Continuing Education Activity

Chlorthalidone is a medication used in the management and treatment of hypertension. It is in the thiazide-like diuretics class of drugs. This activity reviews chlorthalidone's indications, action, and contraindications as a valuable agent in managing hypertension, edema, and calcium nephrolithiasis. This activity will highlight the mechanism of action, adverse event profile, and pharmacokinetics of chlorthalidone. Identifying these properties is essential for interprofessional team members to manage patients with hypertension effectively.

Objectives:

• Identify the mechanism of action of chlorthalidone.
• Describe the potential adverse effects of chlorthalidone.
• Outline appropriate monitoring for patients on therapy with chlorthalidone.
• Summarize interprofessional team strategies for improving care coordination and communication to advance proper chlorthalidone administration and verify medication allergies.

Indications

Chlorthalidone is a thiazide-like sulfonamide-derived diuretic that has been FDA approved since 1960 to manage hypertension.[1] Chlorthalidone is a first-line agent for the treatment of hypertension.[2] This medication is utilized both as an isolated agent and in combination with other antihypertensive drugs, including beta-blockers or clonidine.

It is also used in the treatment of edema.[3] The utility for edema comes in multiple settings, including congestive heart failure, hepatic cirrhosis, corticosteroid therapy, as well as renal dysfunction, including chronic renal failure, nephrotic syndrome, and acute glomerular nephritis.[3] Chlorthalidone should also be considered in the treatment of calcium nephrolithiasis, Meniere disease, and diabetes insipidus, although it does not have FDA approval to treat these conditions.[4][5] Chlorthalidone treats these conditions by antagonizing sodium chloride co-transporter in the distal convoluted tubule (DCT) in the loop of Henle.[6] 

Chlorthalidone's first indication was as an antihypertensive agent. It is effective in the management of blood pressure by decreasing intravascular volume through promoted diuresis. Per the 2017 guideline for the prevention, detection, evaluation, and management of high blood pressure, chlorthalidone can be used as a first-line age in the setting of hypertension when there are no contraindications or contributory comorbidities.[7] However, patients with cerebrovascular disease, advanced chronic kidney disease, diabetes, and heart failure treatment would preferably receive therapy with angiotensin-converting enzyme inhibiting medication (ACE-I). These guidelines suggest that dihydropyridine calcium channel blockers and thiazide-like diuretics are the preferred agents in the absence of comorbidities because of better cardiovascular outcomes, specifically the reduced risk of heart failure and cerebral vascular accident.[8]

Of note, the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) trial compared other first-line antihypertensives such as calcium channel blockers and angiotensin-converting-enzyme-inhibitors(ACE-I) against chlorthalidone. ALLHAT concluded that thiazide-like diuretics should be considered in the first-line treatment in hypertensive patients as chlorthalidone had less association with stroke than ACE-I and less association with heart failure compared to calcium channel blockers. The results of this study were attributed to the earlier and more significant decrease in blood pressure, specifically systolic, from chlorthalidone compared to lisinopril and amlodipine.[8]

Thiazide-like Medication Versus Thiazide-type Diuretics

Thiazide-type medications, most commonly hydrochlorothiazide (HCTZ), have been around longer than thiazide-like antihypertensives and were previously utilized more substantially. However, multiple studies have shown a preference for thiazide-like medications over their original counterparts. A 2015 systematic review showed that chlorthalidone alleviated hypertensive burden by about 5.1 mmHg of systolic blood pressure than HCTZ, finding chlorthalidone more potent than HCTZ.[9] 

In addition to potency, studies have demonstrated that chlorthalidone holds a longer duration of action than HCTZ, 24 hours with chlorthalidone versus 6 to 12 hours with HCTZ. This increased duration of action allows for the increased flexibility of dosing.[9] A study has shown that as a result of this longer duration of action that chlorthalidone is 1.5 to 2.0 times more efficacious at lowering systolic blood pressure than HCTZ (comparative antihypertensive effects between hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.)[10] 

Cardiovascular Outcomes

With consideration of any antihypertensive medication, the effect of cardiovascular outcomes is of the highest priority. The ALLHAT trial showed a decreased risk of heart failure exacerbation and cerebral vascular accidents compared to amlodipine and lisinopril, respectively.[8][11] Additionally, a meta-analysis in 2012, including over 100000 patients, concluded that chlorthalidone and thiazide-like diuretics lowered the risk of heart failure by twenty-one percent and cardiovascular events by twelve percent. In comparison, thiazide-type HCTZ did not show improved outcomes compared to placebo.[8]

Mechanism of Action

Chlorthalidone exerts its therapeutic action by antagonizing sodium-chloride symporter in the distal convoluted tubule of the nephron. It is similar to a thiazide diuretic in its mechanism of action, although it has a mildly altered chemical structure. Both thiazide and thiazide-like diuretics contain a sulfonamide group that also works to inhibit carbonic anhydrase and its antagonistic action at the distal convoluted tubule.[9]

Chlorthalidone inhibits sodium reabsorption at the level of the distal convoluted tubule and thus chloride via inhibition of the Na/Cl symporter. By removing sodium reabsorption at this location, the distal convoluted tubule of the nephron retains a higher sodium content. This lack of reabsorption alters the osmotic gradient and shifts fluid distribution from the outside of the tubule to the inside of the tubule. The increased osmotic load from its increased sodium concentration leads to elevated intratubular volume, thus promoting its diuretic effect. The increased excretion of sodium and extracellular fluid decreases intravascular water and solute concentration. By lowering the intravascular volume and osmotic gradient, the patient has reduced hydrostatic pressure leading to a clinical reduction in blood pressure.

Administration

Chlorthalidone is available solely as an oral medication.

