- ACRONYMS AND DEFINITIONS
- ACE - ACE inhibitors
- ACR - Albumin-to-creatinine ratio
- ARB - Angiotensin receptor blockers
- AHA/ACC - American Heart Assoc / American College of Cardiology
- BP - Blood Pressure
- CCB - Calcium channel blockers
- CrCl - Creatinine clearance
- DBP - Diastolic blood Pressure
- EAU - European Assoc of Urology
- FDA - U.S. Food and Drug Admin.
- GFR - Glomerular Filtration Rate
- HCTZ - Hydrochlorothiazide
- NT-proBNP - N-terminal of the prohormone brain natriuretic peptide
- PTH - Parathyroid hormone
- SBP - Systolic blood Pressure
- SCr - Serum creatinine
- DRUGS IN CLASS
- NOTE: On this page, the term "THIAZIDES" refers to both thiazide and thiazide-like diuretics collectively. Thiazide-like diuretics have a slightly different chemical structure than thiazides, but their pharmacological and medical properties are similar.
- Thiazide diuretics
- Hydrochlorothiazide (HCTZ, Microzide®)
- Bendroflumethiazide (available in combination product only - Corzide®)
- Chlorothiazide (Diuril®)
- Thiazide-like diuretics
- Metolazone (Zaroxolyn®)
- Chlorthalidone (Thalitone®)
- Indapamide (Lozol®)
- Combination products with ACE inhibitors
- Accuretic® / Quinaretic® (Quinapril + HCTZ)
- Capozide® (Captopril + HCTZ)
- Lotensin HCT® (Benazepril + HCTZ)
- Monopril HCT® (Fosinopril + HCTZ)
- Uniretic® (Moexipril + HCTZ)
- Vaseretic® (Enalapril + HCTZ)
- Zestoretic® / Prinzide® (Lisinopril + HCTZ)
- Combination products with ARBs
- Atacand HCT® (candesartan + HCTZ)
- Avalide® (irbesartan + HCTZ)
- Benicar HCT® (olmesartan + HCTZ)
- Diovan HCT® (valsartan + HCTZ)
- Edarbyclor® (azilsartan + chlorthalidone)
- Hyzaar® (losartan + HCTZ)
- Micardis HCT® (telmisartan + HCTZ)
- Combination products with beta blockers
- Corzide® (Nadolol + bendroflumethiazide)
- Dutoprol® (Metoprolol succinate extended-release + HCTZ)
- Inderide® (Propranolol + HCTZ)
- Lopressor HCT® (Metoprolol + HCTZ)
- Tenoretic® (Atenolol + chlorthalidone)
- Ziac® (Bisoprolol + HCTZ)
- Combination products with ENaC inhibitors
- Maxzide® (HCTZ + triamterene)
- Dyazide® (HCTZ + triamterene)
- Moduretic ®(Amiloride + HCTZ)
- Combination products with spironolactone
- Aldactazide® (HCTZ + spironolactone)
- Combination products with alpha-2 agonists
- Aldoril® (methyldopa + HCTZ)
- Combination products with renin inhibitors
- Tekturna HCT® (aliskiren + HCTZ)
- HCTZ + CCB + ARB
- Exforge HCT® (amlodipine + valsartan + HCTZ)
- Tribenzor® (amlodipine + HCTZ + olmesartan)
- MECHANISM OF ACTION
- General
- Diuretics cause the kidneys to produce more urine, removing fluid from the body. Fluid loss causes blood pressure to decrease, and the workload on the heart is reduced. Diuretics are used to treat conditions where fluid retention is a problem (e.g. heart failure, kidney failure, liver failure).
- Specific
- About 6% of freely filtered sodium is reabsorbed in the distal convoluted tubule of the nephron. Thiazide diuretics block this reabsorption, causing more sodium to be excreted and promoting fluid loss.
- Nephron and diuretics illustration - illustration of the nephron and how diuretics work
- HIGH BLOOD PRESSURE (HYPERTENSION)
- Overview
- The effects of thiazide diuretics on blood pressure have been studied in a number of trials. Results from a large randomized controlled trial and a Cochrane meta-analysis are detailed below.
