Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes

Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti‐inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC₅₀) of AA metabolism was losartan <telmisartan <irbesartan <candesartan <olmesartan <valsartan via CYP2C9, and telmisartan <irbesartan <olmesartan <losartan <candesartan and valsartan via CYP2J2. The order for the HLMs was losartan <telmisartan <irbesartan <olmesartan <candesartan <valsartan. Some ARBs having lower concentration of IC₅₀ indicate that these ARBs might inhibit the AA metabolism in the liver.     

Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation

A recent study has shown that losartan, an AT-1-receptor antagonist, interacts with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors in human platelets. The aim of this study was to analyze the ability of different angiotensin II (Ang II) AT-1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers. Platelets were stimulated with the TxA2 analogue, U46619 (10(-6) M). U46619-stimulated platelet activation was significantly reduced by both losartan and irbesartan in a dose-dependent manner. Only maximal doses of valsartan (5 x 10(-6) M) and the main metabolite of losartan, EXP3174 (5 x 10(-6) M), reduced U46619-induced platelet activation. Whereas the active form of candesartan cilexetil (candesartan, CV-11974) failed to modify platelet activation involved by TxA2, telmisartan showed a higher effect than valsartan and EXP3174 but lower than either losartan and irbesartan. Losartan or irbesartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed with lower ability with the other AT-1 antagonists. Although platelets expressed AT-1-type receptors, exogenous Ang II did not modify platelet activation. This effect was not modified by blocking the AT-2 receptor with PD123319. These results suggest that some AT-1-receptor antagonists reduce TxA2-dependent activation independent of Ang II involvement.     

Identification and determination of selected angiotensin II receptor antagonist group drugs by HPLC method

Losartan potassium, valsartan, telmisartan, irbesartan, eprosartan mesylate and candesartan cilexitil, the angiotensin II receptor antagonists, were analyzed in bulk substances and in tablets: Lorista tablets 50 mg, Diovan tablets 160 mg, Micardis tablets 20 mg, Aprovel tablets 300 mg, Teveten tablets 600 mg and Blopress tablets 16 mg. The conditions for identification by HPLC method in a gradient system and for determination of those compounds in isocratic systems were developed. The determination was carried out using Zorbax SB-Phenyl column with UV-VIS detector set at 230 nm and the following mobile phases: 0.1 mol/L sodium acetate (pH = 5.5) - acetonitrile - methanol in 35:9:6 v/v/v ratio for eprosartan mesylate and valsartan, in 15:6:4 v/v/v ratio for losartan potassium and irbesartan and in 10:9:6 v/v/v ratio for telmisartan and candesartan cilexitil. The recovery from simulated tablets was determined and amounted to: for eprosartan mesylate - 99.04%, valsartan - 100.0%, losartan potassium - 100.03%, irbesartan - 100.35%, telmisartan - 100.06% and candesartan cilexitil - 100.40%.     

Subclinical alteration of taste sensitivity induced by candesartan in healthy subjects

AIMS: There have been case reports of taste disturbance for the angiotensin II receptor blockers losartan and valsartan, but not for candesartan. This study was undertaken to examine whether candesartan causes taste disturbance. METHODS: Candesartan cilexetil (4 mg day(-1)) or vehicle was given to healthy volunteers (n = 8) for 7 days in a randomized, double-blind, placebo-controlled, cross-over design with a 2-week washout period. Clinical gustometry using the filter-paper disc test and electrogustometry were sequentially performed before and at the end of each trial. Serum and salivary zinc concentrations were also measured. RESULTS: Detection thresholds of four basic tastes (sweet, salty, sour and bitter) determined by the paper disc test were significantly (P < 0.05 in all tests) worsened (i.e. score of test increased) after repeated dosing of the drug, although the subjects did not notice such changes. The mean +/- SEM (and 95% CI) scores of the four tastes at just before the seventh dosing of candesartan or vehicle was 3.38 +/- 0.32 (3.02, 3.74) and 2.63 +/- 0.18 (2.18, 3.08) for sweetness, 3.63 +/- 0.38 (4.49, 2.77) and 2.63 +/- 0.26 (3.27, 1.98) for salt, 4.01 +/- 0.42 (3.04, 4.98) and 2.61 +/- 0.32 (3.35, 1.87) for sourness, 4.01 +/- 0.38 (3.22, 4.80) and 2.99 +/- 0.33 (2.24, 3.74) for bitterness, for candesartan and placebo, respectively. Electrogustometry confirmed the candesartan-related taste disturbance. Serum and salivary zinc concentrations were not influenced by candesartan. CONCLUSIONS: These data suggest that candesartan subclinically reduces taste sensitivity after repeated dosing in healthy subjects. Because similar events are reported for losartan and valsartan in case reports, this adverse effect might be a class effect of angiotensin-II receptor blockers (ARBs).     

