Hydrochlorothiazide


Article Author:
Linda Herman


Article Editor:
Khalid Bashir


Editors In Chief:
Wanda Wright
Cynthia Oster


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Avais Raja
Orawan Chaigasame
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Abdul Waheed
Khalid Alsayouri
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Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
2/15/2019 4:25:08 PM

Indications

Hydrochlorothiazide is a thiazide-type diuretic which has been used clinically for more than half a century. The drug has been widely used to treat hypertension globally and is relatively very safe. Hydrochlorothiazide acts on the distal convoluted tubules and inhibits the sodium chloride co-transporter system. This action leads to a diuretic action and loss of potassium in the urine. The half-life of hydrochlorothiazide varies from 6 to 12 hours. Of the thiazide diuretics, hydrochlorothiazide is the most frequently used for the treatment of hypertension. Unfortunately, over the past decade, the use of hydrochlorothiazide has been declining, and it is being replaced by the angiotensin-converting enzyme inhibitors, which overall are far more effective and have fewer adverse effects.[1][2][3]

  • Indicated as adjunctive therapy to treat edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. (FDA-approved)
  • Indicated to treat edema associated with renal dysfunction. (FDA-approved)
  • Indicated to treat hypertension as a sole agent or adjunct. (FDA-approved) 

There have been countless studies showing that when hydrochlorothiazide is prescribed at doses of 12.5 mg to 25 mg per day, it can lower the systolic blood pressure by 5 mmHg to 7 mmHg and the diastolic blood pressure by 4 mmHg to 5 mmHg over a 24 hour period. While this magnitude of blood pressure lowering is small compared to the angiotensin-converting enzyme inhibitors, calcium channel blockers or beta blockers, the effects of hydrochlorothiazide are more consistent and reliable in almost all populations. At doses of 50 mg, the effects of hydrochlorothiazide are similar to those seen by calcium channel blockers (verapamil), beta-blockers (metoprolol) or angiotensin-converting enzyme inhibitors (enalapril).[4][5][6] [7]

Reducing Risk of Cardiovascular disease

While hydrochlorothiazide is an effective diuretic and does lower blood pressure, the question that has been asked for decades is whether the drug also lowers the risk of cardiovascular disease, like the angiotensin-converting enzyme inhibitors. Several studies have compared the cardiovascular risk reduction for hydrochlorothiazide to the calcium channel blockers and angiotensin-converting enzyme inhibitors. Overall almost all studies show that hydrochloride is not as effective as the ACE inhibitors in reducing harm from cardiovascular disease. In fact, other studies show that while hydrochlorothiazide can lower blood pressure, it doesn't always reduce the left ventricular hypertrophy in patients with hypertension. When compared to the calcium channel blockers, some studies indicate that the use of hydrochlorothiazide is associated with a higher risk of adverse cardiovascular events for any given lowering of systolic blood pressure. [6][8]

Why hydrochlorothiazide does not lower cardiovascular harm while decreasing blood pressure is not known, but laboratory studies suggest that the drug may not be as effective as the other agents in decreasing platelet aggregation or vascular relaxation.

Despite the above concerns, hydrochlorothiazide is still the drug of choice for the treatment of hypertension in many patients. The drug is versatile and can be combined with many other antihypertensive agents without inducing interactions. The drug is easy to administer and dose. The once a day dosing also ensures that patients will remain compliant with therapy in the long run.

Mechanism of Action

Hydrochlorothiazide inhibits sodium chloride transport in the distal convoluted tubule. More sodium is then excreted in the kidney with accompanying fluid. Pharmacological effects begin in about 2 hours after an oral dose, peaks in 4 hours, and lasts for about 6 to 12 hours. Hydrochlorothiazide is not metabolized, and a majority is excreted in the urine unchanged. It also causes a loss of potassium and bicarbonate. 

The long-term actions of hydrochlorothiazide when it comes to reduction in blood pressure is not well understood. When administered acutely the drug does lower blood pressure by promoting diuresis and decreasing plasma volume. However, following chronic use hydrochlorothiazide appears to be reducing blood pressure by decreasing peripheral resistance. How the drug causes vasodilation is not known, but laboratory evidence suggests that it may be inhibiting the enzyme carbonic anhydrase, desensitizing the smooth muscle receptors to the rise in calcium or preventing autoregulation in the kidneys.[2]

Administration

Dosage is 25 mg to 100 mg per day orally for edema and 25 to 50 mg per day orally for hypertension.

