Diuretic actions

Okusa MD, Ellison DH (2000) Physiology and pathophysiology of diuretic actions. In Seldin DW, Giebisch G (eds) The kidney. Physiology and pathophysiology. Lippincott Williams Wilkins, Philadelphia, p. 2877-2922... 

This indoline derivative has antihypertensive and diuretic actions. Indapamide (233) in methanol under nitrogen was irradiated with a medium-pressure mercury lamp through a copper sulphate filter solution for 12 h. The filter removed wavelengths below 300 nm. Products were separated by preparative TLC and identified as 2-methylindoline (234), the formylhydrazide (235), the amide (237) and semicarbazide. The procedure was repeated under oxygen to give the above products plus the urethane (236), acid (238), ester (239) and TV-acetylanthranilic acid [146]. 

These compounds competitively inhibit phosphodiesterase, resulting in an increase in cyclic AMP (see Box 14.3) and subsequent release of adrenaline. This leads to the major effects a stimulation of the central nervous system (CNS), a relaxation of bronchial smooth muscle, and induction of diuresis. These effects vary in the three compounds. Caffeine is the best CNS stimulant, and has weak diuretic action. Theobromine has little stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine. 

The diuretic action of chlorothiazide, like other drugs of this series, is caused by reduced absorption of sodium and chloride ions by the kidneys during their simultaneous, intense excretion from the organism. 

This drug exhibits strong diuretic action during both acidosis and alkalosis. It is used for arterial hypertension, in edematous syndromes of various genesis, congestive effects in cardiovascular insufficiency, nephrosis and nephritis, and toxicosis. It is especially recommended for hypertonic illnesses. It lowers intraocular pressure in a number of cases. Synonyms of this drug are clotride, diupres, diuril, and others. 

Borage Borage officinalis) Uses Oil used for eczema d matitis as a GLA supplement treat colds, coughs, bronchitis anti-inflammatory action used to treat arthritis Action Oil contains gamma linoleic acid (GLA) its metabohtes that are anti-inflammatory topical oil absorbed in skin t fluid retention in stratum comeum mucilage mahe acid components have ejqjectorant diuretic actions contains alkaloids that are hqjatotoxic AvaUable fonns Caps w/ 10-25%... 

This chapter includes an overview of the features of fluid balance and renal function that are essential to understanding diuretic action, a discussion of the uses of diuretics for treating abnormalities of fluid balance, and a detailed description of the various classes of diuretics. The practitioner who is armed with the knowledge of the mechanism of action of diuretic drugs and with appropriate recognition and respect for their potential side effects can use these compounds with a high degree of efficacy and safety. 

Several additional noteworthy features of proximal Na" transport are relevant to diuretic action. First, since several transport proteins mediate proximal Na" reabsorption, no single diuretic would be expected to inhibit all these processes. Consequently, inhibition of any one mechanism leaves the others unaffected and able to... 

Thiazide diuretics act in the distal convoluted tubule, where they block Na -Cl cotransport (Fig. 21.4). The Na" -Cl cotransport takes place on the luminal surface of distal convoluted tubules. Thus, to exert their diuretic action, the thiazides must reach the luminal fluid. Since the thiazide diuretics are largely bound to plasma proteins and therefore are not readily filtered across the glomeruli, access to the luminal fluid is accomplished by the proximal tubule organic acid secretory system. The drugs then travel along the nephron, presumably being concentrated as fluid is abstracted, until they reach their site of inhibitory action in the distal convoluted tubule. 

All of the loop diuretics are available for both oral and parenteral administration. Their onset of action is rapid, usually within 30 minutes after oral and 5 minutes after intravenous administration. They produce peak diuresis in about 2 hours, with a total duration of diuretic action of approximately 6 to 8 hours. Loop diuretics are extensively bound to plasma proteins and are eliminated in the urine by both glomerular filtration and tubular secretion. Approximately a third of an administered dose is excreted by the liver into the bile, from where it may be eliminated in the feces. Only small amounts of these compounds appear to be metabolized by the liver. 

Acetazolamide inhibits the enzyme carbonic anhydrase, and interferes with the ability of the renal tubules to produce and secrete hydrogen ions. And, the diuretic action is due to the decreased sodium biocarbonate absorption in proximal tubules and diminished hydrogensodium exchange in the distal tubules. 

Kidney Methylxanthines exert mild diuretic action by inhibiting tubular reabsorption of sodium and water. In addition, it increases renal blood flow and glomerular filtration rate. 

These agents inhibit the Na-i- ion channei in the iuminai epitheiium. This causes hyperpolarisation of the iuminai membrane and iimits the transfer of cations across the iuminai surface. Flyperpolarisation not only prevents the reabsorption of Na-i- but aiso reduces the excretion of intracellular cations such as K+, Ca2+, Fi+ and Mg2+. The abiiity of sodium ion channel inhibitors to reduce the excretion of K+ is used to conserve body K+ in patients who are taking thiazide or loop diuretics and for this reason they are more commoniy known as the K-i-sparing diuretics. They are rarely used alone because their diuretic action is weak, instead they are administered in combination with thiazide or ioop diuretics for their antikaiuretic effect. Combination therapy is also synergistic when used in the treatment of hypertension. 

