. The level of evidence for supporting the above claims can be considered as moderate. The studies have been critically appraised discussing their strengths, limitations and validity. The considerations are necessary for deciding the reliability of the data found from the studies. The detailed discussion on the studies was helpful for personal learning about the critical appraisal of literature and their inclusion in a review.

References

Balshem, H., Helfand, M., Schünemann, H.J., Oxman, A.D., Kunz, R., Brozek, J., Vist, G.E., Falck-Ytter, Y., Meerpohl, J., Norris, S. and Guyatt, G.H., 2011. GRADE guidelines: 3. Rating the quality of evidence. Journal of clinical epidemiology, 64(4), pp.401-406.

Bavishi, C., Chatterjee, S., Ather, S., Patel, D. and Messerli, F.H., 2015. Beta-blockers in heart failure with preserved ejection fraction: a meta-analysis. Heart failure reviews, 20(2), pp.193-201.

Bazroon, A.A. and Alrashidi, N.F., 2019. Bisoprolol. In StatPearls [Internet]. StatPearls Publishing.

Borlaug, B.A., 2014. The pathophysiology of heart failure with preserved ejection fraction. Nature Reviews Cardiology, 11(9), p.507.

Castagno, D., Jhund, P.S., McMurray, J.J., Lewsey, J.D., Erdmann, E., Zannad, F., Remme, W.J., Lopez‐Sendon, J.L., Lechat, P., Follath, F. and Höglund, C., 2010. Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS‐II) trial. European journal of heart failure, 12(6), pp.607-616.

Eguchi, K., Hoshide, S. and Kario, K., 2015. Effects of celiprolol and bisoprolol on blood pressure, vascular stiffness, and baroreflex sensitivity. American journal of hypertension, 28(7), pp.858-867.

Frithz, G. and Weiner, L., 1986. Long-term effects of bisoprolol on blood pressure, serum lipids, and HDL-cholesterol in patients with essential hypertension. Journal of cardiovascular pharmacology, 8, pp.S134-8.

Froehlich, H., Torres, L., Taeger, T., Schellberg, D., Corletto, A., Kazmi, S., Goode, K., Grundtvig, M., Hole, T., Katus, H.A. and Cleland, J.G., 2017. Bisoprolol compared with carvedilol and metoprolol succinate in the treatment of patients with chronic heart failure. Clinical Research in Cardiology, 106(9), pp.711-721.

Hori, M., Nagai, R., Izumi, T. and Matsuzaki, M., 2014. Efficacy and safety of bisoprolol fumarate compared with carvedilol in Japanese patients with chronic heart failure: results of the randomized, controlled, double-blind, Multistep Administration of bisoprolol IN Chronic Heart Failure II (MAIN-CHF II) study. Heart and vessels, 29(2), pp.238-247.

Hori, M., Nagai, R., Izumi, T. and Matsuzaki, M., 2014. Efficacy and safety of bisoprolol fumarate compared with carvedilol in Japanese patients with chronic heart failure: results of the randomized, controlled, double-blind, Multistep Administration of bisoprolol IN Chronic Heart Failure II (MAIN-CHF II) study. Heart and vessels, 29(2), pp.238-247.

Kelley, E.F., Snyder, E.M. and Johnson, B.D., 2018. Influence of beta-1 adrenergic receptor genotype on cardiovascular response to exercise in healthy subjects. Cardiology research, 9(6), p.343.

Khurana, R., Bin Jardan, Y.A., Wilkie, J. and Brocks, D.R., 2014. Breast milk concentrations of amiodarone, desethylamiodarone, and bisoprolol following short‐term drug exposure: Two case reports. The Journal of Clinical Pharmacology, 54(7), pp.828-831.

Kotecha, D., Gill, S.K., Flather, M.D., Holmes, J., Packer, M., Rosano, G., Böhm, M., McMurray, J.J., Wikstrand, J., Anker, S.D. and Van Veldhuisen, D.J., 2019. Impact of renal impairment on beta-blocker efficacy in patients with heart failure. Journal of the American College of Cardiology, 74(23), pp.2893-2904.

