- AHA/ACC - American Heart Assoc / American College of Cardiology
- BP - Blood Pressure
- CrCl - Creatinine clearance
- EAU - European Assoc of Urology
- FDA - U.S. Food and Drug Admin.
- GFR - Glomerular Filtration Rate
- HCTZ - Hydrochlorothiazide
- JNC 8 - Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure
- 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
- 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 other diuretics
- 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)
- Three-drug products
- Other
- General
- Diuretics cause the kidneys to produce more urine and therefore more
fluid is removed from the body
- Fluid loss causes blood pressure to decrease and it reduces the workload
on the heart
- Diuretics are used to treat a number of conditions where excess body
fluid is a problem - heart failure, kidney failure, liver failure, etc.
- Specific
- The nephron is the fundamental working unit in the kidney
- The "distal convoluted tubule" is part of the nephron
- Thiazide diuretics and thiazide-like diuretics block sodium reabsorption
in the distal convoluted tubule
HIGH BLOOD PRESSURE (HYPERTENSION)
- The effect 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
- Veterans Affairs Cooperative Study Group, NEJM (1993) [PubMed abstract]
- The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
- Main inclusion criteria: DBP 95 - 109 mmHg after blood pressure medication washout period
- Baseline characteristics: average age 59 years; average SBP 152 mmHg, DBP 99 mmHg; black race - 48%
- Patients were randomized to 1 of 7 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 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
- At one year, the following was seen:
- Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
- Average blood pressure reduction at end of titration phase (hydrochlorothiazide): SBP 14 mmHg, DBP 10 mmHg
- Average blood pressure reduction at end of titration phase (placebo): SBP 3 mmHg, DBP 5 mmHg
- The incidence of side effects with HCTZ was similar to placebo
- Cochrane meta-analysis (2014) [PubMed abstract]
- A Cochrane meta-analysis looked at the effects of thiazide diuretics on blood pressure in monotherapy trials
- Average blood pressure reduction with HCTZ compared to placebo:
- HCTZ 6.25 mg/day: SBP -4 mmHg, DBP -2 mmHg
- HCTZ 12.5 mg/day: SBP -6 mmHg, DBP -3 mmHg
- HCTZ 25 mg/day: SBP -8 mmHg, DBP -3 mmHg
- HCTZ 50 mg/day: SBP -11 mmHg, DBP -5 mmHg
- Data based on 33 trials with an average baseline blood pressure of 155/100 mmHg
- Average blood pressure reduction with chlorthalidone compared to placebo:
- Chlorthalidone 12.5 - 75 mg/day: SBP -12 mmHg, DBP -4 mmHg
- Data based on 7 trials with an average baseline blood pressure of 163/88 mmHg
- In the trials that were evaluated, chlorthalidone did not show a dose-dependent effect on blood pressure
- Professional guidelines:
- JNC 8 made the following recommendation:
- Thiazide diuretics are recommended as first-line agents in black and nonblack patients without kidney disease [102]
- See hypertension guidelines for complete recommendations
- StraightHealthcare analysis:
- Thiazide diuretics are cheap, widely used, and have a long history of improving outcomes in hypertension
- For patients with hypertension and no compelling indication for another medication class, thiazide diuretics are a first-line choice
CARDIOVASCULAR DISEASE (CVD)
- In the ALLHAT trial, the effect of chlorthalidone on cardiovascular outcomes was compared to lisinopril and amlodipine in patients with hypertension
- Another arm of the trial used doxazosin, but it was stopped early. The results of that arm are detailed here - ALLHAT doxazosin.