Of the various solutes reabsorbed in the proximal tubule, the most relevant to diuretic action are NaHC03 and NaCI. Of the currently available diuretics, only one group (carbonic anhydrase inhibitors, which block NaHC03 reabsorption) acts predominantly in the PCT. 

Loop diuretics selectively inhibit NaCI reabsorption in the TAL. Because of the large NaCI absorptive capacity of this segment and the fact that the diuretic action of these drugs is not limited by development of acidosis, as is the case with the carbonic anhydrase inhibitors, loop diuretics are the most efficacious diuretic agents currently available. 

A much milder and legal stimulant is caffeine, depicted in Figure 14.27. A number of mechanisms have been proposed for caffeines stimulatory effects. Perhaps the most straightforward mechanism is caffeine s facilitating of the release of norepinephrine into synaptic clefts. Caffeine also exerts many other effects on the body, such as dilation of arteries, relaxation of bronchial and gastrointestinal muscles, diuretic action on the kidneys, and stimulation of stomach-acid secretion. 

Stevia Stevia rebaudiana) Uses Natural sweetener, hypoglycemic and hypotensive properties Actions Multiple chemical components sweetness d/t glycoside, stevioside hypotensive effect may be d/t diuretic action or vasodilation action Available forms Liq extract, powder, caps Notes/SE HA, dizziness, bloating Interactions T Hypotensive effects W/ antihypertensives esp CCB, diuretics EMS Monitor BP does not encourage dental caries may -1-glucose St. John s Wort (Hypericum perforatum) Uses Mild-mod depression, anxiety, anti-inflammatory, immune stimulant/anti-HIV/antiviral, gastritis, insomnia, vitiligo Action MAOI in vitro, not in vivo bacteriostatic bactericidal, T capillary blood flow, uterotonic activity in animals Efficacy Variable benefit w/ mild-mod depression in several trials, but not always seen in clinical practice Available forms Teas, tabs, caps, tine, oil ext for topical use Dose 2-4 g of herb or 0.2-1 mg of total hypericin (standardized extract) daily Notes/SE Photosensitivity (use sunscreen) rash, dizziness, dry mouth, GI distress Interactions Enhance MAOI activity, EtOH, narcotics, sympathomimetics EMS T Risk of photosensitivity Rxns t effects of opioids and sympathomimetics... 

AMP is related to certain mental diseases and may be involved in the action of tranquilizers and antidepressant drugs (60). Whether the ability of diuretic agents such as ethacrynic acid and chlorthalidone to inhibit the enzyme in kidney (68) is related to their diuretic action is also not known. It has been suggested that inhibition of diesterase by diazoxide (59) may explain the hyperglycemic activity of this agent. Several materials are known to activate the enzyme. Imidazole produces strong activation of the enzyme from mammalian tissues (36, 38, 42) but not from E. coli (41). It has been reported (61) that insulin activates the beef heart enzyme in vitro, but it is not known if this has relevance... 

Moses AM, Howanitz J, Miller M. Diuretic action of three sulfonylurea drugs. Ann Intern Med 1973 78(4) 541-4. 

They act on the kidney by depressing the mechanisms that govern the active reabsorption of sodium and chloride ions. They are rapidly excreted by the kidney but their use is hazardous because their action is believed to be due to inorganic mercury ions released by rupture of the carbon-to-mercury bond, probably followed by the firm attachment of the mercury ion to a sulphydryl group of a renal enzyme. The administration of dimercaprol (SO), a strong chelating agent for mercury, removes mercury from the kidney and terminates the diuretic action. It is of interest that Paracelsus used calomel (mercurous chloride) as a diuretic. 

The nettle is rich in vitamins A and C and in minerals, particularly iron, potassium, and silica. Modern scientific studies have focused on its diuretic action. It lowers systolic blood pressure by increasing volume, die root treats symptoms of benign prostatic hyperplasia (BPH) by increasing urine flow and reducing residual urine. Nettle herb is also used for bladder irrigation and to prevent and treat bladder and kidney stones (see Chapter 66). 

There are also many drugs and dietary supplements that may have diuretic action as a side effect, but have a different primary purpose. For example, the supplement creatine is an ergogenic (energy-enhancer), but it also promotes fluid loss with regular use. 

Some diuretics have direct vasodilating effects in addition to their diuretic action. Indapamide is a nonthiazide sulfonamide diuretic with both diuretic and vasodilator activity. As a consequence of vasodilation, cardiac output remains unchanged or increases slightly. Amiloride inhibits smooth muscle responses to contractile stimuli, probably through effects on transmembrane and intracellular calcium movement that are independent of its action on sodium excretion. 

Most diuretics act upon a single anatomic segment of the nephron (Figure 15-1). Because these segments have distinctive transport functions, the first section of this chapter is devoted to a review of those features of renal tubule physiology that are relevant to diuretic action. The second section is devoted to the basic pharmacology of diuretics, and the third section discusses the clinical applications of these drugs. 

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