Thiazide Diuretics

Summary

Thiazide diuretics are a class of drugs that include HCTZ, chlorthalidone, indapamide, and metolazone. Thiazides work by inhibiting the sodium-chloride cotransporter in the distal tubules of the kidneys, increasing the excretion of sodium and water and inducing diuresis. Thiazide diuretics lead to decreased sodium and potassium reabsorption, and increased calcium reabsorption from the urine. 

Clinically, thiazide diuretics are used for inducing diuresis to treat fluid overload states, like heart failure and pulmonary edema. The reduction of blood volume is also useful in the treatment of hypertension. Thiazides can treat nephrogenic diabetes insipidus by stimulating sodium and water reabsorption in the proximal tubule. Finally, because thiazides stimulate calcium reabsorption from urine, they can reduce the risk of osteoporosis and treat calcium oxalate kidney stones.

However, thiazide diuretics do have some adverse effects. For example, these drugs can increase lithium levels to increase the risk of toxicity. Secondly, thiazides can cause hyperuricemia, precipitating an acute gout attack.

Key Points

• Topic Anchor: Thiazide Diuretics
  • Drug name:
    • Hydrochlorothiazide (HCTZ)
    • Chlorthalidone
    • Indapamide
    • Metolazone
  • Mechanism:
    • Blocks Na+Cl- cotransporters in distal tubule
      • Thiazide diuretics block Na+/CI- reabsorption in the distal tubule. This allows more Na- to reach the collecting tubule, enhancing K+ and H+ excretion.
      • ↑ excretion of Na+/K+
      • ↑ absorption of Ca2+, Mg2+
  • Indications:
    • Hypertension
      • Especially in African Americans and elderly patients
      • Thiazide diuretics are presently the first line treatment for essential hypertension in the outpatient setting
      • A thiazide diuretic is one of the initial treatments recommended for essential hypertension in a patient without CHF or diabetes. In patients with CHF or diabetes, an ACE inhibitor should be used instead (mortality benefit).
    • Edema/Diuresis
      • Example states: Heart failure, cirrhosis, nephrotic syndrome, pulmonary edema, peripheral edema.
    • Nephrogenic DI
      • Nephrogenic DI is typically treated with thiazide diuretics (induce mild hypovolemia, increasing proximal tubule sodium and water reabsorption)
    • Related to increased calcium reabsorption:
      • Idiopathic hypercalciuria
      • Treatment of calcium oxalate kidney stones
      • Osteoporosis (see increased calcium above)
        • Thiazide diuretics increase Ca2+ absorption in the distal tubules. Thiazides are associated with increased bone mineral density and are recommended for treatment of hypertension in patients at risk for osteoporosis.
  • Adverse effects:
    • Increased lithium toxicity
      • Lithium is similar to sodium, in that it is filtered and reabsorbed mostly in the proximal tubules (cation transporters). Thiazide diuretics reduce sodium reabsorption in the distal tubule, causing mild volume depletion and hyponatremia that stimulates proximal tubular sodium/lithium reabsorption, which then leads to lithium toxicity over time. (think of it as a feedback loop)
    • Hyperuricemia
      • Thiazide diuretics can lead to hyperuricemia and precipitate an acute gout attack.
    • Sulfa drug (allergy)
    • Electrolyte abnormalities (Hypercalcemia, Hypokalemia, Hyponatremia)
      • Hypercalcemia is particularly noticeable, but can be inferred by increased Ca2+ reabsorption above
    • Metabolic abnormalities (Hyperglycemia, Hyperlipidemia)
      • Thiazide diuretics can cause hyperglycemia, hypercholesterolemia, and hypertriglyceridemia
    • Sexual dysfunction
    • Hypovolemia/Hypotension
      • Contraction metabolic alkalosis
        • In states of volume contraction, aldosterone is upregulated which leads to increased H+ excretion and a resulting metabolic alkalosis.