**1. Introduction**

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Early identification of patients who will be at a higher risk for the development of adverse side effects and who will need dosage adjustment has the potential to help the clinician to limit a patient's exposure to drug side effects. When on multiple medications and complex regimens, cardiac patients are at increased risk and particularly vulnerable to drug interac‐ tions. A rational and informed approach to drug interactions, based on scientific knowledge, can reduce the chance of adverse effects and improve patient outcomes.

Cardiovascular drugs are used to treat various forms of illnesses, but there are often large differences between individual patients in drug response and dosage requirement. Treat‐ ment that has been proven effective for one person can be ineffective or even dangerous for another.

A drug produces its therapeutic effect when it reaches its target concentration in the blood‐ stream. Whether a steady therapeutic concentration is obtained largely depends on the bal‐ ance between the dose administered and the rate at which the body metabolises the drug. An individual patient's response to a drug is not totally predictable. Below the target thera‐ peutic range, a drug may be ineffective or, when it is higher, the drug may cause adverse reactions or become toxic. To ensure the safe and effective action of many drugs, the concen‐ tration in the bloodstream and their clinical effects are monitored. If necessary, the dose can be adjusted or the medication changed to achieve the best possible outcome.

To avoid unintended and untoward adverse drug reactions, the prescriber should use the fundamental principles of pharmacology and pharmacogenetics. Several drugs are metabol‐ ised through the same pathways and knowledge of the potential pathway capacity could help to predict treatment success. Variability in the reaction to medication may be due to

<sup>© 2013</sup> Piatkov et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

age, gender, morbidity, co-medication, food components, smoking and environmental fac‐ tors. However, polymorphisms present in genes, are responsible for most of the variation. Pharmacogenetic research and candidate gene approaches have succeeded in the identifica‐ tion of several genetic factors influencing treatment response. In particular, associations be‐ tween variants in CYP enzymes and transporter genes have been repeatedly associated with different response and treatment--associated side effects [1-6]. Knowledge of pharmacoge‐ nomics is providing a key to understanding fundamentals of the drug interaction process.

Early identification of patients who will be at a higher risk for the development of adverse side effects and who will need dosage adjustment has the potential to help the clinician to limit a patient's exposure to drug side effects. Characterisation of drug metabolising poly‐ morphisms has been shown to be useful for identifying individuals who are poor drug me‐ tabolisers and at risk of developing adverse reactions, and several genotyping methods are already being used in clinical settings (Table1). The evidence provided by pharmacogenetics

and pharmacogenomics can be successfully used for drug interaction interpretation.

Wafarin CYP2C9 1% - Poor Metabolisers, 15% - Intermediate

Clopidogrel *CYP2C19* 4% - Poor Metabolisers, 13% - Intermediate, 20% -

Carvedilol CYP2D6 5% - Poor Metabolisers, 27% - Intermidiate, 1% - Ultra

Warfarin Protein C Deficiencies 1/200 population, 2-5% Patients with Venous

Statins SINM PhyzioType (50 genes) 10-30% Patients on statin (multi-gene biomarker

**Table 1.** Available Pharmacogenetics tests for cardiovascular medication. (\*Western Sydney Population combined

Atorvastatin LDLR 1-5% Familial Cholesterolemia Patients

Ultra fast metabolisers

Drug Interactions, Pharmacogenomics and Cardiovascular Complication

http://dx.doi.org/10.5772/48423

77

fast metabolisers

Thromboembolism

system manufacture results, no data available)

**Drugs Tests of polymorphisms Affected WSLHD Population\***

Warfarin VKORC1 11% with altered function

Isosorbide NAT1, NAT2 10-90%

data. WSLHD population is a mix of Caucasians, Asians and Africans.)

Phenytoin

Metoprolol

Propafenone

Propranolol

Quinidine

Hydralazine

A specific genotype might differ in its frequency in different ethnic populations, leading to differences in drug response. However, gene combination between ethnic groups makes it impossible for the practitioner to simply predict if a drug will be efficient or not. There is no specific genetic definition of ethnicity and ethnicity does not sufficiently separate those for whom a given therapy will be effective.

In contrast, the pharmacogenetics potentially presents a more effective way of identifying responders, nonresponders and potential adverse drug reactions. Pharmacogenetics pro‐ vides defined clinical biomakers for individualised therapy [7].

Personalised medicine can be defined as a form of medicine that uses information about a person's genes, proteins and environment to prevent, diagnose and treat diseases, including predicting therapeutic response, nonresponse and likelihood of adverse reactions. Diagnos‐ tic biomarkers are necessary to successfully select patients for therapy, distinguish likely res‐ ponders from nonresponders, identify patients at high risk for adverse events, or select an appropriate dose for safe and efficacious use of the therapy.

