Which of the following does not increase secondary to thiazide (diuretic) use: serum/plasma cholesterol, serum/plasma uric acid, serum/plasma homocysteine, or serum/plasma sodium?

Serum/Plasma Sodium Does Not Increase Secondary to Thiazide Diuretics

The correct answer is D. Serum/plasma sodium. Thiazide diuretics typically cause hyponatremia (decreased sodium), not increased sodium levels, while they are known to increase serum/plasma cholesterol, uric acid, and homocysteine.

Metabolic Effects of Thiazide Diuretics

Effects on Sodium

• Thiazide diuretics inhibit sodium reabsorption in the distal convoluted tubule, leading to increased sodium excretion
• This can result in hyponatremia, particularly in elderly patients who have a higher risk of this adverse effect 1
• The American College of Cardiology recommends monitoring electrolytes, including sodium, within 2-4 weeks of initiating thiazide therapy due to the risk of hyponatremia 1

Effects on Cholesterol (Option A)

• Thiazide diuretics are known to increase serum cholesterol levels
• According to the JNC 7 guidelines, trials longer than 1 year using modest doses of diuretics generally have not shown significant increases in serum cholesterol, but some effect is still present 2
• In the ALLHAT study, serum cholesterol was 1.6 mg/dL lower in the CCB group and 2.2 mg/dL lower in the ACEI group than in diuretic-treated patients, indicating a relative increase in the diuretic group 2
• Multiple studies have demonstrated that thiazides can increase total cholesterol by 6-7% on average due to raised concentrations of low-density or very low-density lipoprotein cholesterol 3

Effects on Uric Acid (Option B)

• Thiazide diuretics consistently increase serum uric acid levels
• The JNC 7 guidelines specifically note that "uric acid will increase in many patients receiving a diuretic" 2
• A 2019 study found that hyperuricemia is significantly more common in thiazide users (24.5%) compared to non-users (15.3%), with overall mean serum uric acid levels higher in the thiazide group (5.9 ± 2.1 vs. 5.3 ± 2.7 mg/dL) 4
• The mechanism involves volume contraction and competition with uric acid for renal tubular secretion 5

Effects on Homocysteine (Option C)

• While less commonly discussed than other metabolic effects, thiazide diuretics have been associated with increased homocysteine levels
• Elevated homocysteine is an independent risk factor for cerebral arterial or venous thrombosis 2
• This effect may contribute to the cardiovascular risk profile of patients on long-term thiazide therapy

Clinical Implications

Monitoring Recommendations

• Electrolytes and renal function should be checked within 2-4 weeks of initiating thiazide therapy or after dose escalation 1
• Particular attention should be paid to:
  • Potassium levels (risk of hypokalemia)
  • Sodium levels (risk of hyponatremia)
  • Uric acid (risk of hyperuricemia)
  • Glucose (risk of hyperglycemia)
  • Lipid profile (risk of dyslipidemia)

Dosage Considerations

• Lower doses of thiazides (e.g., hydrochlorothiazide 12.5-25 mg or chlorthalidone 12.5-25 mg) may minimize metabolic adverse effects while maintaining antihypertensive efficacy 2, 5
• The potassium-sparing diuretic spironolactone has less effect on lipids than thiazides and may be considered in combination therapy to counteract some metabolic effects 6

In conclusion, while thiazide diuretics can increase serum/plasma cholesterol, uric acid, and homocysteine levels, they typically decrease serum/plasma sodium levels or cause hyponatremia rather than increasing sodium levels, making option D the correct answer.