Investigation of Carcinogenic Impurities of N-Nitrosamines in Sartan Pharmaceutical Products Marketed in Brazil: Development and Validation of Method Based on High-Performance Liquid Chromatography-Tandem Mass Spectrometry

N-nitrosamines (NA) impurities have unexpectedly been found in sartan products, angiotensin II receptor antagonists that are used to control hypertension, representing an urgent concern for industry, global regulators and for the patients. In this study, an HPLC-MS/MS method was developed and validated for the quantification of six NA (N-nitrosodimethylamine, N-Nitroso-N-methyl-4-aminobutyric acid, N-Nitrosodiethylamine, N-ethyl-N-nitroso-2-propanamine, N-nitroso-diisopropylamine and N-nitroso-di-n-butylamine) in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan products. The method was validated in terms of sensitivity, linearity, accuracy, precision, robustness and stability. The limits of quantification were 100, 31.25, 250, 33, 312.5 and 125 µg kg⁻¹ in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan samples, respectively, which met the sensitivity requirements for the limits set by Food and Drug Administration of the United States. The standard curves showed good linearity. The recoveries ranged from 93.06 to 102.23% in losartan matrix, 83 to 85.9% in valsartan, 96.1 to 101.2% in olmesartan, 89.2 to 97.5% in irbesartan, 93.4 to 132.0% in candesartan and 62.3 to 106.2% in telmisartan matrix. The other parameters met the validation criteria, the good sensitivity and precision, high accuracy and simple and fast analysis provides a reliable method for quality control of NA in sartan pharmaceutical products. The developed method was successfully applied for the determination of N-nitrosamines in 71 sartan products marketed in Brazil.     

Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockers

There is a growing body of evidence that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. Indeed, large clinical trials have demonstrated a substantial benefit of the blockade of this system for cardiovascular-organ protection. Although several types of angiotensin II type 1 (AT1) receptor blockers (ARBs) are commercially available for the treatment of patients with hypertension, comparisons of the binding affinity to AT1 receptor among them remain to be elucidated. In this study, we examined the dissociation rate of several ARBs from AT1 receptor in vitro. Angiotensin II time-dependently dissociated telmisartan, olmesartan, candesartan, valsartan, losartan and an active metabolite of losartan, EXP3174, from membrane components containing human AT1 receptor The dissociation rate constant of each ARB was 0.003248, 0.004171, 0.005203, 0.009946, 0.01027 and 0.008561 min(-1), with corresponding half-lives of 213, 166, 133, 70, 67 and 81 min, respectively. These results demonstrate that telmisartan has the strongest binding affinity to AT1 receptor among various ARBs examined herein. The rank order of affinity was telmisartan > olmesartan > candesartan > EXP3174 > or = valsartan > or = losartan. The present findings suggest that telmisartan (Micardis) may have long-lasting blood pressure-lowering effects and superior cardioprotective properties in patients with hypertension due to its strongest AT1 receptor antagonistic ability.     

