The pharmacology and clinical use of diuretics in the treatment of hypertension

The use of diuretic agents has become an accepted and clinically proved method of pharmacological control of hypertension. The reason for blood pressure reduction with sodium depletion is not clarified, but a decrease in circulating plasma volume and change in electrolyte concentrations in the intracellular compartment probably are active factors.

The use of diuretics potentiates the effects of other antihypertensive agents so that a significant reduction in their dose and side effects may be obtained.

The diuretic agents in common use are the multiple thiazide derivatives and chlorthalidone. The thiazide agents may be used interchangeably in equivalently effective doses. The initial application of the diuretics frequently reduces blood pressure in a significant number of patients. However, the addition of other antihypertensive drugs is necessary in order to adequately control the blood pressure in most patients.     

Therapie der Hypertonie mit Diuretika

In the treatment of hypertension, both the thiazide diuretics hydrochlorothiazide and bendroflumethiazide and the "thiazide-like" diuretics chlorthalidone and indapamide are used. Guidelines refer to these as the class of thiazide diuretics suggesting their interchangeability. However, bendroflumethiazide and hydrochlorothiazide, at least in the commonly used low dose range, are less potent with respect to blood pressure lowering and may also be less effective in preventing morbidity and mortality events. This is of great clinical relevance since hydrochlorothiazide is by far the most widely prescribed diuretic. Increasing the dose of hydrochlorothiazide would further reduce tolerability of treatment due to an increase in dose-dependent side effects. The underlying mechanisms of the suggested superiority of chlorthalidone on cardiovascular morbidity and mortality remain unclear. The half-life of chlorthalidone has been estimated at >50?h thus exceeding the half-life of hydrochlorothiazide by about 5-fold. Given the documented irregular intake of antihypertensive drugs, the prolonged efficacy of chlorthalidone makes this agent a "forgiving drug" with a definite advantage over hydrochlorothiazide. On the basis of the available evidence, whenever diuretic treatment is indicated in a hypertensive patient, a thiazide-like agent, preferably chlorthalidone should be employed.     

Elevated hemoglobin A1c and low-density lipoprotein cholesterol levels in thiazide-treated diabetic patients

Despite the well-known hyperglycemic effect of thiazide diuretics, these agents are often administered to diabetic patients. This study compared 89 insulin-treated diabetic patients receiving hydrochlorothiazide, 57 receiving furosemide, and 255 receiving no diuretic. Hemoglobin A1c level was 7.2 +/- 1.8 percent (mean +/- SD) with hydrochlorothiazide, significantly higher than the levels of 5.9 +/- 2.3 percent with furosemide and 6.4 +/- 2.0 percent with no diuretic. Low-density lipoprotein cholesterol level was 154 +/- 43 mg/dl with hydrochlorothiazide, but 134 +/- 42 mg/dl with furosemide and 130 +/- 42 mg/dl with no diuretic. Multivariate analysis showed that the associations remained significant after adjustment for age, sex, race, type and duration of diabetes, body mass index, blood pressure, serum potassium level, insulin dose, and treatment with other medications. These findings suggest that treatment with thiazide diuretics in the diabetic population may increase low-density lipoprotein cholesterol and hemoglobin A1c levels.     

Large dose furosemide therapy for hypertension. Long-term use in 22 patients

A retrospective study of 22 hypertensive patients receiving large oral doses of furosemide (80 to 640 mg daily for 32 ± 7 months) and standard antihypertensive therapy was performed. All patients had moderately severe or severe hypertension. The substitution of furosemide for the previous diuretic agents resulted in a 22 percent average reduction in arterial pressure and significant improvement in the clinical status of 15 patients. The addition of furosemide allowed a reduction in the dose of antihypertensive medication in four patients. Besides preventing the sodium retention and extracellular fluid volume expansion associated with standard antihypertensive agents, large doses of furosemide may have exerted an additional antihypertensive effect. The combination of orally administered furosemide and standard antihypertensive therapy permitted better control of arterial pressure than that obtained with previous diuretic-antihypertensive combinations in the patients studied. The overall safety of large dose furosemide therapy for extended periods of time appears to be relatively good.     

Alternative first-line therapies in geriatric hypertension

Between 45 and 60% of elderly persons have mild to moderate hypertension. In those with combined systolic/diastolic hypertension, blood pressure reduction significantly reduces morbidity and mortality. Secondary causes of hypertension, particularly renovascular, should be considered in elderly patients with a recent history of hypertension. Because of their proven efficacy and low cost, low-dose thiazide diuretics remain an important first-line therapy. Angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blocking agents have also been shown to be effective and well-tolerated in the elderly. Increased attention is being paid to adverse drug effects and to the overall effect of antihypertensive therapy on quality of life. ACE inhibitors are particularly attractive in the elderly due to their possibilities in this area. In the elderly, the combination of a low-dose thiazide diuretic with an ACE inhibitor enhances antihypertensive efficacy while blunting the adverse metabolic effects of the diuretic.     