- The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
- Male veteran
- DBP 95 - 109 mmHg off medications
Baseline characteristics
- Average age 59 years
- Average BP 152/99 mmHg
- Black race - 48%
- Current smoker - 32%
Randomized treatment groups
- Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
- Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
- Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
- Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
- Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
- Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
- Group 2 (186 patients) - Placebo
- There was a washout period of 4 - 8 weeks before randomization
- Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results
Average BP reduction at the end of the titration phase (SBP/DBP mmHg) | ||||||
---|---|---|---|---|---|---|
HCTZ | Atenolol | Captopril | Clonidine | Diltiazem | Prazosin | Placebo |
14 / 10 | 11 / 12 | 9 / 10 | 16 / 12 | 13 / 14 | 12 / 11 | 3 / 5 |
|
Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.
- STUDY
- A Cochrane meta-analysis looked at the effects of thiazide diuretics on blood pressure in monotherapy trials
Average blood pressure reduction with thiazide diuretics compared to placebo (SBP/DBP) | ||||
---|---|---|---|---|
HCTZ 6.25 mg/day | HCTZ 12.5 mg/day | HCTZ 25 mg/day | HCTZ 50 mg/day | Chlor 12.5 - 75 mg/day |
4 / 2 | 6 / 3 | 8 / 3 | 11 / 5 | 12 / 4 |
|
- Professional recommendations
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- CARDIOVASCULAR DISEASE (CVD)
- Overview
- The ALLHAT study detailed below compared chlorthalidone to lisinopril and amlodipine for the prevention of CVD
- The ALLHAT study enrolled 33,357 patients with hypertension and either a history of CVD or risk factors for CVD
Main inclusion criteria
- Age > 55 years
- SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
- One of the following: previous MI or stroke, left ventricular hypertrophy (LVH), type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
- History of hospitalized or treated symptomatic heart failure
- EF < 35%
Baseline characteristics
- Average age 67 years
- Women - 47%
- Average BP - 146/84
- Receiving treatment for hypertension - 90%
- Race: White - 47% | Black - 32% | Hispanic - 16%
- Qualifying risk factor: CVD - 52% | Diabetes - 36% | Smoker - 22% | LVH - 21% | Low HDL - 12%
Randomized treatment groups
- Group 1 (15,255 patients) - Chlorthalidone 12.5 - 25 mg a day
- Group 2 (9048 patients) - Amlodipine 2.5 - 10 mg/day
- Group 3 (9054 patients) - Lisinopril 10 - 40 mg/day
- Treatment was titrated to a BP goal of < 140/90
- If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25-100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
- There was another arm of the study that used doxazosin. That arm was stopped early due to an increased risk of major CVD events. See ALLHAT doxazosin for more.
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results
Duration: Average of 4.9 years | ||||
Outcome | Chlor | Aml | Lis | Comparisons |
---|---|---|---|---|
Primary outcome (6-year rate) | 11.5% | 11.3% | 11.4% | 1 vs 2 p=0.65 | 1 vs 3 p=0.81 |
Overall mortality (6-year rate) | 17.3% | 16.8% | 17.2% | 1 vs 2 p=0.20 | 1 vs 3 p=0.90 |
Stroke (6-year rate) | 5.6% | 5.4% | 6.3% | 1 vs 2 p=0.28 | 1 vs 3 p=0.02 |
Heart failure (6-year rate) | 7.7% | 10% | 8.7% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
Achieved BP goal (< 140/90) at 1 year | 57.8% | 55.2% | 50.6% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
Potassium < 3.5 mEq/L at 2 years | 12.7% | 2.6% | 1.5% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
New-onset diabetes at 4 years | 11.6% | 9.8% | 8.1% | 1 vs 2 p=0.04 | 1 vs 3 p<0.001 |
Findings: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.
- AHA recommendations
- The 2015 AHA recommendations on the treatment of hypertension in patients with CAD state that blood pressure lowering is more important than the class of antihypertensive used. They do not recommend one class of drugs over another. [103]
- Summary
- In the ALLHAT trial, chlorthalidone was equivalent to amlodipine and lisinopril for the primary outcome of fatal coronary heart disease or nonfatal myocardial infarction. Because of its diuretic effect, chlorthalidone was superior to both amlodipine and lisinopril for preventing heart failure. Overall mortality did not differ between the 3 treatments.
- In patients with CVD, achieving good blood pressure control is more important than the class of antihypertensive that is used to achieve it
- HEART FAILURE
- Overview
- Thiazide diuretics are sometimes used in patients with heart failure, although loop diuretics are preferred
- Thiazide diuretics increase the fractional excretion of sodium by 5 - 10% where loop diuretics increase sodium excretion by 20 - 25%. Loop diuretics thus have a larger diuretic effect.