Adverse Effects

All the following adverse reactions have been reported:[9]

  • Weakness
  • Orthostatic hypotension
  • Pancreatitis
  • Jaundice
  • Nausea/Vomiting
  • Sialadenitis
  • Abdominal cramping
  • Diarrhea/Constipation
  • Gastric irritation
  • Aplastic anemia
  • Agranulocytosis
  • Leukopenia
  • Hemolytic anemia
  • Thrombocytopenia
  • Necrotizing angiitis
  • Pneumonitis & pulmonary edema
  • Photosensitivity
  • Fever
  • Urticaria/erythema multiforme/exfoliative dermatitis/TEN
  • Purpura
  • Muscle spasm
  • Vertigo/dizziness
  • Paresthesias
  • Headache
  • Restlessness
  • Transient blurred vision
  • Xanthopsia
  • Impotence

The more serious adverse reactions are:

  • In patients with renal dysfunction, this drug can cause azotemia.[10]
  • HCTZ can cause electrolyte and/or fluid imbalances including hypokalemia, hyponatremia, hypercalcemia, and/or hypomagnesemia. [10]
  • There have been reports of exacerbation of systemic lupus erythematosus with the use of hydrochlorothiazide.  [11]
  • It can cause acute transient myopia and acute angle-closure glaucoma which can occur hours to weeks after beginning the drug.  Risk factors for developing this reaction are a history of sulfonamide or penicillin allergy. [12][13]
  • Hyperuricemia leading to acute gout may occur. 
  • Hyperglycemia can occur and this drug has been known to unmask latent diabetes as well as cause an increase in cholesterol and triglycerides. [14] [15]

Contraindications

Hydrochlorothiazide is contraindicated in all of the following conditions:

  • Anuria
  • Hypersensitivity (should not be given to those with allergies to sulfonamide-derived drugs)[1]

In pregnancy, the drug is a category B drug. It can be used in pregnancy when edema has a pathological cause as those listed in the indications.

Hydrochlorothiazide is excreted in breast milk but appears to be safe for use during lactation. [16]

Monitoring

Electrolytes should be tested on a regular basis. This drug can precipitate hepatic coma in patients with impaired hepatic function.[9][17]

Toxicity

Toxicity results in dehydration and electrolyte deficiencies such as hypokalemia, hypochloremia, and hyponatremia. This occurs because of excessive diuresis.  Treatment is supportive such as fluids and electrolyte replacement. If the patient becomes hypotensive, vasopressors can be used.

Enhancing Healthcare Team Outcomes

Healthcare workers who prescribe HCTZ should be aware of its side effects. While the drug is relatively safe, the patient's electrolyte status has to be monitored regularly. Even though hydrochlorothiazide has been the most widely used thiazide drug for hypertension, more recent evidence indicates that it may not be as effective as some of the other thiazide diuretics. Recent clinical studies indicate that both indapamide and chlorthalidone may be more effective at lowering blood pressure and reducing cardiovascular events, independent of their ability to lower blood pressure. The onus is now on healthcare workers to change their old hydrochlorothiazide prescribing habits and focus more on evidence-based treatment.


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Hydrochlorothiazide - Questions

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A patient with diabetes mellitus has been found to have high blood pressure. Which of the following antihypertensives can worsen diabetes?



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A 71-year-old female, who started a medication for hypertension, develops left flank pain. Vital signs: 154/76 mmHg - 86 bpm - 16/min - afebrile. The physical exam is normal except that the patient is uncomfortable. Urinalysis reveals 50 RBC/HPF. Ultrasound demonstrates a normal aorta and mild left hydronephrosis. Which of the following medications is most likely responsible for the patient's presentation?



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Which antihypertensive drug can lead to the development of serious cardiac arrhythmias?



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A 54-year-old African-American female presents with a blood pressure of 186/98 mmHg. Her medical records demonstrate that she has had an elevated blood pressure each and every time she has been to the office. She admits that she has taken her blood pressure at home at varying times, and it is always greater than 150 mmHg. Which of the following antihypertensive agents would be a good choice to treat her hypertension?



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A 72-year-old female is taking hydrochlorothiazide and a calcium channel blocker as treatment for her hypertension. Her recent lab results demonstrate an increase in her serum calcium and elevated triglyceride and cholesterol levels. Six months ago these values were normal. Which of the listed antihypertensive agents is most likely responsible for these findings?



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Which of the following diuretics has been known to affect lipid levels?



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Where in the kidney does hydrochlorothiazide exert its mechanism of action?



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Which of the following is a common side effect of hydrochlorothiazide?



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Which diuretic has its mechanism of action in the distal convoluted tubules?



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Which diuretic can cause both hyperglycemia and insulin resistance?



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Which medication decreases urinary calcium excretion?



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Which of the following medications can cause hyperglycemia and worsen diabetic control?



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Which of the following is expected to lower urinary calcium excretion?



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Where in the nephron is the site of action of hydrochlorothiazide?