Pathophysiology of antihypertensive therapy with diuretics.

Recent progress in antihypertensive therapy has widened the selection of drugs, and large clinical trials have attracted attention to newer classes of antihypertensives. Consequently, the use of diuretics as antihypertensive agents has been relatively reduced, particularly since the newer drugs are associated with fewer adverse metabolic reactions. However, diuretics have a specific activity of removing sodium from the body fluid, thereby rendering the blood pressure insensitive to sodium intake, relieving the overload to systemic circulation, and normalizing the circadian rhythm of blood pressure from a non-dipper to a dipper pattern. At low doses, diuretics are known to be as effective as all other antihypertensive agents for reducing nearly all types of cardiovascular events. In this brief review, the indication for thiazide diuretics will be discussed based on the pathophysiology of hypertension and antihypertensive therapy with diuretics mainly from the point of view of sodium metabolism. Low-dose diuretics will continue to be an important agent in the treatment of hypertension, mostly in combination with vasodilators such as modulators of the reninangiotensin system and calcium channel blockers.     

Loop Diuretics in the Treatment of Hypertension

Loop diuretics are not recommended in current hypertension guidelines largely due to the lack of outcome data. Nevertheless, they have been shown to lower blood pressure and to offer potential advantages over thiazide-type diuretics. Torsemide offers advantages of longer duration of action and once daily dosing (vs. furosemide and bumetanide) and more reliable bioavailability (vs. furosemide). Studies show that the previously employed high doses of thiazide-type diuretics lower BP more than furosemide. Loop diuretics appear to have a preferable side effect profile (less hyponatremia, hypokalemia, and possibly less glucose intolerance). Studies comparing efficacy and side effect profiles of loop diuretics with the lower, currently widely prescribed, thiazide doses are needed. Research is needed to fill gaps in knowledge and common misconceptions about loop diuretic use in hypertension and to determine their rightful place in the antihypertensive arsenal.     

Pharmacological Properties of Combination Therapies for Hypertension

Single drug therapy for the treatment of hypertension has traditionally been a standard of practice. More recently combination therapy as first-line treatment has gained acceptance both by the medical practice community and the US Food and Drug Administration. The advantages of combinations may be a synergistic or additive antihypertensive effect, metabolic improvement, or both. The combination of a thiazide-type diuretic and a potassium-sparing diuretic has been quite useful in the past to prevent the need for potassium supplementation. The combination of β-adrenoceptor blockade and a thiazide diuretic results in an additive antihypertensive effect that permits the effective use of very low thiazide doses. The mechanism of antihypertensive effects of each member of the combination are complimentary with increased sympathetic outflow and renin-angiotensin axis activation induced by the diuretic being blunted by β₁-adrenergic blockade. Combinations not used as first-line therapy, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockade and a thiazide diuretic, have complimentary antihypertensive mechanisms and have been useful in treating patient groups who do not respond well to converting enzyme inhibitor monotherapy. The combination of a calcium antagonist with diuretic therapy has an additive hypertensive effect as well; however, the complimentary mechanisms are less obvious. Finally, the combination of angiotensin converting enzyme inhibition and calcium antagonist therapy has been useful in selected patients, but again the complimentary mechanisms are less obvious. As first-line therapy, combinations for diuretics and β₁-receptor blockers have been useful for achieving increased antihypertensive effect with decreased adverse drug effect.     

Characterization of the antihypertensive effect of a thiazide diuretic in angiotensin II-induced hypertension

OBJECTIVES : The antihypertensive effect of thiazide diuretics in angiotensin II induced hypertension has never been characterized. In the current study, we sought to determine the effect of a thiazide diuretic on arterial pressure and renal fluid excretion in rats receiving a chronic intravenous infusion of angiotensin II while on fixed normal or high sodium intakes. DESIGN AND METHODS : Male rats were chronically instrumented with arterial and venous catheters for drug injection and direct daily measurements of blood pressure and heart rate. Rats were maintained on high salt intake (HS), 6 mEq/day, or on normal salt intake (NS), 2 mEq/day. Rats were randomly assigned to four groups: HS and NS with 15 day angiotensin II infusion (5 ng/min) and HS and NS without angiotensin II infusion. Trichlormethiazide (TCM), a thiazide diuretic, was orally administered, approximately 10 mg/kg per day, for the middle 5 days of angiotensin II infusion. RESULTS : Only HS rats receiving angiotensin II infusion became hypertensive. Angiotensin II infusion did not produce changes in heart rate, sodium balance or water balance. Chronic administration of TCM significantly reduced mean arterial pressure (MAP) within 24 h in HS rats receiving angiotensin II, but did not affect MAP in any other group. TCM produced a similar loss of Na+ and water in all rats. Blood volumes and plasma electrolytes did not change during the study. CONCLUSIONS : The antihypertensive effects of thiazide diuretics are not due exclusively to volume depletion. We propose that salt and water loss caused by TCM may lower MAP by impairment of salt-sensitive pressor mechanisms activated by angiotensin II.     