- Thiazides may be used as chronic therapy to help lower blood pressure
- Thiazides may be added to loop diuretics to enhance sodium and fluid excretion. See combining thiazide and loop diuretics below for more.
- AHA recommendations
- The AHA/ACC states that thiazide diuretics may be the preferred diuretic in heart failure patients with mild fluid retention because they confer a more persistent blood pressure effect
- Thiazide diuretics are not effective in patients whose CrCl is below 40 ml/min [19]
- KIDNEY DISEASE
- Overview
- Patients with chronic kidney disease retain sodium and fluid, and this causes their blood pressure to rise. Current guidelines state that thiazide diuretics are not as effective in patients with a GFR < 30 ml/min, and loop diuretics are preferred. This guidance has never been confirmed in a randomized controlled trial.
- A small study published in 2021 looked at the effects of chlorthalidone in patients with hypertension and stage 4 kidney disease (GFR < 30 ml/min). That study is detailed below.
- The study enrolled 160 patients with stage 4 kidney disease (GFR < 30 ml/min) and uncontrolled hypertension
Main inclusion criteria
- Stage 4 CKD (GFR 15 to <30 ml/min)
- Uncontrolled hypertension defined as 24-hour ambulatory SBP > 130 or DBP > 80 while receiving ≥ 1 antihypertensive
Main exclusion criteria
- 24-hour ambulatory SBP > 160 or DBP > 100
- History of stroke or MI
- Receiving > 200 mg of furosemide or > 100 mg of torsemide
Baseline characteristics
- Average age 66 years
- Average GFR - 23 ml/min
- Average BP - 140/68 mmHg
- Median spot ACR - 830
- Median NT-proBNP - 590 pg/ml
- Diabetes - 76%
- Receiving loop diuretic - 60%
- Average # of antihypertensives - 3.4
Randomized treatment groups
- Group 1 (81 patients): Chlorthalidone 12.5 - 50 mg once daily (average dose at 12 weeks was 23.1 mg)
- Group 2 (79 patients): Placebo
- The dose used in the assigned regimen was doubled every 4 weeks if, at that time, the patient had a home SBP of 135 mmHg or higher or DBP of 85 mmHg or higher: at week 4, the dose was doubled from 12.5 mg once daily to 25 mg once daily, and at week 8, the dose was doubled to 50 mg once daily (maximum dose). The dose was not increased if the patient had symptomatic orthostatic hypotension, hypercalcemia, moderate hypokalemia (potassium level < 3 mEq/L), acute gout, or recent hospitalization for poorly controlled diabetes. In these instances, the dose was either maintained or decreased, as determined by the investigator.
- There was a 2-week run-in period where antihypertensive doses were standardized for all subjects
- The patients were required to be receiving an ACE inhibitor or ARB or a beta-blocker at the time of randomization
Primary outcome: Change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks
Results
Duration: 12 weeks | |||
Outcome | Chlorthalidone | Placebo | Comparisons |
---|---|---|---|
Primary outcome (SBP mmHg) | -11.0 | -0.5 | p<0.001 |
% change in ACR | -52% | -4% | diff -50%, 95%CI [-60 to -37%] |
% change in NT-proBNP | -30% | -11% | diff -21%, 95%CI [-35 to -4%] |
Change in GFR | -2.7 ml/min | -0.5 ml/min | diff -2.2 ml, 95%CI [-3.3 to -1.0] |
Increase in SCr > 25% | 45% | 13% | N/A |
Hypokalemia | 10% | 0% | N/A |
Hypomagnesemia | 23% | 16% | N/A |
Hyperuricemia | 20% | 9% | N/A |
Hyperglycemia | 16% | 5% | N/A |
Dizziness | 25% | 16% | N/A |
|
Findings: Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as
compared with placebo.
- National Kidney Foundation recommendations
- Thiazide diuretics can be used in patients with a GFR > 30 ml/min/1.73 m²
- Loop diuretics can be used in all patients with chronic kidney disease and should be used in patients with a GFR < 30 ml/min/1.73 m²
- Potassium-sparing diuretics should be used with great caution because of their potential to raise potassium levels [90]
- Summary
- Even though this study was short and small, its results are intriguing. Guidelines from the NKF contend that loop diuretics are preferred when the GFR falls below 30 ml/min because thiazides are not as effective; this study contradicts this guidance. Not only did chlorthalidone lower SBP by 11 mmHg, it also reduced proteinuria and NT-proBNP levels. Side effects were consistent with what is commonly seen with thiazides. Given the difficulty in treating chronic kidney disease, a cheap and effective drug like chlorthalidone would be a blessing. Long-term studies are needed to evaluate hard outcomes.
