How does chlorthalidone compare to other antihypertensive medications. What are the indications and mechanism of action for chlorthalidone. Is chlorthalidone safe for patients with sulfa allergies. How effective is chlorthalidone in managing hypertension and other conditions.

Understanding Chlorthalidone: A Powerful Thiazide-like Diuretic

Chlorthalidone is a thiazide-like diuretic that has been widely used in the management of hypertension since its FDA approval in 1960. As a sulfonamide-derived medication, it plays a crucial role in treating various conditions beyond high blood pressure. But how exactly does chlorthalidone work, and what sets it apart from other antihypertensive medications?

Mechanism of Action

Chlorthalidone’s primary mechanism of action involves antagonizing the sodium chloride co-transporter in the distal convoluted tubule (DCT) of the loop of Henle. This process promotes diuresis, effectively reducing intravascular volume and, consequently, lowering blood pressure. The medication’s unique ability to target this specific area of the kidney contributes to its efficacy in managing hypertension and other related conditions.

Indications for Chlorthalidone Use

While primarily known for its antihypertensive properties, chlorthalidone has several other important indications:

• Hypertension management (as a first-line agent or in combination with other medications)
• Treatment of edema in various conditions (e.g., congestive heart failure, hepatic cirrhosis)
• Management of edema associated with renal dysfunction (chronic renal failure, nephrotic syndrome, acute glomerular nephritis)
• Treatment of calcium nephrolithiasis (off-label use)
• Management of Meniere’s disease (off-label use)
• Treatment of diabetes insipidus (off-label use)

Chlorthalidone vs. Other Antihypertensive Medications: A Comparative Analysis

When it comes to managing hypertension, how does chlorthalidone stack up against other commonly prescribed medications? The ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) trial provided valuable insights into this question.

ALLHAT Trial Findings

The ALLHAT trial compared chlorthalidone with other first-line antihypertensive medications, including calcium channel blockers and angiotensin-converting-enzyme inhibitors (ACE-Is). The results were quite revealing:

• Chlorthalidone showed a lower association with stroke compared to ACE-Is
• It demonstrated a lower association with heart failure compared to calcium channel blockers
• The medication produced an earlier and more significant decrease in systolic blood pressure compared to lisinopril and amlodipine

These findings led to the conclusion that thiazide-like diuretics, such as chlorthalidone, should be considered as first-line treatment for hypertensive patients in the absence of specific comorbidities.

Thiazide-like vs. Thiazide-type Diuretics: Unraveling the Differences

While thiazide-type medications like hydrochlorothiazide (HCTZ) have been around longer, recent studies have shown a preference for thiazide-like medications such as chlorthalidone. But what makes chlorthalidone stand out?

Potency and Duration of Action

A 2015 systematic review revealed that chlorthalidone is more potent than HCTZ, alleviating hypertensive burden by approximately 5.1 mmHg of systolic blood pressure more than HCTZ. Additionally, chlorthalidone boasts a longer duration of action:

• Chlorthalidone: 24-hour duration of action
• HCTZ: 6 to 12-hour duration of action

This extended duration allows for more flexible dosing and contributes to chlorthalidone’s increased efficacy in managing hypertension.

Comparative Efficacy

Studies have shown that chlorthalidone is 1.5 to 2.0 times more efficacious at lowering systolic blood pressure than HCTZ. This superior efficacy, combined with its longer duration of action, makes chlorthalidone an attractive option for managing hypertension in many patients.

Safety Profile and Potential Adverse Effects of Chlorthalidone

While chlorthalidone is generally well-tolerated, it’s essential to be aware of potential adverse effects and contraindications. Understanding these can help healthcare providers and patients make informed decisions about treatment options.

