Continuing Education Activity

Hydrochlorothiazide is a medication approved by the U.S. Food and Drug Administration (FDA) to treat hypertension and peripheral edema. Hydrochlorothiazide is a thiazide-type diuretic that inhibits sodium resorption in the distal convoluted tubules of the kidney. Thiazides, a reliable class of antihypertensive diuretics for over 60 years,[1] have been shown to reduce major cardiovascular events.[2] Thiazides function by directly inhibiting the sodium chloride cotransporter, thereby preventing sodium reabsorption and inducing both natriuresis and diuresis effects. This activity comprehensively reviews the specific indications, mechanism of action, dosing, associated adverse events, contraindications, monitoring, and other clinically relevant information for healthcare professionals involved in managing hypertension and monitoring the effects of hydrochlorothiazide.

Objectives:

• Identify appropriate indications for hydrochlorothiazide in treating hypertension and peripheral edema, considering patient-specific factors.
• Differentiate between hydrochlorothiazide and other thiazide-type diuretics, understanding their comparative effectiveness, adverse effects, and individual patient profiles.
• Apply knowledge of hydrochlorothiazide's mechanism of action, recognizing its impact on sodium resorption and its role in inducing natriuresis and diuresis.
• Collaborate with other interprofessional healthcare professionals to ensure comprehensive care and address any concerns or complications related to hydrochlorothiazide therapy.

Indications

FDA-Approved Indications

Hydrochlorothiazide is a medication approved by the U.S. Food and Drug Administration (FDA) to treat hypertension and peripheral edema. Hydrochlorothiazide is a thiazide-type diuretic that inhibits sodium resorption in the distal convoluted tubules of the kidney. For over 60 years, thiazides have been a reliable class of antihypertensive diuretics that prevent sodium reabsorption and induce natriuresis and diuresis by directly inhibiting the sodium chloride cotransporter.[1] 

Hydrochlorothiazide is FDA-approved for treating essential hypertension either as a primary agent or an adjunct to other antihypertensive therapies.[2] Hydrochlorothiazide was initially approved for the treatment of hypertension in the 1960s.[3] According to some studies, thiazide-type diuretics and calcium channel blockers may lower blood pressure in Black patients more effectively than the renin-angiotensin system (RAS) inhibitors or beta-blockers.[4]

Hydrochlorothiazide is also FDA-approved for the treatment of peripheral edema related to heart failure, corticosteroids, nephrotic syndromes, or estrogen therapy. Usually, loop diuretics are the preferred first-line treatment for peripheral edema, and hydrochlorothiazide is utilized as an adjunctive therapy.[5]

Off-Label Uses

Hydrochlorothiazide can also be used to treat nephrogenic diabetes insipidus and prevent calcium nephrolithiasis, although, currently, it is not an FDA-approved indication.[6][7][8] 

Mechanism of Action

Hydrochlorothiazide directly inhibits the sodium chloride cotransporter located on the apical membrane of the distal convoluted tubules in the kidney. The distal convoluted tubule is responsible for reabsorbing approximately 5% to 10% of the sodium in the kidney.[9] This inhibition increases the concentration of sodium that moves to the collecting ducts by preventing sodium resorption in the distal convoluted tubules. Hydrochlorothiazide reduces the sodium-potassium ATPase pump's activity on the basolateral surface by preventing sodium from crossing the tubular lumen. This action prevents the movement of sodium and water into the interstitial space.

The elevated concentration of positively charged sodium ions moving through the distal convoluted tubule induces an ionic imbalance, further opening the voltage-gated channels. This transient receptor potential triggers an influx of calcium reabsorption from the tubular lumen, facilitated across the basolateral surface through the calcium ATPase pump and sodium-calcium exchanger. Reabsorption of calcium in the distal convoluted tubules contributes to approximately 7% to 10% of filtered calcium retention.[10]

Aldosterone, the mineralocorticoid, is responsible for the modulation of sodium reabsorption and potassium excretion in the collecting ducts of the kidney. Elevated sodium concentration in the collecting duct prompts aldosterone to bind to the mineralocorticoid receptor, initiating the transcription of ion transport protein channels.[11] This leads to sodium reabsorption through the epithelial sodium channels in the principal cells and potassium excretion in the intercalated cells,[12] resulting in natriuresis and diuresis effects.