- PREVENTION OF KIDNEY STONES
- Overview
- Eighty percent of kidney stones are calcium-based stones [26]
- Thiazide diuretics cause the kidneys to retain calcium (loop diuretics cause calcium loss)
- Because of this, thiazide diuretics can be used to prevent the formation of calcium-based kidney stones (thiazides prevent the calcium from reaching the urine where kidney stones are formed)
- Results from a Cochrane meta-analysis that looked at the effects of different medications on preventing kidney stones is presented below
- STUDY
- A Cochrane meta-analysis evaluated trials where thiazides were used to prevent stones in people who excrete too much calcium into the urine (hypercalciuria)
- The meta-analysis found the following effect of thiazides when compared to other interventions:
- Thiazides increased the relative chance of being stone-free by 61% (4 trials)
- Thiazides decreased the rate of stone formation by 0.18 stones per patient per year (3 trials) [95]
- Professional guidelines
- See kidney stone prevention for recommendations on using thiazide diuretics to prevent kidney stones
- Summary
- Thiazide diuretics have been shown to decrease the occurrence of kidney stones in patients who excrete too much calcium (hypercalciuria), and in those who excrete normal amounts of calcium [25,26]
- Patients who have experienced a calcium-based kidney stone would likely benefit from taking a thiazide diuretic
- OSTEOPOROSIS / FRACTURE PREVENTION
- Overview
- Osteoporosis is a condition marked by bone demineralization that leads to an increased risk of fracture
- Thiazide diuretics cause the kidneys to retain calcium which may be beneficial in preventing osteoporosis
- A small randomized controlled trial that evaluated the effects of HCTZ on osteoporosis outcomes is detailed below. A cohort study that looked at the risk of fracture in the ALLHAT study is also reviewed.
- A study in the Annals of Internal Medicine enrolled healthy men and women aged 60 - 79 years
Main inclusion criteria
- Age 60 - 79 years
- Normotensive
- Bone mineral density (BMD) within 2 standard deviations of normal for their age (Z-score ± 2)
Main exclusion criteria
- Taking bisphosphonates or hormone replacement therapy
- Serious heart disease
- Proteinuria
- Elevated serum creatinine
- Hyponatremia
- Hypokalemia
- Gout
- Use of any diuretics or BP medications
- Risk factors for osteoporosis (e.g. corticosteroids, malabsorptive conditions, etc.)
Baseline characteristics
- Average age 68 years
- Average BMD women (total hip) - 0.768 g/cm²
- Average BMD men (total hip) ∼ 0.945 g/cm²
- Average calcium intake (women) - 1100 - 1400 mg/day
- Average calcium intake (men) - 770 - 944 mg/day
Randomized treatment groups
- Group 1 (105 patients) Placebo once daily
- Group 2 (108 patients) HCTZ 12.5 mg once daily
- Group 3 (107 patients) HCTZ 25 mg once daily
- All subjects were given advice to consume 1000 - 1500 mg of calcium a day
- BMD measurements were taken every 6 months
Primary outcome: Percent change in BMD at the total hip over 3 years
Results
Duration: 3 years | ||||
Outcome | Placebo | HCTZ 12.5 mg | HCTZ 25 mg | Comparisons |
---|---|---|---|---|
Primary outcome (% change in women) | -0.81% | -0.06% | +0.62% | 1 vs 2, diff 0.75, 95%CI [-0.43 to 1.92] | 1 vs 3, diff 1.43, 95%CI [0.25 to 2.60] |
Primary outcome (% change in men) | +0.54% | +1.36% | +0.58% | 1 vs 2, diff 0.83, 95%CI [-0.60 to 2.25] | 1 vs 3, diff 0.04, 95%CI [-1.42 to 1.51] |
Still taking assigned medication at 3 years (men) | 81.6% | 89.7% | 60.5% | N/A |
|
Findings: In healthy older adults, low-dose hydrochlorothiazide preserves bone mineral density at the hip and spine. The modest effects observed over 3 years, if accumulated over 10 to 20 years, may explain the one-third reduction in risk for hip fracture associated with thiazide in many epidemiologic studies.