Common Side Effects

Some of the more frequently reported side effects of chlorthalidone include:

• Electrolyte imbalances (particularly hypokalemia and hyponatremia)
• Hyperuricemia
• Hyperglycemia
• Hyperlipidemia
• Orthostatic hypotension
• Photosensitivity

Contraindications and Precautions

Chlorthalidone should be used with caution or avoided in certain patient populations, including:

• Patients with severe renal impairment
• Individuals with a history of gout
• Patients with known sulfonamide allergies
• Those with severe hepatic disease

Chlorthalidone and Sulfa Allergies: Addressing Cross-Reactivity Concerns

Given that chlorthalidone is a sulfonamide-derived medication, there are often questions about its safety in patients with known sulfa allergies. Is cross-reactivity a significant concern?

Understanding Sulfa Allergies

Sulfa allergies typically refer to allergic reactions to sulfonamide antibiotics. However, not all sulfonamide-containing medications carry the same risk of allergic reactions. Chlorthalidone, while structurally related to sulfonamides, does not contain the N1 heterocyclic ring that is associated with most allergic reactions to sulfa antibiotics.

Risk of Cross-Reactivity

The risk of cross-reactivity between chlorthalidone and sulfa antibiotics is generally considered low. However, caution is still advised when prescribing chlorthalidone to patients with a history of severe sulfa allergies. It’s crucial to weigh the potential benefits against the risks and monitor patients closely for any signs of allergic reactions.

Optimal Dosing and Administration of Chlorthalidone

Proper dosing and administration of chlorthalidone are crucial for maximizing its therapeutic benefits while minimizing potential side effects. How should healthcare providers approach dosing this medication?

Standard Dosing Guidelines

For hypertension management in adults, the typical dosing regimen for chlorthalidone is as follows:

• Initial dose: 12.5 mg once daily
• Maintenance dose: 12.5 to 25 mg once daily
• Maximum dose: 100 mg once daily (rarely needed)

Dosing may be adjusted based on individual patient response and tolerability. The medication’s long duration of action allows for once-daily dosing, typically in the morning to minimize nighttime diuresis.

Special Populations

Dosing adjustments may be necessary for certain patient populations:

• Elderly patients: Start with lower doses and titrate slowly
• Patients with renal impairment: Use with caution and monitor renal function closely
• Patients with hepatic impairment: No specific dosing adjustments are recommended, but use caution

Monitoring and Follow-up for Patients on Chlorthalidone Therapy

Regular monitoring is essential for patients taking chlorthalidone to ensure optimal therapeutic effects and minimize potential complications. What should healthcare providers focus on during follow-up visits?

Key Monitoring Parameters

The following parameters should be regularly assessed in patients on chlorthalidone therapy:

1. Blood pressure: Monitor for therapeutic response and adjust dosing as needed
2. Electrolyte levels: Particularly potassium and sodium, to detect and manage any imbalances
3. Renal function: Monitor serum creatinine and estimated glomerular filtration rate (eGFR)
4. Blood glucose levels: Watch for potential hyperglycemia, especially in patients with diabetes or at risk for diabetes
5. Uric acid levels: Monitor for hyperuricemia, particularly in patients with a history of gout
6. Lipid profile: Assess for any significant changes in cholesterol levels

Frequency of Monitoring

The frequency of monitoring may vary based on individual patient factors, but a general guideline could include:

• Initial follow-up: Within 2-4 weeks of starting therapy
• Subsequent follow-ups: Every 3-6 months for stable patients
• More frequent monitoring: For patients with comorbidities or those experiencing side effects

Interprofessional Team Strategies for Optimizing Chlorthalidone Use

Effective management of patients on chlorthalidone therapy requires a collaborative approach involving various healthcare professionals. How can interprofessional teams work together to improve patient outcomes?

Role of Different Healthcare Providers

Each member of the healthcare team plays a crucial role in optimizing chlorthalidone therapy:

• Physicians: Prescribe and adjust dosing, manage overall treatment plan
• Pharmacists: Review medication interactions, provide patient education on proper use and potential side effects
• Nurses: Monitor vital signs, assist with patient education, and report any concerns to the prescribing physician
• Dietitians: Provide guidance on dietary modifications to support medication therapy (e.g., low-sodium diets)
• Laboratory technicians: Perform and interpret regular blood tests for electrolyte and metabolic monitoring

Improving Communication and Care Coordination

To enhance patient care and minimize potential complications, interprofessional teams should focus on:

1. Regular team meetings or case conferences to discuss patient progress and concerns
2. Implementing standardized protocols for monitoring and follow-up
3. Utilizing electronic health records to share real-time patient information across the care team
4. Developing patient education materials that incorporate input from all relevant healthcare disciplines
5. Establishing clear lines of communication for reporting adverse events or medication concerns

By adopting these strategies, healthcare teams can ensure that patients receive comprehensive, coordinated care while on chlorthalidone therapy, ultimately leading to better blood pressure control and improved overall health outcomes.

