Potassium-Sparing Diuretics: Mineralocorticoid Antagonists and Sodium Channel Antagonists
Spironolactone, an inhibitor of the mineralocorticoid receptor, has been used for many years. Although once quite popular, especially in combination with a thiazide diuretic, spironolactone nearly fell out of view (except for its use as a medical treatmentfor primary aldosteronism) until it was resurrected for its value in the treatment of congestive heart failure. As indicated by the comments related to our case study, spironolactone can be highly effective in many patients with refractory hypertension in combination with a thiazide-type diuretic and can correct hypokalemia as well. However, gynecomastia is a limiting adversereaction for men treated with spironolactone because of the antiandrogen effect of this drug. Premenopausal women treated with spironolactone may develop menstrual irregularities, so that spironolactone is most likely to have sustained acceptance only by postmenopausal women. Eplerenone has recently been developed as a selective mineralocorticoid antagonist whose adverse effect profile is far more acceptable to a broader range of patients compared with spironolactone. Eplerenone should be considered an alternative for those who have a good clinical response tospironolactone but who develop unacceptable adverse reactions.
Amiloride and triamterene are also customarily used drugs that inhibit the epithelial sodium transport channel (ENaC) of the collecting duct. The overall activity of this channel is controlled by the action of aldosterone. The ENaC inhibitors reduce potassium excretion as a consequence of their inhibition of the ENaC in preventing sodium resorption. The ENaC inhibitors have, in general, a minimal effect on blood pressure as monotherapy and are most effective for their potassium-sparing effects. The combination of a thiazide-type diuretic and amiloride (Co-amilizide) as initial treatment has been directly compared in a large randomized outcome trial (INSIGHT) with the long-acting calcium channel blocker, nifedipine GITS. The results of this trial found no statistically significant difference between the two treatments. However, a nonsignificant trend favored the diuretic combinationIt is likely that, in the United States
Rarely, salt-sensitive hypertensives may have gain-of-function mutations of the ENaC, resulting in an autosomal recessive trait (Liddle’s syndrome), which conveys a curative role for amiloride in this setting. It has been suggested that heterozygotic patterns may account for salt-sensitive and amiloride-responsive hypertension in some larger population groupsLoop-Active Agents
As indicated by the Figure, furosemide and its analogs (bumetanide or torsemide) interrupt resorption of sodium, calcium, and potassium in the distal renal tubule at the ascending limb of the loop of Henle at sites distinct from the thiazide-sensitive loci. These loop-active agents have a short duration of action and, for treatment of hypertension, must be given twice daily. Renalinsufficiency reflected by reduced creatinine clearance limits the effectiveness of thiazide-type diuretics. In contrast, furosemide is highly effective despite renal impairment, although high doses are often needed when serum creatinine increases. The loop-active diuretics may cause hypokalemia, which can be countered by potassium supplementation or potassium-sparing diuretics. Close monitoring of serum potassium is necessary in these circumstances. Unlike the thiazide-type agents, the loop-active diuretics increase calcium excretion and can reduce serum calcium as a treatment for hypercalcemia
CLINICAL PHARMACOLOGY OF THIAZIDES
Chemistry and Mechanism of Action
Diuretic therapy for hypertension originated in 1937 with the discovery that sulfonamides caused acidemia and mild diuresis by inhibiting carbonic anhydrase in the proximal tubule.3,4Chlorothiazide, a benzothiadiazine derivative, was isolated during a search for more potent inhibitors of carbonic anhydrase5; chlorothiazide was found to be a more effective diuretic and also to unexpectedly increase the excretion of chloride, rather than bicarbonate.6 This effect on excretion eventually led to identification of the upstream portion of the distal convoluted tubule as the major site of action of the thiazides, where they interfere with sodium reabsorption by inhibiting the electroneutral sodium–chloride symporter Activity against carbonic anhydrase, although maintained by some thiazides, is considered irrelevant to their mechanism of action, since sodium that is rejected proximally is reabsorbed downstream in the renal tubule in the thick ascending limb. Despite structural variation among the different congeners, the term thiazide diuretic includes all diuretics believed to have a primary action in the distal tubule.
