Cardiovascular pharmacogenetics
Introduction
Pharmacogenetics is the determination of the genetic contribution to individual variations in response to pharmacotherapy, and is central to the concept of personalized medicine. Developments in genome-based technology, including the availability of whole genome single nucleotide polymorphism (SNP) arrays, have provided researchers with an opportunity to assess variability in human reactions to pharmacotherapeutics and other exogenous substances as a function of intrinsic human genetic variability (Caulfield et al., 2003). It has become a common practice in pre-clinical and clinical drug testing to include a pharmacogenetic component, in order to select for drugs that have greater efficacy with fewer side effects, as well as fewer variations in individual response.
Pharmacogenetics underlies several observations dating back more than half a century that suggested the existence of genetic variation in drug metabolism pathways. Two examples include the enzyme butyrylcholinesterase that metabolizes suxamethonium chloride (scoline), used to induce muscle paralysis in anesthesia, and N-acetyltransferase that metabolizes isoniazid which is used in the treatment of tuberculosis. Reduced or absent enzyme activity in either case leads to toxicity, which manifests as prolonged muscle relaxation (scoline apnoea) in the case of the former, and as hepatotoxicity and neurotoxicity in the latter. Another example is glucose-6-phosphate dehydrogenase deficiency which is the most common disease-producing enzymopathy in humans, affecting nearly 400 million people worldwide (Frank, 2005). This enzyme, which is absent in 5–14% of Black individuals, is associated with the risk of developing drug-induced hemolytic anemia in response to a large number of currently employed drugs (Kaplan et al., 2004).
Optimal drug type and dose depend on many factors including age, organ function, concomitant therapy, lifestyle, ethnicity, drug interactions, gender, the nature of the disease and pharmacogenetics. Despite this multitude of factors, plasma drug concentrations, which in many but not all cases mirror drug concentrations at target sites, frequently reflect genetic variations in molecules involved in drug metabolism. It is estimated that more than 50% of adverse drug reactions are in fact dose-related and that in some drug classes, up to 50% of individuals do not respond to a “standard” dose of the drug.
The potential consequences of genetic polymorphisms on drug metabolism include the following:
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Drug toxicity and adverse drug reactions
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Reduced compliance
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Decreased effective dose
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Requirement for higher doses in order to be efficacious
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Extended pharmacological effects
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Lack of drug efficacy
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Exacerbation of drug–drug interactions
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Metabolism by alternative pathways leading to the generation of metabolites with deleterious effects
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Lack of prodrug activation
From a functional perspective, when considering the underlying genetic contribution to adverse drug reactions and therapeutic efficacy, two broad categories can be delineated. These include pharmacokinetics and pharmacodynamics. Pharmacokinetics describes the fate of drugs following administration to patients. It includes the extent and rate of absorption (drug entry into the circulation), distribution (drug dispersion or dissemination in body fluids and tissues), metabolism (transformation into water-soluble metabolites) and excretion (elimination from the body). Recently, the term “liberation” has also been included, which describes the process of drug release from the initial formulation.
Pharmacodynamics describes the study of the physiological effects of drugs on the body and the mechanisms of drug action including the relationship between drug concentration and effect. An important example includes drug–receptor interactions. Pharmacodynamics is often summarized as the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug.
To date, the large majority of pharmacokinetic studies have focused on genetic polymorphisms of the cytochrome P450 (CYP450) family of enzymes as well as a growing list of transporter proteins that influence drug absorption, distribution, and excretion. CYP450 enzymes are responsible for the biotransformation of xenobiotic compounds and the metabolism of most commonly prescribed medications. The most intensely studied have been CYP2D6, CYP2C9, and CYP2C19, for which polymorphic forms have been implicated in a significant number of adverse drug reactions as well as lack of response/efficacy. However, developments in the field have also extended to pharmacodynamic determinants of drug response which include cellular receptors.
In this review, we have highlighted areas that are currently topical in both pharmacodynamic and pharmacokinetic aspects of cardiovascular drug pharmacogenetics. However, it is not our intention to provide an exhaustive overview of either pharmacodynamics or pharmacokinetics, and as will become apparent, data is lacking in either one of these areas for several classes of cardiovascular drugs which has affected the symmetry of the review. As a result we have had to limit our discussion to one of the two areas (i.e. either pharmacodynamics or pharmacokinetics) for certain drug classes.
