Pharmacogenetics of cardiovascular drugs
Abstract
Individual variations in the patient's response to the administered drugs are a frequent and important clinical problem in medicine and pharmacology. It is especially important to consider these issues when counting cardiovascular disease (CVD) treatment, since CVD are characterised by high incidence in the population, making cardiovascular drugs the most prescribed medication. Currently used medical therapies are adapted to best fit the needs of a wide population of patients who can benefit from it, despite the fact that a certain number of individuals will suffer from inadequate therapeutic effects or even intoxication. By examining the genetic basis that causes individual variations in the response to drugs, pharmacogenetics enables the personalisation of drug therapy, with the aim to identify patients who are exposed to an increased risk of serious drug side effects and those missing the maximum drug effectiveness. Polymorphism of genes that encode protein units of enzymes involved in the drug metabolism, mainly cytochrome P450 enzymes, receptors and drug transporters, affect both pharmacokinetics and pharmacodynamics of drugs often prescribed for CVD, such as beta blockers, ACE inhibitors, warfarin, clopidogrel and statins. This approach in cardiological practice would enable adjusting the therapy for patients based on gene polymorphisms, by changing the dose of the existing drugs or using another drug of choice. Although including pharmacogenetics in daily clinical practice would bring along large diagnostic costs, as well as potential legal and ethical dilemmas, a substantial number of patients, overall society and the health system in general could benefit from enhanced therapeutic effects as well as decreased side effects of the applied therapy.
References
1. Mancinelli L, Cronin M, Sadée W. Pharmacogenomics: The promise of personalized medicine. Vol. 2, AAPS PharmSci. 2000. p. 29–41.
2. Johnson JA. Pharmacogenetics: potential for individualized drug therapy through genetics. Vol. 19, Trends in Genetics. 2003. p. 660–6. Available from:
3. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Rev Esp Cardiol. 2022 Jun;75(6):523.
4. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Rev Esp Cardiol. 2019 Feb;72(2):160.
5. Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism. Vol. 37, Annual Review of Pharmacology and Toxicology. 1997. p. 269–96.
6. Licinio J, Wong ML. Pharmacogenomics: The Search for Individualized Therapies. John Wiley & Sons; 2009. 599 p.
7. Waring RH. Cytochrome P450: genotype to phenotype. Xenobiotica. 2020 Jan;50(1):9–18.
8. Kirchheiner J, Heesch C, Bauer S, Meisel C, Seringer A, Goldammer M, et al. Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol
pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2004 Oct;76(4):302–12.
9. Pacanowski MA, Gong Y, Cooper-Dehoff RM, Schork NJ, Shriver MD, Langaee TY, et al. beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin Pharmacol Ther. 2008 Dec;84(6):715–21.
10. Danser AHJ, Jan Danser AH, Schunkert H. Renin–angiotensin system gene polymorphisms: potential mechanisms for their association with cardiovascular diseases. Vol. 410, European Journal of Pharmacology. 2000. p. 303–16.
11. Johnson JA, Humma LM. Pharmacogenetics of cardiovascular drugs. Brief Funct Genomic Proteomic. 2002 Feb;1(1):66–79.
12. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999 Feb 27;353(9154):717–9.
13. Tavares LC, Marcatto LR, Santos PCJL. Genotype-guided warfarin therapy: current status. Pharmacogenomics. 2018 May;19(7):667–85.
14. Shuldiner AR. Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy. Vol. 302, JAMA. 2009. p. 849.
15. Duarte JD, Cavallari LH. Pharmacogenetics to guide cardiovascular drug therapy. Vol. 18, Nature Reviews Cardiology. 2021. p. 649–65. Available from:
16. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3473–8.
17. Altman RB, Altman R, Flockhart D, Goldstein DB. Principles of Pharmacogenetics and Pharmacogenomics. Cambridge University Press; 2012. 283 p.
18. Lam YWF, Scott SR. Pharmacogenomics: Challenges and Opportunities in Therapeutic Implementation. Academic Press; 2018. 442 p.