- STUDY
- Design: Cohort study (N=33,357) using data from ALLHAT study participants
- Treatment: Chlorthalidone 12.5 - 25 mg a day vs Amlodipine 2.5 - 10 mg/day vs Lisinopril 10 - 40 mg/day
- Primary outcome: Hip and pelvic fracture hospitalizations
- Results:
- Active trial (average 4.9 years): Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR 0.75, 95%CI [0.58 - 0.98], p=0.04) but not significantly different compared with those randomized to receive amlodipine (HR 0.82, 95%CI [0.63 - 1.08] p=0.17)
- Active trial + post-trial (average 7.8 years): The cumulative incidence of fractures was not significantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR 0.87, 95%CI [0.74 - 1.03], p=0.10) and vs each medication separately
- Findings: These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications.
- Summary
- Thiazide diuretics may have a modest effect in preventing osteoporosis and fractures
- Larger and longer trials are needed to draw firm conclusions
- HYDROCHLOROTHIAZIDE (HCTZ) VS CHLORTHALIDONE
- Overview
- HCTZ is one of the most widely prescribed medications in the world, and it is available in more combination products than any other diuretic
- Chlorthalidone is prescribed much less than HCTZ, and it is available in far fewer combination products
- The reason for this disparity is unclear because most large blood pressure trials demonstrating the effectiveness of thiazides have used chlorthalidone and not HCTZ (ex. ALLHAT, ANBP2, SHEP)
- Comparison of HCTZ and Chlorthalidone
- Dose equivalence: Chlorthalidone 12.5 mg is generally considered equivalent to HCTZ 25 mg
- Drug half-life (long-term dosing): HCTZ 8 - 15 hours Chlorthalidone 45 - 60 hours
- Duration of effect (long-term dosing): HCTZ 16 - 24 hours Chlorthalidone 48 - 72 hours [86]
- Blood pressure effect: In trials, chlorthalidone generally has a superior blood pressure lowering effect over the entire 24 hour dosing interval [87,88]
- Incidence of low potassium: At comparable doses, the effect on potassium is about the same [87]
- Summary
- It's unclear why HCTZ is prescribed to such a greater degree than chlorthalidone
- Some experts hypothesize that the disparity is related to the perception that chlorthalidone causes a higher incidence of low potassium than HCTZ. Randomized trials have not shown this. [87]
- Chlorthalidone has a much longer half-life and duration of effect. This likely improves overall blood pressure control when compared to HCTZ which has a shorter half-life. [87, 88]
- Chlorthalidone has been shown to improve outcomes in some of the largest hypertension trials performed (ex. ALLHAT - over 30,000 patients) [87]
- Chlorthalidone is an effective agent for hypertension that is under-prescribed
- COMBINING THIAZIDE AND LOOP DIURETICS
- Overview
- Over time, the effectiveness of loop diuretics can wane as the kidneys adapt to chronic diuretic therapy
- Patients with obvious fluid overload who do not respond to optimal doses of loop diuretics may benefit from the addition of a thiazide diuretic
- Effectiveness
- In studies, combination therapy has yielded a significant diuretic response in > 90% of patients
- Fluid loss (measured as weight loss) of 1 kg a day is common, but 3 - 5 kg loss over 24 hours has been seen
- Adverse effects
- Low potassium (hypokalemia) is a major concern with combination diuretic therapy
- Serum potassium reductions of 0.4 - 0.8 mEq/L are common even with potassium supplements
- Increases in serum creatinine, sodium loss (hyponatremia), and dehydration are also a concern
- Thiazide choice
- Metolazone has been studied the most in combination therapy, but other thiazides (HCTZ, chlorothiazide) have also been shown to be effective [20]
- A small study (N=60) published in 2020 compared the effects of oral metolazone, IV chlorothiazide, or tolvaptan when added to high-dose furosemide in heart failure patients with diuretic resistance. All 3 therapies achieved similar weight loss at 48 hours. [PMID 31838029]
- Dosing
- Metolazone 2.5 - 10 mg once a day, or 2.5 - 10 mg two to three times a week
- HCTZ 25 - 100 mg once a day
- Intravenous chlorothiazide 500 - 1000 mg given once or twice a day or intermittently [19,20]
- Summary
- When optimal doses of loop diuretics become ineffective, adding a thiazide diuretic can have a profound effect
- Electrolytes and fluid balance must be monitored closely when loop diuretics are combined with thiazides
- SIDE EFFECTS
- Potassium loss
- Thiazide diuretics increase the delivery of sodium to the distal collecting duct, and this promotes potassium excretion. The effects of HCTZ and chlorthalidone on serum potassium levels are discussed below.
