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What is Hydrochlorothiazide? + Uses, Mechanism & Dosage

Written by Carlos Tello, PhD (Molecular Biology) | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Carlos Tello, PhD (Molecular Biology) | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Hydrochlorothiazide is among the most frequently prescribed drugs worldwide, approved for high blood pressure and water retention (edema). Read on to learn more about how it works and what it’s used for.

Disclaimer: By writing this post, we are not recommending this drug. Some of our readers requested that we commission a post on it and we are providing a summary of the information available in the scientific and clinical literature, along with a list of evidence-based natural alternatives. Please discuss your medications with your doctor.

What Is Hydrochlorothiazide?

Hydrochlorothiazide is a diuretic mainly used for high blood pressure and water retention. It belongs to the class of thiazide diuretics (or benzothiadiazines). Thiazide diuretics promote the flushing of sodium and water in urine by blocking sodium uptake in the kidneys [1, 2, 3].

Hydrochlorothiazide has become the most commonly prescribed drug for high blood pressure since it was launched in 1959. In 2008, almost 48 million prescriptions for hydrochlorothiazide alone and over 87 million for its combination with other drugs were written in the US. Of these, 97% were for low-dose (12.5 or 25 mg/day) hydrochlorothiazide [4].

Hydrochlorothiazide is approved by the FDA for treating [1]:

  • High blood pressure
  • Water retention (edema) due to kidney failure, heart failure, liver damage (cirrhosis), and corticosteroid or estrogen therapy

Although not approved by the FDA, doctors may prescribe hydrochlorothiazide for the following conditions [2]:

  • Kidney stones
  • Diabetes insipidus
  • Osteoporosis
  • Ménière’s disease, a disorder of the inner ear
  • Acid buildup in the body from kidney dysfunction (renal tubular acidosis)

An important drawback of thiazide diuretics is an increased potassium excretion, which may alter the heart rate and cause serious complications. Their combination with potassium-sparing diuretics (triamterene, amiloride, spironolactone) can prevent this adverse effect [5].

Hydrochlorothiazide is a commonly prescribed diuretic drug which promotes the flushing of sodium and water in the urine. It is approved for high blood pressure and edema, and it has a handful of off-label uses.

Mechanism of Action

Hydrochlorothiazide and other thiazide diuretics block a kidney cell protein (SLC12A3) that absorbs sodium and chloride from the urine. By doing so, they increase the flushing of sodium, chloride, and water, while reducing their reuptake into the blood [2].

Hydrochlorothiazide starts to act within 2 h, peaks after 4 h, and lasts for 6 – 24 h [6].

At first (over 2 – 12 weeks), hydrochlorothiazide lowers blood pressure by reducing blood volume. As less blood is pumped by the heart, the blood vessels relax. The drug continues to lower blood pressure long-term, probably by keeping the blood vessels widened [7, 8].

On the downside, low blood volume activates a compensatory pathway in the body (called the renin-angiotensin system). This pathway flushes more potassium and builds up uric acid, which triggers the main adverse effects: low potassium and gout [9, 5].

Hydrochlorothiazide blocks the reabsorption of sodium and chloride during urine production in the kidneys. This increases the amount of sodium, chloride, and water excreted in the urine.

Uses of Hydrochlorothiazide

Follow your doctor’s instructions carefully. Take hydrochlorothiazide as recommended and do not change its dose and frequency or stop taking it without your doctor’s approval. Your healthcare provider may recommend that you combine it with other medications (such as other diuretics). Talk to your doctor if your condition doesn’t improve or if it worsens.

Approved Uses

1) High Blood Pressure

Hydrochlorothiazide Alone

The use of hydrochlorothiazide for reducing blood pressure has been well established since the 1950s. According to data from 33 clinical trials and almost 14k people, this diuretic (6.25 – 50 mg/day) effectively reduces blood pressure, higher doses having a stronger effect [10, 11].

However, other diuretics (called thiazide-like) may be more effective and safer than hydrochlorothiazide. One such diuretic (chlorthalidone 6.25 – 25 mg/day) reduced high blood pressure to a greater and longer-lasting extent in over 100 studies. 2 clinical trials confirmed this by directly comparing the two drugs on 78 people [12, 13, 14, 15].