生物样品中沙坦类药物检测方法研究进展

沙坦类药物是临床上治疗高血压的一线药物,包括洛沙坦、缬沙坦、厄贝沙坦、奥美沙坦、替米沙坦、坎地沙坦、依普沙坦等。文中对生物样品中此类降压药的色谱检测法作一综述,介绍作者的实验室使用的简单灵敏的色谱检测方法。这些新方法能促进沙坦类药物的药代动力学研究和低剂量给药药物浓度监测的发展,对于药物的进一步开发和临床用药浓度监测有非常重要的作用。     

Simultaneous determination of hydrochlorothiazide and several angiotensin-II-receptor antagonists by capillary electrophoresis

We have investigated the capability of the capillary zone electrophoretic (CZE) and micellar electrokinetic capillary chromatographic (MEKC) methods to simultaneously separate hydrochlorothiazide and six angiotensin-II-receptor antagonists (ARA-IIs): candesartan, eprosartan mesylate, irbesartan, losartan potassium, telmisartan, and valsartan. The CZE and MEKC methods are suitable for the qualitative and quantitative determination of combined HCT/ARA-IIs in pharmaceutical formulations. Depending on the ARA-II, at least one of the two methods can be used for each combination. The two methods have been validated in terms of their linearity of response, reproducibility, and accuracy.     

Antihypertensive Effects of Olmesartan Compared with Other Angiotensin Receptor Blockers

Objectives: Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been shown to be effective and well tolerated in hypertensive patients. Olmesartan is the seventh angiotensin receptor blocker licensed by the US Food and Drug Administration. The aim of this meta-analysis was to determine the efficacy and tolerability of olmesartan medoxomil in comparison with other ARBs. Data Sources: Reports of randomized controlled trials (RCTs) of olmesartan versus other ARBs were identified through a systematic search of PubMed (up to July 2010), EMBASE (1980 to July 2010), SinoMed (up to July 2010), and the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 7, 2010). Review Methods: Pertinent studies were selected through extensive searches of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and SinoMed. Two of the authors abstracted data from the identified studies independently. Criteria for inclusion in our meta-analyses were randomized clinical trials in which patients were receiving an ARB and outcome data for blood pressure reduction or the incidence of adverse events were available. Quantitative and qualitative analyses of data from all RCTs meeting the criteria were performed. Our meta-analysis was undertaken according to the Quality of Reporting Meta-analyses (QUOROM) statement. Results: Twenty-two studies with data from 4892 patients were considered for analyses. Olmesartan provided greater diastolic blood pressure (DBP) and systolic blood pressure (SBP) reductions compared with losartan (DBP: 95% confidence interval [CI] 0.59, 2.62; SBP: 95% CI 0.46, 5.92). Olmesartan provided greater SBP reductions compared with valsartan (95% CI 0.29, 3.16). Similar blood pressure response rates and incidence of adverse events were found with losartan, valsartan, candesartan, and irbesartan. Conclusion: Olmesartan provides better antihypertensive efficacy than losartan and valsartan and has no association with an increased risk of adverse events in comparison with losartan, valsartan, candesartan, and irbesartan.     

Angiotensin II Receptor Antagonists Alone and Combined with Hydrochlorothiazide

Angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics have an accepted place in the management of hypertension. Most patients require combination therapy with two or more drugs to adequately control blood pressure to targets recommended by European and international guidelines. ARBs and the thiazide diuretic hydrochlorothiazide have complementary modes of action. Fixed-dose combinations of an ARB and low-dose hydrochlorothiazide provide a convenient and effective treatment option for patients who do not achieve blood pressure targets on monotherapy, without compromising the placebo-like tolerability of ARBs. In Europe, fixed-dose combinations with hydrochlorothiazide currently are available for the ARBs candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Recently, a number of studies have focused on the use of ARBs in monotherapy and in combination therapy, in conditions including congestive heart failure, post-myocardial infarction management, hypertension with cardiovascular risk factors, and diabetic and non-diabetic nephropathy. Evidence from these studies suggests a beneficial role beyond the antihypertensive effect of these therapies in providing protection against cardiovascular, renovascular, and cerebrovascular events.     

