Continuing Education Activity

Thiazide diuretics are an FDA-approved class of drugs that inhibit the reabsorption of 3% to 5% of luminal sodium in the distal convoluted tubule of the nephron. By doing so, thiazide diuretics promote natriuresis and diuresis. Three thiazide diuretics are the most commonly used: hydrochlorothiazide (HCTZ), chlorthalidone, and indapamide. HCTZ and chlorthalidone are FDA-approved for clinical use in the management of primary hypertension. 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. 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. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, toxicity, and monitoring, of thiazide diuretics, so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Objectives:

• Review the mechanism of action of thiazide diuretics.
• Identify the indications for various agents in the thiazide diuretic drug class.
• Summarize the adverse events and contraindications associated with the thiazide diuretic class of drugs.
• Describe interprofessional team strategies for improving care coordination and communication to properly use thiazide diuretics to improve patient outcomes in the varied scenarios where they are effective.

Indications

Thiazide diuretics are an FDA-approved class of drugs that inhibit reabsorption of 3% to 5% of luminal sodium in the distal convoluted tubule of the nephron. By doing so, thiazide diuretics promote natriuresis and diuresis. Three thiazide diuretics are commonly used: 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 severely hypertensive patients.

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.

Thiazide diuretics are also indicated for use (although not FDA-approved) for nephrolithiasis, osteoporosis, and diabetes insipidus.[1][2]

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 decreasing the action of the sodium-potassium (Na/K) pump and decreasing Na and water passage to the interstitium.[3]

The method of activation of thiazide diuretics is to cause 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 Na levels produces many adverse effects. The MOA and its effects on the nephron will be more thoroughly discussed below and will be referred to 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/Ca channel, resulting in increased calcium reabsorption into the interstitium in exchange for Na return to the DCT.

Inhibition of the Na/Cl channel in the proximal segment of the distal convoluted tubule results in increased delivery of sodium to the distal segment of the distal convoluted tubule and collecting tubule. This increase in Na increase causes the aldosterone-sensitive Na/K pump to increase sodium reabsorption in the principal cells. This exchange increases Na transfer into the interstitium and increases K transfer into the collecting tubules and lumen. This loss of K then causes intercalated cells in the collecting tubule (CT) to increase K reabsorption via the K/H+ pump and is also aldosterone-mediated.

Through aldosterone-mediated sodium retention that is precipitated by an increased Na flow to the CT, the CT will exhibit increased reabsorption of Na and excretion of both K and H ions into the urine.[4]

Administration

Thiazide diuretics are administered orally as tablets. Patients should take these agents in the morning with food. HCTZ and chlorthalidone have different dosing requirements for their indicated FDA use listed above. Generally, for hypertension treatment, both drugs require a lower dosage starting at 25 mg daily and may be increased to 50 mg or 100 mg, respectively. The dosage should be increased based on the individual therapeutic needs of the patient. For patients suffering from fluid buildup and edema, dosing starts at 50 mg to 100 mg and 50 mg to 200 mg, respectively.[5][6][7]

Adverse Effects

Adverse effects of thiazide diuretics stem from the ionic imbalance caused due to the initial Na loss in the DCT.

• Hypokalemia. Most widely recognized, the first adverse effect of thiazide diuretics is hypokalemia. As discussed above, hypokalemia is a sequela of the aldosterone-mediated actions of the Na/K pump in the CT. Hypokalemia can be life-threatening and requires monitored during the first 2-3 weeks of HCTZ therapy.
• Hyponatremia. The MOA of thiazide diuretics is to decrease sodium reabsorption and therefore decreased fluid reabsorption; this directly causes decreased levels of circulating sodium. If hyponatremia were to occur, it would happen during the first 2 to 3 weeks of therapy; after this time, the patient is in a new steady state in which further sodium and water losses do not occur.
• Metabolic alkalosis. Patients on thiazide diuretics may experience a hypokalemic metabolic alkalosis due to the increase in aldosterone-mediated K and H ions excretion in the intercalated cells of the CT.
• Hypercalcemia. By increasing calcium reabsorption from the luminal membrane into the interstitium in exchange for sodium, thiazides reduce urine calcium levels and increase blood calcium. However, if indicated, this effect of thiazide diuretics makes thiazides useful for nephrolithiasis and osteoporosis treatment. Decreased urinary calcium decreases stone development in the kidney, and increased blood calcium is beneficial for patients with osteoporosis and promotes bone health.
• Hyperglycemia. Thiazide diuretics cause hypokalemia; at the level of the pancreatic B cells, this hypokalemia causes hyperpolarization of the B cell and decreases insulin secretion. Decreased K in the interstitium keeps the K channels open for an extended time, which causes the hyperpolarization of the cell. This hyperpolarization does not allow the voltage-gated calcium channels to open. When intracellular calcium does not increase through calcium influx via the voltage-gated calcium channels, exocytosis of insulin granules does not occur in the pancreatic B cells.
• Hyperuricemia. Thiazide diuretics cause hyperuricemia and increase the risk of developing gout. Thiazides directly increase urate reabsorption in the proximal tubule by using the OAT 1 anion exchanger on the basolateral membrane and the OAT 4 urate anion exchanger on the luminal membrane. At the OAT 1 exchanger, thiazides enter the proximal convoluted tubule, in replacement of urate, for an anion, increasing urate in the interstitium. The OAT 4 exchanger exchanges thiazides for urate in the lumen, causing increased urate in the proximal convoluted tubule that then crosses the basolateral membrane and therefore increases urate in the interstitium.
• Hyperlipidemia. The mechanism of hyperlipidemia with thiazide treatment is unclear. However, it appears to be an acute response to high-dose thiazide treatment.
• Sulfonamide allergy. Thiazide diuretics are sulfa-containing drugs. Patients with sulfa allergies taking thiazides may experience headaches, rash, hives, swelling of the mouth and lips, wheezing or trouble breathing, asthma attack, and anaphylaxis.

Adverse effects of taking these medications also include a possible increased risk of developing acute pancreatitis. T hypothesized that thiazides 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 the use of the thiazide diuretic, and they should not be re-prescribed this medication.[8][9][10]

Contraindications

Thiazide diuretics are contraindicated for use in patients with anuria and sulfonamide allergies.

Enhancing Healthcare Team Outcomes

An Evidence-based Approach to Thiazide Diuretics

Besides physicians, the use of thiazide diuretics is also monitored by pharmacists and nurses, collaborating with clinicians as an interprofessional team. In most cases, a thiazide is prescribed for long periods, and hence, patient electrolyte levels require monitoring. Also, polypharmacy must be avoided, especially in the elderly. Patients need education on the adverse effects of these agents and their presentation. For those patients with heart problems and susceptibility to arrhythmias, the levels of potassium must be closely followed. Also, the patient needs to be weighed at each visit to ensure that the fluid overload is resolving. Patients prone to hypokalemia must receive education on the consumption of foods that are rich in potassium. Finally, the clinical team needs to follow the patient's lipid levels need to be followed as thiazides c cause hyperlipidemia. By utilizing an interprofessional team approach, these adverse events can remain in check, and therapeutic benefit maximized.[11][12] [Level 5] 

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 outpatients 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.[13][14] [Level V]