The diuretic indapamide in low doses (1.5 – 2.5 mg/day) was as effective and safe as hydrochlorothiazide in over 300 people, having an even stronger effect in some populations (black, Indian, elderly, those with kidney failure or only high systolic pressure) [16, 17, 18, 19, 20, 21, 22].

Bendroflumethiazide is another diuretic that works just as well but at lower doses (2.5 – 5 mg) (81 people) [23, 24].

By encouraging more sodium and water to be removed from the blood and excreted in the urine, hydrochlorothiazide reduces blood pressure.

Hydrochlorothiazide in Combination with Other Drugs

Therapy with a single diuretic effectively lowers blood pressure in only 50% of people. The combination of hydrochlorothiazide with at least one more drug additionally reduces blood pressure and allows for lower dosing [25].

To justify the use of multiple blood-pressure-lowering drugs, it’s important to understand how the body controls blood pressure. The key pathway involved is called the renin-angiotensin system, which raises blood pressure.

The kidneys produce an enzyme called renin, which makes angiotensin I in the blood (from angiotensinogen). Next, the crucial angiotensin-converting enzyme (ACE) makes the potentially harmful angiotensin II (from angiotensin I). Angiotensin II narrows blood vessels, increases salt production, and raises the water-retaining hormone aldosterone [26, 27].

In combination with drugs that block this pathway, hydrochlorothiazide will have a stronger blood-pressure-lowering effect. The following drugs are often added to hydrochlorothiazide:

  • ACE inhibitors (ACEIs) block the key enzyme that makes angiotensin II (ACE) [28]. These combinations are quite common. They mostly reduce blood pressure more effectively than either drug alone (with enalapril, captopril, quinapril, fosinopril, benazepril, zofenopril, but NOT lisinopril; 12 trials, > 3,000 people) [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41].
  • Angiotensin II receptor blockers block the activity of angiotensin II [42]. Such combinations lowered blood pressure and were well tolerated in 18 clinical trials of almost 15,000 people (with olmesartan, losartan, telmisartan, valsartan, irbesartan, candesartan) [43, 44, 45, 46, 47, 48, 49, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59].
  • Beta-blockers prevent renin production, aside from blocking the effects of epinephrine [60]. They helped additionally lower blood pressure in 5 clinical trials on over 1,000 people (with bisoprolol, nebivolol, metoprolol, atenolol) [61, 62, 63, 64, 65].
  • Renin blockers bind to and block renin [66]. Hydrochlorothiazide was more effective combined with the renin blocker aliskiren in 2 trials on almost 4,000 people [67, 68].

Hydrochlorothiazide is also sometimes combined with other blood-pressure-lowering drugs such as calcium channel blockers (amlodipine) [69].

Basically, the effect intensifies as more pathways that contribute to high blood pressure are blocked. This may allow for the dosage of each individual drug to be lowered and can potentially reduce side effects. On the downside, side effects are still possible and can be more complex.

Hydrochlorothiazide is sometimes combined with ACE inhibitors, angiotensin II receptor blockers, beta-blockers, or renin blockers to enhance the hypotensive effect of each drug.

Triple Combinations

In people who don’t respond to 2 drugs, a third drug is added. The most common combinations include hydrochlorothiazide, the calcium channel blocker amlodipine, and a sartan (Azilsartan, Valsartan, Olmesartan, Telmisartan – trials on 8,000 people in total) or Aliskiren [70, 71, 72, 73, 74, 75, 76].

2) Water Retention

Water retention occurs when excess fluids move from the blood vessels into the cavities formed between tissues in the body (interstitium). This happens if the pressure inside the blood vessels becomes higher than in the tissues (especially if the blood protein levels are low). It can be caused by heart failure, kidney disease, or liver cirrhosis [77].

Heart Failure

In people with heart failure, the heart becomes weaker and pumps less blood. The kidneys attempt to compensate by absorbing more water and salt. Fluids build up and people usually experience high blood pressure along with heart failure [78].

Small studies on 35 people back in the late 1950s showed that hydrochlorothiazide (50 – 100 mg 2x/day) can reduce water retention in heart failure [79, 80, 81].