4种血管紧张素Ⅱ受体拮抗药治疗轻中度高血压的成本-效果分析

目的:评价4种血管紧张素Ⅱ受体拮抗药治疗轻中度高血压的成本-效果。方法:104例轻、中度高血压患者分为4组,分别应用替米沙坦、氯沙坦钾、厄贝沙坦、缬沙坦治疗,8wk后比较临床效果并进行成本-效果分析。结果:4种用药方案在疗效比较上差异无统计学意义(P>0·05),成本分别为684·00、760·80、659·20、720·80元,成本-效果比分别为7·74、9·51、7·91、8·07。结论:替米沙坦从药物经济学的角度分析为治疗轻中度高血压的较优药物。     

Candesartan cilexetil: an update of its use in essential hypertension

Candesartan cilexetil is converted to the angiotensin II receptor antagonist candesartan during absorption from the gastrointestinal tract. The selective and competitive binding of candesartan to the angiotensin II type 1 (AT(1)) receptor prevents binding of angiotensin II, a key mediator in the renin-angiotensin system. Significant reductions in systolic BP and diastolic BP are achieved with a once-daily dosage of candesartan cilexetil 2 to 32 mg/day in patients with mild to moderate hypertension. In randomised studies, candesartan cilexetil 8 to 16 mg/day was at least as effective as therapeutic dosages of losartan or other angiotensin II receptor antagonists. At a dosage of up to 32 mg/day candesartan cilexetil demonstrated greater antihypertensive efficacy than losartan 50 or 100 mg/day. In comparative trials, candesartan cilexetil demonstrated similar or greater antihypertensive efficacy compared with enalapril or hydrochlorothiazide and equivalent efficacy compared with amlodipine. The efficacy of candesartan cilexetil is not affected by age, and the drug provided significant BP reductions in Black patients and in those with severe hypertension. Long-term clinical studies to assess the effects of treatment with candesartan cilexetil on cardiovascular morbidity and mortality are ongoing. Regression of left ventricular hypertrophy has been seen with candesartan cilexetil treatment in patients with hypertension. Furthermore, the drug has favourable effects on renal function in patients with hypertension with or without coexisting diabetes mellitus. Renal vascular resistance and albumin excretion were reduced following treatment with candesartan cilexetil. Glucose homeostasis and lipid metabolism were not affected by treatment in patients with type 2 diabetes mellitus. Candesartan cilexetil is well tolerated and is not associated with cough, a common adverse effect of angiotensin converting enzyme inhibitor treatment. A pooled analysis of clinical trials found that the tolerability profile of candesartan cilexetil is not significantly different from that of placebo. Adverse events are not dose-related and are generally of mild to moderate severity. Conclusions: Candesartan cilexetil is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data indicate that candesartan cilexetil has antihypertensive efficacy equivalent to that of other major classes of antihypertensive agents and has a long duration of action. Therefore, candesartan cilexetil is a useful therapeutic option in the management of patients with hypertension.     

Angiotensin II-receptor antagonists: an overview.

Angiotensin II (AT-II)-receptor antagonists are reviewed. Research focused on blocking the renin-angiotensin system (RAS) led to the discovery of angiotensin-converting-enzyme (ACE) inhibitors, which are effective in the treatment of hypertension but are associated with a high frequency of cough and other adverse effects. AT-II-receptor antagonists were developed as agents that would more completely block the RAS and thus decrease the adverse effects seen with ACE inhibitors. AT-II-receptor antagonists include losartan, valsartan, irbesartan, candesartan, eprosartan, telmisartan, and tasosartan. Several clinical trials have demonstrated that AT-II-receptor antagonists are as effective as calcium-channel blockers, beta-blockers, and ACE inhibitors in the treatment of hypertension and induce fewer adverse effects. The adverse effects of AT-II-receptor antagonists--dizziness, headache, upper-respiratory-tract infection, cough, and gastrointestinal disturbances--occur at about the same rate as with placebo. [corrected]. All available AT-II-receptor antagonists seem to be equally effective in reducing both systolic and diastolic blood pressure, and they are comparable in cost. Currently, AT-II-receptor antagonists are used either as monotherapy in patients who cannot tolerate ACE inhibitors or in combination with other antihypertensive agents. Angiotensin II-receptor antagonists are well tolerated and are as effective as ACE inhibitors in decreasing blood pressure.     

