Medical Pharmacology Chapter 26:  Renal Pharmacology

• Thiazides

  • Introduction:

    • Thiazides inhibit NaCl transport at the distal convoluted tubule

    • Prototypical thiazide:  hydrochlorothiazide

     

  • Thiazides and Related Sulfonamide Diuretics

    Bendroflumethazide	Benzthiazide	Chlorothiazide	Chlorthalidone
    Hydrochlorothiazide	Hydroflumethiazide	Indapamide	Methyclothiazide
    Metolazone	Polythiazide	Quinethazone	Trichlomethiazide

  •   Properties:

    • Oral administration

    • Secreted by the organic acid secretory system

      • Competes with uric acid for secretion, uric acid secretory rates may decline.

    • Differences between thiazides:

      • Chlorothiazide (Diuril): less lipid soluble (requires relatively large doses)

      • Chlorthalidone (Hygroton): slowly absorbed -- longer duration of action

      • Indapamide (Lozol): mainly biliary secretion

  • Mechanism of action:

    • Diuretic action: Inhibition of NaCl reabsorption from the distal convoluted tubule (luminal side).

    • Enhanced calcium reabsorption in the distal convoluted tubule (unknown mechanism).

      • Thiazides infrequently cause hypercalcemia but can unmask hypercalcemia due to other causes such as carcinoma, sarcoidosis, or hyperparathyroidism.

  • Clinical Uses:

    • Hypertension

    • Congestive heart failure

    • Nephrolithiasis (due to idiopathic hypercalciuria

    • Nephrogenic diabetes insipidus

  •  Toxicity:

    • Hypokalemic metabolic alkalosis and hyperuricemia

    • Impaired carbohydrate tolerance

      • May induce hyperglycemia associated with:

        • Impaired pancreatic insulin release

        • Decreased tissue glucose utilization

        • Hyperglycemia may be partially reversed by correcting a hypokalemic state

    • Hyperlipidemia

      • 5% to 15% increase in serum cholesterol and an increase in low-density lipoproteins.

    •  Hyponatremia:

      • Significant adverse effect, occasionally life-threatening

      • Mechanism:

        • Hypovolemia-induced increase in ADH

        • Reduced renal diluting capacity

        • Increased thirst

        • Prevention: decreasing the drug dose or limiting fluid intake

    • Allergic reactions:

      • Thiazides are sulfonamides: cross-reactivity within the group

      • Photosensitivity  (rare)

      • Dermatitis (rare)

      • Extremely rare reactions:

        • Hemolytic anemia

        • Thrombocytopenia

        • Acute necrotizing pancreatitis

    • Other reactions:

      • Weakness

      • Ftigue

      • Paresthesias