**2.2. Diuretics**

**2. Hypertensive drugs**

78 Drug Discovery

mon first line treatment for hypertension [8].

ethnic and gender subgroups [10].

avoid drug interactions.

**2.1. β-blockers**

sociations [13, 14].

Hypertension is a common condition associated with increased risk of stroke, heart failure, ischemic heart disease, and chronic renal failure. Thiazide diuretics, β-blockers, ACE inhibi‐ tors, angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) are a com‐

Despite availability of many effective agents, only about 40 percent [9] of treated hyperten‐ sive patients have their blood pressure controlled, mostly due to the unpredictable individu‐ al responses to treatment. Blood pressure responses to monotherapy vary widely within

Numerous studies have tried to establish associations between genetic polymorphisms and response to antihypertensive drugs. New developments in pharmacogenetics and pharma‐ cogenomics already offer in pharmacogenetics and pharmacogenomics already offers the opportunity to provide individualised drug therapy on the basis of a person's genetic make‐ up for some drugs, despite varied approaches in study designs and methodology. These tests are provided by several laboratories and available at some hospitals; pharmacogenetic methods will not only help to achieve treatment goals and limit adverse effects, but also

β-blockers through binding to β-adrenergic receptors (BAR) antagonise the binding of en‐ dogenous agonists. Variations in the gene encoding the β1-adrenergic receptor probably in‐ fluence the treatment outcome. Two single nucleotide polymorphism (SNPs), resulting in Ser49Gly and Arg389Gly were identified and these variants demonstrate altered biological function in vitro, including enhanced agonist induced adenylyl cyclase activation by Gly49

Some studies have shown that the Arg389Arg genotype and Ser49/Arg389 haplotype are as‐

The differential survival of Acute Coronary Syndrome (ACS) patients treated with βblockers was associated with patients' β-adrenergic receptors 2 variant Gly16Arg and Gln27Glu genotypes; however, β-adrenergic receptors 1 variants showed no significant as‐

No significant correlation has been found for outcomes of death, MI or stroke in coronary artery disease patients on atenolol treatment and β-adrenergic receptors variants or haplo‐ types [15] and β-adrenergic receptors 2 variants in MI and stroke outcomes. However, the case-control study found significant interaction with two SNPs in β-adrenergic receptors

Angiotensin-converting enzyme (ACE) genes variations were also associated with β-block‐ ers therapy outcome. In heart failure, patients survival without a transplant, has been as‐ sociated with the angiotensin-converting enzyme I/D genotype (insertion/deletion).

sociated with a greater response to blood pressure-lowering metoprolol [12].

compared to Ser49 and by Arg389 compared to Gly389 [11].

variant and cardiovascular complications [16, 17].

Diuretics may act at a number of sites, including the proximal tubule, the Loop of Henle, and the distal and collecting tubules. Diuretics are thought to indirectly activate the reninangiotensin-aldosterone system and block sensitivity of blood vessels to catecholamines. Thiazide diuretics are the drug of choice for initial therapy, but genes responsible for renal sodium reabsorption can affect the patient's responsiveness to diuretic therapy.

Antihypertensive response in black African Americans is found to be associated with locus at chromosome12q15 [30, 31] where the FRS2 gene is located, which is involved in fibroblast growth factor signalling. FRS2 plays a role in vascular smooth muscle cell regulation.

Genome-wide association (GWA) studies are aimed at identifying common genetic variants modulating disease susceptibility, physiological traits and variable drug responses. These studies also provide further evidence for the large effects that single gene variants may exert for some drugs. GWA has explained relatively large proportions of variability compared to studies of traits such as disease susceptibility or physiological measurements. GWAS dem‐ onstrated that SNPs in lysozyme and Yeats domain-containing protein 4 (YEATS4 ) were as‐ sociated with response to diuretic [30].

Lynch et al. found that C carriers of the NPPA T2238C variant, which codes for the precur‐ sor of atrial natriuretic polypeptide, had more favourable clinical outcomes when treated with a diuretic, whereas individuals homozygous for the T allele responded better to a calci‐ um channel blocker [32].

The insertion/deletion (I/D) in the angiotensin I-converting enzyme (ACE) gene is one of the candidates for studies. The D allele has been associated with more improvement in coronary endothelial dysfunction with ACE inhibitor therapy than the I allele [48]. Reductions in sys‐ tolic and diastolic blood pressures were significantly greater for patients with the D/D geno‐

Drug Interactions, Pharmacogenomics and Cardiovascular Complication

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

81

Diastolic blood pressure tended to decrease more for the ACE I/I genotype than for other ACE genotypes and the I/I genotype was also predictive of greater diastolic blood pressure decline [50]. Decline in renal function during ACE inhibitor treatment tended to be greater in heart failure patients with the ACE I/I genotype [51]. The I/I genotype has also been asso‐ ciated with increased susceptibility to the development of cough during ACE inhibitor ther‐ apy. After four weeks of therapy with an ACE inhibitor in healthy volunteers, the threshold for cough was significantly reduced for the I/I genotype but not the D/D genotype [52].

Another gene of interest is the angiotensinogen (AGT) gene. It was reported that the angio‐ tensinogen 235Met/Thr polymorphism is also associated with RAS activity and drug re‐ sponses. In subjects on ACE inhibitor monotherapy with 235Thr allele the response is higher than in the control group. Systolic and diastolic blood pressures were higher and the likeli‐ hood of using two or more antihypertensive medications was 2.1 times higher with the

An association with polymorphisms in the angiotensin AT1 receptor (AGT1R) gene and ACE inhibitors' efficiency are found in some studies. The AGT1R mediates some negative effects of angiotensin II, such as vasoconstriction, cardiac remodelling, and aldosterone se‐ cretion. Angiotensin II blockers bind to angiotensin II receptors, thereby antagonizing the ef‐ fect of angiotensin II, a potent vasoconstrictor [54]. The 1166C allele of AGT1R has been associated with increased arterial responsiveness to angiotensin II in ischemic heart disease and increased aortic stiffness in hypertension. During ACE inhibitor treatment, reductions in aortic stiffness were reported to be three times greater in carriers of the 1166C allele than in 1166A homozygotes [55, 56]. AGTR1 (C573T) and ACE (ID) association between ACE in‐ hibitor therapy and increased MI risk for carriers of the AGTR1 C573 allele were reported; however, no significant interaction between ACE inhibitor treatment and ACE (ID) alleles for either stroke or MI were found [28]. One research group found no associations between BP response and ACE (ID), AGTR1 (A1166C), CYP11B2 (-344 C/T), AGT (-6 A/G) [57].

After 12 weeks of treatment with irbesartan (Angiotensin II Blocker), plasma concentration of the drug was related to change in systolic BP in TT homozygotes of AGTR1 (C5245T) but

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‐

type than for patients with the I/D and I/I genotypes [49].

235Thr polymorphism [53].

not for other genotypes [58].

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

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

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‐ sure response with thiazides [27, 35].

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