Introduction
Hypertension management and clinical practice guidelines
Pharmacokinetics and mode of action of first-line hypertensive drugs
Amlodipine
Pharmacokinetics | Effect | Reference |
---|---|---|
Bioavailability | Amlodipine is orally administrated with a bioavailability of 64–90%. | |
Absorption | Amlodipine reach peak plasma concentration (tmax) 6–12 h after administration, while steady state plasma concentrations will be reached within 7–8 days of daily dosing. | |
Distribution | Amlodipine has a high volume of distribution (21 L/kg) and a large proportion of the dose is distributed in the tissue with ~ 90% of the circulating drug being bound to the plasma membrane. | |
Metabolism | Amlodipine is extensively metabolized in the liver into its inactive metabolites via CYP3A4/5. | |
Elimination | Amlodipine is slowly cleared with an elimination half-life of 40 to 60 h. If discontinued, BP returned to baseline after 1 week. Urine is the major route of elimination. Amlodipine is converted to inactive metabolites (60%), which are excreted into the urine while 10% of the excreted drug remains unchanged. Amlodipine is converted from dihydropyridinebmoiety to a pyridine derivative (M9). Fecal excretion accounts for 20–25% of the dose |
Hydrochlorothiazide
Pharmacokinetics | Effect | References |
---|---|---|
Bioavailability | Oral administration of the drug ranges from 25 to 75 mg/day, and has a bioavailability of 60–80%. | |
Absorption | Gastrointestinal absorption of the drug is rapid and peak plasma concentration is achieved at ~ 2 h. With the majority of the drug is absorbed in the duodenum and the upper jejunum. | |
Distribution | The drug is transported ~ 40% bound to plasma proteins and it can also accumulate in erythrocytes. The ratio between the drug in erythrocytes and plasma averages 3.5. Another report showed the concentration of the drug in erythrocytes could be as high nine-fold to that of plasma. | |
Metabolism | Limited evidence exists related to the metabolism of this drug. However, 2-amino-4-chloro-1,3-benzenedisulfonamide and chlorothiazide are some of the metabolites that have been detected in urine after administration of this drug. | |
Elimination | The half-life of HCTZ is estimated to be 5 to 14 h. The main excretion route for this drug is the kidneys, with the mean renal clearance of ~ 300 mL/min and greater than 95% of the absorbed drug shown to be excreted unchanged in urine. |
Pharmacogenomics and inter-individual variation of hypertensive drug therapy, amlodipine and HCTZ
Gene | SNP | Treatment outcome | Population | References |
---|---|---|---|---|
ABCB1
| rs1045642 | Gender differences and SNPs in ABCB1 gene (2677G/T and 3435C/T) showed increased oral clearance of amlodipine. Males require higher concentration of amlodipine. | Asian | |
ACE
| rs200148 rs4291 | For SNP rs200148 in the African-American cohort, the A allele frequency is higher in the chlorthalidone treatment group as compared to the amlodipine group. Promoter mutations in rs4291 were associated with lower fasting glucose for the model AA/AT compared to the TT. | African-American and Caucasian | [42] |
CACNA1D
| rs312481 rs3774426 | A significant reduction in BP was observed for the combined presence of the identified SNPs (rs312481G/A and rs3774426C/T). Individuals with CC genotype responded better as measured by lowered SBP. | Asian | |
CACNA1C
| rs527974 rs2239050 and rs2238032 | Identified SNP 527974G/A was able to decrease BP significantly after treatment. However, none of the identified SNPs were similar to those identified in the Brenner study. | Asian | |
Estonian Genome Project found that patients with the combined identified SNP had an increased efficacy to amlodipine treatment outcome. | Caucasian | |||
CYP3A4
| rs2246709 rs2740574 | Blood pressure response was gender specific and associated with African-American population with genotypes (16090T/C and 392 A/G). | African-American and | |
Gender differences was observed but not significant and, CYP3A5*3 does not affect amlodipine efficacy. | Asian | |||
CYP3A5
| rs776746 | CYP3A5 6986A/G was not associated with decrease in BP response in African-American population. But, a significant reduction in BP occurred in Chinese and Korean cohort, CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. Gender differences was observed but not significant and, CYP3A5*3 does not affect amlodipine efficacy. | African-American/Asian | |
GNB3
| rs5443 | Splice variant is associated with the DBP lowering effect of telmisartan but not amlodipine in Chinese. | Asian | [50] |
MDR1
| G2677T/C3435T | Discordant results with the C3435T found that the plasma drug concentration of amlodipine in healthy volunteers of the MDR1 C3435T mutant allele carrier was lower than that of the CC type. However, according to the study of Cai and colleagues, the MDR1 C3435T mutant did not influence the effect of amlodipine in renal transplant patients with hypertension. Therefore, further investigations are required to elucidate the impact of the MDR1 C3435T polymorphism on the pharmacokinetics and efficacy of amlodipine. | Caucasian and Asian | |
NOS1AP
| rs10494366 | Significance (SNPs at this gene as relevant to stroke pharmacogenetics. | African-American | [52] |
NPPA
| rs5065 | The 2238T/C variant had lower event rates were for the C allele carriers than for the TT homozygous when comparing chlorthalidone and amlodipine. The AA genotype responds better to amlodipine. | Multiple races and ethnic groups | [53] |
NUMA1
| rs10898815 | Increased response as determined by a greater decrease in DBP but SBP blood pressure. | Multiple races and ethnic groups | [44] |
PICALM
