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Thiazide Diuretics
Indications
Thiazide diuretics can be classified into 2 categories based on their molecular structure: thiazide-type (TT) diuretics and thiazide-like (TL) diuretics. Examples of thiazide-type diuretics include hydrochlorothiazide, chlorothiazide, and methyclothiazide. Thiazide-like diuretics such as indapamide, metolazone, and chlorthalidone possess different molecular structures but share similar mechanisms of action. A meta-analysis of randomized controlled studies in patients with hypertension demonstrated that thiazide-like diuretics provide a 12% greater reduction in cardiovascular events and a 21% greater reduction in heart failure risk compared to thiazide-type diuretics, with comparable adverse event rates across treatments.[1]
FDA-Approved Indications
Thiazide diuretics are FDA-approved medications that inhibit the reabsorption of 3% to 5% of sodium in the distal convoluted tubule, promoting natriuresis and diuresis. The 3 most commonly administered thiazide diuretics are hydrochlorothiazide (HCTZ), chlorthalidone, and indapamide. HCTZ and chlorthalidone are FDA-approved for clinical use in the management of primary hypertension. Clinicians use these agents as either the sole modality of treatment or in conjunction with other antihypertensive drugs to effectively increase therapeutic response in patients who are severely hypertensive. HCTZ and chlorthalidone are also FDA-approved for clinical use in adjunctive therapy in edema that is associated with chronic heart failure (CHF), hepatic cirrhosis, corticosteroids, and estrogen therapy. These agents are also used to manage edema caused by various forms of renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. Indapamide is FDA-approved for the treatment of salt and fluid retention associated with CHF and in the management of primary hypertension as either the sole treatment or in conjunction with other antihypertensive drugs. As stipulated by the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines, antihypertensive drug therapy should initiate with first-line agents such as thiazide diuretics, calcium channel blockers (CCBs), and angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).[2] According to the guidelines from the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA), the use of a thiazide in conjunction with a loop diuretic should be reserved for patients with heart failure and congestive symptoms who demonstrate inadequate response to moderate- or high-dose loop diuretic therapy, to mitigate the potential for electrolyte disturbances. They can help overcome diuretic resistance in heart failure.[3][4] Thiazides are also used as second-line agents for the management of edema associated with nephrotic syndrome. The initial treatment for edema in nephrotic syndrome is loop diuretics.[5]
Off-Label Uses
Thiazide diuretics may also be administered (though they are not FDA-approved) for nephrolithiasis, osteoporosis, and diabetes insipidus.[6][7] According to the American Urological Association guidelines, thiazide diuretics can be used in patients with recurrent calcium stones with high urine calcium.[8] A systematic review and meta-analysis indicate that thiazide diuretics reduce fracture incidence compared to placebo or other antihypertensive treatments. No reduction in hip fractures was observed. However, thiazides are not the first-line agent for osteoporosis.[9] Meta-analyses indicate that angiotensin-converting enzyme inhibitors (ACEIs), dihydropyridine calcium channel blockers (CCBs), and thiazide-like diuretics may offer prevention against stroke, cardiovascular mortality, and all-cause mortality in hypertension.[10] According to American Heart Association/American Stroke Association guidelines in adults with hypertension, thiazides and thiazide-like diuretics, CCBs, ACEIs, and ARBs are recommended as initial antihypertensive drug therapies for the primary prevention of stroke.[11] Thiazide diuretics are a therapeutic option for nephrogenic diabetes insipidus (NDI). These medications are effective because they cause mild volume depletion, decreasing urine production.[12][13]
Mechanism of Action
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Mechanism of Action