The human genome consists of approximately 3 billion base pairs (NCBI database) and the sequence of these varies among individuals. These variations can change the function of proteins that interact with a drug and hence, the response to a drug may differ among indi‐ viduals. Sequence variations in drug-disposition genes can alter the pharmacokinetics of a drug and those in drug-target genes can change the pharmacodynamics of a drug.

When a genetic polymorphism alters the function of a protein that is involved in the absorp‐ tion, metabolism, distribution and excretion of a drug, the concentrations of the parent drug or its active metabolites may be affected. For example, *CYP2D6*\*4 polymorphism leads to lower activity of a metabolising enzyme and the plasma concentrations of the parent drug metabolised by cytochrome P-450 isoenzyme 2D6 may increase and concentration of metab‐ olites may decrease (some antidepressants). As a result, it could lead to the development of toxicity. For prodrugs, when metabolites have pharmacologic activity, the genetic polymor‐ phism may reduce the drug response (some analgesics). Genetic polymorphisms that change the activity of the drug target (pharmacodynamics) may also alter the drug response. For example, vitamin K epoxide reductase complex subunit 1 gene polymorphisms influ‐ ence warfarin response and β1-adrenergic receptor gene polymorphisms after β-blocker re‐ sponse. Therefore, drugs can compete for binding sites on the receptors or be metabolised by the same enzyme, consequently create dug-drug interaction problem.

The information about pharmacogenetic terms and recourses is presented in the Appendix.

Early identification of patients who will be at a higher risk for the development of adverse side effects and who will need dosage adjustment has the potential to help the clinician to limit a patient's exposure to drug side effects. Characterisation of drug metabolising poly‐ morphisms has been shown to be useful for identifying individuals who are poor drug me‐ tabolisers and at risk of developing adverse reactions, and several genotyping methods are already being used in clinical settings (Table1). The evidence provided by pharmacogenetics and pharmacogenomics can be successfully used for drug interaction interpretation.

age, gender, morbidity, co-medication, food components, smoking and environmental fac‐ tors. However, polymorphisms present in genes, are responsible for most of the variation. Pharmacogenetic research and candidate gene approaches have succeeded in the identifica‐ tion of several genetic factors influencing treatment response. In particular, associations be‐ tween variants in CYP enzymes and transporter genes have been repeatedly associated with different response and treatment--associated side effects [1-6]. Knowledge of pharmacoge‐ nomics is providing a key to understanding fundamentals of the drug interaction process.

A specific genotype might differ in its frequency in different ethnic populations, leading to differences in drug response. However, gene combination between ethnic groups makes it impossible for the practitioner to simply predict if a drug will be efficient or not. There is no specific genetic definition of ethnicity and ethnicity does not sufficiently separate those for

In contrast, the pharmacogenetics potentially presents a more effective way of identifying responders, nonresponders and potential adverse drug reactions. Pharmacogenetics pro‐

Personalised medicine can be defined as a form of medicine that uses information about a person's genes, proteins and environment to prevent, diagnose and treat diseases, including predicting therapeutic response, nonresponse and likelihood of adverse reactions. Diagnos‐ tic biomarkers are necessary to successfully select patients for therapy, distinguish likely res‐ ponders from nonresponders, identify patients at high risk for adverse events, or select an

The human genome consists of approximately 3 billion base pairs (NCBI database) and the sequence of these varies among individuals. These variations can change the function of proteins that interact with a drug and hence, the response to a drug may differ among indi‐ viduals. Sequence variations in drug-disposition genes can alter the pharmacokinetics of a

When a genetic polymorphism alters the function of a protein that is involved in the absorp‐ tion, metabolism, distribution and excretion of a drug, the concentrations of the parent drug or its active metabolites may be affected. For example, *CYP2D6*\*4 polymorphism leads to lower activity of a metabolising enzyme and the plasma concentrations of the parent drug metabolised by cytochrome P-450 isoenzyme 2D6 may increase and concentration of metab‐ olites may decrease (some antidepressants). As a result, it could lead to the development of toxicity. For prodrugs, when metabolites have pharmacologic activity, the genetic polymor‐ phism may reduce the drug response (some analgesics). Genetic polymorphisms that change the activity of the drug target (pharmacodynamics) may also alter the drug response. For example, vitamin K epoxide reductase complex subunit 1 gene polymorphisms influ‐ ence warfarin response and β1-adrenergic receptor gene polymorphisms after β-blocker re‐ sponse. Therefore, drugs can compete for binding sites on the receptors or be metabolised

The information about pharmacogenetic terms and recourses is presented in the Appendix.

drug and those in drug-target genes can change the pharmacodynamics of a drug.

by the same enzyme, consequently create dug-drug interaction problem.

whom a given therapy will be effective.

76 Drug Discovery

vides defined clinical biomakers for individualised therapy [7].

appropriate dose for safe and efficacious use of the therapy.


**Table 1.** Available Pharmacogenetics tests for cardiovascular medication. (\*Western Sydney Population combined data. WSLHD population is a mix of Caucasians, Asians and Africans.)