Pharmacokinetics
The pharmacokinetic activities of thiazides are not uniform. All are absorbed orally and have volumes of distribution equal to or greater than body weight. Thiazides are extensively bound to plasma proteins, which helps limit their filtration by the glomeruli, in effect trapping the diuretic in the vascular space and allowing for its delivery to secretory sites of the renal proximal tubular cells. Organic anion transporters may also assist by concentrating thiazides in the tubular lumen.11
The onset of action occurs after approximately 2 to 3 hours for most thiazides, with little natriuretic effect beyond 6 hours. Their metabolism, bioavailability, and plasma half-lives are variable. The latter two pharmacokinetic features are the most clinically relevant, as they determine the dose and frequency of administration. Chlorothiazide is relatively insoluble in lipids, and large doses are required to achieve levels sufficient to reach the site of action. Hydrochlorothiazide has relatively greater bioavailability; approximately 60 to 70% is absorbed, and food intake enhances absorption. Some thiazides undergo extensive metabolism, whereas others are excreted nearly intact in urine. A 50% reduction in hydrochlorothiazide absorption is observed in patients with heart failure. Relatively little else is known about the influence of disease on the pharmacokinetics of thiazides
Most thiazides have a half-life of approximately 8 to 12 hours, just permitting effective once-daily dosing.Among thiazides, chlorthalidone is uniquely long-acting, with an elimination half-life of 50 to 60 hours, owing to its large volume of distribution. Nearly 99% of chlorthalidone is bound to erythrocyte carbonic anhydrase, and the drug has a stronger inhibitory effect than other thiazides against several catalytically active mammalian isoforms. The substantial partitioning of chlorthalidone into erythrocytes creates a tissue reservoir that allows the constant seeping of chlorthalidone back into plasma, through which it exerts its therapeutic effect. This depot effect of chlorthalidone may be advantageous in patients who occasionally miss doses, and the agent appears to retain measurable efficacy when given less frequently than once daily.
Pharmacodynamics
Hemodynamic Effects
The hemodynamic effects of thiazides can be separated into short-term and long-term phases Initial decreases in blood pressure are attributed to the reductions in extracellular fluid and plasma volumes, leading to depressed cardiac preload and output.19 Dextran administration during this short-term phase will restore plasma volume and blood pressure to pretreatment levels. Counterregulatory activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system induces a transient rise in peripheral vascular resistance, although this is not usually sufficient to negate the blood-pressure reduction. Combining a thiazide with an angiotensin-converting–enzyme (ACE) inhibitor or an angiotensin II–receptor blocker (ARB) can oppose this transient rise in resistance and increase the antihypertensive response.
The long-term antihypertensive response to thiazides cannot be reliably predicted by the degree of initial reduction in plasma volume, which eventually returns to near-normal levels. Volume expansion due to the use of dextran at this stage no longer restores the blood pressure to pretreatment levels. A more likely explanation for the persistent antihypertensive effects of most thiazides is an overall reduction in systemic resistance, although the exact mechanisms are unclear.24Evidence suggests that chlorthalidone may not lower systemic resistance, even after 8 to 12 months of therapy, indicating that other mechanisms may be responsible. It is not yet clear whether thiazides have direct vasodilatory properties or induce a reverse autoregulation phenomenon; they have also been proposed to cause structural membrane changes or altered ion gradients. A simpler possibility is that a low level of prolonged diuresis produced by long-term thiazide administration may maintain a nominal state of volume contraction, thereby promoting a downward shift in vascular resistance.
Thiazides have substantial residual effects after discontinuation. Rapid volume expansion, weight gain, and decreased renin levels occur after stopping thiazides, but blood pressure rises slowly and does not immediately reach pretreatment levels. With adherence to lifestyle modifications (e.g., weight loss, reduction in sodium and alcohol intake), nearly 70% of patients may not require antihypertensive medications for up to 1 year after long-term thiazide-based therapy is withdrawn.