In adults, the pharmacological effects of hydrochlorothiazide commence within 2 hours, peak after 4 hours, and persist for approximately 6 to 12 hours.[13] As the kidney is the primary excretory route for the medication, patients with renal impairment may exhibit a prolonged half-life and increased plasma concentration. Although no dosage adjustment is recommended for impaired renal function, the medication is unlikely to be effective in cases of severe renal impairment with a creatinine clearance of less than 10.[14]

The initial diuresis and natriuresis effect mediated by the kidney causes an initial decrease in blood pressure through volume loss.[15] Over time, hydrochlorothiazide has demonstrated the ability to sustain blood pressure reduction by causing vasodilation and reducing peripheral vascular resistance.[16] Despite various proposed mechanisms, the exact mechanism by which hydrochlorothiazide causes peripheral vasodilation is not well understood. 

Administration

Available Dosage Forms and Strengths

Hydrochlorothiazide is available in tablet or capsule form for oral administration, with strengths ranging from 12.5 mg, 25 mg, to 50 mg.

Adult Dosages

Starting dosages vary depending on treatment indication and patient population. Healthcare providers recommend administering hydrochlorothiazide early in the day to prevent nocturia.

For the treatment of chronic hypertension, the recommended initial starting dosage of hydrochlorothiazide is 12.5 to 25 mg daily, with titration to a maximum daily dosage of 50 mg once daily after 2 to 4 weeks.[2] In the management of peripheral edema, an initial starting dosage of 25 to 50 mg may be prescribed once or twice daily, with a maximum daily dose of up to 200 mg.[17] Hydrochlorothiazide may be used to treat polyuria in nephrogenic diabetes insipidus, with an initial dosage of 25 mg administered twice daily.[18] The recommended initial hydrochlorothiazide dosage is 25 mg daily to prevent calcium nephrolithiasis. The dosage can be adjusted to 1 or 2 doses daily, with a maximum recommended daily dosage of 50 or 100 mg.[19]

Cardiovascular Outcomes

Untreated hypertension is associated with adverse cardiovascular remodeling and an elevated risk of major adverse cardiovascular events. Selecting an appropriate antihypertensive therapy should be personalized to the patient, considering all other existing comorbid conditions. The 2017 guidelines for hypertension management offer a class I-A recommendation for thiazide-type diuretics, calcium channel blockers, or RAS inhibitors as initial agents.[20] However, in patients with chronic kidney disease, diabetes mellitus, coronary artery disease, or congestive heart failure, hydrochlorothiazide is not the initially preferred therapy.

Thiazide-type diuretics can be used as an adjunct to other antihypertensive medications, including RAS inhibitors, calcium channel blockers, beta-blockers, mineralocorticoid receptor antagonists, or other diuretics. The 2008 ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension) trial demonstrated the significant superiority of benazepril-amlodipine over benazepril-hydrochlorothiazide in patients at high risk of experiencing cardiovascular events.[21] Most other large randomized controlled trials comparing hydrochlorothiazide to other therapies have focused on hydrochlorothiazide as a single antihypertensive agent rather than an adjunct to treatment. In the future, it may be more relevant to investigate the effects of hydrochlorothiazide as a second or third agent in specific patient populations, considering their existing comorbidities.

Adverse Effects

Although hydrochlorothiazide is generally well tolerated, this medication has been associated with various adverse effects, as mentioned below. In most cases, patients on increased doses of hydrochlorothiazide are at a higher risk of developing any adverse reactions.

Electrolyte derangements: Hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia, and hyperchloremic alkalosis may occur as a result of hydrochlorothiazide blocking the sodium chloride cotransporter in the distal convoluted tubules as described earlier.[5] Therapy with loop diuretics or doses greater than 25 mg may cause electrolyte abnormalities.[22]

Hyperglycemia: Hydrochlorothiazide has been associated with higher levels of fasting blood glucose. Although the exact mechanism behind HCTZ-induced hyperglycemia is not well understood, it is hypothesized that decreased potassium levels may reduce insulin secretion by the pancreas.[23] Caution is advised when prescribing hydrochlorothiazide to patients with a preexisting history of diabetes mellitus or impaired glucose metabolism.