Chlorthalidone – StatPearls – NCBI Bookshelf

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.

Access free multiple choice questions on this topic.

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]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

HOLLANDER W, WILKINS RW. Chlorothiazide: a new type of drug for the treatment of arterial hypertension. BMQ. 1957 Sep;8(3):69-75. [PubMed: 13471453]

2.

Thanikgaivasan V. Letter – Diuretics in primary hypertension – Reloaded. Indian Heart J. 2017 Mar-Apr;69(2):284. [PMC free article: PMC5414989] [PubMed: 28460781]

3.

Akbari P, Khorasani-Zadeh A. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jan 23, 2023. Thiazide Diuretics. [PubMed: 30422513]

4.

Roush GC, Abdelfattah R, Song S, Ernst ME, Sica DA, Kostis JB. Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium-sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis. J Clin Hypertens (Greenwich). 2018 Oct;20(10):1507-1515. [PMC free article: PMC8030834] [PubMed: 30251403]

5.

Riley M, Hernandez AK, Kuznia AL. High Blood Pressure in Children and Adolescents. Am Fam Physician. 2018 Oct 15;98(8):486-494. [PubMed: 30277729]

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Greger R, Lohrmann E, Schlatter E. Action of diuretics at the cellular level. Clin Nephrol. 1992;38 Suppl 1:S64-8. [PubMed: 1338305]

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Zhou Y, Jia L, Lu B, Gu G, Hu H, Zhang Z, Bai L, Cui W. Updated hypertension prevalence, awareness, and control rates based on the 2017ACC/AHA high blood pressure guideline. J Clin Hypertens (Greenwich). 2019 Jun;21(6):758-765. [PMC free article: PMC8030613] [PubMed: 31131983]

8.

Dewland TA, Soliman EZ, Davis BR, Magnani JW, Yamal JM, Piller LB, Haywood LJ, Alonso A, Albert CM, Marcus GM., Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Collaborative Research Group. Effect of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) on Conduction System Disease. JAMA Intern Med. 2016 Aug 01;176(8):1085-92. [PubMed: 27367818]

9.

Dineva S, Uzunova K, Pavlova V, Filipova E, Kalinov K, Vekov T. Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide-meta-analysis. J Hum Hypertens. 2019 Nov;33(11):766-774. [PMC free article: PMC6892412] [PubMed: 31595024]

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Pareek AK, Messerli FH, Chandurkar NB, Dharmadhikari SK, Godbole AV, Kshirsagar PP, Agarwal MA, Sharma KH, Mathur SL, Kumbla MM. Efficacy of Low-Dose Chlorthalidone and Hydrochlorothiazide as Assessed by 24-h Ambulatory Blood Pressure Monitoring. J Am Coll Cardiol. 2016 Feb 02;67(4):379-389. [PubMed: 26821625]

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Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012 Jun;59(6):1110-7. [PubMed: 22526259]

12.

By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019 Apr;67(4):674-694. [PubMed: 30693946]

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Cooney D, Milfred-LaForest S, Rahman M. Diuretics for hypertension: Hydrochlorothiazide or chlorthalidone? Cleve Clin J Med. 2015 Aug;82(8):527-33. [PubMed: 26270432]

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Hsieh TC, Kuperman GJ, Jaggi T, Hojnowski-Diaz P, Fiskio J, Williams DH, Bates DW, Gandhi TK. Characteristics and consequences of drug allergy alert overrides in a computerized physician order entry system. J Am Med Inform Assoc. 2004 Nov-Dec;11(6):482-91. [PMC free article: PMC524628] [PubMed: 15298998]

Disclosure: Connor Kerndt declares no relevant financial relationships with ineligible companies.