- ALLHAT study - Chlorthalidone vs Lisinopril vs Amlodipine for CVD, JAMA (2002) [PubMed abstract]
- The ALLHAT study enrolled 33,357 patients with hypertension and at least one risk factor for heart disease
- 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 and/or EF < 35%
- Baseline characteristics: average age 67 years; race, white - 47%, black - 32%, hispanic - 16%; women - 47%; average BP - 146/84; receiving treatment for hypertension - 90%;
qualifying risk factor, CVD - 52%, diabetes - 36%, smoker - 22%, LVH - 21%, low HDL - 12%
- Patients were assigned in a 1.7:1:1 ratio to 1 of 3 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 wa 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
- After an average follow-up of 4.9 years, the following was seen:
- Primary outcome (6-year rate per 100 patients): Group 1 - 11.5, Group 2 - 11.3, Group 3 - 11.4 (1 vs 2, p=0.65; 1 vs 3, p=0.81)
- Overall mortality (6-year rate per 100 patients): Group 1 - 17.3, Group 2 - 16.8, Group 3 - 17.2 (1 vs 2, p=0.20; 1 vs 3, p=0.90)
- Stroke (6-year rate per 100 patients): Group 1 - 5.6, Group 2 - 5.4, Group 3 - 6.3 (1 vs 2, p=0.28; 1 vs 3, p=0.02)
- Heart failure (6-year rate per 100 patients): Group 1 - 7.7, Group 2 - 10.2, Group 3 - 8.7 (1 vs 2, p<0.001; 1 vs 3, p<0.001)
- Achieved BP goal (< 140/90) at 1 year: Group 1 - 57.8%, Group 2 - 55.2%, Group 3 - 50.6% (1 vs 2, p<0.001; 1 vs 3, p<0.001)
- Potassium < 3.5 mEq/L at 2 years: Group 1 - 12.7%, Group 2 - 2.6%, Group 3 - 1.5% (1 vs 2, p<0.001; 1 vs 3, p<0.001)
- New-onset diabetes at 4 years: Group 1 - 11.6%, Group 2 - 9.8%, Group 3 - 8.1% (1 vs 2, p=0.04; 1 vs 3, p<0.001)
- StraightHealthcare analysis:
- In the ALLHAT trial, chlorthalidone was equivalent to amlodipine and lisinopril for the primary outcome. Chlorthalidone was superior to lisinopril for stroke prevention and superior
to both amlodipine and lisinopril for preventing heart failure. Hypokalemia and new-onset diabetes both occurred more frequently with chlorthalidone.
- Thiazide diuretics are cheap and effective medications that make good first-line agents in most patients with hypertension
- See JNC 8 hypertension guidelines for more
HEART FAILURE
- 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
- Professional guidelines:
- 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 40ml/min [19]
CHRONIC KIDNEY DISEASE
- Patients with chronic kidney disease tend to retain sodium and fluid,
and this causes their blood pressure to rise
- Thiazide and loop diuretics help to alleviate this effect
- Thiazide diuretics tend to become less effective as kidney function
decreases where loop diuretics tend to maintain their effectiveness
- Professional guidelines:
- The National Kidney Foundation recommends the following in chronic kidney disease:
- Thiazide diuretics can be used in patients with a
GFR > 30 ml/min/1.73m²
- Loop diuretics can be used in all patients with chronic kidney
disease and should be used in patients with a GFR < 30 ml/min/1.73m²
- Potassium-sparing diuretics should be used with great caution
because of their potential to raise potassium levels [90]
PREVENTION OF CALCIUM-BASED KIDNEY STONES
- 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)
- Clinical trials
- A number of small trials have shown that thiazide diuretics decrease the
rate of calcium stone recurrence
- In these trials, the following effects were seen when thiazides were compared to placebo or no treatment:
- In clinical trials lasting 2-4 years, thiazides decreased the rate of
stone formation by 0.11 - 0.36 stones per patient per year [25]
- Cochrane meta-analysis
- 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:
- StraightHealthcare analysis:
- 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
- Thiazide diuretics cause the kidneys to retain calcium which may be beneficial in preventing osteoporosis
- One small randomized controlled trial has evaluated the effects of HCTZ on osteoporosis outcomes
- RANDOMIZED CONTROLLED TRIALS
- HCTZ vs Placebo for Osteoporosis Prevention, Annals of Internal Medicine (2000)
[PubMed abstract]
- 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
- Patients were randomized to 1 of 3 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
- After 3 years, the following effects were seen:
- Primary outcome (% change in women): Group 1 -0.81%, Group 2 -0.06%, Group 3 +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): Group 1 +0.54%, Group 2 +1.36%, Group 3 +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): Group 1 - 81.6%, Group 2 - 89.7%, Group 3 - 60.5%
- Groups 2 and 3 had more hypokalemia requiring potassium supplements than Group 1 [27]
- OBSERVATIONAL STUDIES
- Association of chlorthalidone, amlodipine, and lisinopril with hip and pelvic fractures in the ALLHAT Trial, JAMA Internal Medicine (2017)
