E. OSMOTIC DIURETICS

   Mechanisms
   * Osmotic agents shift water between compartments because they are less
      permeant through biologic membranes than is water. Their own permeance
      varies from relatively high (urea) to very low (mannitol). They have no
      direct effect on ion transport, but often cause shifts of ions by in-
      ducing bulk water flow and changing steady-state water concentration in
      body compartments.
   Major indications
   * Mannitol is labeled to promote diuresis, especially in the prevention of
      acute renal failure from, eg, increased pigment load due to transfusion
      reaction, and to promote excretion of toxic substances.

   * Isosorbide, urea, glycerin, mannitol are labeled to reduce intraocular
      pressure preor intraoperatively in acute glaucoma. See chapter 22.
   * Mannitol and urea are approved to reduce intracranial pressure and
      cerebral edema. See chapter 16.

   Pharmacokinetics (see Table 6-3)
   * Absorption: Mannitol and urea are used intravenously. Glycerin and
      isosorbide are usually given orally.
   * Distribution: Mannitol and glycerin are restricted to the extracellular
      space. Isosorbide and urea eventually penetrate the total body water.
      Isosorbide and urea penetrate the eye better than the other agents in
      this group; they are preferred for the rapid reduction of intraocular
      pressure.
   * Elimination: Except for isosorbide, these agents have short half-lives.
      They are all freely filtered at the glomerulus. Glycerin is sig-
      nificantly metabolized by the liver.

   Contraindications and Warnings
   * Hypersensitivity, anuria, pulmonary edema, active intracranial bleeding.
   * Hepatic failure: do not use urea.
   * Fluid and electrolyte imbalance (warning): may be exacerbated by osmotic
      water shifts and diuresis. Administration should always be accompanied
      by monitoring of vascular pressures and serum electrolytes, with re-
      placement as appropriate.

   Adverse Reactions   * CV: hypotension, hypovolemia, heart failure, pulmonary congestion,
      phlebitis at site of administration (solutions are very hypertonic).
   * CNS: headache, blurred vision, dizziness, disorientation, convulsions.
   * GI: nausea, vomiting.

   Toxicity and Overdosage
   * Extension of adverse reactions.
   Interactions
   * Because these agents act by physical effects on water distribution and
      not at receptors, interactions with other drugs are rare.

    II. DRUGS THAT MODIFY WATER EXCRETION

   Mechanisms
   * Antidiuretic hormone (vasopressin) and its semisynthetic derivative,
      desmopressin (DDAVP) act in the collecting duct of the nephron to in-
      crease its permeability to water and thereby increase the reabsorption
      of water. They act at specific receptors to increase the synthesis of
      cAMP in the cell. They are of no value in the treatment of nephrogenic
      diabetes insipidus since the defect in this condition lies distal to
      the ADH receptor.
   * The thiazides reduce diluting ability of the kidney by the mechanism de-
      scribed in Section I.A.; loop diuretics decrease diluting ability by
      reducing the osmotic gradient set up in the medulla of the kidney. Fur-
      thermore, diuretic-induced reduction in blood volume stimulates sodium
      and water retention in the proximal tubule. These agents can therefore
      reduce the volume of urine produced in diabetes insipidus; in
      nephrogenic diabetes insipidus they constitute, along with sodium
      restriction, the major mode of therapy.
   * Lithium and certain antibiotics, notably demeclocyline, inhibit the ac-
      tion of ADH in the kidney at some point distal to the generation of
      cAMP, and produce a drug-induced nephrogenic diabetes insipidus. This
       is usually an undesired effect, but in the syndrome of inappropriate
      ADH secretion (SIADH), demeclocyline can be used to ameliorate the ex-
      cessive water retention and hyponatremia associated with these hormone-
      producing tumors.

     A. Antidiuretic agents (ADH, desmopressin, lypressin):
   Indications
   * Pituitary diabetes insipidus: ADH or desmopressin. (In nephrogenic
      diabetes insipidus use thiazides and water restriction.)

   Pharmacokinetics (see Table 6-4)
   * Absorption: these polypeptides are hydrolyzed in the GI tract and must
      be given parenterally as nasal snuff or sprays, or by IM or SC injec-
      tion.
   * Elimination: peptide hydrolysis in the blood and tissues is responsible
      for the elimination of these compounds.

   Contraindications and Warnings
   * Hypersensitivity to ADH or its analogs. Warnings: smooth muscle effects
      are usually mild; use caution in patients with severe coronary artery
      disease, hypertension, or pregnancy.
   Adverse Reactions
   * Allergic responses
   * Local irritation in response to intranasal administration.
   * Increased smooth muscle activity may result in diarrhea, coronary
      vasoconstriction, hypertension.

   Toxicity and Overdosage
   * Extensions of adverse reactions.
   Interactions
   * Chlorpropamide, carbamazepine, and clofibrate may potentiate the
      antidiuretic action of these agents.

     B. Inhibitors of ADH (Demeclocycline)

   Major indications
   * SIADH: demeclocycline and water restriction.

   Pharmacokinetics (Table 6-4 and Chapter 10)
   * Absorption: good absorption from the gut.
   * Elimination: primarily by biliary and renal excretion.

   Contraindications and Warnings
   * Hypersensitivity
   * Age under 8 (effects on bones and teeth, see  Chapter 10).

   Adverse Reactions
   * Teeth, skin: Discoloration and abnormal development of teeth before
      eruption. Photosensitivity.
   * GI: Nausea, vomiting, diarrhea.
   * Liver: Impairment of liver function, especially with large parenteral
      doses (unlikely in SIADH).
   * Superinfection with yeasts and normally innocuous bacteria may occur.

   Toxicity and Overdosage
   * Rare, see chapter 10.
   Interactions
   * Demeclocycline interferes with the bactericidal action of penicillins.
   * Antacids (including milk) may interfere with the absorption of
      tetracyclines.

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