Hydrochlorothiazide had a slightly stronger effect than another similar diuretic (quinethazone) in a small trial on 7 people. In turn, different diuretics (ticrynafen, furosemide, and indapamide) were as effective as hydrochlorothiazide but had fewer adverse effects in 3 trials on over 100 people [82, 83, 84, 85].

Hydrochlorothiazide enhanced the effect of the loop diuretic furosemide in a trial on 20 people with heart failure, but the combination increased the risk of low potassium. This can be avoided by combining hydrochlorothiazide with a potassium-sparing diuretic, as seen in 5 trials on over 100 people) [86, 87, 88, 89, 90, 91].

Heart failure causes a weakening of the heart muscles, which results in less blood pumping, increased water and salt absorption, and a buildup of fluid. Hydrochlorothiazide may be prescribed to reduce water retention in these cases.

Kidney Failure

In people with kidney failure, high blood sodium levels cause water retention. Hydrochlorothiazide can be used to reduce sodium and water retention [92].

In 2 old studies on 3 people, hydrochlorothiazide combined with the potassium-sparing diuretic spironolactone or the corticosteroid prednisone improved swelling, increased sodium elimination, and reduced potassium excretion [93, 81].

Liver Cirrhosis

Liver cirrhosis can cause water retention in the belly (ascites), due to sodium buildup, impaired blood flow, and kidney dysfunction [94].

Hydrochlorothiazide (alone or in combination with the corticosteroid prednisone) improved water retention caused by liver cirrhosis in 4 old clinical trials on 21 people [95, 96, 97, 81].

Other Causes

Water retention is common during pregnancy. In an old clinical trial on almost 100 pregnant women, hydrochlorothiazide and other thiazides improved water retention and decreased blood sodium and potassium levels without damaging the unborn babies [98].

The antidiabetic drug rosiglitazone can cause water retention. In a clinical trial on 260 people with water retention from this drug, both hydrochlorothiazide and the potassium-sparing diuretic spironolactone helped [99].

Hydrochlorothiazide is often prescribed for excess fluid buildup in the tissues (edema), which may be caused by heart failure, kidney failure, liver cirrhosis, or other causes.

Off-Label Uses

1) Diabetes Insipidus

Diabetes insipidus is a rare condition characterized by increased thirst and large amounts of diluted urine. It is caused by low levels of the antidiuretic hormone vasopressin, due to not enough of it being produced, its breakdown (as in pregnancy by the placenta), from drinking too much water, or from kidney defects [100].

Desmopressin is an analog of vasopressin and the drug of choice. Hydrochlorothiazide is an alternative that improved this condition in studies on 13 children and 2 adults [101, 102, 103].

Hereditary nephrogenic diabetes insipidus is diagnosed during early childhood and usually resolved with thiazide diuretics. Hydrochlorothiazide is normally combined with other drugs (amiloride, indomethacin, rofecoxib, or desmopressin) [104, 105, 106, 107, 108, 109, 110, 111, 112].

Non-hereditary nephrogenic diabetes insipidus is caused by drugs or surgical procedures that damage the kidneys. Hydrochlorothiazide resolved symptoms in 4 adults [113, 114, 115, 116].

Desmopressin is the drug of choice for diabetes insipidus, but hydrochlorothiazide is an off-label alternative for patients who cannot take or do not respond well to desmopressin.

2) Calcium Imbalance

Hydrochlorothiazide and other thiazides stimulate calcium uptake into the blood by the kidneys, causing less calcium to be flushed and preventing or improving calcium deficiency [117].

Kidney Stones

Kidney stones are an increasing problem worldwide. 80 – 90% of kidney stones are made of calcium salts. Disorders that increase calcium flushing with the urine were the main cause of kidney stones in a study on over 200 people [118, 119, 120].

Hydrochlorothiazide (alone, combined with amiloride, or with a drug for osteoporosis called alendronate) reduced kidney stone formation in trials on over 1,000 adults and almost 200 children [121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132].

However, the thiazide diuretics indapamide and chlorthalidone were more effective than hydrochlorothiazide and could be used at lower doses in 2 studies on over 100 people with kidney stones [133, 134].

Hydrochlorothiazide is occasionally used off-label to reduce kidneys tone formation, though other thiazide diuretics were more effective in clinical trials.

Osteoporosis

Thiazide diuretics may prevent calcium deficiency in osteoporosis. In 4 studies on over 24,000 people, thiazide use was linked to a reduced risk of bone fractures and mineral loss [135, 136, 137, 138, 139].