Disclosure: Jayesh Patel declares no relevant financial relationships with ineligible companies.

Cross-Reactivity Between Sulfonamides and Loop or Thiazide Diuretics: Is it a Theoretical or Actual Risk?

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Allergy Clin Immunol Int. Author manuscript; available in PMC 2012 Jun 1.

Published in final edited form as:

Allergy Clin Immunol Int. 2000; 12(1): 26–28.

doi: 10.1027/0838-1925.12.1.26

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Author information Copyright and License information Disclaimer

This is a case report of furosemide use in a woman with acute renal transplant rejection and history of anaphylaxis to sulfonamide and a review of the literature.

Allergists are consulted about the question of hypersensitivity to loop or thiazide diuretics in patients with a history of sulfonamide allergy because it is thought that there is a risk of cross-reactivity from common sulfonamide constituents of these compounds. In text references and drug-package inserts, reference is made to this risk. For example, the package insert for furosemide states that “patients allergic to sulfonamides may also be allergic to furosemide” [1]. Therefore, in clinical practice, the use of thiazide or some loop diuretics is often avoided in patients with a prior history of sulfonamide allergy. The literature on this topic, however, is sparse and not well documented. We report an instructive case of a woman with a history of anaphylaxis to sulfonamides who subsequently received furosemide while undergoing acute renal transplant rejection.

A 30-year-old woman was the recipient of a cadaveric renal transplant because of end-stage renal disease secondary to insulin-dependent diabetes mellitus. She tolerated the transplant well, and for 3 years was maintained on cyclosporin at 4 mg/kg/day without complications.

At age 33, she developed an acute onset of fever, hematuria, headaches, progressive weight gain, and pain in the allograft area. She was admitted to the hospital with elevated creatinine levels and presumed organ rejection. She was given two doses of 3 mg/kg intravenous solumedrol 12 h apart on hospital day 1. A single dose of 1.3 mg/kg intravenous furosemide was administered after the patient became oliguric on day 2. She was then transferred to our institution for further management.

After transfer, she was given a 5 mg/kg intravenous loading dose of solumedrol and started 1 mg/kg oral prednisone. In addition, tacrolimus (FK506) rescue was given at 0.075 mg/kg per day. A renal biopsy was performed and showed widespread polymorphonuclear infiltrate with many eosinophils and a lymphocytic tubulitis consistent with acute rejection.

Twenty years previously, the patient had anaphylaxis after taking one oral dose of sulfamethoxazole and trimethoprim. She immediately developed urticaria and shortness of breath. At the emergency room she was hypotensive. Her symptoms resolved several hours later after treatment with epinephrine, diphenhydramine, steroids, and intravenous fluids. She had no further use of the medication and had no history of other drug allergies. There was no family history of medication allergies.

On transfer her complete cell blood count (CBC) was normal. Because of her history of sulfonamide allergy, loop and thiazide diuretics were avoided and she was given ethacrynic acid at 1 mg/kg intravenously daily to improve her urine output. After 2 weeks of therapy, she developed pancytopenia, a known complication of ethacrynic acid, which was then discontinued. Within 2 weeks, her CBC returned to normal in all indices.

Because of her sensitivity to the ethacrynic acid, her history of sulfonamide allergy, and evidence of numerous eosinophils on the renal biopsy, an allergy consultation was requested. Of particular concern was an appropriate diuretic to use for this patient. The drug of choice was furosemide, but there was concern about her history of sulfonamide allergy and the eosinophilia on renal biopsy which was taken within 2 days of a single dose of intravenous furosemide given at the referring medical center.

After review of the clinical history and pertinent literature, we offered the opinion that furosemide may be safely tried in this patient [2–4]. We concluded that it was unlikely that furosemide caused the eosinophilia on renal biopsy since eosinophilia is a pathologic finding consistent with acute allograft rejection [5, 6]. Furosemide was given repeatedly during the admission with no evidence of acute allergy, rashes, or eosinophilia.