Tolerance to Diuretics
The use of diuretics elicits both short- and long-term adaptations intended to protect intravascular volume. Short-term tolerance may result from a period of post-dose antinatriuresis triggered by the initial reduction in extracellular fluid volume, corresponding to a decline in the drug level in plasma and tubular fluid to below the diuretic threshold. Activation of the renin–angiotensin–aldosterone system and the sympathetic nervous system, as well as suppression of the secretion of atrial natriuretic peptide and renal prostaglandin, also contribute to short-term tolerance. Post-dose sodium retention is significantly influenced by dietary sodium intake. Sodium restriction promotes an overall negative sodium balance and enhances the therapeutic response to thiazides, whereas persistently high dietary sodium offsets this effect.
Long-term diuretic adaptation, or the braking effect, refers to a gradual return of the sodium–chloride balance to an electroneutral level. Persistent volume removal appears to trigger long-term activation of the renin–angiotensin–aldosterone system, increasing circulating angiotensin II levels, which in turn promotes increased proximal sodium reabsorption and limits the overall delivery of sodium to the distal site. Other volume-independent mechanisms may be involved, including the up-regulation of sodium transporters downstream from the primary site of diuretic action and structural hypertrophy of distal nephron segments.
Tolerance to diuretics can be overcome by administering higher doses or combinations of diuretics. For example, synergistic diuresis occurs when a thiazide is added to loop-diuretic monotherapy in patients with edema. Occult volume expansion can be present in patients with resistant hypertension, despite existing diuretic therapy; increasing the dose of diuretics may improve the blood pressure.33 High doses and combinations of diuretics must be used carefully to avoid renal injury and marked electrolyte disturbances.
DIURETIC THERAPY FOR HYPERTENSIVE PATIENTS
Many physicians consider thiazides the diuretics of choice for long-term therapy. On average, after adjustment for reductions seen with the use of placebo, thiazides induce a reduction in the systolic and diastolic blood pressures of 10 to 15 mm Hg and 5 to 10 mm Hg, respectively. Hypertension responding preferentially to thiazides is considered to be low-renin or salt-sensitive hypertension. The elderly, blacks, and patients with characteristics associated with high cardiac output (e.g., obesity) tend to have this type of hypertension. Thiazides also correct the hypertension and electrolyte abnormalities associated with pseudohypoaldosteronism type 2 (Gordon's syndrome), a rare mendelian form of hypertension in which the sodium–chloride symporter is excessively active. Thiazides potentiate other antihypertensive agents when they are used in combination, often producing an additive decrease in blood pressure. The addition of a thiazide minimizes racial differences usually observed in response to monotherapy with inhibitors of the renin–angiotensin–aldosterone system, and the use of such an inhibitor can lessen the degree of the hypokalemia and the metabolic perturbations that may be evoked by thiazides.
The dosing of thiazides has evolved in parallel to our progressive understanding of their mechanism of action and dose–response relationships. Earlier use of high doses was based on the belief that efficacy was directly linked to the amount of renal sodium excretion and reduction in plasma volume; the larger the dose, the greater the assumed reduction in blood pressure. However, thiazides are now used in substantially smaller doses, and the term low-dose thiazide has become synonymous with hydrochlorothiazide at a dose of 12.5 to 25 mg per day (or the equivalent dose of another thiazide). Approximately 50% of patients will respond initially to these low doses. In the Systolic Hypertension in the Elderly Program (SHEP), chlorthalidone given at a dose of 12.5 mg per day controlled blood pressure, for several years, in more than 50% of patients. Increasing the dose of hydrochlorothiazide from 12.5 to 25 mg per day may result in a response in an additional 20% (approximately) of patients; at 50 mg per day, 80 to 90% of patients should have measurable decreases in blood pressure. Increased electrolyte losses at the higher doses of diuretics may preclude their routine use.
For many hypertensive patients, several agents will be needed to achieve desired blood-pressure targets. Combination regimens that include a thiazide can achieve therapeutic synergy while minimizing adverse effects. The lack of appropriate diuretic use is often identified as the primary drug-related cause of resistance to treatment.
Diuretics in Renal Impairment
Thiazides are typically considered ineffective when the glomerular filtration rate decreases below 30 to 40 ml per minute per 1.73 m2 of body-surface area, although direct evidence is lacking. Small studies have shown that thiazides can elicit an antihypertensive response in patients with chronic kidney disease.however, their use in patients with severe renal impairment remains impractical, for two reasons: first, the reduced glomerular filtration rate limits the overall filtered sodium load reaching the distal tubule; and second, reabsorption in the distal tubule is only modestly effective as compared with that in the large-capacity, thick ascending limb.12 These features underscore the rationale for substituting so-called high-ceiling diuretics that act more proximally, in the loop of Henle, in hypertensive patients with renal impairment.
