Extracellular fluid volume

The integrity of mammalian kidneys is vital to body homeostasis, because the kidneys play the principal role in the excretion of metabolic wastes and the regulation of extracellular fluid volume, electrolyte balance, and acid-base... 

FIGURE 10-2. Distribution of body fluids showing the extracellular fluid volume, intracellular body fluid volume, and total body fluids in a 70 kg adult. Extracellular volume (ECV) comprises 14 liters of total body fluid (42 liters). Plasma volume makes up approximately 3 liters of the 14 liters of ECV. Intracellular volume accounts for the remaining 28 liters of total body fluids with roughly 2 liters being located within the red blood cells. Blood volume (approximately 5 liters) is also depicted and is made up of primarily red blood cells and plasma. (Reprinted from Guyton AC, Hall JE. Textbook of Medical Physiology. 8th ed. Philadelphia Saunders, 1991 275, with permission.)... 

Diuretics are a group of therapeutic agents designed to reduce the volume of body fluids. Their mechanism of action is at the level of the kidney and involves an increase in the excretion of Na+ and Cl ions and, consequently, an increase in urine production. As discussed in Chapter 2, sodium is the predominant extracellular cation and, due to its osmotic effects, a primary determinant of extracellular fluid volume. Therefore, if more sodium is excreted in the urine, then more water is also lost, thus reducing the volume of extracellular fluids including the plasma. 

Sodium is the major extracellular cation. Because of its osmotic effects, changes in sodium content in the body have an important influence on extracellular fluid volume, including plasma volume. For example, excess sodium leads to the retention of water and an increase in plasma volume. Increased plasma volume then causes an increase in blood pressure. Conversely, sodium deficit leads to water loss and decreased plasma volume. A decrease in plasma volume then causes a decrease in blood pressure. Therefore, homeostatic mechanisms involved in the regulation of plasma volume and blood pressure involve regulation of sodium content, or sodium balance, in the body. 

Acutely, diuretics lower BP by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and, consequently, BP. The initial drop in cardiac output causes a compensatory increase in peripheral vascular resistance. With chronic diuretic therapy, the extracellular fluid volume and plasma volume return almost to pretreatment levels, and peripheral vascular resistance falls below its pretreatment baseline. The reduction in peripheral vascular resistance is responsible for the long-term hypotensive effects. Thiazides lower BP by mobilizing sodium and water from arteriolar walls, which may contribute to decreased peripheral vascular resistance. 

Some physiological volumes are known or have been estimated. Over two decades ago, Oie and Tozer proposed a relationship between the volume of distribution of a drug and its extent of plasma and tissue binding, using various fixed values for plasma and extracellular fluid volumes [1], This equation has been utilized in some methods used for prediction of steady-state VD, which will be discussed later ... 

Despite their successful use for at least 20 years, the mechanisms by which they lower the blood pressure remain uncertain. Theories to explain the antihypertensive effectiveness of the diuretic agents have included a) alteration of sodium and water content on arterial smooth muscle, b) the induction of a decreased vascular response to catecholamines, c) a decrease in blood volume and total extracellular fluid volume, and d) a direct vasodilator action independent from the diuretic effect(12). 

Ratio of binding proteins in extracellular fluid (except plasma) to binding proteins in plasma Correlation coefficient Elimination half-life Volume of distribution Volume of extracellular fluid Volume of plasma Volume of remaining fluid... 

Distribution in the body is determined by the ability to penetrate membranous barriers (p. 20). Hydrophilic substances (e.g., inulin) are neither taken up into cells nor bound to cell surface structures and can, thus, be used to determine the extracellular fluid volume (2). Some lipophilic substances diffuse through the cell membrane and, as a result, achieve a uniform distribution (3). 

Mobilization of edemas (A) In edema there is swelling of tissues due to accumulation of fluid, chiefly in the extracellular (interstitial) space. When a diuretic is given, increased renal excretion of Na and H2O causes a reduction in plasma volume with hemoconcentra-tion. As a result, plasma protein concentration rises along with oncotic pressure. As the latter operates to attract water, fluid will shift from interstitium into the capillary bed. The fluid content of tissues thus falls and the edemas recede. The decrease in plasma volume and interstitial volume means a diminution of the extracellular fluid volume (EFV). Depending on the condition, use is made of thiazides, loop diuretics, aldosterone antagonists, and osmotic diuretics. 