It has long been taught that loop and thiazide diuretics pose a theoretical risk of cross sensitivity in a patient with allergy to sulfonamide antimicrobials due to their common SO₂-NH_x structure (see ) [1]. In an extensive review of the literature, we found only four published cases of possible cross-reactivity between loop or thiazide diuretics and sulfonamides [2–4]. summarizes these cases. All of these cases involved only a circumstantial reaction between reactions to drugs in the two categories.

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Structural formulas for the sulfonamide antimicrobials and diuretics used in the reported cases. SO₂-NH_x groups are highlighted.

Table 1

Published cases of putative sulfonamide-diuretic cross sensitivity

Case	Age (years) and sex	Case
1	56, F	Papular rash developed 17 days after one dose oral sulfadimethoxine. One year later developed papular pigmented rash after oral chloramidobenzole. Four weeks later developed rash after oral acetazolamide. Two years later developed rash after oral hydrochlorthiazide [2]
2	66, F	Exanthem developed shortly after sulfamethoxypyridazine. Five years later developed blisters 24 hours after oral quinethazon [2]
3	55, M	Patient was on glisoxepid, a oral hypoglycemic. One tablet of furosemide caused nausea, edema, vomiting, and diarrhea. Addition of glibenclamid, an oral hypoglycemic caused worsening symptoms. Skin tests by scratch weakly positive to sulfamethoxazole but no documented challenge done [3]
4	68, F	Indapamide caused fixed drug eruption and was confirmed with repeat oral challenge. Oral challenge with sulfamethoxazole and sulfadiazine were positive but were negative to furosemide [4]

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In case 1 the subject developed a papular rash 17 days after one oral dose of sulfadimethoxine. One year later, a papular pigmented rash developed after oral chloramidabenzole and acetazolamide. Two years later a similar papular rash developed while taking oral hydrochorothiazide [2]. In case 2, an exanthem developed shortly after sulfamethoxypyridazine. Five years later, blisters developed after oral quinethazon, a thiazide diuretic [2]. These reactions were not consistent with immunoglobulin E (IgE)-mediated hypersensitivity. They could reflect T-cell cross-reactivity, in a delayed-type hypersensitivity reaction. The cases are also consistent with multiple independent drug allergy. No immunologic or challenge studies were performed. In case 3, a patient on oral glisoxepid (an oral hypoglycemic), edema and gastrointestinal symptoms developed after one tablet of furosemide. Glibenclamide, another oral hypoglycemic, was started with worsening of symptoms. Skin tests were weakly positive to sulfamethoxazole, but no oral challenge was done [3]. The weakly positive skin test is difficult to interpret since most investigators have failed to elicit positive skin tests to sulfamethoxazole even in patients with good history of IgE-dependent reactions [5]. It is also interesting to note that the patient tolerated the oral hypoglycemic glisoxepide but did not tolerate glibenclamide, which both have internal SO₂-NH_x moieties (see ). In case 4, a fixed drug eruption developed on the oral diuretic, indapamide. Subsequent oral challenges to sulfonamide antimicrobials were positive, but the more structurally similar furosemide failed to elicit a response to oral challenge [4]. The patient could have had an independent allergy to the sulfonamide antimicrobial.

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Structural formulas for some oral hypoglycemics. SO₂-NH_x groups are highlighted.

compares the chemical structures of the sulfonamide antimicrobials with the thiazide and loop diuretics reported in these cases [1–3]. The common structural component of a SO₂-NH_x moiety is the theoretical basis for presumed cross-reactivity between such compounds [6].

The use of thiazide or loop diuretics in the general population is quite common, especially in geriatric, renal, and cardiac patients, and allergy to sulfonamide antimicrobials has been estimated to have a prevalence of only 5% [6]. It seems reasonable that if there were appreciable cross-reactivity between these medications, clearer cases of clinical cross-sensitivity would be more numerous. It remains possible that many such cases go unreported. Furthermore, what the published cases do illustrate is that putative cross-sensitivity was most often manifest as cutaneous rashes and late onset signs suggestive of T-cell pathogenesis rather than IgE antibody-dependent reactions.