Metabolic changes with antihypertensive therapy of the salt-sensitive patient

Recent evidence suggests that metabolic changes that occur with antihypertensive agents may influence cardiovascular risk. Diuretic therapy is particularly appropriate for the salt-sensitive hypertensive patient. However, diuretic-induced electrolyte abnormalities may lead to ventricular arrhythmias, even in patients with uncomplicated essential hypertension. Antihypertensive drugs may change circulating lipoprotein levels, which may influence the development of atherosclerosis. Therefore, serum cholesterol and triglyceride levels should be monitored when antihypertensive drugs are administered that can cause hyperlipidemia. Weight reduction and diet therapy should be used because these may have a greater effect on reducing hyperlipidemia, though choice of antihypertensive agents is important. In addition, glucose tolerance may worsen with thiazide therapy, perhaps because newer evidence suggests that insulin resistance is common in essential hypertension. This glucose intolerance may be corrected with potassium repletion or substitution of bumetanide for thiazide. The calcium antagonists may be substituted for diuretic therapy, or other classes of antihypertensive drugs may be used with a reduced dose of diuretic drug if these metabolic changes persist. Thus, attention to metabolic changes may be as important as blood pressure reduction in treatment of the salt-sensitive hypertensive patient.     

Low-Dose Aldosterone Blockade as a New Treatment Paradigm for Controlling Resistant Hypertension

Treatment of resistant hypertension requires confirmation of true resistance, diagnosis and treatment of secondary causes of hypertension, adoption of appropriate lifestyle modifications, and effective use of multidrug antihypertensive regimens. Excessive volume retention often underlies resistant hypertension, so diuretics are generally necessary to achieve blood pressure (BP) goals. Although treatment regimens consisting of 3 or more agents have not been systematically evaluated, the author has found a triple regimen consisting of a thiazide diuretic, a calcium channel blocker, and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to be generally effective and well tolerated. Although hydrochlorothiazide is more widely used, chlorthalidone provides better BP reduction and should be preferentially used in patients with resistant hypertension, particularly if the patient remains uncontrolled on hydrochlorothiazide. Recent studies have demonstrated that low doses of aldosterone antagonists, when added to multi-drug regimens that include a thiazide diuretic and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, provide significant additional BP reduction, seemingly exceeding what would be expected with addition of alternative classes of agents. The degree of BP reduction induced by aldosterone blockade has been similar in patients with and without evidence of aldosterone excess. Aldosterone antagonists are generally safe and well tolerated. The most common adverse effect of low-dose spironolactone has been breast tenderness, occurring in about 10% of men. Hyperkalemia is uncommon, but can occur, necessitating biochemical monitoring. Risk of hyperkalemia is increased in patients with chronic kidney disease or diabetes, elderly patients, and patients already receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.     

Treatment of hypertension in the elderly—What have we learned from the recent trials?

Summary Treatment of hypertension in the elderly has so far mainly been based on clinical judgment and very few large controlled trials. During the last year several large new trials have been published, the so-called STOP-Hypertension, SHEP, and MRC trials. All have shown that drug treatment of hypertension in the elderly (65–85 years) with permanent diastolic hypertension or isolated systolic hypertension reduces stroke incidence. Most patients have needed combined drug treatment with diuretics and beta-blockers. When thiazide diuretics are used, serum postassium should be followed very closely and most likely amiloride should be added to the thiazide therapy, since this was done both in the STOP and the MRC trials. Since many elderly patients with hypertension suffer from other diseases that might represent contraindications to thiazide diuretics or beta-blockers, the choice of drug must be made after careful clinical evaluation. With the newer classes of antihypertensive agents (calcium antagonists, ACE inhibitors and alpha-blockers) side effects are probably seen less often, but long-term data on morbidity and mortality are still lacking.     

