DIURETICS (Diuretica, synonym: diuretic means, diuretics) — the pharmaceuticals increasing allocation by kidneys of ions of sodium and water and causing in this regard reduction of content of liquid in fabrics and serous cavities of an organism.
There is no standard classification of M. of page. They are classified by different signs (depending on a chemical structure, features of the caused effect and the mechanism of action).
On features of caused M.'s effect of page divide into saluretics, kaliysberegayushchy and osmotic. Saluretics strengthen allocation from an organism of ions of sodium, potassium, etc. Carry to them: 1) derivatives sulfamoylanthranilic to - you, e.g. furosemide (see) and close to it on structure and action bumetanid; 2) derivatives dichlorophenoxyacetic to - you, napr, Acidum etacrynicum (see); 3) derivatives of a petrolthiadiazine — hlortiazid, dichlothiazide (see) and close to them on structure and action Chlortalidonum and Clopamidum; 4) inhibitors of a karboangidraza — Diacarbum (see); 5) organic compounds of mercury (mercury diuretics) — mercusal (see), Novuritum (see), Promeranum (see); 6) derivatives of xanthine — theobromine (see), theophylline (see), Euphyllinum (see). Antagonists of Aldosteronum carry to kaliysberegayushchy M. the page differing in ability to detain allocation of potassium ions from an organism — Spironolactonum (see), etc., and also derivatives of aminopteridine, e.g. Triamterenum (see), and Pyrazinamidum, napr, amiloride. Carry to group of osmotic diuretics mannitol (see) and urea (see). Increase in a diuresis salts of potassium, glucose cause as well other osmotically active agents, napr. Drugs of nek-ry possess diuretic action medicinal plants (see) — a horsetail field, an orthosiphon, a bearberry, etc.
The basic and almost important effect of M. of page is increase in allocation of ions of sodium (tab). Highly effective M. pages (furosemide and ethacrynic to - that) increase allocation of ions of sodium to 25% of the quantity (a filtrational charge of sodium) filtered in balls whereas normal the excreted fraction makes less than 1% of size of a filtrational charge of this ion. At introduction inside these M.' action by the village develops within the first hour and continues within 4 — 9 hour. At intravenous administration their action develops in a few minutes and continues within 1,5 — 3 hour. Derivatives of a petrolthiadiazine at intake render effect in 1 — 2 hour and work within 10 — 12 hour. They increase the excreted fraction of sodium to 8%. The natriuretic effect at Chlortalidonum is longer, than at petrolthiadiazines. Clopamidum on natriuretic effect exceeds petrolthiadiazines and by efficiency is close to furosemide. Mercury diuretics increase the excreted fraction of sodium to 20%. However now they almost lost the practical value in connection with high toxicity.
Along with release of sodium M. of page promote allocation of other ions. So, many saluretics strengthen removal from an organism of potassium ions that can lead to the phenomena hypopotassemias (see). At the same time strengthening of a kaliyurez results from passive processes in a distal tubule: a large amount of nereabsorbirovanny sodium reaches a distal tubule and exchanges on the potassium cosecreted in a gleam of a tubule. Besides, nek-ry M. pages increase negative electric potential in a gleam of a tubule. Thereof positively charged ions of potassium pass from internal environment of canal cells into the gleam of nephron having the increased negative potential, and, thus, losses of potassium with urine increase. Kaliysberegayushchy diuretics reduce release of potassium with urine, and in this regard often apply them in combination with furosemide and petrolthiadiazines to elimination of undesirable gipokaliyemichesky action of the last.
In total M. pages in a varying degree strengthen allocation of ions of chlorine and at prolonged use can promote development of gipokhloremichesky alkalosis (see). Inhibitors of a karboangidraza strengthen excretion with urine of hydrocarbonates that can lead to development of metabolic acidosis (see) and to easing of diuretic effect.
Nek-rye M. of page, in particular derivatives of a petrolthiadiazine, actively cosecrete cells of a canalicular epithelium and competitively slow down secretion uric to - you. At the same time also raises its reabsorptions in tubules. As a result contents uric to - you can increase in blood. Action of petrolthiadiazines, and also furosemide can be followed by a hyperglycemia. M.'s most of page increases activity of a renin of a blood plasma owing to reduction of volume of extracellular liquid, and also probably owing to stimulation of a zone of a dense spot (macula densa) in a distal tubule a large number of the ions of chlorine and sodium passing on nephron. Both mechanisms lead to the increased emission of a renin in blood by cells of the juxtaglomerular device of a kidney. Have such effect furosemide, ethacrynic to - that, organic compounds of mercury, petrolthiadiazines, Spironolactonum. The mannitol reduces secretion of a renin kidneys.
Mechanisms of action The m of page can be considered in three aspects: from the point of view of effect of drugs on various departments of nephron, on influence on biochemical, processes in a kidney and from the point of view of influence on permeability of separate cellular membranes of a wall of a tubule and intercellular intervals, to-rye define flows of ions through a wall of a tubule.