Celecoxib is the first of a new family of nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cycloxy-genase 2 while sparing cycloxygenase 1, and thas clinically been shown to have less side effects of gastrointestinal bleeding than currently available NSAIDs [7]. Celecoxib also has a SO₂-NH_x side group [7] (see ). While clinical experience is still limited, if we accept the lack of substantial evidence for cross-reactivity among common SO₂-NH_x, structures, we might anticipate that the actual risk of cross-reactions with this medication may also be small.

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Structural formula for the new cycloxygenase 2 inhibitor, celecoxib. The SO₂-NH_x group is highlighted.

Another instructive point in our current case is that while eosinophils on pathologic biopsy may suggest drug hypersensitivity, alternative explanations must also be considered. Acute renal transplant rejection can manifest eosinophil infiltrates, as we believe is illustrated in this case [8, 9]. How eosinophils participate in allograph rejection is not clear [8].

In conclusion, this case reports an uneventful treatment with furosemide in a patient with a history of anaphylaxis to a sulfonamide antibiotic. A review of the literature suggests that while there is a theoretical concern about cross-reactivity among sulfonamide antibiotics, loop or thiazide diuretics, and oral hypoglycemics, the actual risk will likely be small. Further immunochemical research will be needed to define more clearly the frequency and degree of cross reactivity attributable to various drugs with common SO₂-NH_x structures.

We wish to thank Anna Nowak-Wegrzyn, MD, for providing translation of German language publications. Supported by NIH Institutional Training Grant # A107007.

Wanda Phipatanakul, Division of Allergy and Immunology, Departments of Pediatrics, CMSC 1102, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore MD, 21287-3923, USA (tel. +1 410 955-5883, fax +1 410 955-0229, ude.uhj.hclew@pihpw)

N. Franklin Adkinson, Jr, Division of Allergy and Immunology, Department of Medicine, Johns Hopldns University School of Medicine, Baltimore MD, 21287-3923, USA.

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3. Ummenhofer B, Djawari D. Cross-allergy between sulfonamide diuretics, probenecid, sulfamethoxazole and sulphonyl-urea compounds. Dtsch Med Wochenschr. 1979;104:514–517. [PubMed] [Google Scholar]

4. De Barrio M, Tornero P, Zubeldia JM, Sierra Z, Matheu V, Herrero T. Fixed drug eruption induced by indapamide. Cross-reactivity with sulfonamides. J Invest Allerg Clin Immunol. 1998;8:253–255. [PubMed] [Google Scholar]

5. Macy E. Current sulfamethoxazole skin test reagents fail to predict recurrent adverse reactions. J Allergy Clin Immunol. 1995;95:121. [Google Scholar]

6. Weinstein L, Madoff MA, Samer CM. The sulfonamides. New Engl J Med. 1960;263:952–957. [PubMed] [Google Scholar]

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8. Hongwei W, Nanra RS, Stein A, Avis L, Price A, Hibberd AD. Eosinophils in acute renal allograft rejection. Transplant Immunol. 1994;2:41. [PubMed] [Google Scholar]

9. Magil A, et al. Acute interstitial nephritis associated with thiazide diuretics. Clinical and pathological observations in three cases. Am J Med. 1980;69:939. [PubMed] [Google Scholar]

Chlorthalidone | is… What is chlorthalidone?

Chlorthalidone (oxodoline, hygroton) is a diuretic thiazide-like drug used both as a separate active substance and as part of combined drugs.

Randomized study of the drug was carried out in the framework of ALLHAT, THOMS, All-Russian multicenter study VOSTOK.

Suppresses active reabsorption of Na ⁺ , mainly in the peripheral renal tubules (cortical segment of the loop of Henle), increasing the excretion of Na ⁺ , Cl ⁻ and water. The excretion of K ⁺ and Mg ²⁺ through the kidneys increases, while the excretion of Ca ²⁺ decreases. It causes a slight decrease in blood pressure, the severity of the hypotensive effect gradually increases and manifests itself in full 2-4 weeks after the start of therapy. At the beginning of therapy causes a significant decrease in the volume of extracellular fluid, BCC and IOC; however, after several weeks of use, these indicators return to levels close to the original. Like thiazide diuretics, it causes a decrease in polyuria in patients with renal diabetes insipidus. The onset of action is 2-4 hours after ingestion, the maximum effect is 12 hours later, the duration of action is 2-3 days.