Metolazone, a quinazoline derivative, is an exception among thiazides because it retains its efficacy in patients who have renal insufficiency or other diuretic-resistance states. Its effect is limited by slow, erratic absorption; the more predictable bioavailability of other thiazides makes them better suited as long-term therapy of hypertension. Metolazone should be reserved for use in combination with loop diuretics in patients with volume overload whose fluid and electrolyte balance are being closely monitored. It is administered daily for a short period (3 to 5 days), with administration reduced to thrice weekly after this period or after euvolemia is achieved.
Loop Diuretics
Diuretics that act in the loop of Henle can lower blood pressure but are less effective in the long term than thiazides. Most loop diuretics have a short duration of action (approximately 6 hours), resulting in an initial diuresis that is followed closely by a period of antinatriuresis lasting up to 18 hours per day when the drug is administered once daily. A net neutral sodium balance, or even a positive balance, can occur with the use of loop diuretics. These agents are most appropriate for the treatment of hypertension that is complicated by a reduced glomerular filtration rate (<30 to 40 ml per minute per 1.73 m2 of body-surface area) or by volume overload (e.g., in congestive heart failure or the nephrotic syndrome); in patients with such complications, loop diuretics provide consistent natriuresis and diuresis. Furosemide should be administered twice daily, whereas torsemide is a longer-acting alternative that may be administered once daily.
Potassium-Sparing Agents and Mineralocorticoid-Receptor Antagonists
Potassium-sparing agents induce only minimal natriuresis and are relatively ineffective in lowering blood pressure .Their primary value is their ability to reduce the loss of potassium when they are used with thiazides. They also avert the urinary loss of magnesium, which is important, since restoration of magnesium balance is necessary for optimal correction of diuretic-induced hypokalemia. Triamterene is commonly administered with hydrochlorothiazide, although other fixed-dose combinations of thiazides and potassium-sparing agents are available. Amiloride, an epithelial sodium-channel blocker, is reportedly more effective than spironolactone as therapy in blacks who have resistance to treatment.
The phenomenon of aldosterone escape, whereby aldosterone activity is incompletely suppressed in hypertensive patients who are receiving inhibitors of the renin–angiotensin–aldosterone system, can lead to increased salt and water retention. Agents that block the effect of aldosterone are useful for treating this retention. Spironolactone, a nonselective mineralocorticoid-receptor antagonist, is well absorbed and has a long half-life (approximately 20 hours), attributable to its active metabolites.43Spironolactone not only corrects thiazide-induced potassium and magnesium losses, but also, in low doses (12.5 to 50 mg per day), provides additive hypotensive effects in patients who have resistance to treatment.44 Spironolactone remains effective when renal function is impaired, but patients must be monitored carefully for the development of hyperkalemia. Eplerenone, a newer agent that is more selective for aldosterone than for androgen and progesterone receptors, is associated with less gynecomastia and breast tenderness than is found with spironolactone. However, direct comparisons of the efficacies of eplerenone and spironolactone in patients with treatment-resistant hypertension are lacking.
DIURETICS IN TRIALS WITH CARDIOVASCULAR END POINTS
The efficacy of thiazides in reducing the risk of major cardiovascular events was first established in 1967, in the landmark Veterans Affairs Cooperative Study.45 In the ensuing years, thiazide regimens have proved highly effective in the prevention of stroke, coronary heart disease, and heart failure (see the Supplementary Appendix, available with the full text of this article at NEJM.org).