[PubMed abstract]
- DESIGN: Cohort study using data from ALLHAT study participants. In the ALLHAT study,
patients with hypertension were randomized to chlorthalidone 12.5 - 25 mg a day, amlodipine 2.5 - 10 mg/day, or lisinopril 10 - 40 mg/day
- STUDY POPULATION:
- Cohort 1 (15,255 patients) - Patients initially randomized to chlorthalidone
- Cohort 2 (9048 patients) - Patients initially randomized to amlodipine
- Cohort 3 (9054 patients) - Patients initially randomized to lisinopril
- PRIMARY OUTCOME: Hip and pelvic fracture hospitalizations
- FOLLOW-UP: Active trial - average 4.9 years; Active trial + post-trial - average of 7.8 years
- FINDINGS:
- Active trial: 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: The cumulative incidence of fractures was nonsignificantly 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
- Cochrane meta-analysis
- A Cochrane meta-analysis looked at cohort studies that evaluated the association of thiazides with hip fractures
- The analysis found that thiazide users had a 24% lower risk for hip fractures than nonusers (5 trials) [96]
- StraightHealthcare analysis:
- 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 12.5mg is generally
considered equivalent to HCTZ 25mg
- 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]
- StraightHealthcare analysis:
- 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
- COMBINATION THERAPY
- 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 1kg a day is common, but 3-5kg
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 - 0.8mEq/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]
- Dosing
- Recommended dosing:
- Metolazone 2.5 - 10mg once a day, or 2.5 - 10mg two to three times a
week
- HCTZ 25 - 100mg once a day
- Intravenous chlorothiazide 500 - 1000mg given once or twice a day or
intermittently [19,20]
- StraightHealthcare analysis:
- 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
- LOW POTASSIUM (HYPOKALEMIA)
- All thiazide diuretics can cause significant
potassium loss
- Potassium loss tends to increase with higher doses
- Chlorthalidone
- Two large randomized trials involving chlorthalidone reported
average potassium changes among participants
- In the ALLHAT trial, 15,255 patients who were randomized to
chlorthalidone (12.5 - 25mg a day) had an average decrease in
potassium levels of 0.2 mEq/L after 4 years of therapy [97]
- In the SHEP trial, 2365 patients who were randomized to
chlorthalidone (12.5 - 25mg a day) had an average decrease in
potassium levels of 0.4 mEq/L after 1 year of therapy [87]
- Hydrochlorothiazide
- Compelling trials that measured potassium changes with HCTZ are
scant
- We found one, small randomized trial that measured potassium changes
with HCTZ at doses commonly seen in clinical practice
- In a small trial, 268 patients who were receiving 25 - 50mg 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 25mg HCTZ a day, 80% on
50mg) [98]
- StraightHealthcare analysis:
- Thiazides cause potassium loss typically in the range of 0.2 - 0.4mEq/L
- It is important to monitor potassium levels periodically when taking a
thiazide
- Combining a thiazide with an ACE inhibitor or a potassium-sparing
diuretic can attenuate this effect
- When given in comparable doses, chlorthalidone and HCTZ appear to cause
the same amount of potassium loss
- INCREASED URINATION
- Because diuretics promote fluid loss by the kidneys, they all
can cause increased urination
- This effect is greatest with loop diuretics and less with
thiazides and potassium-sparing diuretics
- LOW SODIUM (HYPONATREMIA)
- Thiazide diuretics may lead to significant sodium loss
- AJM cohort study
- A cohort study in the American Journal of Medicine
looked at the risk of low sodium (defined as sodium ≤ 130mEq/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]
- StraightHealthcare analysis:
- Thiazides can cause low sodium levels in a significant number of
patients
- It is important to check sodium levels periodically in patients taking
thiazides
- Risk factors for thiazide-induced hyponatremia may 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, 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 9.2mg/dl
- Placebo group fasting blood sugar increased by 5.6mg/dl
- New cases of diabetes were not significantly different between the
groups [32]
- ALLHAT trial
- In the ALLHAT trial, 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 8.5mg/dl
- Amlodipine group fasting blood sugar increased by 5.5mg/dl
- The odds of developing diabetes was significantly higher in the
chlorthalidone group when compared to the amlodipine and lisinopril groups
[100]
- Professional guidelines:
- The ADA recommends thiazides as a second-line treatment for
hypertension in diabetics (ACE inhibitor or ARB are first-line) [83]
- StraightHealthcare analysis:
