E. OSMOTIC DIURETICS Mechanisms Osmotic agents shift water between compartments because th

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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. References 1. Acetazolamide for acute mountain sickness. FDA Bull 1983; 13: 27. 2. Ashraf N et al: Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981; 70: 1141. 3. Brater DC: Determinants of the overall response to furosemide: pharmacokinetics and pharmacodynamics. Fed Proc 1983; 42: 1711. 4. Beerman B, Groschinsky-Grind M: Clinical pharmacokinetics of diuretics. Clin Pharmacokinet 1980; 5: 221. 5. Chaffman M et al: Indapamide: Review of its pharmacodynamic properties and therapeutic efficacy in hypertension. Drugs 1984; 28: 189. 6. DeTroyer A: Demeclocycline: treatment for syndrome of inappropriate antidiuretic hormone secretion. JAMA 1977; 237: 589. 7. Greene MK, et al: Acetazolamide in prevention of acute mountain sick- ness: a double-blind controlled cross-over study. Br Med J 1981; 183: 811. 8. Maclean D, Tudhope GR: Modern diuretic treatment. Br Med J 1983; 286: 1419. 9. Narins RG, Chusid P: Diuretic use in critical care. Am J Cardiol 1986; 57: 26A 10. Schuster C-J, et al: Blood volume following diuresis induced by furosemide. Am J Med 1984; 76: 585. 11. Tiller DJ, Mudge GH: Pharmacologic agents used in management of acute renal failure. Kidney Int 1980; 18: 700.

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