- Chlorthalidone
- Two large randomized trials involving chlorthalidone reported average potassium changes among participants
- In the ALLHAT trial, 8,315 patients who were randomized to chlorthalidone (12.5 - 25 mg a day) had an average decrease in potassium levels of 0.2 mEq/L after 4 years of therapy. About 8% of these patients were taking potassium supplements. [97]
- In the SHEP trial, 2365 patients who were randomized to chlorthalidone (12.5 - 25 mg a day) had an average decrease in potassium levels of 0.4 mEq/L after 1 year of therapy, and the incidence of potassium levels < 3.5 mmol/L was 7.2%. The number of patients receiving potassium supplements is not noted. [87]
- Hydrochlorothiazide
- Compelling trials that measured potassium changes with HCTZ are scant
- In a small trial, 268 patients who were receiving 25 - 50 mg of HCTZ a day had an average decrease in potassium levels of 0.47 mEq/L after 6 months of therapy (20% of patients were taking 25 mg HCTZ a day, 80% on 50 mg) [98]
- Summary
- Thiazide diuretics promote potassium loss, and at typical doses, serum potassium levels decrease by 0.2 - 0.4 mEq/L on average. Potassium levels should be checked periodically in patients taking thiazide diuretics. The addition of an ACE inhibitor, ARB, or potassium-sparing diuretic can help to attenuate this effect.
- When given in comparable doses, chlorthalidone and HCTZ appear to cause the same amount of potassium loss
- Increased urination
- Thiazide diuretics promote sodium and fluid loss, and this may also increase urination. The effects of thiazide diuretics on fluid loss are less than what is seen with loop diuretics.
- Low sodium (hyponatremia)
- Thiazide diuretics promote renal sodium excretion, and with long-term use, they can cause hyponatremia. The study below looked at the risk of hyponatremia in patients receiving thiazide diuretics.
- STUDY
- A cohort study in the American Journal of Medicine looked at the risk of low sodium (defined as sodium ≤ 130 mEq/L) in patients taking thiazides compared to patients not taking thiazides
- The study utilized a medical database to ascertain information
- The following results were seen when patients taking thiazides were compared to nonusers:
- Patients taking thiazides had a 61% greater risk for hyponatremia than nonusers
- Incidence rates for hyponatremia were 14 cases per 100 people per year for thiazide-users compared to 8.7 cases per 100 people per year for nonusers
- The risk for hospitalization associated with hyponatremia was not significantly different between the two groups
- The risk for hyponatremia started early in therapy (within 90 days), and the median time to hyponatremia in thiazide-users was 1.75 years
- The risk continued to increase over a 10-year period [99]
- Summary
- Thiazide diuretics can cause hyponatremia in a significant number of patients, and sodium levels should be checked periodically. Risk factors for thiazide-induced hyponatremia include advanced age, female sex, and certain medications (NSAIDS, SSRI antidepressants). [24, 99]
- Elevated blood sugar / diabetes risk
- Thiazide diuretics have been shown to cause blood sugar levels to rise, and subsequently, they can increase the risk of developing diabetes
- SHEP trial
- In the SHEP trial [PMID 2046107], patients receiving chlorthalidone had a significantly greater increase in fasting blood sugar after three years than patients receiving placebo
- Chlorthalidone group fasting blood sugar increased by 9.2 mg/dl
- Placebo group fasting blood sugar increased by 5.6 mg/dl
- New cases of diabetes were not significantly different between the groups [32]
- ALLHAT study
- In the ALLHAT study, patients receiving chlorthalidone had a significantly greater increase in fasting blood sugar after two years than patients receiving amlodipine
- Chlorthalidone group fasting blood sugar increased by 8.5 mg/dl
- Amlodipine group fasting blood sugar increased by 5.5 mg/dl
- The odds of developing diabetes was significantly higher in the chlorthalidone group when compared to the amlodipine and lisinopril groups [100]
- Summary
- Thiazide diuretics have a slight negative effect on blood sugar control
- There is some evidence that this effect may be worsened by low potassium levels that can also be caused by thiazides. Treating low potassium levels may help attenuate the risk of increased blood sugar. [94]
- The proven benefits of thiazides in hypertension outcomes will outweigh their negative effect on blood sugars in the majority of patients
- Uric acid (gout risk)
- Gout is an inflammatory joint disease caused by monosodium urate crystal formation in joints. Monosodium crystal formation is precipitated by high uric acid concentrations in the blood.
