Diuretics for hypertension: Hydrochlorothiazide or chlorthalidone?
ABSTRACTThiazide diuretics are the cornerstone of treatment of hypertension in most patients. Hydrochlorothiazide is the most commonly used thiazide diuretic in the United States, but interest in chlorthalidone is increasing. The authors summarize the literature comparing these two agents.
KEY POINTS
- Chlorthalidone has a longer duration of action and a longer half-life than hydrochlorothiazide.
- Chlorthalidone may be more potent than hydrochlorothiazide in lowering blood pressure, but it also may be associated with more metabolic adverse effects, such as hypokalemia.
- No study has conclusively shown either drug to be better in preventing adverse clinical outcomes.
- These differences should be considered when making choices about thiazide diuretic therapy for hypertension.
ADVERSE EFFECTS
Electrolyte disturbances are a common adverse effect of thiazide diuretics.
Hypokalemia. All thiazide diuretics cause potassium wasting. The frequency of hypokalemia depends on the dose, frequency of administration, diet, and other pharmacologic agents used.
Two large clinical trials, the Systolic Hypertension in the Elderly Program and ALLHAT, found that chlorthalidone caused hypokalemia requiring therapy in about 6% to 8% of patients.38,39 Chlorthalidone therapy was associated with a lowering of serum potassium levels of 0.2 to 0.5 mmol/L.36 In ALLHAT, chlorthalidone was associated with a reduction in potassium levels of approximately 0.2 mmol/L after 4 years.38
All diuretics require monitoring of electrolytes, especially during the first 2 weeks of therapy. Once a steady state is reached, patients are not usually at risk of hypokalemia unless the dose is increased, extrarenal losses of potassium increase, or dietary potassium is reduced.
Other electrolyte changes. Thiazide and thiazide-like diuretics can cause other metabolic and endocrine abnormalities such as hypochloremic alkalosis, hyponatremia, and hypercalcemia.40,41 They can also cause photosensitivity and can precipitate gout.42
Observational studies have suggested that metabolic adverse effects such as hypokalemia and hyperuricemia are more common with chlorthalidone than with hydrochlorothiazide.43 It is prudent to monitor laboratory values periodically in patients on diuretic therapy.
DRUG INTERACTIONS
The drug interaction profiles of hydrochlorothiazide and chlorthalidone are also similar. The most common interactions are pharmacodynamic interactions resulting from potassium depletion caused by the diuretics.
Antiarrythymic drugs. Hypokalemia is a risk factor for arrhythmias such as torsades de pointes, and the risk is magnified with concomitant therapy with antiarrhythmic agents that prolong the QT interval independently of serum potassium concentration (eg, sotalol, dronedarone, ibutilide, propafenone). Therefore, combinations of drugs that can cause hypokalemia (eg, diuretics) and antiarrhythmic agents require vigilant monitoring of potassium and appropriate replenishment.44
Dofetilide is a class III antiarrhythmic agent and, like other antiarrhythmic drugs, carries a risk of QT prolongation and torsades de pointes, which is magnified by hypokalemia.45 In addition, dofetilide undergoes active tubular secretion in the kidney via the cation transport system, which is inhibited by hydrochlorothiazide.45 The resulting increase in plasma concentrations of dofetilide may magnify the risk of arrhythmias. Chlorthalidone has not been specifically studied in combination with dofetilide, but thiazide diuretics in general are thought to have a similar effect on tubular secretion and, therefore, should be considered similar to hydrochlorothiazide in this regard.
Digoxin. Similarly, digoxin toxicity may be enhanced in hypokalemia. As with antiarrhythmic agents, serum potassium should be carefully monitored and replenished appropriately when diuretics are used in combination with digoxin.
Lithium is reabsorbed in the proximal tubule along with sodium. Diuretics including hydrochlorothiazide and chlorthalidone that alter sodium reabsorption can also alter lithium absorption.46 When sodium reabsorption is decreased, lithium ion reabsorption is increased and may result in lithium toxicity. Although this combination is not contraindicated, monitoring of serum lithium concentrations and clinical signs and symptoms of lithium toxicity is recommended during initiation and dose adjustments of thiazide diuretics.
Nonsteroidal anti-inflammatory drugs can decrease the natriuretic, diuretic, and antihypertensive effects of both hydrochlorothiazide and chlorthalidone.47
Renin-angiotensin-aldosterone system antagonists, ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and the renin inhibitor aliskiren, have potentially beneficial interactions with hydrochlorothiazide and chlorthalidone, producing additive decreases in blood pressure when coadministered with these diuretics. These effects may be particularly potent early in concomitant therapy and allow use of lower doses of diuretics, typically 12.5 mg of hydrochlorothiazide in combination therapy.
LONG-TERM EFFECTS ON CARDIOVASCULAR EVENTS
The long-term goal in treating hypertension is to lower the risk of cardiovascular disease. Therefore, the clinician needs to consider the effect of antihypertensive drug therapy on long-term clinical outcomes.
Antihypertensive drug therapy based on thiazide diuretics has been shown to lower cardiovascular risk when compared with placebo.48 In addition, the effect of chlorthalidone-based antihypertensive therapy was similar to that of other antihypertensive drug classes in preventing most cardiovascular outcomes in ALLHAT.4
However, no study has directly compared hydrochlorothiazide and chlorthalidone with the primary outcome of reduction in long-term cardiovascular events. The data to date come from observational studies and meta-analyses. For example, in a retrospective analysis of the Multiple Risk Factor Intervention Trial, cardiovascular events were significantly fewer in those receiving chlorthalidone vs hydrochlorothiazide (P = .0016).43
In a systematic review and meta-analysis, chlorthalidone was associated with a 23% lower risk of heart failure and a 21% lower risk of all cardiovascular events.49
However, a Canadian observational study of 29,873 patients found no difference in the composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction between chlorthalidone recipients (3.2 events per 100 person-years) and hydrochlorothiazide recipients (3.4 events per 100 person-years; adjusted hazard ratio 0.93, 95% confidence interval 0.81–1.06).50
In summary, it is unclear whether chlorthalidone or hydrochlorothiazide is superior in preventing cardiovascular events.
SUMMARY
Thiazide and thiazidelike diuretics play an important role in managing hypertension in most patients. The eighth Joint National Committee guidelines do not recommend either hydrochlorothiazide or chlorthalidone over the other. The target dose recommendations are hydrochlorothiazide 25 to 50 mg or chlorthalidone 12.5 to 25 mg daily, with lower doses considered for the elderly.
There are important differences between hydrochlorothiazide and chlorthalidone in pharmacology, potency, and frequency of metabolic side effects. Clinicians should consider these factors to tailor the choice of thiazide diuretic therapy in hypertensive patients.
