Not just chlorthalidone: evidence-based, single tablet, diuretic alternatives to hydrochlorothiazide for hypertension.

Accounting for 15 % of deaths worldwide, hypertension is often treated with hydrochlorothiazide (HCTZ) (50 million prescriptions annually). HCTZ has a <24-h duration of action, is less potent than chlorthalidone and all major antihypertensive drug classes, and is inferior to four antihypertensive drugs for cardiovascular event (CVE) reduction. If there were alternative diuretics, why prescribe HCTZ? Chlorthalidone is often offered as an alternative to HCTZ, but has limited pharmaceutical formulations. However, there are seven evidence-based, single-tablet, alternative diuretics. For reducing CVE, the following are superior to their comparators: chlorthalidone versus four antihypertensives in multiple hypertensive populations; indapamide versus placebo in elderly Chinese (and versus enalapril for left ventricular hypertrophy), triamterene-HCTZ versus placebo in elderly Europeans, amiloride-HCTZ versus three antihypertensives, and indapamide-perindopril versus placebo in three populations. Additionally, chlorthalidone-azilsartan and spironolactone-HCTZ are potent combinations The aldosterone antagonist component of the latter combination has been shown to reduce total mortality by 30 % in heart failure. Five of these seven have multiple dose formulations. Six cost $4-$77 monthly. In conclusion, based on both scientific and practical grounds, new prescriptions for HCTZ are rarely justified.

Assessment and management of hypertension in transplant patients.

Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients.

Thiazide and loop diuretics.

KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Although chlorthalidone and hydrochlorothiazide are structurally similar, they are very different pharmacokinetically, with chlorthalidone having both an extremely long half-life (approximately 40 to 60 hours) and a large volume of distribution, with gradual elimination from the plasma compartment by tubular secretion. • Furosemide usage, the most widely used diuretic in the loop diuretic class, can be complicated by extremely erratic absorption, with a bioavailability range of 12% to 112%. • Chlorthalidone, at a dose of 25 mg, is comparatively more potent than 50 mg of hydrochlorothiazide, particularly as related to overnight blood pressure reduction. • In ALLHAT, there was no difference among chlorthalidone, amlodipine, lisinopril, and doxazosin for the primary outcome or mortality. • Secondary outcomes were similar except for a 38% higher rate of heart failure with amlodipine; a 10% higher rate of combined cardiovascular disease, a 15% higher rate of stroke, and a 19% higher rate of heart failure with lisinopril; and a 20% higher rate of cardiovascular disease, a 20% higher rate of stroke (40% higher rate in blacks), and an 80% higher rate of heart failure with doxazosin, compared with chlorthalidone. • The ACCOMPLISH study may affect future practice guidelines as a result of its findings favoring the amlodipine/benazepril combination; however, the generalizability to patient populations with a lesser cardiovascular risk profile remains in question and the dose of hydrochlorothiazide was only 12.5 mg to 25 mg daily, which was a dose lower than that used in placebo-controlled trials using hydrochlorothiazide. • Certain low-renin patient groups (eg, blacks, the elderly, and diabetics) as well as those who manifest the metabolic syndrome are commonly more responsive to thiazide-type diuretic therapy. • Diuretics can be successfully combined with ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, centrally acting agents, and even calcium channel blockers. • Although thiazide-type diuretics are among the best-tolerated antihypertensive agents in terms of symptomatic adverse effects, diuretic-related adverse side effects include those with established mechanisms (eg, such as electrolyte changes and/or metabolic abnormalities) and other side effects, which are less well understood mechanistically (eg, impotence), although the latter is not universally accepted as a diuretic-related side effect. • Thiazide-induced hypokalemia is associated with increased blood glucose, and treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent diabetes. • Thiazide-induced hyperuricemia occurs as a result of volume contraction and competition with uric acid for renal tubular secretion, but does not necessarily contraindicate using a thiazide, especially if a uric acid-lowering drug such as allopurinol is being used. • Adverse interactions include the blunting of thiazide effects by nonsteroidal anti-inflammatory drugs and the potential to increase fatigue, lethargy, and increase in glucose when combined with ß-blockers. • Thiazide-type diuretics are useful first-line agents in the treatment of hypertension because they have been proven to reduce cardiovascular mortality and morbidity in systolic and diastolic forms of hypertension and do so at low cost. • Loop diuretics should not be used as first-line therapy in hypertension since there are no outcome data with them. They should be reserved for conditions of clinically significant fluid overload (eg, heart failure and significant fluid retention with vasodilator drugs, such as minoxidil) or with advanced renal failure and can be combined with thiazide-type diuretics.

Transdermal clonidine: therapeutic considerations.

Transdermal clonidine was approved by the US Food and Drug Administration in 1984 for the treatment of mild-to-moderate hypertension alone or in combination with a diuretic. Clonidine is released from the patch at a constant rate and thus displays a pharmacokinetic pattern not dissimilar to that of infusion therapy. Transdermal clonidine, like oral clonidine, is effective first- or second-line therapy for most forms of hypertension. More recently, transdermal clonidine has found alternative uses in the areas of smoking cessation, posttraumatic stress disorder, menopausal hot flashes, and alcohol and opiate withdrawal syndromes. The not infrequent development of a dermatitis, together with a substantially greater cost than oral clonidine, have been the major undoings for transdermal clonidine.

ACE inhibitor intolerance and lessons learned from the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) trials.

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trials looked at the effects of candesartan in addition to best possible treatment for heart failure in 7601 patients. CHARM encompassed three studies in discrete populations, including patients with left ventricular dysfunction taking angiotensin-converting enzyme (ACE) inhibitors (CHARM-Added), patients with maintained left ventricular function (CHARM-Preserved), and patients with left ventricular dysfunction and an intolerance to ACE inhibitors (CHARM-Alternative). CHARM-Alternative was considered a success in that its participants experienced a significant reduction in each component of the study's primary end point, which was a composite of cardiovascular death or hospitalization for heart failure, over a median follow-up of 34 months. Candesartan was by and large well tolerated in these ACE-inhibitor intolerant patients; thus, the findings of this study provide additional support for the effectiveness of angiotensin receptor blocker therapy in heart failure patients poorly tolerant of an ACE inhibitor; however, candesartan was not convincingly shown to improve the incidence/severity of hypotension, hyperkalemia, and glomerular filtration rate reductions that were the basis for ACE inhibitor intolerance in approximately 25% of the study population.