- 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)
- Thiazide diuretics cause the kidneys to retain uric acid which can
lead to higher blood uric acid levels
- High uric acid levels can precipitate or worsen gout, an
inflammatory joint disease
- SHEP trial
- In the SHEP trial, 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 0.90mg/dl
- Placebo group uric acid level increased by 0.30mg/dl [32]
- Other studies
- A number of cohort and case-control studies have found that the risk
of gout is elevated among users of thiazide diuretics [39]
- StraightHealthcare analysis:
- 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
- LOW MAGNESIUM (HYPOMAGNESEMIA)
- Thiazides may cause the kidneys to excrete (lose) magnesium
- The magnitude and significance of this effect is not
well-defined
- There is no evidence that monitoring magnesium levels in
patients taking thiazides is beneficial [101]
- HIGH CALCIUM LEVELS (HYPERCALCEMIA)
- Thiazide diuretics cause the kidneys to retain calcium. This may
lead to elevated blood calcium levels
- The overall significance and magnitude of this effect is not
well-defined
- We found one study that measured the incidence of thiazide-associated
hypercalcemia using a medical database from a community in Minnesota
- The incidence of thiazide-associated calcium level elevations was 7.7
cases per 100,000 thiazide-exposed patients per year [33]
- StraightHealthcare analysis:
- Elevated calcium levels associated with thiazide therapy appear to be
rare
- It may take up to 3 months for thiazide-associated calcium elevations to
return to normal once the thiazide is stopped [33]
- 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, patients taking chlorthalidone for 3 years had a
significant increase in triglycerides from baseline of 24.5mg/dl (compared
to a placebo increase of 8.0mg/dl) [32]
- StraightHealthcare analysis:
- It is unclear if thiazides negatively affect lipid parameters
- Since thiazides promote fluid loss, part of the observed effect may be
secondary to hemoconcentration (increase 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
- Limiting sun exposure and using sunscreen can help prevent reactions [85]
- 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)
- KIDNEY DISEASE
- Patients with significant kidney disease need diuretics to help
increase fluid elimination
- In general, thiazides lose their effectiveness once the CrCl falls
below 30 ml/min
- Loop diuretics are preferred in these patients
- Thiazides may be used in combination with loop diuretics in patients
with CrCl < 30ml/min see combining thiazide and loop diuretics above
- LIVER DISEASE
- Cirrhosis
- Mild to moderate liver disease
- Dosage adjustments are not typically needed
- SULFA ALLERGY
- Loop and thiazide diuretics contain a sulfonamide group in their structure
- The sulfonamide group is different from the one that is found in sulfa-based antibiotics
- Patients with a history of allergy to sulfa-based antibiotics may have a slight increase in risk of an allergic reaction to thiazide and loop diuretics
- Cross-reactivity between sulfa-based antibiotics and sulfonamide nonantibiotics, NEJM (2003)
[PubMed abstract]
- 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
and loop 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
- In addition, 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 [84]
- StraightHealthcare analysis:
- Loop and thiazide diuretics may be prescribed to patients with a history of sulfa-based antibiotic allergy
- Patients should be aware that a cross-sensitivity reaction may occur with a risk of around 10%
- Patients with a history of severe reactions to sulfa-based antibiotics should avoid nonantibiotic sulfonamides if they can. If not, then 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 (hydrochlorothiazide and indapamide)
- 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
- 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
- The parathyroid gland release parathyroid hormone
- Parathyroid hormone increases blood levels of calcium
- In hyperparathyroidism, the gland releases too much hormone and
calcium levels can be elevated
- Thiazides cause calcium retention and may therefore unmask or
exacerbate hyperparathyroidism
- Thiazides should be stopped in patients with elevated calcium
levels, and parathyroid hormone levels should be checked
- It may take up to 3 months for thiazide-associated calcium
elevations to return to normal (see
high calcium levels above)
- NOTE: Drug
interactions presented here are NOT all-inclusive. Other interactions may
exist. The interactions presented here are meant to encompass commonly
prescribed medications and/or interactions that are well-documented. Always
consult your physician or pharmacist before taking medications concurrently.