Comparative pharmacodynamics and pharmacokinetics of candesartan and losartan in man

The angiotensin II antagonistic effects of candesartan and losartan were compared in-vivo after single and repeated doses. Effects were related to antagonistic activity in plasma. In this double-blind, crossover study, 12 healthy male volunteers received, in random order, daily oral doses of 8 mg candesartan cilexetil or 50 mg losartan for seven days. On day 1 and day 8, dynamics and kinetics were assessed up to 48 h after dosing. Antagonistic effect was determined from the antagonist-induced rightward shifts of the diastolic blood pressure response curves to exogenously administered angiotensin II measured as the dose ratio (DR). The antagonistic activity in plasma was measured using an ex-vivo/in-vitro radioreceptor assay. Specific high-performance liquid chromatography assays determined plasma concentrations of candesartan, losartan and its active metabolite EXP-3174. The pharmacokinetic properties of candesartan and losartan were comparable and antagonistic activity in plasma almost identical (ratio candesartan: losartan = 0.97 and 1-2 after single and multiple doses, respectively). However, the antagonistic effects of candesartan and losartan in-vivo were quite different. Twenty-four hours after single dosing with candesartan a clinically relevant rightward shift in the angiotensin II dose-response curve (DR= 3.2) occurred that was more pronounced than that following losartan administration (DR=2.1, ratio candesartan: losartan= 1.65). Twenty-four hours after multiple doses of candesartan or losartan, the values of the DR were 4.8 and 2.3, respectively (ratio candesartan: losartan = 1.94). The values of DR for candesartan were significantly higher compared with losartan between 6 and 36h after a single dose and between 3 and 24 h post-dose following multiple dose administration. A counter-clockwise hysteresis was apparent between antagonistic activity in plasma and antagonistic effect. Despite equivalent angiotensin II antagonistic activity in plasma, the pharmacodynamic effect of candesartan cilexetil was greater than that of losartan. Candesartan appeared to have a slower off-rate from the angiotensin AT1-receptor compared with losartan, nevertheless differences in distributional phenomena or the extent of insurmountable antagonistic activity cannot be ruled out.     

Inhibitory effects of angiotensin receptor blockers on CYP2C9 activity in human liver microsomes

We investigated the inhibitory effects of the angiotensin receptor blockers (ARBs), candesartan, irbesartan, losartan, losartan active metabolite (EXP-3174), olmesartan, telmisartan and valsartan (0.3-300 microM), on the CYP2C9 activity in human liver microsomes using (S)-(-)-warfarin as a typical CYP2C9 substrate. Except for olmesartan and valsartan, these ARBs inhibited the activity of 7-hydroxylation of (S)-(-)-warfarin with IC50 values of 39.5-116 microM. Of six synthetic derivatives of olmesartan, five compounds which possess either alkyl groups or a chloro group at the same position as that of the hydroxyisopropyl group in olmesartan inhibited CYP2C9 activity with IC50 values of 21.7-161 microM. Olmesartan and the olmesartan analogue, RNH-6272, both having a hydroxyisopropyl group, showed no inhibition, indicating that the hydrophilicity of this group greatly contributes to the lack of CYP2C9 inhibition by these two compounds. A three-dimensional model for docking between EXP-3174 and CYP2C9 indicated that the chloro group of EXP-3174 is oriented to a hydrophobic pocket in the CYP2C9 active site, indicating that the lipophilicity of the group present in ARBs at the position corresponding to that of the hydroxyisopropyl group in olmesartan is important in inhibiting CYP2C9 activity.     