Hydrochlorothiazide (12.5 – 50 mg/day) preserved bone mineral density in clinical trials on over 1,000 people (alone or in combination with drugs for high blood pressure or for bone loss) [140, 141, 142, 143, 144, 145].

Hydrochlorothiazide also prevented bone loss in rats and mice with osteoporosis [146, 147, 148].

Hydrochlorothiazide preserved bone mineral density in clinical studies of people with osteoporosis, but it is not frequently prescribed for this purpose.

Hypoparathyroidism

Hypoparathyroidism is caused by a lack of the hormone that releases calcium from the bones into the blood (parathyroid hormone). It leads to low calcium and high phosphate blood levels, which can be triggered by damage or removal of the parathyroid gland, genetic or autoimmune causes [149].

In an observational study on 97 people with hypoparathyroidism, 26 required hydrochlorothiazide in addition to calcium and vitamin D to restore calcium balance [150].

Only one case describes hydrochlorothiazide use for hypoparathyroidism in a pregnant woman. It helped improve calcium levels without damaging the baby [151].

There is some clinical evidence of hydrochlorothiazide helping people with hypoparathyroidism restore calcium balance, but it is not usually prescribed for this purpose.

Vitamin D Intake

Vitamin D is used to improve calcium-phosphate disorders caused by hormonal and kidney disorders. However, its long-term use can cause excessive calcium flushing. In an observational study on 19 children and teenagers taking vitamin D, hydrochlorothiazide restored normal urine calcium levels [152, 153].

Dent’s Disease

Dent’s disease is a rare inherited kidney defect characterized by high protein and calcium in the urine, calcium buildup in the kidneys, and kidney damage [154].

Hydrochlorothiazide reduced excessive calcium flushing in 12 children with Dent’s disease but didn’t in 3 (possibly due to the different mutations causing the condition) [155, 156, 154, 157, 158, 159, 160].

3) Ménière’s Disease

Ménière’s disease is a disorder of the inner ear that causes vertigo, temporary hearing loss, ringing in the ears (tinnitus), and stuffy ears. It’s caused by the buildup of fluid in the inner ear [161].

In 4 studies on almost 200 people with this disease, hydrochlorothiazide reduced vertigo and hearing loss. It was much more effective in people with fluctuating symptoms than in more severe cases. In one study on 54 people, it only reduced hearing loss [162, 163, 164, 165, 166].

In a clinical trial on 33 people, a combination of hydrochlorothiazide and another diuretic (triamterene) improved only vertigo. According to a survey of 186 doctors, 72.8% still used this combination to manage Ménière’s disease [167, 168].

In clinical research, hydrochlorothiazide reduced vertigo and hearing loss in people with Ménière’s disease. It is often used in combination with triamterene, another diuretic, for this purpose.

4) Renal Tubular Acidosis

Renal tubular acidosis (RTA) is an acid-base disorder in which acid accumulates in the body because the kidneys fail to flush it. RTA can be hereditary or caused by autoimmune diseases (lupus, rheumatoid arthritis), toxins, and chronic kidney disease [169].

Hydrochlorothiazide (10 – 38 mg/day) restored normal acid excretion into the urine in 4 children with RTA caused by genetic mutations [170, 171, 172, 173].

Genetic Predispositions & Pharmacogenetics

Blood Pressure Reduction

The kidney protein SLC12A3 takes up sodium and chloride. Because this protein is the target of hydrochlorothiazide, variants can alter the drug’s effects [174].

Genes associated with increased response to hydrochlorothiazide include:

In turn, the following genes are associated with high blood pressure despite hydrochlorothiazide therapy (reduced response):

  • SH2B3 (rs3184504 variant C, but only in African Americans) [179]
  • FGF5 (rs1458038 variant T in a closed region) [179]
  • NOS3 (D298N mutation) [184]
  • TGFBR2 (rs3773661 variants G and C and rs7256241 variants TT and GG in women and rs1036096 variant T in men) [183]
  • SLC22A8 (rs10792367 variant C in a closed region) [185]
  • TXNDC11 and SNN (rs3784921 variant G in a region between them) [186]

A polymorphism in ALDH1A2 (rs261316 variant T) was associated with reduced response to combined therapy of hydrochlorothiazide and atenolol [187].

