What are the side effects of Diuril (chlorothiazide) and the recommended laboratory monitoring, particularly in older patients or those with renal impairment?

Side Effects of Diuril (Chlorothiazide)

Diuril causes significant electrolyte disturbances, particularly hyponatremia (up to 17%) and hypokalemia (up to 8%), along with volume depletion effects that are especially dangerous in elderly patients, requiring mandatory monitoring of renal function and electrolytes. 1

Major Adverse Effects

Electrolyte Disturbances (Most Critical)

Hyponatremia:

• Occurs in up to 17% of patients, with elderly women at highest risk 2
• Can cause confusion, delirium, and irreversible brain damage, adding to age-related dementia 2
• The greatest electrolyte shifts occur within the first 3 days of administration 3
• Thiazides are potentially inappropriate medications (PIMs) in elderly patients with a history of hyponatremia 4, 5

Hypokalemia:

• Occurs in up to 8% of patients 2
• May precipitate life-threatening cardiac arrhythmias and sudden death 4, 3, 1
• Causes muscular weakness and adynamia 2
• Sensitizes the heart to digitalis toxicity, increasing ventricular irritability 1
• Develops especially with brisk diuresis, severe cirrhosis, or prolonged therapy 1

Hypomagnesemia:

• Thiazides increase urinary magnesium excretion 1
• Contributes to cardiac arrhythmia risk 4

Volume Depletion Effects

Cardiovascular complications:

• Hypovolemia and postural hypotension 4
• Increased fall risk, particularly in elderly patients 4, 6
• Syncope episodes are causally related to thiazide use 6
• Poor sleep and nocturia 4

Renal effects:

• Pre-renal azotemia and dehydration 4, 1
• Acute kidney injury is significantly more common in thiazide users (22.1% vs 7%) 6
• Thiazides become ineffective when GFR falls below 30 mL/min 4, 3

Metabolic Disturbances

Glucose metabolism:

• Thiazides have the strongest diabetogenic activity among antihypertensive drugs 2
• Hyperglycemia may occur; latent diabetes may become manifest 1
• Thiazide-induced hypokalemia is associated with increased blood glucose 7

Lipid and uric acid:

• Increases in cholesterol and triglyceride levels 1
• Hyperuricemia may occur; acute gout may be precipitated 1
• Hyperuricemia results from volume contraction and competition with uric acid for renal tubular secretion 7

Calcium metabolism:

• Thiazides may decrease urinary calcium excretion 1
• May cause intermittent and slight elevation of serum calcium 1
• Marked hypercalcemia may indicate hidden hyperparathyroidism 1

Monitoring Requirements

Initial monitoring (critical first 3 days):

• The FDA mandates periodic determination of serum electrolytes in at-risk patients 3, 1
• Check electrolyte levels and eGFR within 4 weeks of initiation and following dose escalation 3

Ongoing monitoring:

• Monitor renal function and electrolytes every 3-6 months for stable patients 4, 3
• More frequent monitoring required if concurrent ACE inhibitor/ARB use or renal impairment 3
• Monitor supine and standing blood pressure to detect orthostatic hypotension 3

Warning signs requiring immediate evaluation:

• Dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures 1
• Muscle pains or cramps, muscular fatigue 1
• Hypotension, oliguria, tachycardia 1
• Gastrointestinal disturbances such as nausea and vomiting 1
• Unexplained neurological symptoms consistent with hyponatremic encephalopathy 3

Special Populations at Highest Risk

Elderly patients (≥75 years):

• Thiazides are PIMs in elderly with history of gout, diabetes, hyperlipidemia, or CrCl <30 mL/min 4
• PIM for ankle edema without signs of heart failure or as first-line therapy of hypertension 4
• More susceptible to orthostatic hypotension, renal function deterioration, and electrolyte abnormalities 3
• Elderly women face substantially elevated risk of hyponatremia 3

Patients with renal impairment:

• This drug is substantially excreted by the kidney; risk of toxic reactions is greater in patients with impaired renal function 1
• If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy 1

Patients with poor mobility or urinary incontinence:

• Use caution in patients with poor mobility or urinary incontinence 4

Critical Drug Interactions

Increased toxicity risk:

• Lithium should generally not be given with diuretics; diuretics reduce renal clearance of lithium and add high risk of lithium toxicity 1
• Digitalis: hypokalemia sensitizes or exaggerates response to toxic effects of digitalis 1

Reduced diuretic efficacy:

• NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects 1

Additive effects:

• Alcohol, barbiturates, or narcotics: potentiation of orthostatic hypotension 1
• Corticosteroids, ACTH: intensified electrolyte depletion, particularly hypokalemia 1

Common Pitfalls to Avoid

• Do not use thiazides in patients with CrCl <30 mL/min; switch to loop diuretics 4, 3
• Avoid in patients with history of hyponatremia 5
• Do not administer salt for dilutional hyponatremia in edematous patients; use water restriction instead 1
• If correcting severe hyponatremia, do not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 5, 3
• Instruct patients to hold or reduce doses during acute illness with vomiting, diarrhea, or decreased oral intake 3
• Discontinue thiazides before carrying out tests for parathyroid function 1