Thiazide diuretics exert their diuretic effect via blockage of the sodium-chloride (Na+/Cl-) channel in the proximal segment of the distal convoluted tubule (DCT). When the Na+/Cl- channel is blocked, decreased levels of sodium cross the luminal membrane, thus reducing the action of the sodium-potassium (Na+/K+) pump and reducing sodium and water passage to the interstitium.[14] The activation method of thiazide diuretics causes a change in Na+ concentration distal to the DCT. Subsequently, ionic channels and pumps work to balance disrupted Na+ levels. This secondary change to balance sodium levels produces many adverse effects. The effects on the nephron are discussed below in the Adverse Effects section. The blockage of the Na+/Cl- channel causes an increase in sodium and water retention in the lumen and a decrease in Na+ in the DCT. At the same time, blockage of the Na+/Cl- channel increases the flow of ions through the Na+/Ca2+ channel, resulting in increased calcium reabsorption into the interstitium in exchange for sodium return to the DCT. Inhibition of the Na+/Cl- channel in the proximal segment of the DCT results in increased delivery of sodium to the distal segment of the DCT and collecting tubule. This increased Na+ level causes the aldosterone-sensitive Na+/K+ pump to increase sodium reabsorption in the principal cells. This exchange increases Na+ transfer into the interstitium and K+ transfer into the collecting tubules and lumen. This loss of K+ then causes intercalated cells in the collecting tubule to increase K+ reabsorption via the K+/H+ pump, which is also aldosterone-mediated. Aldosterone-mediated sodium retention, precipitated by an increased Na+ flow to the collecting tubule, results in increased reabsorption of Na+ and excretion of both K+ and H+ ions into the urine.[15]
Pharmacokinetics
Absorption: Chlorthalidone's onset of action is about 2.6 hours after oral administration. Hydrochlorothiazide takes effect within 2 hours, peaks at 4 hours, and lasts 6 to 12 hours. Indopamide reaches peak blood concentrations within 2 hours. Metolazone has a quick onset, with diuresis beginning within 1 hour and lasting 24 hours.
Distribution: Chlorthalidone is 75% bound to plasma proteins and has a high affinity for erythrocyte carbonic anhydrase. Hydrochlorothiazide crosses the placenta but does not penetrate the blood-brain barrier and is excreted in breast milk. Indapamide is preferentially taken up by erythrocytes in peripheral blood.
Metabolism: Metabolism data on chlorthalidone and hydrochlorothiazide are limited. Indapamide is extensively metabolized, with 7% excreted unchanged. The urinary excretion of 14C-labeled metabolites demonstrates a biphasic pattern and a terminal half-life of 26 hours. Metolazone is metabolized in the liver.[16]
Elimination: Chlorthalidone is excreted unchanged by the kidneys, with a half-life of about 40 hours. Hydrochlorothiazide is eliminated by the kidneys, with 61% excreted unchanged in 24 hours and a plasma half-life of 5.6 to 14.8 hours. Indapamide is 70% excreted by the kidneys and 23% via the gastrointestinal tract, with a half-life of around 14 hours. Metolazone is mainly excreted unchanged in urine and induces diuresis in patients with low glomerular filtration rates.[17]
Administration
Available Dosage Forms and Strengths
Thiazide diuretics are administered orally as tablets. Patients should take these agents in the morning with food. Hydrochlorothiazide is available in 12.5 mg, 25 mg, and 50 mg tablets. Chlorthalidone comes in 15 mg, 25 mg, 50 mg, and 100 mg tablets. Indapamide is available in 1.25 mg and 2.5 mg tablets. Metolazone is provided in 2.5 mg, 5 mg, and 10 mg tablets.[18][19][20]
Adult Dosage
Hypertension: The ACC/AHA guideline-directed dosage is listed below, and can be titrated according to therapeutic response.[2]
- Chlorthalidone: 12.5 to 25 mg once daily
- Hydrochlorothiazide: 25 to 50 mg once daily
- Indapamide: 1.25 to 2.5 mg once daily
- Metolazone: 2.5 to 5 mg once daily
Congestive heart failure: The standard and maximum recommended doses for congestion in patients with chronic heart failure are given below according to ACC/AHA/HFSA guidelines.[4] For patients with acute decompensated heart failure and pulmonary edema ("Warm and Wet"), IV diuretics are preferred.[21]
- Chlorthalidone: 12.5 to 25 mg once daily, with a maximum dose of 100 mg
- Hydrochlorothiazide: 25 mg once or twice daily, with a maximum dose of 200 mg
- Indapamide: 2.5 mg once daily, with a maximum dose of 5 mg
- Metolazone: 2.5 mg once daily, with a maximum dose of 20 mg
Specific Patient Populations
Hepatic impairment: Thiazides should be used with caution in patients with liver disease since alterations of fluid and electrolyte levels can precipitate hepatic coma. For patients with cirrhosis-associated edema, spironolactone and loop diuretics are administered.[22]