坎地沙坦酯片治疗原发性高血压118例

目的:比较国产坎地沙坦酯片与氯沙坦治疗轻、中度原发性高血压的疗效和安全性。方法:多中心、随机、双盲、双模拟、阳性药平行对照试验。经2 wk安慰剂导入期,238例原发性高血压病人进入8 wk治疗期,每日1次服用坎地沙坦酯片8 mg(n=118),或氯沙坦片50 mg(n=120),2 wk后如舒张压≥12 kPa则剂量加倍。结果:2组病人的血压均得到明显地降低(P<0.01);坎地沙坦酯组总有效率为82.2%,氯沙坦组为84.2%,2组间没有显著差异。坎地沙坦酯组和氯沙坦组收缩压和舒张压的降压谷峰(T/P)比值分别为0.75,0.71和0.76,0.94。结论:对轻、中度原发性高血压病人坎地沙坦酯片是一种有效、安全且易耐受的降压药,每日1次能维持24 h降压效应。     

抗高血压药物血管紧张素Ⅱ的1型受体阻断剂研究进展

本文主要对氯沙坦、缬沙坦、伊贝沙坦、替米沙坦、坎地沙坦、依普罗沙坦的特点进行介绍，指出氯沙坦跟氢氯噻嗪或氨氯地平合用可以增加疗效。坎地沙坦抑制AT1受体结合作用最强，替米沙坦消除半衰期最长，并对血管紧张素AT1受体阻断剂在高血压方面作个疗效评价。     

Functional comparison of the antagonistic properties of some Angiotensin II type 1 receptor blockers on the contraction elicited by Angiotensin II and thromboxane A2 on human saphenous veins

We previously described on human vascular preparations that, in addition to its antagonistic properties on Angiotensin II type 1 (AT1) receptor, losartan could also inhibit the contraction elicited by the stable thromboxane A2 mimetic U46619. The present study was designed (1) to investigate, in human vascular preparations (the saphenous veins) whether these antagonistic properties on thromboxane A2/prostaglandin H2 (TP) receptor were shared by some other AT1 receptor antagonists (irbesartan and valsartan) and the active metabolite of losartan EXP3174, and (2) to compare their antagonistic properties on TP receptors to their antagonistic properties on AT1 receptors. In the presence of indomethacin (10 microM) and Nomega-nitro-L-arginine (100 microM), irbesartan, valsartan, and EXP3174 induced a rightward shift of U46619- and angiotensin II-induced contraction. The inhibitory effect of irbesartan, valsartan, and EXP3174 on U46619-induced contraction was significant from 100 microM while their inhibitory effect on the contraction elicited by angiotensin II was significant from 1 nM. With regard to the plasma therapeutic concentrations of irbesartan, valsartan, and EXP3174, these data suggest that TP receptor blockade does not account for the antihypertensive effects of these AT1 receptor blockers.     

Switch strategies in the management of hypertension: a cost minimisation analysis of angiotensin receptor blocker based regimen

ABSTRACT

Background and objective: Budgetary pressures within health care systems have led many health care providers to consider the switching of patients on long term anti­hypertensive medication to agents with the lowest acquisition price. The long term success of this strategy hinges on price differentials remaining stable, an assumption that may not be valid in drug classes where patent expiry times vary. The treatment of hypertension using angiotensin receptor blockers (ARBs) represents just such a case. The present study, therefore, modelled the 5-year cost consequences of treatment based on losartan, candesartan, valsartan and irbesartan, based on expected patent expiry dates.

Methods: A Markov model was constructed, applying dose-specific blood-pressure lowering and costs to a cohort of uncontrolled mild–moderate hypertensive patients and assessing the anticipated cost of treatment over a 5 year period. A probabilistic approach was adopted to account for between-patient and between-treatment differences.

Results: For both undiscounted and discounted models, a losartan-based regimen represents the least costly option of the four agents tested. Median (IQR) discounted expenditure per patient for each agent was: losartan: £506 (£441–£650), candesartan: £610 (£542–£766), valsartan: £809 (£796–£1078), irbesartan £696 (£694–£934).

Conclusion: Switching hypertensive patients taking ARBs to the agent with the lowest current acquisition cost may yield only transient budgetary savings. Once patent expiry is taken into account, this model suggests that maintaining or switching patients to losartan would yield considerably greater savings over 5 years.