Chapter: Modern Pharmacology with Clinical Applications: Diuretic Drugs

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Osmotic Diuretics

Osmotic diuretics owe their effects to the physical re-tention of fluid within the nephron rather than to direct action on cellular sodium transport.

Osmotic Diuretics

Osmotic diuretics owe their effects to the physical re-tention of fluid within the nephron rather than to direct action on cellular sodium transport. These compounds are not electrolytes, and they are freely filtered at the glomerulus and not reabsorbed to a significant extent. Ideally, these drugs should be water-soluble com-pounds, well absorbed after oral administration, freely filtered at the glomerulus, poorly reabsorbed by the tubule, and devoid of pharmacological effects. The pro-totype is mannitol (Osmitrol), an unmetabolizable poly-saccharide derivative of sucrose. Other clinically avail-able osmotic diuretics include glycerin (Glycerol, Osmoglyn, and the topical agent Ophthalgan), isosor-bide (Ismotic), and urea (Ureaphil, Urevert). Since these osmotic agents act in part to retard tubule fluid reab-sorption, the amount of diuresis produced is propor-tional to the quantity of osmotic diuretic administered. Therefore, unless large quantities of a particular os-motic diuretic are given, the increase in urinary volume will not be marked.

Ideally, the distribution of osmotic diuretics should be largely confined to the vascular system, although this can lead to excessive expansion of the vascular com-partment. Such an overexpansion could precipitate pul-monary edema or increase cardiac work or both. This is largely the result of rapid transfer of fluid from the in-terstitial to the vascular compartment. Practically speaking, however, few osmotic diuretics are available for therapeutic use. These agents, therefore, should be given cautiously to patients with compromised cardiac function.

Mechanism of Action

The renal response to osmotic diuretics is probably due to the interplay of several factors. The primary effect in-volves an increased fluid loss caused by the osmotically active diuretic molecules; this results in reduced NA+ and water reabsorption from the proximal tubule.

An additional contributing factor to the diuresis in-duced by osmotic diuretics is the increase in renal medullary blood flow that follows their administration. This medullary hyperemia reduces the cortex– medullary osmolar gradient by carrying away intersti-tial NA+ and urea. This partial reduction of the osmolar gradient impairs normal reabsorption of tubular water, which occurs from the descending limb of Henle and the collecting duct.

Finally, there is an additional increase in electrolyte excretion due to impairment of ascending limb and dis-tal tubule NA+ reabsorption; this occurs as a result of lowered tubular NA+ concentration and the increased tubular fluid flow rate.

Individual Agents Mannitol

Mannitol (Osmitrol) is a six-carbon sugar that does not undergo appreciable metabolic degradation. It is not absorbed from the gastrointestinal tract and there- fore must be given intravenously. Humans do not reab-sorb it in the proximal tubules.

Mannitol is particularly useful in clinical conditions characterized by hypotension and decreased glomeru-lar filtration. These symptoms are usually the result of some physical trauma or surgical procedure. Mannitol is useful in maintaining kidney function in these condi-tions, since even at reduced rates of filtration, a suffi-cient amount of the sugar may enter the tubular fluid to exert an osmotic effect and thus continue urine forma-tion. However, if circulatory failure is profound and glomerular filtration is severely compromised or absent, not enough mannitol may reach the tubules to be effec-tive. The ability to maintain urine flow when renal shut-down might otherwise be expected aids in preventing kidney tubular damage. In addition, mannitol has been used to reduce cerebral edema during neurosurgery, to reduce intraocular pressure before surgery for glau-coma, and to promote the elimination of ingested toxic substances.

The major characteristics of the renal response to mannitol diuresis include a fall in urine osmolality and a decrease in the osmolality of the interstitial fluid of the renal medulla. The quantity of urine formation and NA+ excretion is generally proportional to the amount of mannitol excreted. Although there is a significant inhibi-tion of proximal water reabsorption, the effects of man-nitol on proximal NA+ reabsorption are not marked.

The major adverse reactions associated with manni-tol administration are headache, nausea, vomiting, chest pain, and hyponatremia. Too rapid an administration of large amounts may cause an excessive shift of fluid from the intracellular to the extracellular compartment and result in congestive heart failure.

Glycerin

The primary use of anhydrous glycerin (Ophthalgan) is as an osmotic agent that is applied topically to reduce corneal edema. Orally administered glycerin (Glycerol, Osmoglyn) is used to reduce intraocular pressure and vitreous volume before ocular surgery.

Urea

The use of urea (Ureaphil, Urevert) has declined in recent years owing both to its disagreeable taste and to the increasing use of mannitol for the same purposes. When used to reduce cerebrospinal fluid pressure, urea is generally given by intravenous drip. Because of its po-tential to expand the extracellular fluid volume, urea is contraindicated in patients with severe impairment of renal, hepatic, or cardiac function or active intracranial bleeding.

Isosorbide

Isosorbide (Ismotic) is an orally effective, osmoti-cally active drug that is most commonly used for theemergency treatment of acute angle-closure glaucoma. It should not be confused with isosorbide dinitrate, an antianginal drug.

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