Extracellular fluid volume, diuretics

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. 

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. 

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). 

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. 

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. 

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. 

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. 

Diuretics, particularly the thiazides, are useful antihypertensives. They cause an initial loss of sodium with a parallel contraction of the blood and extracellular fluid volume. The effect may reach 10% of total body sodium but it is not maintained. After several months of treatment, the main blood pressure lowering effect appears to reflect a reduced responsiveness of resistance vessels to endogenous... 

Ascites is a defined compartment of the extracellular fluid volume, which is difficult to mobilize. If the reduction in weight is inadequate after appropriate basic therapy (< 1.2 kg after 4 days), stage II should be initiated with the cautious administration of diuretics. The steps already detailed for stage I are to be continued, whereby the intake of dietary sodium is restricted even further (= 3g/day). (s. tab. 16.12)... 

Diuretics (see 19.17 Diuretics) are prescribed for hypertension that is not caused by renal-angiotensin-aldosterone involvement because diuretics increase rennin serum level. Diuretics promote sodium depletion decreasing extracellular fluid volume. Commonly prescribed diuretics are ... 

Edema is a common manifestation of volume overload and extracellular fluid volume expansion. Clinicians should evaluate patients for signs and symptoms of volume overload (e.g., pitting edema, rales, ascites, shortness of breath, and increased weight). Blood pressure monitoring in the clinic setting and at home if feasible to detect hypertension is also warranted. As kidney disease progresses dietary intervention and diuretic therapy (based on the degree of kidney function) will likely become necessary. 

The distal tubule secretes 80% of the uric acid content in urine. The reabsorption of most of the uric acid (98%) in the glomerular filtrate takes place in the proximal tubule. This reabsorption can be inhibited by thiazide diuretics, thus increasing uric acid excretion in urine. The chronic use of diuretics, however, by depleting the extracellular fluid volume provides a stimulus for uric acid reabsorption. Drugs that promote uric acid excretion (uricosuric drugs) include probenecid, sulfinpyrazole, and salicylates in high doses. In low doses salicylates depress uric acid excretion. 

Diuretics may cause reductions in glomerular filtration rate either by a direct effect to constrict the renal arterial supply or secondary to their induction of extracellular fluid volume contraction. Listed in Table 1 are the renal hemodynamic alterations induced in the experimental animal or in man by the most commonly employed currently available diuretic agents. Acetazolamide, a proximally active agent and the prototypical carbonic anhydrase inhibitor (Figure 1), consistently reduces renal blood flow by 25 to 37% and... 

A major use of loop diuretics is in the treatment of acute pulmonary edema. A rapid increase in venous capacitance in conjunction with a brisk natriuresis reduces left ventricular filling pressures and thereby rapidly relieves pulmonary edema. Loop diuretics are also used widely for the treatment of chronic CHE when diminution of extracellular fluid volume is desirable to minimize venous and pulmonary congestion. In this regard, a metaanalysis of randomized clinical trials demonstrates that diuretics cause a significant reduction in mortality and the risk of worsening heart failure, as well as an improvement. 

Diuretics are drugs that increase the rate of urine flow clinically useful diuretics also increase the rate of excretion of Na+ (natiiuresis) and an accompanying anion, usually CD. Most clinical applications of diuretics aim to reduce extracellular fluid volume by decreasing total-body NaCl content. Although continued administration of a diuretic causes a sustained net deficit in total-body Na+, the time course of natriuresis is finite because renal compensatory mechanisms bring Na+ excretion in line with Na+ intake, a phenomenon known as diuretic braking. Compensatory mechanisms include activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone axis, decreased arterial blood pressure (which reduces pressure natriuresis), hypertrophy of renal epithelial cells, increased expression of renal epithelial transporters, and perhaps alterations in natriuretic hormones such as atrial natriuretic peptide. 

By extracting water from intracellular compartments, osmotic diuretics expand the extracellular fluid volume, decrease blood viscosity, and inhibit renin release. These effects increase RBF, and the increase in renal medullary blood flow removes NaCl and urea from the renal medulla, thus reducing medullary tonicity. Under some circumstances, prostaglandins may contribute to the renal vasodilation and medullary washout induced by osmotic diuretics. A reduction in medullary tonicity causes a decrease in the extraction of water from the DTL, which limits the concentration of NaCl in the tubular fluid entering the ATL. This latter effect diminishes the passive reabsorption of NaCl in the ATL. In addition, osmotic diuretics may also interfere with transport processes in the TAL. 

Osmotic diuretics induce few adverse effects, but expansion of the extracellular fluid volume can occur, as noted above. Alteration of blood sodium levels can be seen, and these drugs should not be used in anuric or unresponsive patients. If cranial bleeding is present, mannitol or urea should not be used. 

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