**3. Calcium Channel Blockers (CCBs)**

with a diuretic, whereas individuals homozygous for the T allele responded better to a calci‐

Patients with SNP of T594M gene (epithelial sodium channel) variant responded more fa‐ vourably to amiloride therapy for BP control than to thiazide-based drugs. In cases of severe hypokalemia, potassium-sparing diuretics such as amiloride or triamterene should be used

NEDD4L is also a candidate gene with a documented functional SNP, a role in sodium reab‐ sorption, and several studies have found an association between this SNP and blood pres‐

A common functional polymorphism resulting in Gly460Trp in the α-adducin gene ADD1 has been associated with response to thiazides. This finding led to the development of a novel antihypertensive drug class targeting adducin [36, 37]. Manunta et al. performed sin‐ gle SNP association analysis and combination analysis on ADD1 (Gly460Trp), NEDD4L, WNK1 in a 4-week diuretic trial. They found ADD1 460Trp carriers had significantly greater BP reduction than Gly460 homozygotes. When considered together, there was a significant trend in decreases of systolic blood pressure (SBP) (ranging from −3.4 mm Hg to −23.2 mm Hg) for different combinations of genotypes [35].The ADD1 Gly460Trp polymorphism has been associated with an increased risk of myocardial infarction or stroke during thiazide di‐ uretic treatment [38] In contrast, these findings were not confirmed by other studies [39, 40].

The 825T allele in the G-protein is probably associated with a sodium-sensitive form of hy‐ pertension. Blood pressure declines for both the C/T and T/T genotypes were significantly greater than for the C/C genotype. The study revealed that the decreases in blood pressure varied on the basis of genotype and even after multiple regression analysis, genotype re‐

Numerous genes from the renin-angiotensin system (RAS) pathway have been shown to play a key role in the regulation of blood pressure and influence the cardiovascular sys‐ tem. Several pharmacogenetic studies of the RAS were conducted. However, due to the complexity of RAS, associations between drug efficiency and polymorphisms are not

Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II in plasma and tissue and prevent the degradation of bradykinin. Clinically, ACE inhibitors reduce peripheral vascular resistance and pulmonary capillary wedge pres‐ sure and increase cardiac output and renal blood flow. Treatment with ACE inhibitors in hypertension has been associated with improvements in vascular compliance, regression of left ventricular hypertrophy, improved systolic and diastolic function, and improvements in insulin sensitivity [46]. One study showed that ACE DD polymorphism is associated with poor collateral circulation (PCC). PCC in patients carrying the D allele may be associated

with endothelial dysfunction and elevated blood ACE levels in these patients [47].

um channel blocker [32].

80 Drug Discovery

sure response with thiazides [27, 35].

according to serum sodium and potassium levels [33, 34].

mained a significant predictor of blood pressure lowering [41].

**2.3. Renin-angiotensin system inhibitors**

consistent [42-45].

Drugs in this class block voltage-gated calcium channels in the heart and vasculature, there‐ by reducing intracellular calcium. Calcium channel blockers drugs vary in their effect on cardiac versus vascular calcium channels. CCBs fall into three subclasses: phenylalkyla‐ mines, which are selective for the myocardium; dihydropyridines which mostly affecting smooth muscle and benzothiazepines with a broad range.

Vitamin K is required by proteins C and S, together with clotting factors II, VII, IX, and X, to allow assembly of the procoagulant enzyme complexes necessary to generate fibrin. Warfar‐ in as an anticoagulant agent has the ability to interfere with the recycling of vitamin K in the liver. The pharmacologic effect of warfarin is mediated by the inhibition of vitamin K epox‐

Drug Interactions, Pharmacogenomics and Cardiovascular Complication

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

83

Warfarin consists of (R)- and (S)-warfarin enantiomers. (R)- and (S)-warfarins differ in their relative plasma concentrations, in their antithrombotic potency and in the specific isoen‐ zymes responsible for their metabolism. (S)-warfarin has a 3 to 5 times greater anticoagulant effect than the (R)-enantiomer and accounts for 60% to 70% of warfarin's overall anticoagu‐

The activity of the CYP2C9 enzyme has a significant impact on the clearance of (S)-warfarin and as a consequence on anticoagulant effect. In the presence of genetic variations where the activity of CYP2C9 is reduced, clearance of (S)-warfarin is also reduced. Activity of CYP2C9 between individuals can vary by more than 20-fold. (R)-warfarin is metabilised by multiple

While several single-nucleotide polymorphisms of CYP2C9 have been reported, the CYP2C9\*2 (Cysl44/Ile359) and CYP2C9\*3 (Argl44/Leu359) polymorphisms have been identi‐ fied as clinically relevant [72]. Both of these variants are associated with decreased enzymat‐

Homozygous CYP2C9\*3 variant genotypes have only 5% to 10% metabolic efficiency com‐ pared to the wild-type genotype. As a result, compared to wild-type CYP2C9\*1\*1 controls, enzyme activity and the median maintenance warfarin dose for CYP2C9\*3\*1 heterozygotes was reduced by 40%, and by approximately 90% for CYP2C9\*3\*3 homozygotes [72-74].

Furuya [79] and Steward [75] showed that the CYP2C9\*2 variant is also associated with re‐ duced warfarin elimination. Heterozygotes demonstrate 40% and homozygotes 15% of the wild-type enzyme activity, causing dose adjustment for heterozygote CYP2C9\*2 individuals

Margaglione [76] has also demonstrated bleeding rates as high as 27.9 per 100 patient-years in carriers of CYP variants. In this study, findings were adjusted for other common variables associated with increased bleeding risk, such as increased age, drug interactions and abnor‐

Several studies of the \*2 and \*3 CYP2C9 polymorphisms consistently show that patients with at least one CYP2C9 allele polymorphism have reduced warfarin requirements [76, 80-84]. Freeman [85] reported reduced warfarin weekly dosages for carriers of CYP2C9\*2 or CYP2C9\*3 alleles compared with patients who were homozygous for the wild-type allele (0.307 mg/kg/wk and 0.397 mg/kg/wk, respectively). Taube [83] compared warfarin mainte‐ nance dosages in 683 patients carrying different CYP2C9 genotypes. Mean warfarin mainte‐ nance dosages were 86% in patients with CYP2C9\*1\*2, 79% in patients with CYP2C9\*1\*3, 82% in compound heterozygotes CYP2C9\*2/\*3, and 61% in patients homozygous for CYP2C9\*2. Furthermore, Aithal [80] warns that even when warfarin dosages are decreased,

lant activity. (S)-warfarin is metabolised almost exclusively by CYP2C9 [68-70].

ide reductase complex subunit 1 (EC 1.1.4.1) [67].

different CYP enzymes [71].

down to 20% less than the standard dose.

ic activity [24, 73-78].

mal liver function.

A few studies describe some association; three SNPs in CACNA1C had significant associa‐ tions with treatment in a study of BP lowering with calcium channel blockers [59]; between CYP3A5\*3 and \*6 variants and verapamil treatment for BP and hypertension risk outcomes in blacks and Hispanics [60]; individuals that are homozygous for the T allele of NPPA T2238C had more favourable clinical outcomes when treated with a calcium channel blocker whereas C carriers responded better to a diuretic [32]. Beta Adrenergic Receptor 1 (BAR1) Ser49-Arg389 haplotype carriers had higher death rates than those with other haplotypes when treated with verapamil [15].
