What are the serious side effects of chlorthalidone?

The Food and Drug Administration considers a side effect serious if it is life-threatening, requires a hospital stay, or causes permanent damage or disability.¹ The agency requires medication guides be issued when, in their view, serious side effects could occur while taking a medication. There is no medication guide issued for chlorthalidone.²  

However, serious side effects can occur. They include low levels of sodium^3–6 and potassium,^3,7–11 gout,^12,13 new-onset diabetes,^14–17 and allergic reactions.¹⁸

Electrolyte Disturbances

The manufacturer’s drug information warns that hypokalemia and other electrolyte disturbances including hyponatremia and hypochloremic alkalosis are common among chlorthalidone users.¹⁴ Absolute frequency of hypokalemia and hyponatremia are not reported in the package insert¹⁴ or the Lexicomp database.¹⁸ Manufacturers advise that patients should have periodic serum electrolyte determinations during therapy and that patients be advised to report signs of electrolyte imbalances. These include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, or nausea and vomiting. Severe electrolyte disturbances can be life-threatening.¹⁹   

Hypokalemia

Low serum potassium was once estimated to occur in up to 40% of outpatients taking thiazide diuretics.⁷ This effect is dose-dependent and is less likely with the lower doses of chlorthalidone prescribed today.⁸ Hypokalemia can cause serious cardiac arrythmias.^3,9 The safest approach to minimizing hypokalemia is to ensure adequate dietary potassium intake, but it may not be effective.¹⁰ In some cases, potassium supplements may be needed.

Dhalla et al compared the safety and efficacy of chlorthalidone with hydrochlorothiazide (HCTZ) in hypertensive patients over 66 years of age in a prospective cohort study.¹¹ Compared to patients taking HCTZ, patients treated with chlorthalidone were more likely to be hospitalized with hypokalemia (adjusted hazard ratio [HR] 3.06, 95% confidence interval [CI] [2.04 – 4.58]) or hyponatremia (adjusted HR 1.68, 95% CI [1.24 – 2.28]).

Hyponatremia

Hyponatremia is defined as serum sodium level below 134 mmol/L.⁴ It is estimated to occur in up to 22% of hospitalized patients.³ Thiazide diuretics are one of the most common causes of hyponatremia.^3,4 The symptoms are primarily neurological including headache, nausea, and vomiting due to cerebral edema. Severe hyponatremia is a medical emergency and can cause seizures, coma, and death. Treatment may involve discontinuing the diuretic, if that is the cause, and reversing the imbalance with fluid restriction, electrolyte replacement, and drug therapy.

Van Blijderveen et al conducted a population-based case-control study of patients identified within the Dutch Integrated Primary Care Information database between 1996 and 2011.⁵ Cases with laboratory evidence of hyponatremia (defined as <130 mmol/L serum sodium) or a history of hospitalization for hyponatremia were matched with controls from the database on age, gender, and practice. Patients with malignancy, heart failure, liver failure, diabetes, or those on chemotherapy were excluded because these conditions are known to cause hyponatremia. A total of 1,033 cases of hyponatremia met the inclusion criteria. Exposure to medication (including chlorthalidone and HCTZ) was obtained from prescription files in the database. Hyponatremia was more common among patients taking chlorthalidone than those taking HCTZ at equal dose per day with an adjusted odds ratio [OR] of 2.09 (95% CI [1.13 – 3.88]) for 12.5 milligrams per day and OR of 1.72 (95% CI [1.15 – 2.57]) for 25 milligrams per day.

The Duke Clinical Research Group Beers Criteria Medication List has determined that chlorthalidone may be inappropriate or should be used with caution in geriatric populations because of the potential to cause or exacerbate a syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia.⁶ They recommend monitoring sodium concentration closely when initiating or adjusting the dose in older adults.

Hyperglycemia and New-Onset Diabetes

Blood glucose levels may rise in some patients taking chlorthalidone.¹⁴ Kostis et al evaluated cardiovascular mortality in patients on diuretics among the participants in the Systolic Hypertension in the Elderly Program (SHEP).¹⁵ The SHEP trial was a placebo-controlled, double-blind randomized multi-center trial. Patients were randomized to receive either chlorthalidone (12.5 mg to 25 mg per day) or placebo.¹⁶ They found that chlorthalidone increased new onset diabetes (defined as serum glucose ≥126 mg/dL) as opposed to placebo. Initially, 384 patients (16.3%) were diabetic in the active treatment group versus 415 (17.5%) in the placebo group. During the course of the study, an additional 258 subjects (13.0%) developed diabetes in the chlorthalidone group versus 169 subjects (8.7%) in the placebo group (p<0.0001) However, patients who had diabetes associated with chlorthalidone had no significant increase in cardiovascular events and had a better prognosis than did those who had preexisting diabetes.