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A patient with diabetes mellitus complains of difficulty controlling her blood sugar. When gathering the history, she reports that her provider added a new antihypertensive drug about 2 weeks ago. What drug was likely added to her medication regimen?



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Which of the following diuretics acts on the distal segment of the nephron?



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What effect does hydrochlorothiazide have on urine calcium level?



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Which of the following is the brand name for bisoprolol and hydrochlorothiazide combination?



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What is a typical dosing range for hydrochlorothiazide when treating hypertension?



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Microzide is the brand name for which of the following drugs?



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Which of the following drugs is contraindicated in patients with anuria?



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A patient was started on a medication to treat his hypertension. Three months later, she presents to the clinic and blood work reveals hyperglycemia, despite the fact that the patient was fasting overnight. Which of the following agents may be responsible for the laboratory finding?



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A patient with a history of hypertension only presents with complaints of a fever. During the evaluation, the chemistry demonstrates a potassium of 3.0 and a glucose of 162. Which of the following medications could be responsible for these lab results?



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A white female is determined to require treatment for hypertension. She is presently taking levothyroxine for her hypothyroidism. Her known allergies are ragweed and sulfa-based antibiotics. Which of the following medications should not be started to manage her hypertension?



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In each of the following combination brand medications: Dyazide, Zestoretic, and Hyzaar, what is the common active ingredient they all share?



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A middle-aged client is found to have high blood pressure on three different occasions. It is decided to start him on hydrochlorothiazide 25 mg once a day. Which of the following is true regarding this medication? Select all that apply.



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A 67-year-old male admitted with congestive heart failure and hypertension arrives at the unit. The provider continues the home medication regimen retrieved from the medication reconciliation form on admission: hydrochlorothiazide 50 mg orally twice a day. The patient relates this is a new medication prescribed by his provider in the office. He filled it but has never taken it. He started feeling sick, so he drove to the emergency department to get another opinion. What potential complications related to this medication will warrant a call be placed to the provider for further clarification before administering the first dose? Select all that apply.



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Hydrochlorothiazide - References

References

Núñez-Acevedo B,Domínguez-Ortega J,Rodríguez-Jiménez B,Kindelan-Recarte C,Pérez-Fernández MA, [Severe and rare adverse reaction to hydrochlorothiazide]. Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993). 2018 Oct-Dec;     [PubMed]
Akbari P,Khorasani-Zadeh A, Thiazide Diuretics 2018 Jan;     [PubMed]
Heymann WR, The Expanding Saga of Hydrochlorothiazide and Skin Cancer. Journal of the American Academy of Dermatology. 2018 Dec 7;     [PubMed]
Dhayat NA,Faller N,Bonny O,Mohebbi N,Ritter A,Pellegrini L,Bedino G,Schönholzer C,Venzin RM,Hüsler C,Koneth I,Del Giorno R,Gabutti L,Amico P,Mayr M,Odermatt U,Buchkremer F,Ernandez T,Stoermann-Chopard C,Teta D,Rintelen F,Roumet M,Irincheeva I,Trelle S,Tamò L,Roth B,Vogt B,Fuster DG, Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial. BMC nephrology. 2018 Dec 10;     [PubMed]
Peng X,Zhao B,Zhang L,Jiang L,Yuan T,Wang Y,Wang H,Ma J,Li N,Zheng K,Nie M,Li X,Xing X,Chen L, Hydrochlorothiazide Test as a Tool in the Diagnosis of Gitelman Syndrome in Chinese Patients. Frontiers in endocrinology. 2018;     [PubMed]
Roush GC,Abdelfattah R,Song S,Ernst ME,Sica DA,Kostis JB, Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis. Journal of clinical hypertension (Greenwich, Conn.). 2018 Oct;     [PubMed]
Michaelis TC,Sontheimer RD,Lowe GC, An update in drug-induced subacute cutaneous lupus erythematosus. Dermatology online journal. 2017 Mar 15;     [PubMed]
Lee GC,Tam CP,Danesh-Meyer HV,Myers JS,Katz LJ, Bilateral angle closure glaucoma induced by sulphonamide-derived medications. Clinical     [PubMed]
Geanon JD,Perkins TW, Bilateral acute angle-closure glaucoma associated with drug sensitivity to hydrochlorothiazide. Archives of ophthalmology (Chicago, Ill. : 1960). 1995 Oct;     [PubMed]
Musini VM,Nazer M,Bassett K,Wright JM, Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. The Cochrane database of systematic reviews. 2014 May 29     [PubMed]
Roush GC,Holford TR,Guddati AK, Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension (Dallas, Tex. : 1979). 2012 Jun     [PubMed]
Sica DA,Carter B,Cushman W,Hamm L, Thiazide and loop diuretics. Journal of clinical hypertension (Greenwich, Conn.). 2011 Sep     [PubMed]
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