Pharmacogenomics of amlodipine and hydrochlorothiazide therapy and the quest for improved control of hypertension: a mini review

Abstract

Blood pressure (BP) is a complex trait that is regulated by multiple physiological pathways and include but is not limited to extracellular fluid volume homeostasis, cardiac contractility, and vascular tone through renal, neural, or endocrine systems. Uncontrolled hypertension (HTN) has been associated with an increased mortality risk. Therefore, understanding the genetics that underpins and influence BP regulation will have a major impact on public health. Moreover, uncontrolled HTN has been linked to inter-individual variation in the drugs’ response and this has been associated with an individual’s genetics architecture. However, the identification of candidate genes that underpin the genetic basis of HTN remains a major challenge. To date, few variants associated with inter-individual BP regulation have been identified and replicated. Research in this field has accelerated over the past 5 years as a direct result of on-going genome-wide association studies (GWAS) and the progress in the identification of rare gene variants and mutations, epigenetic markers, and the regulatory pathways involved in the pathophysiology of BP. In this review we describe and enhance our current understanding of how genetic variants account for the observed variability in BP response in patients on first-line antihypertensive drugs, amlodipine and hydrochlorothiazide.

Pharmacogenomics of Hypertension Treatment

“…Calcium channel blockers (CCBs) are drugs that bind to and block mainly the L-type calcium channels present on cardiac and vascular smooth muscle cells (SMCs) [ 16 ]. They prevent calcium ions from entering into vascular smooth muscles, which results in muscle relaxation and vasodilation and leads to a decrease in vascular resistance and, consequently, diminished arterial BP [ 17 ].…”

“…Numerous studies have indicated that the single-nucleotide polymorphisms (SNPs) in genes encoding different ion channels, including the large-conductance voltage and calcium-sensitive potassium channel β1 ( KCNMB1 ), the voltage-gated calcium channels α1C ( CACNA1C ), α1D ( CACNA1D ) and β2 ( CACNB2 ), and ERG potassium channel ( KCNH2 ), can modify the antihypertensive responses to CCB and the risk of adverse cardiovascular outcomes [ 1 , 19 , 20 , 21 , 22 , 23 ]. Furthermore, variations in the genes coding the family of HECT domain E3 ubiquitin ligases (NEDD4L) and ATP-binding cassette subfamily B member 1 (ABCB1) have been shown to participate in the regulation of blood pressure (BP) in response to anti-hypertensive drugs [ 11 , 16 ]. The result of the INVEST-GENES study demonstrated that the KCNMB1 genotype can influence responses to verapamil SR in White, Hispanic, and Black hypertensive patients with cardiovascular disease (CAD) [ 19 ].…”

“…Langaee et al [ 29 ] used a haplotype approach to investigate the effect of CYP3A5 mutations on BP responses to verapamil in Black, Hispanic, and White individuals. In their study, blood pressure responses to verapamil, to a small extent, depended on the number of CYP3A5 functional alleles in the first two populations, but not in the third one; carriers of two functional alleles showed the worst response to the treatment [ 16 , 29 ]. The activity of the cytochrome P450 3A4/5 (CYP3A4/5) enzymes is also important for amlodipine, which is a first-line long-acting CCB that inhibits vasoconstriction and improves blood flow by hampering calcium influx via the L-type calcium channels into vascular SMCs [ 16 , 30 ].…”

“…In their study, blood pressure responses to verapamil, to a small extent, depended on the number of CYP3A5 functional alleles in the first two populations, but not in the third one; carriers of two functional alleles showed the worst response to the treatment [ 16 , 29 ]. The activity of the cytochrome P450 3A4/5 (CYP3A4/5) enzymes is also important for amlodipine, which is a first-line long-acting CCB that inhibits vasoconstriction and improves blood flow by hampering calcium influx via the L-type calcium channels into vascular SMCs [ 16 , 30 ]. According to past studies, polymorphisms within genes that encode the enzymes participating in amlodipine metabolic break-down into inactive pyridine metabolites (M9) affect this drug’s activity and thus modify patients’ anti-hypertension responses to treatment [ 16 , 31 ].…”

Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: A single-dose and two-period crossover randomized study

“…Hypertension is one of the most common risk factors associated with cardiovascular disease, stroke, and can lead to severe complications [1]. Amlodipine, a dihydropyridine calcium antagonist, has therapeutic effect on hypertension and angina pectoris [2]. Amlodipine is an racemic mixture, including (R) and (S)amlodipine, but only the latter has therapeutic activity [3].…”