Half a Century of Hydrochlorothiazide: Facts, Fads, Fiction, and Follies

Division of Cardiology, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
The American journal of medicine (Impact Factor: 5). 10/2011; 124(10):896-9. DOI: 10.1016/j.amjmed.2011.05.009
Source: PubMed


Hydrochlorothiazide (HCTZ) has become by far the most commonly prescribed antihypertensive drug in the US. In 2008, 47.8 million prescriptions were written for HCTZ alone and 87.1 million prescriptions for HCTZ combinations. However, there is no evidence that HCTZ in its usual dose of 12.5-25 mg daily reduces myocardial infarction, stroke, or death. In a meta-analysis of 19 randomized trials with over 1400 patients, the 24-hour decrease in blood pressure with HCTZ was inferior to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers (P <.001 for all). Even in combination with an angiotensin-converting enzyme inhibitor, HCTZ was found to reduce morbidity and mortality less well than a calcium channel blocker. As measured by the adherence rate, thiazides are less well tolerated than any other drug class. Because outcome data at the usual daily dose of 12.5-25 mg are lacking, antihypertensive efficacy is paltry, and adherence is poor, HCTZ is an inappropriate first-line drug in hypertension. If a "thiazide-type" diuretic is indicated, either chlorthalidone or indapamide should be selected.

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    • "Hydrochlorothiazide (HCTZ) is the most widely used diuretic in the world for the treatment of mild and moderate hypertension [18], [19]. Despite being a specific inhibitor of NCC in the DCT hydrochlorothiazide causes a very mild diuretic response [18]–[20]. This observation is in agreement with studies indicating that NCC deletion in mouse causes very little salt wasting under basal conditions [21]. "
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    ABSTRACT: Carbonic anhydrase inhibitors (CAI) are mild diuretics, hence not widely used in fluid overloaded states. They are however the treatment of choice for certain non-kidney conditions. Thiazides, specific inhibitors of Na-Cl cotransport (NCC), are mild agents and the most widely used diuretics in the world for control of mild hypertension. In addition to inhibiting the salt reabsorption in the proximal tubule, CAIs down-regulate pendrin, therefore leaving NCC as the major salt absorbing transporter in the distal nephron, and hence allowing for massive diuresis by the inhibitors of NCC in the setting of increased delivery of salt from the proximal tubule. Daily treatment of rats with acetazolamide (ACTZ), a known CAI, for 10 days caused mild diuresis whereas daily treatment with hydrochlorothiazide (HCTZ) for 4 days caused hardly any diuresis. However, treatment of rats that were pretreated with ACTZ for 6 days with a combination of ACTZ plus HCTZ for 4 additional days increased the urine output by greater than 2 fold (p<0.001, n = 5) compared to ACTZ-treated animals. Sodium excretion increased by 80% in the ACTZ plus HCTZ group and animals developed significant volume depletion, metabolic alkalosis and pre-renal failure. Molecular studies demonstrated ∼75% reduction in pendrin expression by ACTZ. The increased urine output in ACTZ/HCTZ treated rats was associated with a significant reduction in urine osmolality and reduced membrane localization of AQP-2 (aquaporin2). These results indicate that ACTZ down-regulates pendrin expression and leaves NCC as the major salt absorbing transporter in the distal nephron in the setting of increased delivery of salt from the proximal tubule. Despite being considered mild agents individually, we propose that the combination of ACTZ and HCTZ is a powerful diuretic regimen.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Azilsartan medoxomil is the only ARB that has been approved for use in a fixed dose combination with the diuretic chlorthalidone whereas other ARBs are sold in fixed dose combinations with hydrochlorothiazide. This is noteworthy because of evidence indicating that typically used doses of chlorthalidone are more effective in lowering BP and may afford greater CV protection than typically used doses of hydrochlorothiazide.47,48 In a head-to-head, randomized trial, the combination of 40 mg azilsartan medoxomil plus 25 mg chlorthalidone was found to lower BP significantly more than the combination of 40 mg olmesartan medoxomil plus 25 mg hydrochlorothiazide.49 "
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    ABSTRACT: Azilsartan, an angiotensin II type 1 (AT(1)) receptor blocker (ARB), was recently approved by regulatory authorities for treatment of hypertension and is the 8th ARB to join the clinical market. This article discusses the medical reasons for introducing a new AT(1) receptor blocker and reviews the experimental and clinical studies that have compared the functional properties of azilsartan to those of other ARBs. The main question addressed is: Does azilsartan have distinguishing features that should motivate choosing it over any of the other sartans for use in clinical practice? Based on studies conducted to date in hypertensive patients without serious comorbidities, azilsartan appears to be characterized by a superior ability to control 24-hour systolic blood pressure (BP) relative to other widely used ARBs including valsartan, olmesartan, and candesartan, and presumably others as well (eg, losartan). Compared to these other ARBs, azilsartan may increase the BP target control and response rate by an absolute value of 8%-10%. Greater antihypertensive effects of azilsartan might be due in part to its unusually potent and persistent ability to inhibit binding of angiotensin II to AT(1) receptors. Preclinical studies have indicated that azilsartan may also have potentially beneficial effects on cellular mechanisms of cardiometabolic disease and insulin sensitizing activity that could involve more than just blockade of AT(1) receptors and/or reduction in BP. However, the clinical relevance of these additional actions is unknown. Given that the general ability of antihypertensive drugs to protect against target organ damage is largely mediated by their ability to decrease BP, the enhanced antihypertensive effects of azilsartan should serve to justify clinical interest in this ARB relative to other molecules in the class that have a lower capacity to reduce BP.
    Full-text · Article · Feb 2012 · Vascular Health and Risk Management
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    ABSTRACT: In most hypertensive patients, more than one antihypertensive compound is necessary to achieve the target level of blood pressure (BP). Combining two antihypertensive agents from two different classes results in a greater BP reduction than doubling the dose of one agent. It is also applicable for treatment initiation, especially in patients at high cardiovascular risk. This strategy is reflected in current guidelines on hypertension treatment. Although several two-drug combinations are suitable for clinical use, evidence of risk of cardiovascular events and death reduction from recent large-scale trials differs from one combination to another. The best evidence comes from outcome studies with an ACE inhibitor and dihydropyridine calcium antagonist combination, that of perindopril/ amlodipine, particularly in the ASCOT trial. The combination of an ACE inhibitor plus thiazide-like diuretic such as perindopril/indapamide is also supported by favourable results from large-scale trials (PROGRESS, ADVANCE and HYVET). Whenever it is possible, fixed-dose combinations (e.g. perindopril arginine/amlodipine or perindopril arginine/ indapamide) rather than individual drugs should be used.
    Full-text · Article · Jan 2012 · Cardiology Letters
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