Renal impairment: Loop diuretics are preferred for patients with CKD. Fluid overload is a common cause of hypertension in chronic kidney disease (CKD), and diuretics are generally considered effective agents for lowering blood pressure when used at appropriate doses, with or without the concomitant use of renin-angiotensin system inhibitors (RASi). Thiazide diuretics lose effectiveness during diuresis and blood pressure reduction as glomerular filtration rate (GFR) declines; however, drugs such as chlorthalidone, metolazone, and indapamide maintain this efficacy at GFRs <30 mL/min/1.73 m². Loop diuretics remain effective at lower GFRs (<30 mL/min/1.73 m²). When combined with a loop diuretic, thiazides are particularly effective in inducing diuresis but are associated with a risk of acute kidney injury, hypokalemia, and hypomagnesemia.[23][24]
Pregnancy considerations: According to the American College of Obstetricians and Gynecologists (ACOG), thiazides are regarded as second-line agents for hypertension during pregnancy. Theoretically, thiazides can cause intravascular volume depletion, which may lead to fetal growth restriction/oligohydramnios. The data available regarding thiazides in this setting is controversial; administer with caution. Regardless, a discussion with the mother regarding the risk is required.[25]
Breastfeeding considerations: According to the literature review, low-dose thiazides appear acceptable during lactation. However, they should be administered with caution, as aggressive diuresis with large doses may suppress postpartum lactation.[26][27]
Pediatric patients: According to the American Academy of Pediatrics (AAP), pharmacologic treatment of hypertension in children and adolescents is suggested with an ACE inhibitor, ARB, calcium channel blocker, or a thiazide diuretic.[28]
Older patients: The initial dosage should be low in older patients due to reduced renal, hepatic, or cardiac function and comorbidities. Thiazides should be administered with caution in these patients.
Adverse Effects
Adverse effects of thiazide diuretics stem from the ionic imbalance caused by the initial Na+ loss in the DCT.
- Hypokalemia: The most widely recognized adverse effect of thiazide diuretics is hypokalemia. As discussed, hypokalemia is a sequela of the aldosterone-mediated actions of the Na+/K+ pump in the collecting tubule. Hypokalemia can be life-threatening and requires monitoring during the first 3 weeks of HCTZ therapy.
- Hyponatremia: Thiazide diuretics act to reduce sodium reabsorption and, therefore, decrease fluid reabsorption; this directly causes reduced levels of circulating sodium. Hyponatremia typically occurs within the first 2 to 3 weeks of therapy; afterward, the patient reaches a new steady state where further sodium and water losses are unlikely.[29]
- Metabolic alkalosis: Patients receiving thiazide diuretics may experience hypokalemic metabolic alkalosis due to increased aldosterone-mediated K+ and H+ excretion in the intercalated cells of the collecting tubule.
- Hypercalcemia: Thiazides reduce urine calcium levels and increase blood calcium by increasing calcium reabsorption from the luminal membrane into the interstitium in exchange for sodium. However, this effect of thiazide diuretics makes thiazides useful for nephrolithiasis if indicated.
- Hyperglycemia: Thiazide diuretics can cause hypokalemia, leading to hyperpolarization of pancreatic β-cells and reduced insulin secretion. Low potassium levels keep potassium channels open longer, preventing the opening of voltage-gated calcium channels. As a result, insufficient calcium influx hinders insulin granule exocytosis, leading to reduced insulin secretion.
- Hyperuricemia: Thiazide diuretics cause hyperuricemia and increase the risk of developing gout. Thiazides directly increase urate reabsorption in the proximal tubule using the OAT 1 anion exchanger on the basolateral membrane and the luminal membrane's OAT 4 urate anion exchanger. At the OAT 1 exchanger, thiazides enter the proximal convoluted tubule, replacing urate with an anion and increasing urate in the interstitium. OAT 4 exchanges thiazides for urate in the lumen, causing increased urate levels in the proximal convoluted tubule that cross the basolateral membrane, increasing urate levels in the interstitium.
- Hyperlipidemia: The mechanism of hyperlipidemia with thiazide treatment is unclear; however, it is more commonly observed at high doses of thiazides.
