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Main Classes of Drugs
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Angiotensin II receptorantagonist (blocker)AzilsartanCandesartanEprosartanIrbesartanLosartanOlmesartanTelmisartanValsartan
Single-Pill Combination Treatments in Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Today, dual combinations containing an RAS blocker and a diuretic (thiazide, chlorthalidone, indapamide) belong to the most frequently used associations in the management of hypertension. There is strong physiological rationale for this association. Indeed, the negative sodium balance induced by the diuretic triggers the release of renin and the production of angiotensin II. Hence the maintenance of BP becomes angiotensin II-dependent. In this context, blockade of the reactive activation of the RAS enhances the BP-lowering effect of diuretics. Conversely, the diuretic-induced stimulation of aldosterone leading to hypokalaemia is blunted with the administration of the RAS blocker, therefore preserving an intact potassium balance (19,27). This combination is generally well tolerated, and several studies have demonstrated that the association of an RAS blocker and a diuretic is superior to a high dose of the RAS blocker alone to lower BP. Recently, the issue of which is the best diuretic has been the topic of some discussions. Indeed, there is some clinical evidence that chlorthalidone reduces cardiovascular events in hypertension better than hydrochlorothiazide (HCTZ) (28), and differences in potency between HCTZ and chlorthalidone in favour of the latter have been clearly demonstrated (29). However, almost all combinations associate an RAS blocker with low doses of HCTZ except for azilsartan, which has been developed in association with chlorthalidone, and perindopril, which is associated with low doses of indapamide (30,31). This latter is effective in lowering BP (32) and/or preventing cardiovascular events (30). Recent comparative studies have shown that the SPC of azilsartan modoxomil and chlorthalidone induces a greater fall in 24-h ambulatory BP than azilsartan/HCTZ (33) or olmesartan/HCTZ (34) (Figure 41.3).
Unique mode of binding between angiotensin II type 1 receptor and its blockers
Published in Clinical and Experimental Hypertension, 2019
Yoshino Matsuo, Yasunori Suematsu, Sayo Tomita, Kohei Tashiro, Takashi Kuwano, Ken Kitajima, Shin-ichiro Miura
Angiotensin II (Ang II) type 1 receptor (AT1R) mediates most known pathophysiological cardiovascular functions (1,2). AT1R blockers (ARBs) inhibit the diverse effects of Ang II, such as vasoconstriction and cell proliferation. ARBs have been shown to have molecule-specific effects in addition to class effects. We previously indicated that each ARB has a unique binding mode for AT1R (3–5). We proposed that these molecule-specific effects may be due to small differences in the molecular structure of each ARB. In a clinical setting, azilsartan (AZL) provided a more potent 24-h sustained antihypertensive effect than candesartan (CAN) (6). Treatment with AZL medoxomil lowered 24-h blood pressure (BP) significantly more than treatment with olmesartan medoxomil or valsartan (7,8). A carboxyl group of CAN or AZL was important for binding to AT1R (9,10). AZL has been shown to bind tightly to and dissociate slowly from AT1R in comparison to other ARBs (11). Recently, Zhang et al. successfully determined the room-temperature crystal structure of the AT1R in complex with its selective antagonist. Docking simulations of ARBs to the AT1R structure further clarified both the common and distinct binding modes for ARBs (12). There may be interactions between Arg167 in the AT1R and 5-oxo-1,2,4-oxadiazole in AZL and the tetrazole ring in CAN.
Preparation and in vitro/in vivo evaluation of azilsartan osmotic pump tablets based on the preformulation investigation
Published in Drug Development and Industrial Pharmacy, 2019
Nini Li, Ling Fan, Biao Wu, Genlai Dai, Chengjun Jiang, Yan Guo, Dianlei Wang
Azilsartan, a new generation of angiotensin II receptor blocker (ARB), was approved for the treatment of hypertension in Japan in 2012. It is the main active metabolite of azilsartan medoxomil with a molecular formula of C22H20N4O5 [1]. Azilsartan selectively binds to the angiotensin II AT1 receptor to inhibit the actions of angiotension II and results in lowering blood pressure (BP) [2]. It has been reported that azilsartan exerted a more potent and sustained BP-lowering effect than existing ARBs [3,4]. However, the poor solubility of azilsartan against the release of drug and presents a serious obstacle for its clinical application. Although azilsartan has a long half-life, whether it can keep constant effective plasma level is not known yet [5]. One of the important principles of hypertension treatment is the requirement for stable blood pressure. Long-acting drugs administered once a day for 24 h are actively recommended for the purpose of smoothly controlling the blood pressure and effectively preventing target organ damage. The key of maintaining a long-lasting, stable anti-hypertension is a stable drug level. As a consequence, with the purpose of controlling the drug release to maintain stable effective plasma concentration, reducing its adverse reactions and increasing patient compliance, there is a growing need for developing a osmotic pump tablet with improved azilsartan solubility.
An international multicenter observational non-interventional prospective study of the efficacy of azilsartan medoxomil in overweight or obese patients with arterial hypertension (CONSTANT)
Published in Current Medical Research and Opinion, 2021
Irina E. Chazova, Yulia V. Zhernakova
In accordance with the results of the present study, azilsartan medoxomil either in monotherapy regimen or in free combinations with other drugs provided effective BP control with high frequency of target BP achievement, regardless of sex, age and BMI of patients. Given the high efficacy, good safety profile and the small number of AE noted in this study, azilsartan medoxomil could be considered as the drug of choice for the treatment of hypertension in patients with overweight or obesity.