Strength: 25 mg, 50 mg

Hypertension: starting from 12.5 to 25 mg daily, maximum dose: 100 mg daily

Heart failure: starting from 12.5 mg or 25 mg daily, maximum dose: 100 mg daily 

Generalized edema: starting from 50 g or 100 mg daily, maximum dose: 200 mg daily

Calcium nephrolithiasis: 25 mg/daily

The age of the patient is also an essential consideration while determining the dose. The geriatric population (i.e., over 65 years) should receive lower dosing of chlorthalidone, starting with 6.25 mg to 12.5 mg daily and titrated slowly, as mentioned above.

Chlorthalidone is available solely as an oral medication. Chlorthalidone comes in pills of 25 mg and 50 mg, which can be split for adequate dosing. Dosing regimens vary depending on clinical indication. For the treatment of heart failure, guidelines recommend dosing start at 12.5 mg or 25 mg daily and can be titrated up to 100 mg daily as necessary. For generalized edema, dosing begins with 50 to 100 mg daily and can be titrated to a maximum of 200 mg daily. As outlined above, chlorthalidone can also be utilized to manage calcium nephrolithiasis, which is generalized administered at 25 mg/daily. The age of the patient is also an essential consideration while determining the dose. The geriatric population, patients older than 65 years of age, should receive lower dosing of chlorthalidone, starting with 6.25 to 12.5 mg titrated to a maximum of 25mg/daily. Diuretic medication, such as chlorthalidone, is a Beers criteria medication and should be used cautiously.[12]

Adverse Effects

Significant adverse effects are electrolyte derangement (hypokalemia, hyponatremia, etc.), hypersensitivity reaction, and precipitation of acute gout attacks. 

The adverse effects of chlorthalidone span across most organ systems to differing degrees and manifestations. Of significance, as a result of promoted diuresis and altering of nephron physiology, electrolyte derangement is a commonly reported adverse effect of this medication. Most commonly, chlorthalidone includes hypokalemia but may also cause hyponatremia or hypochloremia. These known derangements make monitoring serum electrolytes essential for patients receiving chlorthalidone periodically throughout hypertensive management. 

Reported side effects (per the Food and Drug Administration):

• Gastrointestinal side effects: anorexia, stomach irritation, nausea, emesis, cramping, loose stools, constipation, and pancreatitis.
• Neurologic reactions: paresthesias, dizziness, and headaches
• Hematologic reactions: aplastic anemia, leukopenia, agranulocytosis, and thrombocytopenia.
• Cardiovascular reaction: orthostatic hypotension
• Dermatologic reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (cutaneous vasculitis), Lyell syndrome (toxic epidermal necrolysis).
• Other adverse reactions: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, impotence

Contraindications

Absolute Contraindications

• Hypersensitivity to chlorthalidone
• Hypersensitivity to the sulfonamides-derived medications
• Significant electrolyte derangement (severe hypokalemia, severe hyponatremia)
• Anuria

Relative Contraindication

• Advanced chronic kidney disease
• Orthostatic hypotension
• Syncope
• Geriatric population (age greater than 65 due to risk of hyponatremia)
• Pregnancy
• Hypercalcemia
• Severe hyperuricemia or gout

Monitoring

The following items require periodic monitoring when the patients take chlorthalidone. 

• Serum electrolytes: Serum sodium, potassium, chloride, and calcium levels should be checked periodically.[13] 
• Fluid status and Blood pressure: All patients taking chlorthalidone require observation for dryness of mouth, thirst, lethargy, hypotension, oliguria, tachycardia, palpitations, and gastrointestinal disturbances, such as nausea and vomiting. Chlorthalidone is a diuretic, so an inappropriately high dose can cause severe volume depletion.  
• Magnesium level: It can increase the urinary excretion of magnesium and may result in hypomagnesemia.
• Uric acid level: Hyperuricemia may occur, or frank gout may be precipitated in certain patients receiving chlorthalidone.
• Serum glucose level: serum glucose may increase with chronic use. 

There is insufficient research performed to check teratogenicity, but chlorthalidone should be used during pregnancy only if absolutely necessary. 

Toxicity

Symptoms of acute overdosage:

• Nausea
• Weakness
• Dizziness (due to severe hypotension)
• Electrolyte disturbances (such as hypokalemia, hyponatremia, and hypomagnesemia)

Treatment of acute overdosage:

• No specific antidote is available
• Gastric lavage
• Supportive management includes intravenous dextrose or normal saline for hypotension, intravenous potassium chloride for severe hypokalemia

Enhancing Healthcare Team Outcomes

As a sulfonamide-derived medication, the prescribing clinician needs to review relevant allergies when prescribing chlorthalidone. An interprofessional team approach, including clinicians (MDs, DOs, NPs, PAs), specialists, mid-level practitioners, nurses, and pharmacists, can help to maintain updated allergies. A review of allergies can start upon reception by asking patients to review their previous chart and update relevant sections, including allergies. While in a hospital setting, it can be prompted before administration by the nurse. In a pharmacy setting, the pharmacist can inquire before the dispersal of the medication. Additionally, EMR now allows an additional barrier with risk-advisory when prescribing medication to which patients are allergic.[14] 

In addition to allergies, clinicians, nurses, and pharmacists are responsible for counseling the patient, verifying dosing, and monitoring for adverse events. Pharmacists must also perform medication reconciliation to preclude any possible drug-drug interactions and notify the other interprofessional healthcare team members when concerns arise.

Updating the type of adverse reaction occurring with the allergy is vital to avoid and characterize the true allergy. Deciphering whether a true allergy or previous side-effect from a medication is crucial as it changes therapeutic options for the patient.[14] [Level 3] The interprofessional paradigm will contribute to positive patient outcomes when using chlorthalidone. [Level 5]