Indications: chronic heart failure stage II, arterial hypertension, cirrhosis of the liver with portal hypertension, nephrosis, nephritis, late preeclampsia (nephropathy, edema, eclampsia), fluid retention on the background of premenstrual syndrome, diabetes insipidus, dysproteinemic edema, obesity. With prolonged use, as well as with its simultaneous use with cardiac glycosides, glucocorticosteroids, ACTH, in order to prevent hypokalemia, it is recommended to prescribe potassium preparations (contraindicated when taking ACE inhibitors) or potassium-sparing diuretics (half dose of veroshpiron 12.5 instead of 25 with simultaneous administration of ACE inhibitors and chlorthalidone).

Contraindications: Hypersensitivity (including to sulfonamide derivatives, which include thiazide diuretics), hypokalemia, acute renal failure (anuria), hepatic coma, acute hepatitis, diabetes mellitus (severe forms), gout, lactation. With caution in renal and / or liver failure, allergic reactions, bronchial asthma, systemic lupus erythematosus. Side effects: From the digestive system: nausea, vomiting, gastrospasm, constipation or diarrhea, intrahepatic cholestasis, jaundice, pancreatitis. From the nervous system: dizziness, paresthesia, asthenia (excessive fatigue or weakness), disorientation, apathy, From the senses: xanthopsia, visual impairment. On the part of the hematopoietic organs: thrombocytopenia, leukopenia, agranulocytosis, eosinophilia, aplastic anemia. From the cardiovascular system: orthostatic hypotension (may increase under the influence of ethanol, anesthetics and sedative drugs), arrhythmia (due to hypokalemia). Laboratory indicators: hypokalemia, hyponatremia (including accompanied by neurological symptoms – nausea), hypomagnesemia, hypochloremic alkalosis, hypercalcemia, hyperuricemia (gout), hyperglycemia, glucosuria, hyperlipidemia. Allergic reactions: urticaria, photosensitivity. Other: muscle spasm, decreased potency. Overdose symptoms: dizziness, nausea, drowsiness, hypovolemia, excessive decrease in blood pressure, arrhythmia, convulsions. Treatment: gastric lavage, oral administration of activated charcoal; symptomatic therapy (including intravenous administration of saline solutions to restore the electrolyte balance of the blood).

Dosage and administration: Inside. With long-term therapy, it is recommended to prescribe the lowest effective dose sufficient to maintain the optimal effect, especially in elderly patients. With a mild degree of arterial hypertension – 25 mg 1 time per day or 50 mg 3 times a week; if necessary, it is possible to increase the dose to 50 mg / day. With edematous syndrome, the initial dose is 100-120 mg every other day; in severe cases – 100-120 mg / day for the first few days (doses above 120 mg usually do not cause an increase in the diuretic effect), then it is necessary to switch to a maintenance dose – 100-50-25 mg / day 3 times a week. Renal diabetes insipidus (in adults): initial dose – 100 mg 2 times a day, maintenance dose – 50 mg per day. The average daily dose for children is 2 mg/kg.

Special instructions: During the period of treatment, it is necessary to periodically determine blood electrolytes, especially in patients taking digitalis preparations. It is not recommended to prescribe a very strict salt-free diet to patients. If signs of hypokalemia appear (myasthenia gravis, rhythm disturbances) or if patients have an additional possibility of K + loss (with vomiting, diarrhea, malnutrition, liver cirrhosis, hyperaldosteronism, ACTH therapy, GCS), K + replacement therapy is indicated. In patients with hyperlipidemia, serum lipids should be constantly monitored (in case of an increase in their concentration, therapy should be discontinued). While taking thiazide diuretics, an exacerbation of SLE was noted. Although no such effects have been observed with chlorthalidone, caution should be exercised when prescribing it to patients with SLE.