| rs588076 | Patients with the GG genotype and hypertension may have a greater decrease in blood pressure. | Multiple races and ethnic groups | [44] |
POR
| rs1057868 | 1509 C/T genotypes had no significant impact on the blood drug concentration and efficacy of amlodipine due to sample size. | Asian | [42] |
RYR3
| rs877087 | Reduced BP response was observed. | Caucasian | [54] |
TANC2
| rs2429427 | Reduced BP response was observed. | Multiple races | [44] |
Gene | SNP | Treatment outcome | Population | References |
---|---|---|---|---|
ACE
| rs4303 | BP response was altered by genotype. | African-American | [55] |
ADD1
| rs4961 | BP response was altered by genotype carriers of the risk (T) allele. The T carriers responded better to low-dose diuretic therapy compared to the G allele risk carriers. | African-American, Caucasian and Asian | |
WNK1
NEDD4L
| rs880054 rs4149601 rs292499 | SNP in ADD1, WNK1, and NEDD4L, when present in combination, may have significant effects on renal sodium handling, BP, and antihypertensive response to thiazides. However, variants in WNK1 and NEDD4L genes have shown conflicting associations with BP. | ||
AGT
| rs5051 rs699 | T allele correlate with a higher incidence of uncontrolled hypertension and it is more frequent in African population compared to Caucasian. | African-American and Caucasian | [65] |
AGTR1
| rs5186 | In African-American females, A allele is associated with increased reduction in BP. | African-American and Caucasian | [66] |
ALDH1A3
| rs3825926 | SNP influenced response to hydrochlorothiazide treatment, 101445441A/G. | Caucasian | |
ANKFN1
| rs9915451 | G allele has a decreased response to treatment in people with uncontrolled hypertension compare to the A allele. | Caucasian | [69] |
CLIC5
| rs321329 | SNP influenced response to hydrochlorothiazide treatment, 45722988A/G. | Caucasian | |
CSMD1 and CUB | rs2776546 and rs11993031 | AA genotype increased BP response to HCTZ compared to AT and TT genotype. | Caucasian | [69] |
DOT1L
| rs2269879 | SNP was strongly associated with greater SBP and DBP blood in Caucasians. | Caucasian | [71] |
FBXL17
| rs4431329 | Patients with the AA genotype and essential hypertension may have an increased response when treated with hydrochlorothiazide as compared to patients with the AT or TT genotypes. | Caucasian | [69] |
FGF5
| rs1458038 | The T allele near FGF5 was associated with higher BP and higher risk for HTN in Caucasian individuals. The authors found that the CC genotype better respond to anti-HTN drugs compared to the TT and TC genotype. This SNP was also strongly associated with BP in East Asians and South Asians and only marginally in African-Americans. Caucasian hypertensive individuals with the risk allele for HTN (T) might respond better to atenolol, than to HCTZ. | African-American, Caucasian, and Asian | |
FTO
| rs4784333 | C allele increased uric acid levels in subjects on HCTZ monotherapy plus subjects who started treatment on atenolol and then had HCTZ added. Result was not significant after Bonferroni correction. | African-American | [75] |
GNAS-EDN3
| rs2273359 | Carriers of the CG genotype at this locus had a better BP response compared to the CC genotype. | African-American and Caucasian | [76] |
FOS
DUSP1
PPP1R15A
| rs11065987 | Representative SNP of rs11065987, rs653178, rs10774625, and rs11066301, all of which are in high linkage disequilibrium with each other. The A allele of rs11065987 was associated with a greater decrease in both systolic and diastolic blood pressure following treatment with HCTZ compared to the GG genotype. | Caucasian | [77] |
GPR83
| rs3758785 | The AA genotype may have increased response to hydrochlorothiazide in people with essential hypertension as compared to patients with genotype GG or AG. | African- American | [78] |
H3K4me1
| rs11750990 | SNP identified to be associated with SBP response in the GWAS meta-analysis of Caucasians. | Caucasian | |
HSD3B1
| rs6203 rs3765945 rs1047303 | CC genotype associated with higher BP response and more significant in males. TC haplotype of SNP rs3765945 and rs1047303 have been significantly associated with SBP. | African-American | [72] |
KCNJ1
| rs59172778 | SNP increase fasting blood glucose levels. | African-American and Caucasian | |
LUC7L2
| rs6947309 | SNP elevated in African-Americans but not Caucasians. | African-American and Caucasian | [75] |
NEDD4L
| rs4149601 | Carriers with the G allele have a greater BP reduction as compared to the AA homozygotes. | African-American and Caucasian | |
PRKCA
| rs16960228 | BP responses were consistently greater in carriers of the A allele than in GG homozygotes. | Caucasians | |
SH2B3
| rs3184504 | The C allele (nonsynonymous, T/C, Trp/Arg) was associated with reduced BP in Caucasians, whereas in African-Americans the C allele is associated with a slight increase in blood. | African-American and Caucasian | [74] |
STK39
| rs6749447 | The A minor allele has been associated with 2.0 mmHg higher SBP and a 1.0 mmHg higher DBP. | Caucasian | |
TET2
| rs12505746 | SNP in GENRES cohort was associated with DBP, but not with SBP. | Caucasian | [69] |
TTC6
| rs177852 | CC + CT are associated with increased response to HCTZ in people with HTN as compared to genotype TT. As greater antihypertensive efficacy of HCTZ was observed in Blacks compared to Whites. | African-American | [72] |
UGGT2
| rs9590353 | SNP was associated with a lower decrease in DBP pressure after HCTZ treatment. | Caucasian | [69] |
12q Loci
LYZ, YEATS4,
FRS2
| rs317689, rs315135, rs7297610 | Haplotype (ATC) was more frequently observed in the African population was more frequently observed in the African population, whereas the poor responders had either an ACT or ATT haplotype. | African-American and Caucasian |