Mercury diuretic action

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]. 

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 present classes of diuretic drugs have contributed much useful information to the chemist and to the biologist. From the mercurial diuretics, on the biological side, some facts have been learned about their site of action, if not the exact mechanism of action, and they have been helpful in the study of the site of the transport of various ions by the kidney. The importance of sulfhydryl enzyme systems has been demonstrated, although the specific enzyme has not been identified. On the chemical side, the chemist has learned about the structural requirements for useful activity, the nature of the carbon-mercury attachment, and the organic structures most useful as carrying moieties for mercury. 

Ethacrynic acid (Table 10-11) is a powerful loop diuretic whose molecular mechanism of action is not fully clear. However, it has marked pharmacodynamic similarities to the mercurial diuretics such as merbaphen (see above) and mersalyl, both of which are also phenoxyacetic acid derivatives, as well as in vitro and in vivo comparability in its reaction with SH groups It competes with them for the same receptors. It is not surprising that an analogy, if not identity, of mechanism of action at the cellular level has been proposed. Equation 10.5, which illustrates a Michael-type addition, might represent a possible enzyme inactivation. 

The mercurial diuretics essentially contain in an organic molecule. They usually inhibit sodium reabsorption in the proximal tubuler and ascending loop of Henle. There may be slight effect in the distal tubule where inhibition of chloride reabsorption also occurs. The mercurials have been foimd to enhance excretion though potassium loss is less than that produced by many other diuretics. However, the overall action of mercurial diuretics is invariably increased by acidification of urine. The mercurial diuretics are not very much used in clinical practices due to their pronormced and marked side-effects viz., mercurialism, hypersensitivity and excessive diuresis which may lead to electrolyte depletion and vascular complications. Most of the mercurials are administered by intramuscular route and the availability of orally active diru etics has limited their use. 

The mechanism of action of the mercurial diuretics described under Section 13.2.1 are stated as under ... 

The drug happens to be powerful loop diuretic whose exact molecular mechanism of action is not yet fully understood. Interestingly, it has been observed that it does possess marked pharmaeodynamie similarities of the mercurial diuretics like mersalyl which being a phenoxyacetic structural analogue. Besides, it exhibits both in vivo and in vivo compatibility in its reaction with SH moieties. Moreover, it logically competes with them for the same receptors. 

The acidotic diuretics are essentially the inorganie eompoimds having a eation funetion. Examples are-ammonium or calcium, combined with a fixed anion viz., chloride ion, which causes two vital, actions, namely systemic hyperchloremic acidosis and weak diuretic effect. These eompoimds e.g., ammonium chloride, calcium chloride) invariably potentiate the diuretic action of mercurial diuretics and hence may be administered at least 48-72 hours prior to the treatment of a mercurial compound so as to facilitate hyperehloremic acidosis. Recently, insoluble cation exchange resins have been used to act as diuretics by this mechanism. 

From his studies with ethacrynic acid, Cafruny concludes that ethacrynic acid does react with protein-bound sulfhydryl of renal cells. He further states that the data indicate that ethacrynic acid occupies the same "receptors and may share the same mechanism of action as the mercurials" and that ethacrynic acid "probably blocks reabsorption of soditjm in the same way as mercurials and in most respects is the "non-mercurial mercurial" diuretic it was designed to be". 

The site of action of mercurial diuretics is predominantly intrarenal. An increased release of sodium ion is found along with water, and the conclusion is that the reabsorption of Na is inhibited by binding at transport sites. The interference with sodium transport from the urine to the renal tubules, which cleanse the blood and effect recycling of the glomerular filtrate produced by the kidney, thus decreases the reabsorption of both the salt and water and results in increased efflux. 

Amino- and hydrazino-quinazolines exhibited antibacterial activity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was made. " The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by, 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines. 7-Chloro-6-sulfonamido-4(37I)quinazolinones are more effective than the mercury diuretics and can be administered orally. The 1 -dihydro derivatives are even more effective and one (59) has been marketed under the name Quinethazone. ... 

The medicinal use of mercurials can also be traced back over 3000 years. They were used by Discorides Pedanius and Pliny as a treatment for syphilis and various skin disorders (Farler 1952). During the eighth and eleventh centuries, Mesue, Rhazas, and Avicenna are also reported to have used mercurial ointments as medicines (Magos 1975). In 1881, the antiseptic action of HgCl2 was demonstrated, and between 1900 and 1920 mercurials were introduced for diuretic... 

Even today, after the development of many powerful and useful new drugs, the organomercurials are unique among these potent diuretics, in spite of their several disadvantages. The mercurials cause little or minimal potassium loss and, in fact, under certain conditions, may exhibit a potassium-sparing action. They are not known to disturb carbohydrate metabolism. They do not cause uric acid retention and certain of them have been shown to have a uricosuric action in man. Whether these desirable properties are a consequence of their structure and mode of action or result from the intermittent or spaced manner of administration is not clear. But these properties of the mercurials continue to be a challenge to the medicinal chemist and present objectives for the design of new structures. 

This approach to the design of structures that mimic the diuretic activity of the mercurials has led to the extremely potent compounds that lack certain of the disadvantages of the mercury-containing drugs and may share, in part, a common mechanism of action. However, other desirable attributes of the mercurials have not been reproduced. Ethacrynic acid, the only compound that has had extensive study both in animals and in man, causes potassium loss and uric acid retention and perhaps some disturbance of glucose metabolism although this latter effect appears to be minimal compared to that observed with many diuretics of the sulfonamide class. 

The number of proteins capable of metal interaction is enormous but actions of gold in arthritis (Chapter 11), and mercury in diuretics (Chapter 12.1), are two examples which may be traced to enzyme inhibition. The antibacterial effect of mercury is also probably due to enzyme inhibition (Chapter 9.1.1), contrasting with the inhibition of DNA synthesis by silver (Chapter 9.1.2). 

Antibacterial complexes such as silver sulfadiazene and some mercurials also manifest antiviral activity [51, 52]. Mersalyl, a diuretic (Chapter 12), has some in vivo action when mice treated with lethal doses of coxsackie virus are then administered the mercury complex [53]. The levels needed for 100% inactivation in vitro by mercurials is dependent on the virus, and thiols reverse the antiviral effect [54]. Conformational changes and breakdown into subunits have also been observed after mercury treatment [51],... 

Miscellaneous biological effects of well-defined metal complexes include nitroprusside as vasodilator, neuromuscular blocking by large metal cations, and diuretic effects of mercury complexes. Their mechanisms of action all involve complicated inhibition of enzymes. 

The diuretic activity and pharmacological properties of the organic mercurials and of ethacrynic acid and furosemide are already well-documented. Discussion of these agents will be confined to recent studies pertaining to their biochemical mechanisms of action. 

Modern diuretics contain no mercury. Many of them, like amiloride (N-amidino-3,5 diamino-6-chloropyrazine-2-carboxamide) and the pteri-dine diuretic, triamterene ( Dytac ) (r. i), act on the membrane lining the distal tubule, preventing resorption of sodium ions (and hence of water) (Crabbe, 1968 Wiebelhaus et al. 1965). The simpler molecule 2,4-diamino-6,7-dimethylpteridine is almost as active. Others, like frus-emide and ethacrynic acid, seem to act somewhat similarly. It is less certain that the thiazides, such as (14.2), act in this way. For more information on the action of diuretics, see Suki, Eknoyan, and Martinez-Maldonado... 

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