So-called loopback diuretics (furosemide, ethacrynic to - that) work throughout the thick ascending department of a Henle's loop located in cortical and a medulla of a kidney. In a Henle's loop these drugs oppress active transport of ions of chlorine that is the reason of diuretic effect since together with ions of chlorine a large number of ions of sodium is allocated. Other M.S. can influence a reabsorption of ions in a Henle's loop too, but they act or not on all its extent as petrolthiadiazines, or their effect it is expressed more weakly. And ethacrynic to - that vessels of a kidney can expand furosemide and cause redistribution of a renal blood-groove that is followed by reduction of hypertonicity of a medulla. Nevertheless changes of a hemodynamics are not the main reason for a natriuresis. Assume that nek-ry biochemical, mechanisms, napr, inhibition of Na+-, K+ - a dependent adenozintrifosfataza and glycolysis in tissues of a kidney, can be the cornerstone of decrease in active transport of ions a wall of a tubule.
Derivatives of a petrolthiadiazine, Clopamidum and Chlortalidonum unlike furosemide and ethacrynic to - you render effect only on a cortical segment of a Henle's loop where suppress transport of ions of chlorine and do not exert impact on department of a Henle's loop in a medulla of a kidney. It is possible therefore their diuretic effect is expressed more weakly, than the previous group M. has a page. Derivatives of a petrolthiadiazine can affect also proximal department of nephron where they inhibit a karboangidraza and at the expense of it strengthen allocation with urine of hydrocarbonates and phosphates.
Inhibitors of a karboangidraza reduce a reabsorption of hydrosodium carbonate in a proximal tubule, lower secretion of hydrogen ions in a gleam of a tubule, on to-rye in usual conditions reabsorbiruyemy ions of sodium exchange. Inhibitors of a karboangidraza increase allocation with urine of hydrocarbonates and phosphates. Secretion of hydrogen ions decreases in a nek-swarm of degree and in a distal tubule that promotes development of diuretic effect. The mechanism of oppression of a karboangidraza is not finalized by these drugs. Assume that Diacarbum and connections similar to it stimulate adenyl cyclase; it leads to braking of a karboangidraza.
Organic compounds of mercury affect the thick ascending department of a Henle's loop and reduce in it active transport of ions of chlorine. However this effect at mercury diuretics is expressed more weakly, than at furosemide and ethacrynic to - you. The considerable natriuretic effect of mercury diuretics can be explained them with action throughout nephron, including a proximal tubule. In this department of nephron they increase permeability of a wall of a tubule for ions and water, obviously, as a result of increase in permeability of intercellular intervals that leads to decrease in a reabsorption. Biochemical, the mechanism of effect of mercury diuretics consists in blocking of sulphhydryl groups of the enzymes providing active transport of ions. The same mechanisms, obviously, are the cornerstone also of toxic effect of drugs of this group.
Ksantinovy diuretics cause a moderate natriuresis thanks to increase in delivery of sodium and water from proximal department of nephron in distal. It can be a consequence of increase in glomerular filtering, a cut is observed at effect of xanthines, and also increases of a blood-groove on peritubulyarny capillaries in a proximal tubule. Thus, the basic in the mechanism of action of M. of page of this group should be considered their influence on blood circulation in a kidney though it is impossible to exclude also their direct inhibiting effect on a reabsorption of sodium in a proximal tubule. It is obvious also that ksantinovy diuretics can affect processes of transport of ions by blocking of enzyme of phosphodiesterase.
Pages work with Kaliysberegayushchiye M. in collective tubes. They strengthen release of sodium with urine, at the same time reducing allocation of potassium ions and hydrogen. On the mechanism of action pages divide these M. into two groups. Include Spironolactonum in one of them, to-ry is a structural analog and the competitive antagonist Aldosteronum (see). It competitively inhibits receptors of Aldosteronum in protoplasm of cells of collective tubes in this connection Aldosteronum is terminated and permeability for sodium (lyumenalny) cellular membrane turned into a gleam of a tubule decreases. Ions of sodium cannot enter a canal cell and reabsorbirovatsya. Kaliysberegayushchiye M. the page of other group (Triamterenum, amiloride) are non-competitive antagonists of Aldosteronum and directly reduce permeability of a lyumenalny cellular membrane for sodium. Unlike Spironolactonum their effect remains in the absence of Aldosteronum. Reduction of allocation of potassium ions and hydrogen with urine results from decrease in negative intra canalicular potential.
Osmotic diuretics, having filtered in balls and collecting in tubules, increase in them osmotic pressure and reabsorptions of water of hl interfere. obr. in a proximal tubule. Besides, in a proximal tubule intercellular intervals increase and the fluid flow from an interstitium in a tubule increases. Decrease in secretion of a renin the juxtaglomerular device of a kidney at these M.S.' action leads to expansion of the bringing arterioles and build-up of pressure in balls owing to what filtering increases. The blood stream through a medulla raises.