Genetic variations in dozens of genes may affect blood pressure regulation and, therefore, the way the body responds to hydrochlorothiazide. Some mutations have been directly linked to a reduced response to this diuretic.

Bone Mineral Density

In a study on over 100 people, women with DD polymorphisms in the angiotensin-converting enzyme gene (ACE) experienced enhanced bone mineral density from hydrochlorothiazide (those with the II + ID mutation didn’t) [143].

Blood Sugar Levels

Variants of HMGCS2 (rs9943291 variant G), SLC2A2 (rs11920090 variant A), KCNJ1 (rs12795437 variant C and rs11600347 variant A), and TCF7L2 (rs4506565 variant T, rs7903146, rs7901695 variant T, and rs12243326 variant C) were associated with a greater risk of high blood sugar and diabetes from hydrochlorothiazide therapy [188, 189, 190, 191].

Potassium Loss

WNK1 is a protein that activates several sodium and chloride uptake proteins, including SLC12A3. Variants in WNK1 (rs4980973 variants AA and AG) have been associated with increased potassium loss in response to hydrochlorothiazide therapy. Additionally, versions of this protein that alter SLC12A3 activation may increase or reduce the effect of hydrochlorothiazide on blood pressure [192, 193].

Blood Uric Acid

Variants of LUC7L2 (rs6947309 variant T), ANKRD17 (rs16849146 variant C), FTO (rs4784333 variant C), PADI4 (rs2477134 variant G), and PARD3B (rs236829 variant T) in African Americans and GRIN3A (rs1418243 variant A) in white people have been associated with increased uric acid buildup in the blood in response to hydrochlorothiazide [194].

Many genes and genetic variants have been associated with blood pressure control and response to hydrochlorothiazide.

Drug Forms

Hydrochlorothiazide comes as oral tablets and capsules. The available strengths are 12.5, 25, and 50 mg.

Hydrochlorothiazide is available as a generic drug or sold under commercial brand names such as:

  • Hydrodiuril
  • Microzide
  • Zide
  • Esidrix
  • Oretic
  • Aquazide H
  • Hydrocot

Dosage

The following doses are typical:

  • High blood pressure: 12.5 – 50 mg/day (alone) or 6.25 – 25 mg/day (in double and triple combinations) in adults and teenagers [195, 196, 12, 197]
  • Water retention: typically 25 – 100 mg/day in adults, but up to 300 mg/day have been used in clinical trials [198, 86, 93, 81]
  • Diabetes insipidus: 50 mg 2x/day in adults and 1 – 3 mg/kg per day in children [113, 102, 105]
  • Kidney stone prevention: 25 – 50 mg 2x/day in adults and 1 mg/kg per day in children [121, 122, 131]
  • Osteoporosis: 12.5 – 50 mg/day in adults [142, 140]
  • Hypoparathyroidism: 12.5 – 25 mg/day in adults [150]
  • Calcium deficiency due to vitamin D therapy: 1 – 2 mg/kg in children [153]
  • Dent’s disease: 0.2 – 2 mg/kg per day in children [160, 155]
  • Ménière’s disease: 25 mg 2x – 3x/day in adults [162, 164]
  • Renal tubular acidosis: 10 – 38 mg/day in children [170, 173]

Limitations and Caveats

Because diabetes insipidus, Dent’s disease, and renal tubular acidosis are relatively rare, most information on their treatment with hydrochlorothiazide has been obtained from case studies. This makes it difficult to compare doses, combined therapies, and adverse effects.

Takeaway

Hydrochlorothiazide is a diuretic mostly used to treat high blood pressure and water retention. It prevents the reuptake of sodium from the urine back into the bloodstream and so increases sodium and water excretion in the urine. In this way, it reduces blood pressure and resolves edema.

Off-label, some doctors prescribe it to treat diabetes insipidus, disorders of low calcium, Ménière’s disease, and renal tubular acidosis. It is often combined with other drugs for a stronger effect, although side effects are not uncommon.

Further Reading

About the Author

Carlos Tello

Carlos Tello

PhD (Molecular Biology)
Carlos received his PhD and MS from the Universidad de Sevilla.
Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.

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