Angiotensin II receptor antagonists in arterial hypertension

Angiotensin II receptor antagonists (AT-1) represent a new group of orally active antihypertensive agents. Activation on AT-1 receptor leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone with production of thirst, and promote growth of vascular and cardiac muscle; these effects are blocked by AT-1 antagonist agents. The first chemically useful, orally active AT-1 receptor antagonist was losartan, followed by other agents currently in clinical use, such as: valsartan, eprosartan, irbesartan, telmisartan, candesartan, and many others under investigation. AT-1 receptor antagonists are effective in reducing high blood pressure in hypertensive patients. Monotherapy in mild to moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of a thiazide diuretic is added, 60 to 70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme inhibitors, diuretics, calcium antagonists and beta-blocking agents. Tolerability has been reported to be very good. AT-1 receptor antagonists would be a drug of choice in otherwise well-controlled hypertensive patients treated with angiotensin-converting enzyme inhibitors who developed cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted.     

Diuretics in arterial hypertension: a firm commitment for the 90's?

A clinical pharmacology review of thiazide diuretics is presented in this paper, highlighting the mechanism of action, dosage considerations in order to optimize both the monotherapy or combination treatment, most relevant metabolic effects and adverse reactions, and clinically significant drug interactions. Reference is made to several attemps of limiting or reducing the popularity of their use which took place in mid eighties. At present, there are no data to substantiate that diuretics are implicated for the lack of a consistent reduction in coronary heart disease events. As a consequence of the renewed interest in the development of drugs with diuretic antihypertensive action, the physiologic changes associated with the use of indapamide have been briefly characterized. This agent is also perceived as having more favourable neutral metabolic profile at subnatriuretic dosage. After careful consideration of relevant scientific evidence and a critical appraisal of individualized approach to antihypertensive therapy, diuretics should be given serious consideration as valid alternative to modern antihypertensive agents in years to come.     

Should Two-Drug Initial Therapy for Hypertension Be Recommended for All Patients?

Hypertension is a common disorder linked to increases in cardiovascular mortality and morbidity. Effective treatment decreases this excess mortality. Therapy with a single antihypertensive agent fails to achieve blood pressure goals in up to 75 % of patients. Compared to monotherapy, combination antihypertensive therapy, especially with fixed-dose (single pill) formulations, may more effectively control blood pressure and improve medication persistence while decreasing adverse effects, healthcare costs, and physician therapeutic inertia. Certain combinations, such as a calcium channel blocker and angiotensin converting enzyme inhibitor, have been associated with similar or fewer adverse effects and better outcomes than other combinations. In contrast, other combinations such as thiazide diuretics and β-blockers may cause more adverse effects than monotherapy. When choosing a thiazide diuretic, chlorthalidone is preferable to hydrochlorothiazide, given better efficacy and cardiovascular outcomes. Initial combination antihypertensive therapy may benefit patients with stage I or II hypertension and more widespread use should be encouraged.     

Abdominal obesity is associated with potassium depletion and changes in glucose homeostasis during diuretic therapy

The activation of the renin-angiotensin system (RAS) is an important mechanism that contributes to hypertension in obese individuals. Thiazide diuretics also activate the RAS in response to volume contraction and can lead to a decrease in serum potassium values and glucose metabolism abnormalities. To evaluate the impact of abdominal obesity on potassium depletion and glucose homeostasis in hypertensive patients receiving thiazide therapy, the authors studied 329 hypertensive patients without known diabetes or impaired renal function. Patients were stratified into 2 major groups according to whether they used thiazide diuretic therapy, and each group was further divided in 2 subgroups according to the presence of abdominal obesity. The authors demonstrated that obese patients receiving diuretic therapy had lower plasma potassium levels and higher glucose values compared with nonobese patients receiving diuretic therapy. In conclusion, abdominal obesity predisposes to potassium depletion during diuretic therapy in association with effects on glucose homeostasis.     

Compliance With the Treatment of Hypertension: The Potential of Combination Therapy

J Clin Hypertens (Greenwich). 2010;12:40–46. ^© 2009 Wiley Periodicals, Inc.
Patient adherence to antihypertensive medication is vital to ensure the successful treatment of hypertension. Low levels of adherence to and persistence with prescribed therapy are major factors leading to the current poor rates of blood pressure control among patients with hypertension. There are many reasons for nonadherence to therapy including patient-, physician-, and therapy-related factors. Poor tolerability has a detrimental effect on adherence, therefore reducing the apparent effectiveness of agents with dose-dependent side effects. Various effective combination therapies are recommended by current guidelines, eg, β-blocker plus calcium channel blocker (CCB), angiotensin receptor blocker (ARB) plus thiazide diuretic, angiotensin-converting enzyme (ACE) inhibitor plus thiazide diuretic, CCB plus thiazide diuretic, ACE inhibitor plus CCB, and ARB plus CCB, and these have the potential to increase adherence to therapy by combining a favorable tolerability profile with once-daily dosing.