Combined meta-analyses and systematic reviews report that, as compared with placebo, thiazide-based therapy reduces relative rates of heart failure (by 41 to 49%), stroke (by 29 to 38%), coronary heart disease (by 14 to 21%), and death from any cause (by 10 to 11%).These and other analyses also show that the benefit from thiazides is broadly similar to that from other antihypertensive drugs, with results consistent across age and sex strata. The largest randomized, blinded study performed to date, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), compared initial treatment consisting of chlorthalidone, at a dose of 12.5 mg per day, with treatment consisting of amlodipine, lisinopril, or doxazosin. The 42,418 high-risk study participants were 55 years of age or older, and 35% were black. The doxazosin treatment was stopped prematurely owing to a significantly greater incidence of heart failure events than with chlorthalidone. At the end of the study, no significant differences were found between the chlorthalidone group and any other treatment group in the rate of the composite primary end point of fatal coronary heart disease or nonfatal myocardial infarction; however, chlorthalidone was superior with respect to several predefined secondary end points, including heart failure (vs. amlodipine and lisinopril) and stroke (vs. lisinopril). The explanation for these findings may be related to the improved blood-pressure control maintained throughout the study in the patients receiving chlorthalidone as compared with those receiving another treatment. Analyses of data stratified on the basis of race and metabolic status consistently indicate that chlorthalidone, used as initial therapy, was not surpassed by any of the three comparison drugs with regard to antihypertensive efficacy or event-rate reduction.
Although chlorthalidone and hydrochlorothiazide have been commonly used in the United States
THERAPEUTIC CONTROVERSIES
The concept of a class effect among thiazides has been promulgated in the absence of comparative studies. In the United States
Hydrochlorothiazide and chlorthalidone are often incorrectly described as equipotent. However, early trials comparing the two drugs often involved the administration of hydrochlorothiazide twice daily to achieve reductions in blood pressure similar to those effected by chlorthalidone When evaluated on the basis of the dose required to achieve equivalent reductions in the systolic blood pressure, 24-hour ambulatory blood-pressure monitoring confirmed that chlorthalidone is approximately twice as potent as hydrochlorothiazide. These findings may be attributable to the ability, with chlorthalidone therapy, to maintain efficacy throughout the night and reduce the gradual rise in blood pressure that may occur during the interval between daily doses.
Whether hydrochlorothiazide and chlorthalidone are interchangeable in reducing the risk of cardiovascular events is questionable. An analysis in the Multiple Risk Factor Intervention Trial (MRFIT) suggested a lower mortality rate in the group randomly assigned to undergo a “special intervention” in clinics predominantly using chlorthalidone than in those predominantly using hydrochlorothiazide, but the assignment to a specific diuretic was not randomized, and the study design precluded an ability to reliably separate diuretic effects from those of the other concurrent interventions. Conversely, a meta-analysis that did not include the MRFIT findings has suggested no significant differences between the two agents.
Optimal Role of Diuretics — Initial or Add-on Therapy?
Despite a long, well-established record of efficacy, the role of thiazides in hypertension therapy continues to provoke debate.68 Based on the benefits observed in studies in which thiazides were used as initial therapy in a stepped-care approach, with agents added sequentially, guidelines for hypertension therapy in the United States
Slightly more than one third of the patients in the United States
Cumulative evidence from trials suggests that the magnitude of blood-pressure lowering is the most important determinant in reducing the cardiovascular risks associated with hypertension. As diuretics are eventually required in many hypertensive patients to achieve blood-pressure goals, debate about their role as initial or add-on therapy may be predominantly academic.
SAFETY AND ADVERSE EFFECTS OF THIAZIDES
Much of the criticism against thiazides is directed toward their adverse-effect profile, but low doses are usually well tolerated and have been shown to improve quality-of-life measures. Most complications of thiazide therapy are related to the dose.Thiazides can reduce the excretion of calcium and uric acid and thereby increase their plasma levels, and the drugs increase potassium and magnesium excretion, potentially leading to hypokalemia and hypomagnesemia. On average, measured plasma potassium levels decrease by about 0.3 to 0.4 mmol per liter with typical dosing of thiazide monotherapy, but coadministration of an ACE inhibitor or an ARB can reduce the incidence of clinically relevant hypokalemia. In ALLHAT, the average potassium level among patients receiving chlorthalidone decreased from 4.3 mmol per liter to 4.1 mmol per liter over a 4-year period.52 The plasma potassium level should be measured at baseline, before the initiation of thiazide monotherapy; a potassium-sparing agent may be considered if the baseline level is less than 3.8 mmol per liter.