In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial the risk of incident diabetes mellitus at four years follow-up was 15% to 30% higher with the thiazide-like diuretic chlorthalidone (11%) versus the calcium channel blocker amlodipine (9.3%), or the angiotensin-converting enzyme inhibitor lisinopril (7.8%).¹⁷ However, the findings also suggested that diabetes associated with chlorthalidone use was associated with less adverse cardiovascular outcomes compared to diabetes that was incident with the use of other antihypertensive medications.

Hyperuricemia and Gout

Elevated levels of uric acid and frank gout have also occurred in people taking chlorthalidone, particularly among patients with a history of gout.¹⁴ Thiazide and thiazide-like diuretics have been found to increase serum urate concentrations by 35%, which can precipitate acute gout attacks, especially in patients with a previous history of gout.^12,13

Allergic Reactions

Hypersensitivity reactions may occur in patients taking chlorthalidone, particularly in patients with a history of allergy or bronchial asthma.¹⁸

Other Serious Side Effects

Other serious but uncommon adverse events estimated to occur in less than 1% of people taking chlorthalidone are:¹⁸

Agranulocytosis, aplastic anemia, cholecystitis, hypercalcemia, hyperglycemia, hypersensitivity reaction, hyperuricemia, hypophosphatemia, leukopenia, necrotizing angiitis, pancreatitis, paresthesia, thrombocytopenia, toxic epidermal necrolysis, vasculitis.

People with certain diseases are at higher risk of serious side effects with chlorthalidone.¹⁸ People with systemic lupus erythematosus may be at risk of exacerbation of disease. People with kidney disease are at increased risk of azotemia. People with liver disease are at risk of hepatic coma due to electrolyte disturbances.

^References

1. Food and Drug Administration. What is a serious adverse event? https://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm. Accessed Oct 21, 2018.
2. Food and Drug Administration. Medication Guides. https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm. Accessed Oct 21, 2018.
3. Mount DB. Fluid and Electrolyte Disturbances. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine, 20e. New York, NY: McGraw-Hill Education; 2018.
4. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008; 52 (1): 144-153.
5. Van Blijderveen JC, Straus SM, Rodenburg EM, et al. Risk of hyponatremia with diuretics: Chlorthalidone versus hydrochlorothiazide. Am J Med 2014; 127 (8): 763-771.
6. Duke Clinical Research Group: Beers Criteria Medication List. https://dcri.org/beers-criteria-medication-list/. Accessed Oct 21, 2018.
7. Cohn JN, Kowey PR, Whelton PK, Prisant LM. New guidelines for potassium replacement in clinical practice. Arch Intern Med 2000; 160 (16): 2429.
8. Musini, VM, Nazer M, Bassett K, Wright JM. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database Syst Rev 2014;(5): CD 003824.
9. Rodenburg EM, Visser LE, Hoorn EJ, et al. Thiazides and the risk of hypokalemia in the general population. J Hypertens 2014; 32 (10): 2092-2097.
10. Gennari FJ. Hypokalemia. N Engl J Med 1998; 339 (7): 451-458.
11. Dhalla I, Gomes T, Yao Z, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults. Ann Intern Med 2013;(January 1993): 447-456.
12. DiNicolantonio JJ, Bhutani J, Lavie CJ, O’Keefe JH. Evidence-based diuretics: focus on chlorthalidone and indapamide. Future Cardiol 2015; 11 (2): 203-217.
13. Franse L V, Pahor M, Di Bari M, et al. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens 2000; 18 (8): 1149-1154.
14. Thalitone (chlorthalidone) [package insert]. East Brunswick, NJ: Casper Pharma LLC; 2018.
15. Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol 2005; 95 (1): 29-35.
16. The SHEP Trial. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265 (24): 3255-3264.
17. Barzilay JI, Davis BR, Pressel SL, et al. Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension the ALLHAT diabetes extension study. Circ Cardiovasc Qual Outcomes 2012; 5 (2): 153-162.
18. Chlorthalidone: Drug Information, Lexi-Comp, Inc. Wolters Kluwer Health, Inc. Riverwoods, IL. Lexicomp Online.
19. Licht JH, Haley RJ, Pugh B, Lewis SB. Diuretic regimens in essential hypertension: a comparison of hypokalemic effects, BP control, and cost. Arch Intern Med 1983; 143 (9): 1694-1699.