- Thiazide diuretics cause the kidneys to retain uric acid which can worsen or precipitate gout
- SHEP trial
- In the SHEP trial [PMID 2046107], patients receiving chlorthalidone had a significantly greater increase in uric acid levels after three years than patients receiving placebo
- Chlorthalidone group uric acid level increased by 0.90 mg/dl
- Placebo group uric acid level increased by 0.30 mg/dl [32]
- Summary
- Thiazide diuretics raise uric acid levels and therefore increase the risk of gout (recurrent and new-onset)
- Individual risk will depend on a patient's baseline uric acid level and the presence of other risk factors (ex. hypertension, heart failure, obesity, diet, etc.)
- In general, patients who have well-controlled gout with normal uric acid levels will likely not be affected by thiazide therapy
- Patients with uncontrolled gout should avoid thiazides
- Magnesium loss
- Thiazide diuretics may increase renal magnesium excretion. The magnitude and significance of this effect is not well-defined. The addition of an ENaC inhibitor can help to attenuate the loss of magnesium that is induced by thiazide diuretics (see magnesium retention with ENaC inhibitors for more). [101]
- Hypercalcemia
- Thiazide diuretics cause the kidneys to retain calcium, and this may lead to hypercalcemia in some patients. The overall significance and magnitude of this effect is not well-defined. A registry study that looked at the risk of thiazide-associated hypercalcemia found an incidence of 7.7 cases per 100,000 thiazide-exposed patients per year. [33]
- Summary
- Hypercalcemia from thiazide diuretic therapy appears to be rare. It may take up to 3 months for thiazide-associated hypercalcemia to resolve once a thiazide is stopped [33]
- Because thiazide diuretics remove calcium from the urine, they are also used to prevent kidney stones (see kidney stone prevention for more).
- Lipid parameters (cholesterol)
- The effect of thiazides on lipid parameters has been inconsistent in trials with some studies showing no effect and others showing a negative effect [34]
- The most consistent effect observed is a slight increase in triglyceride and LDL levels
- In the SHEP trial [PMID 2046107], patients taking chlorthalidone for 3 years had a significant increase in triglycerides from baseline of 24.5 mg/dl (compared to a placebo increase of 8.0 mg/dl) [32]
- Summary
- It is unclear if thiazides negatively affect lipid parameters
- Since thiazides promote fluid loss, part of the observed effect may be secondary to hemoconcentration (increased concentration of blood products secondary to fluid loss) [34]
- The clinical significance of this is most likely negligible
- Photosensitivity
- Thiazide diuretics may cause the skin to become more sensitive to the sun and reactions may occur. An increased risk of nonmelanoma skin cancers has also been observed (see skin cancer below).
- Limiting sun exposure and using sunscreen can help prevent reactions [85]
- Acute myopia and angle-closure glaucoma
- Sulfonamide and sulfonamide-derivative drugs like indapamide and HCTZ have been associated with acute angle-closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift (nearsightedness) and/or choroidal effusions. Symptoms may include an acute decrease in visual acuity and/or ocular pain that typically occurs within hours to weeks of drug initiation.
- If patients develop ocular symptoms while taking indapamide or HCTZ, stop the drug immediately and consult an ophthalmologist. Patients with a history of sulfonamide or penicillin allergy may be at greater risk.
- Skin cancer
- HCTZ has been associated with an increased risk of nonmelanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients
- In one study, the increased risk for SCC in all patients taking HCTZ was approximately 1 additional case per 16,000 patients per year. For white patients taking a cumulative dose of ≥ 50,000 mg, the risk increase was approximately 1 additional case for every 6,700 patients per year.
- Patients on chronic HCTZ therapy may want to limit sun exposure and/or wear protective clothing or sunscreen to help lower their risk of skin cancer
- CONTRAINDICATIONS
- Hydrochlorothiazide
- Anuria (no urine output)
- Sulfonamide allergy - (See sulfa allergy below)
- Chlorothiazide
- Anuria (no urine output)
- Sulfonamide allergy - (See sulfa allergy below)
- Metolazone
- Anuria (no urine output)
- Hepatic coma or precoma
- Sulfonamide allergy - (See sulfa allergy below)
- Chlorthalidone
- Anuria (no urine output)
- Sulfonamide allergy - (See sulfa allergy below)
- Indapamide
- Anuria (no urine output)
- Sulfonamide allergy - (See sulfa allergy below)
- PRECAUTIONS
- Kidney disease
- Diuretics are often necessary to maintain urine output in patients with significant kidney disease. Professional guidelines state that thiazide diuretics may be adequate in patients with a CrCl > 30 ml/min. When CrCl falls below 30 ml/min, loop diuretics, which promote more sodium and fluid loss than thiazides, are preferred. Patients with severe kidney disease may still benefit from thiazides, as a small study (N=160) found that chlorthalidone significantly reduced blood pressure, natriuretic peptide, and proteinuria in patients with CrCl < 30 ml/min (see chlorthalidone in CKD).