Maintaining potassium homeostasis is essential, since epidemiologic evidence implicates hypokalemia in the pathogenesis of thiazide-induced dysglycemia.79 The importance of potassium balance is also emphasized by findings from the SHEP study, in which the rate of coronary events among patients with potassium levels below 3.5 mmol per liter was reduced to a lesser degree than among patients with higher potassium levels. Hypokalemia can be managed with the use of a potassium-sparing agent or supplemental potassium chloride. Potassium-sparing agents are preferred because they correct the underlying cause. Dietary salt restriction can also minimize thiazide-induced potassium losses.
New-onset diabetes has been reported in patients receiving thiazides; however, newly diagnosed diabetes occurs over time in many hypertensive patients, regardless of which class of antihypertensive agent is used. Data suggest that receipt of thiazides, as compared with other antihypertensive agents, over several years may lead to an excess of 3 to 4% of new cases of diabetes.
In ALLHAT, the rates of fatal and nonfatal myocardial infarction were similar among patients receiving chlorthalidone, despite the fact that newly diagnosed diabetes was more frequent in the chlorthalidone group (seen in 11.6% of patients) than in the amlodipine group (9.8%) or the lisinopril group (8.1%). To date, no analyses of ALLHAT data have indicated that the development of diabetes obviates the benefit of the thiazide. Similar findings have been reported in a large meta-analysis and in long-term follow-up data of the SHEP cohort. Despite these reassurances, newly diagnosed diabetes in patients receiving thiazides remains a potential concern, since the period of monitoring for long-term diabetes-related adverse effects on cardiovascular outcomes may have been too short.
Few clinically relevant drug interactions occur with the use of thiazides; most notably, nonsteroidal antiinflammatory drugs diminish the therapeutic effect of thiazides by causing sodium retention. Thiazides can increase serum lipid levels, primarily total cholesterol and low-density lipoprotein cholesterol levels, by approximately 5 to 7% in the first year of therapy
What Are the Side Effects of Diuretics?
Like any drug, diuretics come with potential side effects. They include:
· Frequent urination. This may last for several hours after a dose.
· Electrolyte abnormalities -- Blood test monitoring of electrolytes is important before and during drug use.
· Extreme tiredness or weakness. These effects should decrease as your body adjusts to the medication. Call your doctor if these symptoms persist.
· Muscle cramps or weakness. Be sure that you are taking your potassium supplement correctly, if prescribed. Contact your doctor if these symptoms persist.
· Dizziness, lightheadedness. Try rising more slowly when getting up from a lying or sitting position.
· Blurred vision, confusion, headache, increased perspiration (sweating), and restlessness. If these effects are persistent or severe, contact your doctor.
· Dehydration. Signs include dizziness, extreme thirst, excessive dryness of the mouth, decreased urine output, dark-colored urine, or constipation. If these symptoms occur, don't assume you need more fluids, call your doctor.
· Fever, sore throat, cough, ringing in the ears, unusual bleeding or bruising, rapid and excessive weight loss. Contact your doctor right away.
· Loss of appetite, nausea, vomiting, or muscle cramps. Be sure that you are taking your potassium supplement correctly, if prescribed.
Rarely, potassium-sparing diuretics like Aldactone can cause breast enlargement in men and women, deepening of the voice, increased hair growth and irregular menstrual cycles.
In addition, most diuretics are sulfa drugs.�If you are allergic to sulfa drugs, tell your doctor.
Contact your doctor if you have any other symptoms that cause concern.
Guidelines for Taking Diuretics
Here are some general guidelines if you're taking a diuretic:
· Before a diuretic is prescribed, tell your doctor if you are taking any other medications that may have been prescribed by another physician or any over-the-counter or herbal remedies. Also, tell your doctor if you have any other medical problems.
· Follow your doctor�s instructions on how often you should take the diuretic. If you are taking a single dose a day, it might be better to take it in the morning instead of at night, so that you will not have your sleep interrupted by frequent trips to the bathroom. (This is more pertinent for patients with congestive heart failure or patients with cirrhosis and portal hypertension.)
· While taking a diuretic, have your blood pressure and kidney function tested regularly, as advised by your doctor.
· Keep all appointments with your doctor and the laboratory so that your response to this drug can be monitored.
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