Overview of Hypertension: Diagnosis and Treatment
Hypertension (HTN) is defined as either a systolic blood pressure>140 mmHg or diastolic blood pressure >90 mmHg or both; and is often diagnosed by two or more elevated blood pressure readings.1 According the Joint National Committee (JNC-7) hypertension can be classified according to table 1.
Table 1: JNC-7 Classification of Blood Pressure
|
BP classification
|
Systolic BP (SBP) mmHg
|
Diastolic BP (DBP) mmHg
|
|
Normal
|
<120 mmHg
|
<80 mmHg
|
|
Pre-Hypertension
|
120 - 139 mmHg
|
80 - 90 mmHg
|
|
Stage 1 Hypertension
|
140 - 159 mmHg
|
90 - 99 mmHg
|
|
Stage-2 Hypertension
|
≥ 160 mmHg
|
≥ 100 mmHg
|
According to JNC-7, thiazide-type diuretics are considered the first-line drug/choice for the treatment of stage-1 hypertension.1 The evidence supporting this recommendation are the results of the Veterans Affairs Cooperative Trial (1967), which showed that HTN patients treated with thiazide-type diuretics had a significant reduction in cardiovascular events, including stroke, congestive heart disease, and heart failure as compared to placebo.1,2 The ALLHAT study (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), which involved more than 40,000 hypertensive individuals, showed that there were no differences in the primary CHD outcome or mortality between the thiazide-type diuretic, chlorthalidone; the ACE-I, lisinopril; or the CCB, amlodipine.1,3
It is these results, in addition to numerous other antihypertensive trials, low drug cost, and favorable tolerability that make low-dose diuretics the preferred first line of treatment for many patients with hypertension1-3 It is important to note, however, that the American Heart Association recently published new hypertension guidelines, stating that any of the following: thiazide-type diuretic, ACE-I, ARB, or CCB can be used as first line therapy in patients with stage-1 hypertension. The committee goes on to state that patients presenting with stage-2 hypertension should be started on a combination of antihypertensive medications. Lastly, the American Heart Association states that beta-blockers are no longer recommended as first line drug choice and should be reserved for patients with compelling indications.4
Emerging Literature: Are Chlorthalidone and HCTZ Really Different?
Historically, most clinicians believe that the benefits seen with chlorthalidone can be applied to all thiazide diuretics. However, evidence is raising concerns regarding therapeutic interchange.
In 1990, the Multiple Risk Factor Intervention Trail Research Group (MRFIT), published results from a 10.5 year retrospective study that showed favorable mortality and morbidity trends in patients treated with chlorthalidone, but not in patients treated with HCTZ.5 The findings support that of the ALLHAT study, which showed that chlorthalidone was associated with fewer cardiovascular events including stroke and heart failure. Unlike chlorthalidone, however, low-dose HCTZ has yet to be proven effective at reducing cardiovascular morbidity and mortality when used alone in patients with hypertension.3,5-8 In fact, the Second Australian National Blood Pressure Study (ANBP2) found that HCTZ alone was inferior to an ACE inhibitor at reducing combined mortality and morbidity in men but not in women.9
Moreover, a number of studies comparing HCTZ to other types of antihypertensive agents tended to show favorability for the other agent.10-13A literature review conducted by Carter etal. in 2004 not only showed the lack of evidence supporting interchangeability of chlorthalidone and HCTZ, but that these two drugs actually differ greatly in their pharmacokinetic and pharmacodynamic properties (Table 2).11
|
Table 2: Pharmacokinetic/Pharmacodynamic
|
|
Drug
|
Onset (h)
|
Peak (h)
|
Half-life (h)
|
Duration (h)
|
|
HCTZ
|
2
|
4-6
|
6-9
(single dose)
8-15
(long-term dosing)
|
12
(single dose)
16-24
(long-term dosing)
|
|
Chlorthalidone
|
2-3
|
2-6
|
40
(single dose)
45-60
(long-term dosing)
|
24-48
(single dose)
48-72
(long-term dosing)
|
A randomized, single-blinded, cross-over study, conducted by Ernst et al. in 2006 showed that patients treated with chlorthalidone 25mg had a greater reduction in 24hr systolic ambulatory blood pressure (BP) at 8 weeks as compared to 50mg of HCTZ. The authors attributed the overall reduction in systolic BP to a significantly greater reduction in the nocturnal BP in patients treated with chlorthalidone (Figure 2). Results from this study suggested that chlorthalidone is twice as potent as HCTZ in reducing 24 hour ambulatory BP. The observation was attributed to the longer duration of action of chlorthalidone.10
Due to its pharmacokinetic properties, researchers have suggested twice daily dosing for HCTZ. However, previous clinical trials addressing the administration of HCTZ have shown that twice daily dosing offers no additional benefit in its ability to lower BP.14-16 For example, a randomized, double-blinded, cross-over study conducted by Allen et al. showed twice daily dosage did not improve BP reduction (130/84 mmHg) as compared to once daily dosing (131/85 mmHg); p = 0.22.14 In addition, twice daily dosing could be associated with more adverse reactions.
