Continuing Education Activity

Hydrochlorothiazide (HCTZ) is a thiazide-type diuretic that 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 that lowers blood pressure, but there is also a potassium loss in the urine. This activity outlines the indications, mechanism of action, dosing, important adverse effects, contraindications, monitoring, and toxicity of HCTZ and increases practitioners' knowledge regarding how to approach this medication and use and monitor it effectively to drive better patient outcomes.

Objectives:

• Outline the mechanism of action of HCTZ.
• Identify the indications for using HCTZ.
• Summarize the data on cardiovascular outcomes from HCTZ therapy.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with HCTZ.

Indications

Hydrochlorothiazide is a thiazide-type diuretic that 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, 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 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 treating 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, peak 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 are 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 and 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, like 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.[2]

Enhancing Healthcare Team Outcomes

Clinicians (MDs, DOs, PAs, and NPS) 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 clinicians to change their old hydrochlorothiazide prescribing habits and focus more on evidence-based treatment.

Given the above, HCTZ therapy requires the efforts of an entire interprofessional healthcare team that includes clinicians, specialists, nursing staff, and pharmacists, all working collaboratively and engaging in open communication regarding patient monitoring and changes in patient status. This approach will drive improved patient outcomes while mitigating any potential adverse events. [Level 5]