Lee, H.Y., Chung, W.J., Jeon, H.K., Seo, H.S., Choi, D.J., Jeon, E.S., Kim, J.J., Shin, J.H., Kang, S.M., Lim, S.C. and Baek, S.H., 2016. Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study. The Korean journal of internal medicine, 31(2), p.277.

Lu, H., Wu, C., Howatt, D.A., Balakrishnan, A., Moorleghen, J.J., Chen, X., Zhao, M., Graham, M.J., Mullick, A.E., Crooke, R.M. and Feldman, D.L., 2016. Angiotensinogen exerts effects independent of angiotensin II. Arteriosclerosis, thrombosis, and vascular biology, 36(2), pp.256-265.

Madej, A., Gierek-Ciaciura, S., Haberka, M., Lekston-Madej, J., Basiak, M., DomaÅ„ska, O. and OkopieÅ„, B., 2010. Effects of bisoprolol and cilazapril on the central retinal artery blood flow in patients with essential hypertension—preliminary results. Upsala journal of medical sciences, 115(4), pp.249-252.

Mainguy, V., Girard, D., Maltais, F., Saey, D., Milot, J., Sénéchal, M., Poirier, P. and Provencher, S., 2012. Effect of bisoprolol on respiratory function and exercise capacity in chronic obstructive pulmonary disease. The American journal of cardiology, 110(2), pp.258-263.

Medow, M.S., Kothari, M.L., Goetz, A.M., O'Donnell‐Smith, M.B., Terilli, C. and Stewart, J.M., 2017. Decreasing cerebral oxygen consumption during upright tilt in vasovagal syncope. Physiological reports, 5(10), p.e13286.

Odutayo, A., Wong, C.X., Hsiao, A.J., Hopewell, S., Altman, D.G. and Emdin, C.A., 2016. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. bmj, 354, p.i4482.

Pasternak, B., Mattsson, A., Svanström, H. and Hviid, A., 2015. Comparative effectiveness of bisoprolol and metoprolol succinate in patients with heart failure. International journal of cardiology, 190, pp.4-6.

Pubchem.ncbi.nlm.nih.gov, 2020. Bisoprolol. [online] Pubchem.ncbi.nlm.nih.gov. Available at: <https://pubchem.ncbi.nlm.nih.gov/compound/Bisoprolol> [Accessed 17 March 2020].

Salve, P.S. and Khanwelkar, C.C., 2012. Effects of Cardio selective Beta Blocker Nebivolol on Different Biochemical Parameters in Essential Hypertensive patients. Indian Medical Gazette, 145(10), pp.400-4.

Smith, D.A., Beaumont, K., Maurer, T.S. and Di, L., 2017. Relevance of Half-Life in Drug Design: Miniperspective. Journal of medicinal chemistry, 61(10), pp.4273-4282.

Tang, C.H., Wang, C.C., Chen, T.H., Hong, C.Y. and Sue, Y.M., 2016. Prognostic benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release in hemodialysis patients with heart failure: a 10‐year cohort. Journal of the American Heart Association, 5(1), p.e002584.

Van Campen, J.S., de Boer, K., Van De Veerdonk, M.C., Van Der Bruggen, C.E., Allaart, C.P., Raijmakers, P.G., Heymans, M.W., Marcus, J.T., Harms, H.J., Handoko, M.L. and Frances, S., 2016. Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study. European Respiratory Journal, 48(3), pp.787-796.

Watkins, J.L., Thaker, P.H., Nick, A.M., Ramondetta, L.M., Kumar, S., Urbauer, D.L., Matsuo, K., Squires, K.C., Coleman, R.L., Lutgendorf, S.K. and Ramirez, P.T., 2015. Clinical impact of selective and non-selective beta‐blockers on survival in patients with ovarian cancer. Cancer, 121(19), pp.3444-3451.

Wiysonge, C.S., Bradley, H.A., Volmink, J., Mayosi, B.M. and Opie, L.H., 2017. Beta‐blockers for hypertension. Cochrane database of systematic reviews, (1).

Wu, C.H., Mohammadmoradi, S., Chen, J.Z., Sawada, H., Daugherty, A. and Lu, H.S., 2018. Renin-angiotensin system and cardiovascular functions. Arteriosclerosis, thrombosis, and vascular biology, 38(7), pp.e108-e116.