Section snippets
Cardiovascular drug classes and pharmacogenetics
Cardiovascular risk factors are highly prevalent, remain under diagnosed and inadequately treated (Hunt et al., 2009). For example, hypertension, a major cardiovascular risk factor, is a common disorder that affects approximately 950 million adults worldwide (Kearney et al., 2005). Most drugs are approved and developed on the basis of their performance in large population groups, and although guided by evidence from well controlled clinical trials, they are less informative when treating
Conclusions and future prospects
In this review, we have discussed the potential application of pharmacogenetics to personalized cardiovascular pharmacotherapy by highlighting selected examples of well-characterized genetic loci that affect response to therapy.
In summary, the response to beta-blockers is mediated primarily by an effect on the beta-1 adrenergic receptor encoded by ADRB1. The data on the beta-1 AR G389R locus appears to have functional implications that affect outcome after beta-blocker therapy, and if shown to
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Pharmacogenetic polymorphisms affecting bisoprolol response
2021, Biomedicine and PharmacotherapyCitation Excerpt :An in vitro study demonstrated that CYP3A4 and CYP2D6 enzymes are enrolled in the oxidation of both bisoprolol enantiomers [7]. Anyway, β-blockers are largely prescribed, its use has been widely studied since its discovery in 1960s, new mechanisms of action are still revealed [8] and they are well stablished for various cardiovascular (CV) diseases, but, adverse effects and patients´ intolerance lead to stop the treatment [9]. Interindividual differences about patients´ response to these drugs have been found.
Bisoprolol responses (PK/PD) in hypertensive patients: A cytochrome P450 (CYP) 2D6 targeted polymorphism study
2020, Saudi Journal of Biological SciencesCitation Excerpt :Beta blocker therapy was estimated to cause adverse effect in 5% − 43% of patients with heart failure, and 25% of patients are required to stop taking beta blockers due to this intolerance. Several studies suggest that variability may be due to genetic polymorphisms that lead to variable drug response (Myburgh et al., 2012). Notably, Bisoprolol effectiveness and toxicity were found to be related to systemic drug concentration which could vary between individuals due to clinical factors such as age, comorbidities, environmental, period of treatment, dose, drug-drug interaction, drug-food interaction, and genetic factors (Turner et al., 2018).
Evidence for clinical implementation of pharmacogenomics in cardiac drugs
2015, Mayo Clinic ProceedingsCardiovascular pharmacogenomics; state of current knowledge and implementation in practice
2015, International Journal of CardiologyCitation Excerpt :On the other hand, the other CYP2C9 loss-of-function alleles, i.e. CYP2C9*5, *6, *8, and *11, are more common in Africans with the *8 allele being the most frequent [172,173]. However, it is of note that the loss-of-function SNPs in CYP2C9 are responsible for only 6–18% of overall variability of warfarin dose requirements [174–176]. Recently, a GWAS in African Americans has identified and replicated a clinically significant association between a SNP (rs1277782) in the CYP2C gene cluster, which includes CYP2C9, CYP2C8, CYP2C18 and CYP2C19, and maintenance dose of warfarin [173].
Pharmacogenomics of beta-blockers and statins: Possible implications for perioperative cardiac complications
2012, Journal of Cardiothoracic and Vascular AnesthesiaCitation Excerpt :Nevertheless, it has long been appreciated that variations in plasma drug concentrations are often attributable to genetic polymorphisms in drug-metabolizing enzymes. Several potential consequences of such a genetic variation in drug metabolism include adverse drug reactions, a decrease or lack of effectiveness, prolonged pharmacologic effect, drug-drug interactions, and metabolism by alternative pathways.13 Additional genetic variations affecting drug pharmacokinetics may influence the rates of absorption, distribution, metabolism, and excretion of drugs, whereas the most important functional consequences of genetic variations affecting the pharmacodynamics of drugs are alterations in drug-receptor interactions.12-14
The Role of Gender Pharmacogenetics in the Personalization of Drug Treatment
2023, Journal of Pharmacology and Experimental Therapeutics