Too rapid or excessive administration may result in hypernatremia and alkalosis accompanied by hyperirritability or tetany. Hypernatremia may be associated with edema and exacerbation of CHF due to the retention of water, resulting in an expanded extracellular fluid volume. 

The parameters Vp, Vg and are the plasma and extracellular fluid volumes and the extravascular to intravascular protein (albumin) ratio, respectively. Their values in human, as an example, are 0.0436 and 0.151 L/kg, respectively, with a ratio of 1.4. 

The use of urea (Ureaphil, Ur evert) 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 potential to expand the extracellular fluid volume, urea is contraindicated in patients with severe impairment of renal, hepatic, or cardiac function or active intracranial bleeding. 

Mechanism of Action A sulfonamide derivative that acts as a thiazide diuretic and antihypertensive. As a diuretic, blocks reabsorption of water and the electrolytes sodium and potassium at cortical diluting segment of distal tubule. As an antihypertensive, reduces plasma and extracellular fluid volume, decreases peripheral vascular resistance (PVR) by direct effect on blood vessels. Therapeutic Effect Promotes diuresis, reduces BP. 

Mechanism of Action A thiazide diuretic that blocks reabsorption of sodium, potassium, and water at the distal convoluted tubule also decreases plasma and extracellular fluid volume and peripheral vascular resistance. Therapeutic Effect Produces diuresis lowers BP. 

Urea is contraindicated in patients with severe impairment of renal, hepatic or cardiac function due to their potential effect on expansion of the extracellular fluid volume. 

Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the TAL. Saline solution must be administered to replace urinary losses of Na+ and to provide , so as to avoid extracellular fluid volume depletion. 

Furosemide rarely causes the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (although it has been found useful in treating some patients with SIADH who cannot tolerate water restriction (428)). In furosemide-induced cases (SEDA-7, 246), serum ADH concentrations were raised, total body sodium was normal, total body potassium greatly reduced, and intracellular water raised at the expense of extracellular fluid volume. However, such cases are rare, and no new cases have been published since this complication was reported in SEDA-7. 

The most serious side effects of diuretics are fluid depletion and electrolyte imbalance.13,88 By the very nature of their action, diuretics decrease extracellular fluid volume as well as produce sodium depletion (hyponatremia) and potassium depletion (hypokalemia). Hypokalemia is a particular problem with the thiazide and loop diuretics, but occurs less frequently when the potassium-sparing agents are used. Hypokalemia and other disturbances in fluid and electrolyte balance can produce serious metabolic and cardiac problems and may even prove fatal in some individuals. Consequently, patients must be monitored closely, and the drug dosage should be maintained at the lowest effective dose. Also, potassium supplements are used in some patients to prevent hypokalemia. 

The primary function of the renal system is the elimination of waste products, derived either from endogenous metabolism or from the metabolism of xenobiotics. The latter function is discussed in detail in Chapter 10. The kidney also plays an important role in regulation of body homeostasis, regulating extracellular fluid volume, and electrolyte balance. 

The one-compartment model of distribution assumes that an administered drug is homogeneously distributed throughout the tissue fluids of the body. For instance, ethyl alcohol distributes uniformly throughout the body, and therefore any body fluid may be used to assess its concentration. The two-compartment model of distribution involves two or multiple central or peripheral compartments. The central compartment includes the blood and extracellular fluid volumes of the highly perfused organs (i.e., the brain, heart, liver, and kidney, which receive three fourths of the cardiac output) the peripheral compartment consists of relatively less perfused tissues such as muscle, skin, and fat deposits. When distributive equilibrium has occurred completely, the concentration of drug in the body will be uniform. 

Drugs that show extensive tissue binding are said to have an apparent volume of distribution many times the total body size. For example, digoxin (see Chapter 35), which binds to plasma protein to the extent of 23%, has an apparent volume of distribution of 8 1/kg. The volume of distribution of drugs that do not bind to plasma or tissue proteins varies between the extracellular fluid volume (16 liters) and the total body water (42 liters). Insulin, sodium, and iodine are confined to the extracellular water, whereas caffeine and ethanol are distributed in the total body water. 

The kidney and bladder are very important in toxicology because they are the main route of elimination of hydrophilic toxicant metabolites and because damage to them in the form of impaired kidney function or bladder cancer is one of the major adverse effects of toxicants. The kidney plays a key role in maintaining body homeostasis. The basic unit of the kidney, through which the organ performs its crucial blood filtration action, is the nephron. As the main organ through which fluid is lost from the body, it is vital in the maintenance of extracellular fluid volume. It acts to maintain... 

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