Interaction: Increases the concentration of Li + in the blood (in the case when Li + causes polyuria, chlorthalidone may not have a diuretic, but an antidiuretic effect) and therefore increases the risk of intoxication with Li + drugs. (Chlorthalidone, like thiazide diuretics, is used for diabetes insipidus, including patients who are prescribed lithium.) Enhances the effect of curare-like muscle relaxants and antihypertensive drugs (including guanethidine, methyldopa, ACE inhibitors, beta-blockers, vasodilators, calcium antagonists, MAO inhibitors). Against the background of taking cardiac glycosides, it can aggravate rhythm disturbances resulting from digitalis intoxication. The hypokalemic effect of the drug is enhanced by the concomitant administration of glucocorticosteroids, amphotericin and carbenoxolone. Non-steroidal anti-inflammatory drugs weaken the diuretic and hypotensive effect of the drug. Patients with diabetes may need to adjust (increase or decrease) the dose of insulin and increase the dose of oral hypoglycemic drugs.

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The use of Chlorthalidone

Chlortalidone – composition and form of release of the drug

Chlortalidone: how to take the drug

Chlortalidone – contraindications, side effects

Chlorthalidone’s analogs

Chlorthalidone is a long-acting oral diuretic with antihypertensive activity.

Application of Chlorthalidone

Indications.

Treatment of hypertension, essential or nephrogenic, or isolated systolic hypertension.

Treatment of stable, chronic mild to moderate heart failure (NYHA functional class II or III).

Treatment of edema.

Chlorthalidone – composition and form of release of the drug

1 tablet contains 25 mg or 50 mg of chlorthalidone;

excipients: microcrystalline cellulose, pregelatinized starch, quinoline yellow (E104), sodium starch glycolate, anhydrous colloidal silicon dioxide, stearic acid.

Dosage form. Pills.

Chlorthalidone: how to take the drug

Dosage and administration.

Arterial hypertension.

Monotherapy. For the treatment of hypertension, the recommended starting dose of chlorthalidone for adults is 25 mg daily. This is sufficient to cause the maximum hypotensive effect in most patients. If a decrease in blood pressure does not occur at a dose of 25 mg / day, it can be increased to 50 mg / day. If additional antihypertensive therapy is used, increasing the dose of the drug to more than 50 mg increases metabolic complications and rarely has a therapeutic effect.

Combination therapy. If combination therapy is needed for the treatment of arterial hypertension, the dosage can be adjusted, first of all, when using each drug separately.

Stable chronic heart failure (NYHA functional class II or III).

The recommended starting dose is 25 to 50 mg/day, in severe cases the dose may be increased to 100 to 200 mg/day. The usual maintenance dose is the lowest effective dose, eg 25 to 50 mg daily or every other day. If the response is insufficient, digitalis preparations and/or ACE inhibitors may be added.

Children. The drug is not used in children.

Chlortalidone – contraindications, side effects

Contraindications.

• Hypersensitivity to chlorthalidone or other drugs derived from sulfonamides.
• Anuria.
• Severe hepatic or renal insufficiency (creatinine clearance <30 ml/min).
• Refractory hypokalemia, hypercalcemia and hyponatremia.
• Symptomatic hyperuricemia (history of gout or uric acid stones).
• Hypertension during pregnancy.
• Untreated Addison’s disease.
• Lithium concomitant therapy.
• Children’s age.
• Pregnancy, lactation.
• Intoxication with cardiac glycoside preparations.

Adverse reactions.

From the digestive tract: anorexia, nausea, vomiting, spasms, diarrhea, constipation, jaundice, pancreatitis.

From the side of the nervous system: dizziness, vertigo, paresthesia, headache, xanthopsia.

On the part of the blood system: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, eosinophilia.

Skin: purpura, photosensitivity, rash, urticaria, necrotizing angiitis vasculitis (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis).

From the side of the cardiovascular system: orthostatic hypotension, which may be aggravated by alcohol, barbiturates or drugs.