Can chlorthalidone cause constipation, and how should it be evaluated and managed in a hypertensive patient?

Chlorthalidone and Constipation

Constipation is not a recognized adverse effect of chlorthalidone. The major guideline-documented side effects of this thiazide-like diuretic are electrolyte disturbances (hypokalemia, hyponatremia), metabolic abnormalities (hyperglycemia, hyperuricemia), and renal dysfunction—not gastrointestinal symptoms such as constipation 1.

Documented Adverse Effects of Chlorthalidone

The 2022 ACC/AHA/HFSA Heart Failure Guidelines and supporting evidence identify the following adverse effects associated with chlorthalidone therapy:

Electrolyte Abnormalities

• Hypokalemia is the most significant concern, occurring three times more frequently with chlorthalidone compared to hydrochlorothiazide (adjusted hazard ratio 3.06), with serum potassium <3.5 mEq/L occurring four to five times more often 2, 3.
• Hyponatremia occurs more frequently with chlorthalidone than hydrochlorothiazide (HR 1.31), particularly in elderly patients 4.
• Serum potassium <3.5 mEq/L is associated with loss of cardiovascular protection and increased risk of sudden cardiac death, especially in patients on digitalis 3.

Metabolic Effects

• Hyperglycemia and new-onset diabetes occur more frequently with chlorthalidone, with diabetes incidence of 11.8% after 4 years in the ALLHAT trial, though this did not translate to fewer cardiovascular events 2, 4.
• Hyperuricemia and gout precipitation can occur, particularly in patients with a history of gout 5.

Renal Effects

• Acute renal failure (HR 1.37) and chronic kidney disease (HR 1.24) occur more frequently with chlorthalidone compared to hydrochlorothiazide 4.
• In advanced CKD (eGFR <30 mL/min/1.73 m²), chlorthalidone may precipitate azotemia and requires intensified monitoring 5, 6.

Clinical Evaluation if Constipation Occurs

If a hypertensive patient on chlorthalidone develops constipation, the evaluation should focus on:

Alternative Medication Causes

• Review the patient's complete medication list for known constipating agents (calcium channel blockers, opioids, anticholinergics, iron supplements, calcium supplements) 7.
• Assess for other antihypertensive medications that commonly cause constipation, particularly non-dihydropyridine calcium channel blockers like diltiazem or verapamil 5.

Electrolyte-Related Causes

• Check serum potassium immediately, as severe hypokalemia (<3.0 mEq/L) can cause ileus and constipation through impaired smooth muscle contractility 3.
• Assess for hypokalemia-related symptoms: muscle weakness, cramping, fatigue, or cardiac arrhythmias 3.

Other Medical Causes

• Evaluate for hypothyroidism, hypercalcemia, or other metabolic disorders that can cause both hypertension and constipation 7.
• Assess dietary fiber intake, fluid intake, and physical activity level 7.

Management Approach

If Hypokalemia is Present

• Add a potassium-sparing diuretic (spironolactone 12.5-25 mg daily) rather than merely increasing oral potassium supplementation, as this is more effective for persistent hypokalemia 3.
• Monitor serum potassium within 2-4 weeks after initiation or dose escalation, then every 3-6 months during maintenance therapy 3.

If Constipation Persists Without Hypokalemia

• Consider switching to hydrochlorothiazide if blood pressure control allows, as it has a lower incidence of electrolyte disturbances while maintaining antihypertensive efficacy 4, 8.
• The equivalent dose of hydrochlorothiazide for 25 mg chlorthalidone is 50 mg daily 2.

Common Pitfalls to Avoid

• Do not attribute constipation to chlorthalidone without ruling out other causes, as this is not a documented side effect in major guidelines or clinical trials 1, 7.
• Do not discontinue chlorthalidone prematurely if it is providing superior cardiovascular protection, particularly in patients with heart failure or advanced CKD where chlorthalidone has proven mortality benefit 2, 6.
• Do not overlook severe hypokalemia as a potential cause of ileus masquerading as simple constipation 3.

Monitoring Requirements

Regardless of gastrointestinal symptoms, patients on chlorthalidone require:

• Comprehensive metabolic panel within 2-4 weeks of initiation or dose escalation 5, 3.
• Particular attention to serum potassium, with monitoring every 5-7 days until stable, then every 3-6 months 3.
• Serum uric acid and calcium levels within 2-4 weeks of initiation 5.
• More frequent monitoring in high-risk populations: elderly patients, those with advanced CKD (eGFR <30), or those on concurrent medications affecting potassium 5, 3.