The nek-ry substances which are not relating page to M. can cause diuretic effect. So, e.g., at the hypostases caused by heart failure, the diuretic effect is caused by cardiac glycosides. Increase in a diuresis is observed also under the influence of the substances (albumine, dextrans) promoting development of a hypervolemia.
Indications and contraindications to use.
M of page apply at the developments of stagnation in a small and big circle of blood circulation caused by cardiovascular insufficiency at nephrites, cirrhoses of a liver with the phenomena of portal hypertensia and at other states which are followed by development of an edematous syndrome. As at development of an edematous syndrome the delay of water is preceded by a delay of sodium, diuretics, initially increasing release of sodium, for the second time promote removal of water and reduce hypostases.
M of page apply also to treatment of an idiopathic hypertensia and symptomatic hypertensions. For this purpose apply hl. obr. the derivatives of a petrolthiadiazine, kaliysberegayushchy drugs and M. of page operating in a Henle's loop. Their hypotensive effect is caused by decrease in peripheric vascular resistance owing to decrease in content of sodium and water 'in a vascular wall and reduction of extent of its hydration. The hypovolemia coming owing to loss of sodium and water is other reason of decrease in the ABP. As antihypertensives use hl. obr. petrolthiadiazines and antagonists of Aldosteronum.
Villages (e.g., furosemide) use highly active and high-speed M. for an artificial diuresis at acute poisonings with various medicines and poisons. M.S.'s use is shown after operations with artificial circulation and hemodilution.
Nek-rye M. pages, napr, blockers of a karboangidraza, derivatives of a petrolthiadiazine and urea, apply to treatment of glaucoma. For treatment of acute wet brain as means dehydrational therapy (see) use osmotic diuretics and furosemide. For prevention of an acute renal failure, especially at ischemia of a kidney, apply a mannitol and furosemide, to-rye cause strengthening of current of liquid on tubules and by that obstructions of a gleam of a tubule decomposition products of ischemic cells interfere. Derivatives of a petrolthiadiazine apply to treatment of not diabetes mellitus since they reduce thirst and promote reduction of a polyuria. The mechanism of this paradoxical phenomenon is not quite clear.
M of page are contraindicated at hypotonia, the phenomena of dehydration and a hypovolemia. Other contraindications to M.'s appointment of page are in many respects individual for separate groups of drugs. So, blockers of a karboangidraza are contraindicated at the phenomena of acidosis, and kaliysberegayushchy M. to page — at the phenomena of a hyperpotassemia etc. M.'s most the page cannot be applied at the expressed damages of a liver. At the heavy renal failure which is followed by falloff of glomerular filtering do not apply mercury M. of page, tiazidovy derivatives, veroshpiron, urea.
Collateral by action, page it is connected generally with their ability to strengthen excretion of these or those ions. So, many drugs, especially from among saluretics, cause a hypopotassemia, edges the hl is shown. obr. muscular weakness, changes of an ECG. At the expressed hypopotassemia also arrhythmias of heart, disturbance of functions of kidneys are possible. For prevention and stopping of the phenomena of a hypopotassemia it is necessary to appoint drugs of potassium. Besides, for prevention of a hypopotassemia it is necessary to appoint the diet rich with potassium (potatoes, carrots, beet, apricots, etc.), and saluretics in a combination with kaliysberegayushchy M. S. Nek-rye M. pages can cause a gipokhloremichesky alkalosis, at development to-rogo appoint ammonium chloride and potassium chloride. At prolonged use of furosemide and derivatives of a petrolthiadiazine the exacerbation latentno of the proceeding gout owing to increase in contents uric to - you in blood, and also a decompensation of a diabetes mellitus is possible. At kaliysberegayushchy M.S.' use the phenomena of a hyperpotassemia are possible, edges is eliminated with alternation of administrations of drugs of this group with saluretics.
Table. Change of ionic composition of urine and the maximum excretion of sodium at effect of the main diuretics
Bibliography: Berkhin E. B. Diuretics, M., 1967, bibliogr.; In and N of au grads of A. V. Modern questions of therapeutic use of diuretics, Cardiology, t. 14, No. 7, page 97, 1974; Lebedev A. A. and Kantariya V. A. Diuretics, Kuibyshev, 1976, bibliogr.; Yu. V is ground. Cellular mechanisms of effect of diuretics, Cardiology, t. 13, No. 8, page 5, 1973, bibliogr.; Jacobson H. R. and. To about k k about J. P. Diuretics, Ann. Rev. Pharm. Toxicol., v. 16, p. 201, 1976; The pharmacological basis of therapeutics, ed. by L. S. Goodman a. A. Gilman, p. 817, N. Y. a. o., 1975.
A. A. Lebedev.