Gout: Gout flares may be precipitated by hyperuricemia caused by hydrochlorothiazide, especially in susceptible individuals. The mechanism is related to volume contraction caused by diuresis and increased uric acid reabsorption in the proximal convoluted tubule.[24] Increased uric acid levels and gout flares will often occur within the first weeks of initiating hydrochlorothiazide therapy.[24]

Dyslipidemia: Although the precise mechanism is not well understood, hypercholesterolemia has been associated with hydrochlorothiazide use.[25]

Sulfa allergy: As hydrochlorothiazide contains a sulfonamide group, it is contraindicated in patients with preexisting sulfonamide allergy. Allergic reactions may result in dermatological skin rash, urticaria, toxic epidermal necrolysis, Steven-Johnson syndrome, or anaphylaxis. Limited data exist regarding the cross-reactivity between antibiotic sulfa drugs and other sulfonamide-containing medications.[26]

Ocular disturbance: In rare cases, hydrochlorothiazide therapy has been associated with acute angle-closure glaucoma and transient myopia. In most reported cases, adverse ocular effects typically manifest within the initial days of treatment and are believed to be linked to the sulfonamide structure.[27]

Special considerations: In patients with known cirrhosis, hydrochlorothiazide may cause severe hyponatremia or hepatic encephalopathy. Thus, if healthcare providers prescribe this medication to patients, they should be monitored closely.[28] Clinicians should exercise caution when prescribing hydrochlorothiazide in the immediate preoperative or postoperative period to prevent dehydration.

Contraindications

Hydrochlorothiazide is contraindicated in cases of anuria or preexisting sulfonamide allergy. This medication should be used cautiously in patients with severe hepatic impairment due to the potential risk of developing hepatic coma.[29] In individuals with underlying adrenal insufficiency, hydrochlorothiazide therapy should be avoided.[30]

Monitoring

Patients undergoing hydrochlorothiazide treatment should be regularly monitored for electrolyte imbalances, including sodium, potassium, calcium, and magnesium levels. As hydrochlorothiazide functions as a diuretic, it is essential to clinically monitor patients for signs and symptoms of dehydration and hypervolemia. Patients, particularly those with a known personal or family history of gout, should be monitored for signs and symptoms of acute gout flare when receiving hydrochlorothiazide. Blood pressure should be closely monitored to ensure patients on hydrochlorothiazide treatment achieve and maintain their target blood pressure, minimizing the risk of adverse effects associated with high or low blood pressure. Furthermore, it is crucial for patients with impaired glucose metabolism to closely monitor their blood glucose levels while taking hydrochlorothiazide to prevent hyperglycemia.

Toxicity

Hydrochlorothiazide diuretics may increase photosensitivity and lower the threshold for UV-associated phototoxicity.[31][32]

Enhancing Healthcare Team Outcomes

Healthcare providers frequently prescribe hydrochlorothiazide for the treatment of hypertension or peripheral edema. Despite the long history of thiazide diuretics, all patients on this therapy necessitate careful surveillance, as outlined above, to monitor for electrolyte imbalances and potential adverse effects. Multidisciplinary patient-centered care is essential for monitoring fluid intake and output, blood pressure levels, and other symptoms related to potential electrolyte imbalances triggered by hydrochlorothiazide use. Considering the abovementioned considerations, hydrochlorothiazide therapy necessitates the collaboration of an interprofessional healthcare team comprising clinicians, specialists, nursing staff, and pharmacists. Furthermore, all healthcare team members must collaborate and communicate openly regarding patient monitoring and ongoing assessments.

Hydrochlorothiazide is one of the 3 commonly used thiazide-type diuretics, along with chlorthalidone and chlorothiazide. All thiazide-type diuretics have a comparable chemical structure centered around a benzothiadiazine.[33] Historically, although most clinical trials with thiazide-type diuretics focused on hydrochlorothiazide or chlorthalidone, they lacked direct head-to-head comparisons. Patients were randomized to hydrochlorothiazide or chlorthalidone in a large multicenter clinical trial, revealing no statistically significant difference in major cardiovascular events.[34] Although hydrochlorothiazide monotherapy alone is not the typical approach, the management of antihypertensive treatment necessitates individualized treatment plans and shared decision-making abilities.

Review Questions

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Disclosure: Linda Herman declares no relevant financial relationships with ineligible companies.

Disclosure: Paul Weber declares no relevant financial relationships with ineligible companies.

Disclosure: Khalid Bashir declares no relevant financial relationships with ineligible companies.