What are the potential side effects of thiazide diuretics, such as hydrochlorothiazide (hydrochlorothiazide), in patients with a history of hypertension, heart failure, gout, or impaired renal function?

Thiazide Diuretics Side Effects

Thiazide diuretics cause predictable electrolyte disturbances—most importantly hyponatremia and hypokalemia—along with metabolic effects including hyperuricemia, hyperglycemia, and hyperlipidemia, with the greatest risk occurring in elderly patients, particularly women. 1, 2

Electrolyte Disturbances

Hyponatremia

• Hyponatremia is one of the most serious and common side effects, affecting up to one in seven patients (14%) taking thiazides. 3
• The risk is substantially elevated in elderly patients, particularly women, and those with low body weight. 4, 5
• The greatest electrolyte shifts occur within the first 3 days of thiazide administration, making early monitoring critical. 4
• Symptoms include confusion, falls, seizures, nausea, vomiting, headache, and lethargy consistent with hyponatremic encephalopathy. 4, 2
• Thiazide-induced hyponatremia is life-threatening in severe cases and represents a common cause of hospital admission in the elderly. 2, 3
• Check electrolyte levels within 4 weeks of initiation and following dose escalation. 4
• Instruct patients to hold or reduce doses during acute illness with vomiting, diarrhea, or decreased oral intake. 4

Hypokalemia

• Hypokalemia occurs in approximately 19% of thiazide users and is dose-dependent. 5
• Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias, sensitize the heart to digitalis toxicity, and may contribute to sudden death. 6, 2
• Warning signs include muscle pains, cramps, muscular fatigue, and weakness. 2
• Thiazide-induced hypokalemia is associated with increased blood glucose, and treatment of hypokalemia may reverse glucose intolerance and possibly prevent diabetes. 7
• Hypokalemia may be avoided or treated by potassium supplementation or increased intake of potassium-rich foods. 2

Other Electrolyte Abnormalities

• Hypomagnesemia commonly occurs and can exacerbate cardiac arrhythmias. 2, 8
• Hypochloremic metabolic alkalosis develops with thiazide use. 8
• Hypercalcemia may occur due to decreased calcium excretion; pathologic changes in parathyroid glands with hypercalcemia and hypophosphatemia have been observed with prolonged therapy. 2

Metabolic Side Effects

Hyperuricemia and Gout

• Hyperuricemia or acute gout may be precipitated in certain patients, occurring as a result of volume contraction and competition with uric acid for renal tubular secretion. 1, 2, 7
• Use with caution in patients with history of acute gout unless patient is on uric acid-lowering therapy. 1
• Hyperuricemia does not necessarily contraindicate thiazide use, especially if a uric acid-lowering drug such as allopurinol is being used. 7

Glucose Intolerance and Diabetes

• Latent diabetes mellitus may become manifest, and diabetic patients may require adjustment of their insulin dose. 2
• Thiazides increase glucose and insulin resistance through mechanisms that may be related to hypokalemia. 9, 7
• Thiazides rarely cause non-ketotic hyperosmolar coma. 9

Lipid Effects

• Cholesterol elevation has been reported in some studies, though long-term studies indicate lipid changes are minor. 9

Renal and Volume Effects

Acute Kidney Injury and Azotemia

• Acute kidney injury is significantly more common in thiazide users (22.1% vs 7% in non-users). 5
• Cumulative effects may develop in patients with impaired renal function, potentially precipitating azotemia. 2
• Volume depletion with prerenal azotemia can occur with all thiazides except mildly natriuretic collecting duct agents. 8

Advanced CKD Considerations

• Thiazides, especially chlorthalidone, may be effective for blood pressure management even in advanced CKD (eGFR <30 mL/min/1.73 m²), contrary to common perception. 1
• Chlorthalidone is specifically superior to hydrochlorothiazide in advanced CKD. 6
• Thiazide treatment should not automatically be discontinued when eGFR decreases to <30 mL/min/1.73 m². 1

Cardiovascular and Neurological Effects

Syncope and Falls

• Patients taking thiazide diuretics have significantly more episodes of syncope and falls, which appear causally related to thiazide use. 5
• Orthostatic hypotension may be potentiated when combined with alcohol, barbiturates, or narcotics. 2

Ophthalmologic Effects

Acute Angle-Closure Glaucoma

• Hydrochlorothiazide can cause acute transient myopia and acute angle-closure glaucoma, typically occurring within hours to weeks of drug initiation. 2
• Symptoms include acute onset of decreased visual acuity or ocular pain. 2
• Untreated acute angle-closure glaucoma can lead to permanent vision loss; the primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. 2
• Risk factors include history of sulfonamide or penicillin allergy. 2

Other Side Effects

Dermatologic

• Non-melanoma skin cancer risk is increased; instruct patients to protect skin from the sun and undergo regular skin cancer screening. 2
• Skin rashes may occur as an idiosyncratic reaction. 9

Sexual Dysfunction

• Some reports describe increased sexual dysfunction and impotence, particularly at high doses, though this is not universally accepted as a diuretic-related side effect. 1, 7

Rare Idiosyncratic Reactions

• Interstitial nephritis, noncardiogenic pulmonary edema, pancreatitis, myalgias, and thrombocytopenia are rare but reported. 8, 9

Monitoring Recommendations

The FDA mandates periodic determination of serum electrolytes in at-risk patients, with particular attention to the first 3 days when electrolyte shifts are most significant. 4, 2

• Check electrolytes (sodium, potassium, chloride, magnesium), creatinine/eGFR, uric acid, and fasting glucose within 4 weeks of initiation and following dose escalation. 4, 6
• For stable patients without risk factors, monitor serum electrolytes every 3-6 months; high-risk patients require more frequent monitoring. 4
• During major surgery, ICU admission, or large gastrointestinal losses, frequent laboratory monitoring is necessary. 4

Substance-Specific Differences

Chlorthalidone bears the highest risk for electrolyte disorders, while hydrochlorothiazide carries the lowest risk, with a dose-dependent effect observed across all thiazides. 5

Chlorthalidone is preferred over hydrochlorothiazide based on prolonged half-life (40-60 hours) and proven cardiovascular disease reduction in clinical trials. 1, 6, 7

Critical Drug Interactions

• NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of thiazides. 2, 7
• Lithium should generally not be given with diuretics, as they reduce renal clearance of lithium and greatly increase toxicity risk. 2
• Corticosteroids and ACTH intensify electrolyte depletion, particularly hypokalemia. 2
• Combination with beta-blockers may increase fatigue, lethargy, and glucose elevation. 7