- Sulfonamide allergy: Thiazide diuretics are sulfa-containing drugs. Patients with sulfa allergies who take thiazides may experience headaches, rash, hives, swelling of the mouth and lips, wheezing or trouble breathing, asthma attacks, and anaphylaxis.
- Risk of pancreatitis: There may be an increased risk of developing acute pancreatitis. Thiazides have been hypothesized to have a toxic effect on the pancreas and cause increased pancreatic secretions and pancreatic ischemia. If the clinician observes symptoms of acute pancreatitis, the patient must immediately stop taking the thiazide diuretic, and they should not be re-prescribed this medication.[30][31][32]
Drug-Drug Interactions
- Digitalis glycosides: Diuretic-induced hypokalemia can increase the heart's sensitivity to digitalis, which may lead to serious arrhythmias.
- Corticosteroids or ACTH: Steroids can raise the risk of hypokalemia and cause salt and water retention.
- Curariform drugs: Hypokalemia from diuretics may increase the neuromuscular blocking effects of medications like tubocurarine, which could result in respiratory depression or apnea. Clinicians should consider stopping diuretics before elective surgery.
- Lithium: Thiazide diuretics should not be administered with lithium as they reduce its renal clearance, increasing the risk of lithium toxicity by enhancing its reabsorption in the kidneys.
- Salicylates and other NSAIDs: These drugs can reduce the effectiveness of diuretics. The combination also increases the risk of acute kidney injury.[33]
Contraindications
Thiazide diuretics are contraindicated for patients with anuria and sulfonamide allergies.[34]
Monitoring
The American College of Cardiology (ACC) and American Heart Association (AHA) recommend monitoring patients using team-based care approaches, home blood pressure monitoring (HBPM), and telehealth strategies to assess response to pharmacological therapy for hypertension. Patients should be monitored for hyponatremia, hypokalemia, uric acid, and calcium levels. Patients with gout should be monitored cautiously.[2] Renal function should be monitored regularly.
Toxicity
Signs and Symptoms of Overdose
Hypokalemia, hyponatremia, and dehydration due to excessive diuresis are observed. If digitalis has been concurrently administered, it can exacerbate the risk of cardiac arrhythmias. Overdose can also cause acute kidney injury.[35]
Management of Overdose
Emergency medicine physicians should correct dehydration, hypotension, and electrolyte disturbances. Administer oxygen or initiate mechanical ventilation based on clinical status. The extent to which hydrochlorothiazide is removed through hemodialysis remains uncertain. A case report suggested chlorthalidone may be removed by continuous venovenous hemofiltration with hemodialysis (CVVHDF), but its clinical impact is unclear due to a lack of plasma measurements. Theoretically, hemodialysis could be considered for chlorthalidone overdose. Consultation with the toxicologist/poison control center should be obtained.[36]
Enhancing Healthcare Team Outcomes
An Evidence-based Approach to Thiazide Diuretics
Physicians and advanced practice providers should prescribe thiazides based on the clinical picture. Nurses should monitor vital signs and report if there are any concerns. Pharmacists should review prescriptions, identify drug interactions, and counsel patients about possible risks. Critical care physicians stabilize patients in the event of a thiazide overdose, managing fluid shifts, arrhythmias, and renal impairment while providing supportive care. An interprofessional team approach and communication among clinicians, pharmacists, and nurses are essential for reducing potential adverse effects and enhancing patient outcomes associated with thiazide diuretics. In most cases, a thiazide is prescribed for extended periods; hence, patient electrolyte levels require monitoring. Also, polypharmacy must be avoided, especially in older adults. Patients need education on the adverse effects of these agents and their presentation. The potassium levels must be closely followed for patients with heart problems and susceptibility to arrhythmias. Patients prone to hypokalemia must receive education on the consumption of foods that are rich in potassium. Finally, the clinical team should follow the patient's lipid levels due to the risk of hyperlipidemia. By utilizing an interprofessional team approach, these adverse events can remain in check, and therapeutic benefits can be maximized.[37][38]
Outcomes
Thiazide diuretics have been in use for over half a century and are relatively safe and effective drugs for the treatment of hypertension and heart failure. These drugs are used in outpatient settings to manage chronic edema states. The majority of patients do respond to these agents, and the most common adverse effect reported is hypokalemia. To date, there are only a few reports of arrhythmias in patients taking thiazides.[39][40]
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