- Thiazides may also be added to loop diuretics to overcome tolerance that can develop with loop diuretics (see combining thiazide and loop diuretics for more)
- Liver disease
- Cirrhosis
- Patients with cirrhosis often need diuretics to alleviate and prevent fluid retention. Loop diuretics combined with spironolactone are preferred in these patients (see diuretic therapy in cirrhosis)
- Mild to moderate liver disease
- Dosage adjustments are not typically needed
- Sulfa allergy
- Thiazide diuretics contain a sulfonamide group in their structure, but it is different from the one found in sulfa-based antibiotics. Patients with a history of sulfa-based antibiotic allergy have a small risk of having an allergic reaction to thiazide diuretics. A cohort study that examined the issue is detailed below.
- STUDY
- A cohort study in the NEJM looked at the risk of an allergic reaction to nonantibiotic sulfonamides in patients who had a previous reaction to a sulfa-based antibiotic
- The study found the following:
- Patients with a history of sulfa-based antibiotic allergy who subsequently took nonantibiotic sulfonamides (including thiazide diuretics) had a 10% risk of having a reaction to the nonantibiotic sulfonamide
- In patients without a history of allergic reaction to a sulfa-based antibiotic, 1.6% had a reaction to a nonantibiotic sulfonamide
- Patients with a history of sulfa-based antibiotic allergy had a 14% chance of having a reaction to a penicillin antibiotic. This finding led researchers to conclude that a history of allergic reactions, in general, may be more predictive of a reaction than reactions to any specific medication [15]
- Summary
- Patients with a history of sulfa-based antibiotic allergy have about a 10% chance of reacting to a thiazide diuretic. Patients with a history of severe reaction to sulfa-based antibiotics should avoid nonantibiotic sulfonamides if possible. If not, the initial dosing should be done under medical supervision.
- Gout
- Thiazides can increase uric acid levels. Patients with uncontrolled gout should avoid thiazides.
- See uric acid (gout risk) above
- Prolonged QT syndrome
- Thiazide diuretics may cause hypokalemia which can increase the risk of Torsades de pointes in patients with prolonged QT interval
- Thiazide diuretics should be avoided in patients with congenital long QT syndrome
- Diabetes
- Thiazides may increase blood sugar levels
- See elevated blood sugar/diabetes risk above
- Lupus skin reactions
- Thiazides can increase the sensitivity of the skin to the sun (photosensitivity)
- Cases of lupus-like skin reactions have been reported in patients taking thiazides
- Hyperparathyroidism
- Parathyroid hormone (PTH) is involved in calcium regulation, and its primary action is to raise calcium levels (see calcium regulation). In primary hyperparathyroidism, the parathyroid gland secretes too much PTH and calcium levels are increased. Thiazide diuretic-induced calcium retention can unmask or exacerbate primary hyperparathyroidism.
- Patients with hypercalcemia who are taking thiazide diuretics should discontinue the thiazide and have their parathyroid levels checked. It may take up to 3 months for thiazide-associated hypercalcemia to resolve. [33]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All thiazide diuretics
- Bile acid sequestrants (Questran®, Welchol®, Colestid®) - Bile Acid Sequestrants can interfere with the absorption of thiazide and loop diuretics. Diuretics should be taken 1 hour before or 4 hours after bile acid sequestrants.
- Lithium - Thiazides may reduce the clearance of lithium. Thiazides should not be taken with lithium if possible. Lithium levels should be monitored closely in patients taking thiazides.
- NSAIDS (Advil®, ibuprofen, naprosyn, etc.) - NSAIDS can block the therapeutic effect of all diuretics. Patients should monitor for decreased effectiveness of diuretics when taking NSAIDS for extended periods.
- HCTZ
- Topiramate (Topamax®) - HCTZ may increase topiramate levels
- Metabolism and clearance
- Only indapamide undergoes significant liver metabolism
- Indapamide is a CYP3A4 substrate
- LONG-TERM SAFETY
- Thiazides have been used since the 1960s in millions of patients
- They can have significant side effects
- Their use should always be accompanied with an awareness of possible side effects and appropriate monitoring
- DOSING
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