Medical Pharmacology Chapter 26:  Renal Pharmacology

Adverse Diuretic effects and contraindications

• Adverse Effects:  Carbonic Anhydrase Inhibitors (Acetazolamide)

  • Toxicity:

    • Hyperchloremic metabolic acidosis

      • Due to reduction in body bicarbonate stores

    • Renal stones:

      • Bicarbonate loss is associated with:

        •  Phosphaturia

        •  Hypercalciuria (calcium salts, relatively insoluble at alkaline pH)

    • Renal potassium loss:

      • Increased sodium bicarbonate in the collecting tubule increases the lumen-negative and in inelectrical potential -- enhances potassium excretion

        • Counteracted by potassium chloride administration

    • Others:

      • Drowsiness, parathesias

      • Accumulation in renal failure (CNS toxicity)

      • Hypersensitivity reactions

    •  Contraindications:

      • Hepatic cirrhosis

        • Urinary alkalinization will decrease ammonium ion trapping, increasing the likelihood of hepatic encephalopathy.

         

• Adverse Effects:  Loop Diuretics

  •  Toxicity:

    •  Hypokalemia metabolic alkalosis:

      • Increased delivery of NaCl and water to the collecting duct increases potassium and proton secretion-- causing a hypokalemic metabolic alkalosis

      • In managed by potassium replacement and by ensuring adequate fluid intake

    •  Ototoxicity:

      • Dose-related hearing loss (in usually reversible)

      • More common:

        • With decreased renal function

        • With concurrent administration of other ototoxic drugs such as aminoglycosides

    •  Hyperuricemia:

      • May cause gout

      • Loop diuretics cause increased uric acid reabsorption in the proximal tubule, secondary to hypovolemic states.

    •  Hypomagnesemia: loop diuretics cause:

      1. Reduction in sodium chloride reabsorption

      2. Decreases normal lumen-positive potential (secondary to potassium recycling)

      3. Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)

      4. Therefore, loop diuretics increase magnesium and calcium excretion.

         • Hypomagnesemia may occur in some patients.

         • Reversed by oral magnesium administration

    • Allergic reactions:

      • Furosemide: skin rash, eosinophilia, interstitial nephritis(less often)

    • Other toxicities:

      • Dehydration (may be severe)

      • Hyponatremia (less common than with thiazides thought may occur in patients who increased water intake in response to a hypovolemic thirst)

      • Hypercalcemia may occur in severe dehydration and if a hypercalcemia condition (e.g. oat cell long carcinoma) is also present.

       

• Adverse Effects:  Thiazides

  • Toxicity:

    • Hypokalemic metabolic alkalosis and hyperuricemia

    • Impaired carbohydrate tolerance

      • May induce hyperglycemia

        • 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

      • Fatigue

      • Paresthesias

       

• Adverse Effects:  Osmotic Diuretics

  •  Toxicity:

    • Volume expansion effects -- increased extra cellular fluid volume and hyponatremia may cause:

      • Pulmonary edema, complicating congestive heart failure

    • Headache, nausea, vomiting -- commonly observed

    • Dehydration and hypernatremia:

      • Leads to significant dehydration and in the absence of adequate fluid replacement leads to hypernatremia.

       

• Adverse Effects:  Potassium-Sparing Diuretics

  •  Toxicity:

    • Hyperkalemia:

      • Potassium-sparing diuretics can cause significant hyperkalemia

      • Factors that increase the likelihood of hyperkalemia:

        • Renal disease

        • Presence of agents that reduce renin:

          •   β-blockers

          •   Nonsteroidal anti-inflammatory drugs (NSAIDs)

          •   ACE inhibitors

          •   Angiotensin receptor blockers

      • Hyperkalemia more likely when potassium-sparing diuretics are used as the only diuretic drug or in the presence of renal insufficiency.

        •  Given in combination with thiazides, hypokalemia and metabolic alkalosis associated with thiazide use may be balanced by aldosterone antagonists

        •  Since thiazide adverse effects may predominate (hyponatremia, metabolic alkalosis), due to variations in bioavailability, individual dose adjustment of the two drugs may be better.

    • Hyperchloremic Metabolic Acidosis:

      • Acidosis cause by inhibition of proton secretion along with potassium secretion (similar to type IV renal tubular acidosis

    • Gynecomastia:

      •   Endocrine abnormalities associated with synthetic steroids --spironolactone:

        •    Gynecomastia (breast enlargement)

        •    Impotence

        •    Benign prostatic hyperplasia

    • Acute Renal Failure:

      •   Triamterene (Dyrenium) plus indomethacin

    • Kidney Stones:

      •  Triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing renal stones:

  •  Contraindications:

    • May cause severe (potentially fatal) hyperkalemia

    • Potassium supplements should be discontinued prior to administration of aldosterone antagonists

    • Patients with chronic renal insufficiency are at particular risk

    • Hyperkalemia is also more likely to occur or it if beta-blockers or ACE inhibitors are concurrently administered

    • Impairment of hepatic metabolism of triamterene spironolactone may require dose adjustment