Clinical Impact: Are changes in Pharmacologic Treatment Warranted?
While there are no forthcoming clinical trials comparing HCTZ and chlorthalidone, the above evidence suggests that chlorthalidone and HCTZ are not interchangeable and that the clinical differences between them merits considering chlorthalidone in preference to HCTZ for the treatment of uncomplicated hypertension. Evidence supports a starting dosage of 12.5mg per day increased to a maximum of 25mg per day. It is important to note, however, that even low dosages of chlorthalidone (or HCTZ) can significantly lower serum potassium, placing the patient at a higher risk for cardiac arrest.17 Accordingly, when initiating chlorthalidone (or HCTZ) serum potassium should be routinely monitored.
Although chlorthalidone may be considered the preferred diuretic for monotherapy in patients with uncomplicated hypertension, fixed-dose combination products containing HCTZ should not be discredited. Several clinical trials have shown that antihypertensive efficacy is increased when another agent is paired with HCTZ.3,5-8 Moreover, when paired with a potassium-sparing agent the risk for thiazide-induced hypokalemia significantly decreases. In a randomized, open-label, two-period study HCTZ + triamterene was found to be as effective as HCTZ + potassium supplementation (40 mmol/day) in restoring potassium levels in patients with HCTZ-induced hypokalemia.18 Lastly, fixed-dose combinations have several advantages such as increased patient adherence (reduced pill burden), decreased cost (one prescription versus two), and reduced incidence of adverse side effects.19
References:
1. Chobanian AV, Bakris Gl, Black HR, et al. The seventh report of the Joint National Committee n Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC-7 report. Hypertension. 2003;42:1206-1252.
2. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. JAMA 1970;213:1143-1152.
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major Outcomes in high-risk hypertensive patients randomized to angiotension-converting enzyme inhibitor or calcium channel blocker vs diuretic: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trail (ALLHAT). JAMA. 2002;288:2981-2997
4. American Heart Association Guidelines. <http://www.americanheart.org/presenter.jhtml?identifier=3004556.>
5. Multiple Risk Factor Intervention Trail Research Group. Mortality after 10 ½ years for hypertensive participants in the Multiple Risk Factor Intervention Trail. Circulation. 1990;82:1616-1628.
6. Hypertensive Detection and Follow-up Program Cooperative Group. Five-year findings of the hypertension detection and follow-up program: I-reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA. 1979;242:2562-2571.
7. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264.
8. Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, et al. Treatment of Mild Hypertension Study: final results - Treatment of Mild Hypertension Study Research Group. JAMA 1993;270:713-724.
9. Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl of Med. 2003;348:583-592
10. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47:352-358.
11. Cater BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43:4-9.
12. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl of Med. 2008; 359:2417-2428.
13. Schmieder RE, Philipp T, Guerediaga J, et al. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliksiern: a 12 month randomized, double-blind comparator trail with hydrochlorothiazide. Circulation. 2009; 119:417-425.
14. Allen JH, McKenney JM, Stratton MA, Link K. Antihypertensive effect of hydrochlorthiazide administered once or twice daily. Clin Pharm. 1982;1:239-243
15. De Plaen JF, Vander Elst R, et al. Penbutolol or hydrochlorothiazide on office and ambulatory blood pressure in mild to moderate essential hypertension. Br J Clini Pharmacol. 1989;12:215-221.
16. Lutterodt A, Nattel S, McLeod PJ. Duration of antihypertensive effects of a single daily dose of hydrochlorothiazide. Clin Pharmacol Ther. 1980;27:324-327.
17. Siscovick DS, Raghuanthan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N. Engl J Med. 1194;330:1852-1857.
18. Schnapr H, Freis E, et al. Potassium Restoration in Hypertensive Patients Made Hypokalemiz by HCTZ. Arch Intern Med. 1989;149:2677-2681.
19. WHO expert committee on specifications for pharmaceutical preparations. Thirty-ninth Report. http://apps.who.int/prequal/info_general/documents/TRS929/WHO_TRS_929_annex5FDCs.pdf.
20. Boulet AP, Chockalingam A, et al. Treatment of mild-to-moderate hypertension: comparison between a calcium-channel blocker and a potassium-sparing diuretic. J Cardiovasc Pharmacol. 1991;18(9):S45-50.
21. Trenkwalder P, Plaschke M, et al. Felodipine or Hydrochlorothiazide/triamterene for Treatment of Hypertension in the Elderly: Effects on blood pressure, hypertensive heart disease, metabolic and hormonal parameters. Blood Pressure 1996;5:154-163.
In his position as Chair, Department of Pharmacy Practice and Administration, Dr. Edgren is responsible for the provision of the practice-based educational component of the Saint Joseph College Doctor of Pharmacy Program. He will use his broad base of experience to create a unique program for Saint Joseph College doctoral students.