CLICK HERE for more information on drug interactions.
- HIGH ALERT INTERACTIONS
- All thiazide diuretics
- Lithium
- Thiazides may reduce the clearance of lithium. Thiazides should be avoided
with lithium if possible. Lithium levels should be monitored closely in
patients taking thiazides.
- METABOLISM AND ELIMINATION
- NOTE: Drugs
can be metabolized by more than one enzyme. Drugs may be metabolized by an
enzyme and inhibit/induce the enzyme at the same time. Drug transporters
(ex. p-glycoprotein) can play a role in drug metabolism. Not all drug
interactions are clinically significant. Consult your physician or
pharmacist if you are taking medications together and are concerned about a
possible interaction.
- Only indapamide undergoes significant liver metabolism
- Indapamide
- OTHER
- 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.
- 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.
-
Topiramate (Topamax®) - HCTZ may increase topiramate levels
- 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
- Generic available:
- All thiazides have a generic
- Bendroflumethiazide is only available in a combination product -
Corzide®
- What is PMID?
- PI = Manufacturer's Package Insert
- # PMID
- 1 - 19940300
- 2 - 16145005
- 3 - 12759325
- 4 - 8446138
- 5 - 20821851
- 6 - 19821314
- 7 - 20091662
- 8 - 20687095
- 9 - 20448074
- 10 - 17309946
- 11 - Eplerenone PI
- 12 - 15073471
- 13 - 12842242
- 14 - 19821398
- 15 - 21073363
- 16 - 12668699
- 17 - 10471456
- 18 - 12106936
- 19 - 16160202
- 20 - 21029871
- 21 - 20010338
- 22 - 8373706
- 23 - 2046107
- 24 - 18550938
- 25 - European Association of Urology. Guidelines on Urolithiasis. 2011
- 26 - 20818905
- 27 - 11015164
- 28 - 13679324
- 29 - 2271853
- 30- 2344503
- 31 - 10653441
- 32 - 9554680
- 33 - 17904464
- 34 - 6137813
- 35 - 7388366
- 36 - Demadex PI
- 37 - 8432162
- 38 - 21095025
- 39 - 21285714
- 40 - 16291814
- 41 - 18946066
- 42 - 11733620
- 43 - 18413556
- 44 - 16355285
- 45 - 15656876
- 46 - 19368583
- 47 - 12639869
- 48 - 10672134
- 49 - 9665357
- 50 - 9702848
- 51 - 1486908
- 52 - 5920655
- 53 - 7752176
- 54 - 4102452
- 55 - 1486906
- 56 - Bumetanide PI
- 57 - Furosemide PI
- 58 - 16036053
- 59 - 16342656
- 60 - Aldactone PI
- 61 - 19843067
- 62 - 2050832
- 63 - 3661395
- 64 - 6338681
- 65 - 3189169
- 66 - 19865106
- 67 - 10199763
- 68 - 7104176
- 69 - 3884122
- 70 - 8290411
- 71 - 6409208
- 72 - 6389077
- 73 - 6619267
- 74 - 7282751
- 75 - 3521452
- 76 - 1747638
- 77 - 7431573
- 78 - 19074530
- 79 - 16035375
- 80 - 15601807
- 81 - 12011477
- 82 - 20216123
- 83 - 21193625
- 84 - 14573734
- 85 - 12020173
- 86 - 14638621
- 87 - 20010338
- 88 - 21272751
- 89 - removed
- 90 - Natl Kidney Foundation Guidelines on Hypertension and
Antihypertensive Agents in Chronic Kidney Disease.
Click here
- 91 - 20633946
- 92 - 19475696
- 93 - 19940300
- 94 - 16801488
- 95 - 19160242
- 96 - 21975748
- 97 - 12479763
- 98 - 2318517
- 99 - 22017784
- 100 - 17101936
- 101 - 16119971
- 102 - 24352797
