Structure activity relationship of thiazide diuretics and weight

Chlorothiazide | C7H6ClN3O4S2 - PubChem

structure activity relationship of thiazide diuretics and weight

UNII: W31X2H97FB; CAS number: ; Weight: Average: Torasemide (INN) or torsemide (USAN) is a novel loop diuretic belonging to pridine inducers, inhibitors and structure-activity relationships of human Cytochrome. Hydrochlorothiazide | C7H8ClN3O4S2 | CID - structure, chemical Hydrochlorothiazide is a thiazide diuretic often considered the prototypical member of this class. .. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. To examine the effect of hydrochlorothiazide on Na+ -K+ ATPase activity in. Jan 7, The most common therapeutic class of diuretic includes loop .. with standard diuretic acetazolamide (45 mg/kg body weight in 5 ml of % NaCl solution). Diuretic .. The structure activity relationship study illustrated that the.

This reabsorption of electrolytes and water is so carefully controlled that the osmolality, pH and electrolyte content of plasma and cellular fluids are constantly maintained within extremely narrow normal limits. Reabsorption of sodium ions and corresponding amounts of water to render tubular fluid hypotonic is known to occur in the loop of Henle.

Here, a process similar to that occurring in the proximal renal tubule takes place to provide a final adjustment of the electrolyte excretion in urine. Both sodium ion and water are reabsorbed but the reabsorption of electrolytes and water along the tubule is inversely related to the volume of urine excreted. When large amounts of urine are excreted, as in the presence of potent diuretic substances, correspondingly increased amounts of sodium and other electrolytes are also excreted.

It is important to recognize that thiazide diuretic agents have been shown to be without effect on the loop of Henle, and exert their saluretic effect through an anction at another reabsorptive site as well as by high urine volume excretion.

There is a general agreement of the adverse relationship between sodium ion content in the blood and hypertension. This has given rise to the general therapeutic concept for a need to reduce plasma sodium ion levels. In fact, the antihypertensive action of the thiazide diuretics was originally thought to simulate the beneficial effects produced by low salt diets for the hypertensive patient through renal elimination of salt.

However, long term balance studies have not supported the hypothesis that chronic sodium depletion adequately explains long term antihypertensive effects observed for this class of compounds. Newer experimental studies have indicated that thiazides may decrease the effects of catecholamines which would alter the electrolyte content of the vascular wall.

However, an antihypertensive action occurring apart from the high volume diuresis has not been clinically demonstrated for diuretic agents and current therapy with diuretic drugs is based solely upon their respective diuretic potency and saluretic action. In the course of development of a unified concept of the relationship between sodium ion reabsorption; acidification of urine and the role of carbonic hydrase inhibition in hydrogen ion and bicarbonate transport in the kidney the synthesis of potent chemical agents acting on the kidney, was accomplished.

Chlorothiazide, the first thiazide compound synthesized, was shown to be a potent diuretic and saluretic agent.

structure activity relationship of thiazide diuretics and weight

Following the clinical introduction of chlorothiazide, an expanded series of structurally related chemical compounds were synthesized, all having essentially the same pharmacology, but differing diuretic potencies. Analogues to the earlier series of thiazide diuretic compounds, in which the heterocyclic ring was saturated hydrothiazides were subsequently prepared and shown to possess significantly greater diuretic potency.

However, all thiazide compounds have common structural relationships and all are used on the basis of their common diuretic property. The structural similarities of the group of thiazide diuretic agents, together with their comparative properties are presented in Table I. The natriuretic effect obtained with the separate thiazide derivatives is essentially similar for all thiazide compounds. Although the average daily diuretic does for the thiazide compounds ranges from mg.

The more potent agents have a relatively greater chloretic activity and may even cause a hypochloretic alkalosis in some patients. All thiazide compounds cause potassium loss which is directly related to the magnitude of sodium ion excreted rather than to the particular thiazide employed or its structure. All of the thiazide derivatives inhibit carbonic anhydrase to some extent, but this inhibitory activity does not correlate with the compound's activity as a diuretic agent.

On the other hand, the carbonic anhydrase inhibition observed for the different thiazide compounds does not correlate with their ability to block bicarbonate reabsorption. Benzthiazide is a relatively potent carbonic anhydrase inhibitor, but it does not cause an appreciable clinical alkalimization of urine but rather produces the excretion of nearly equivalent amounts of sodium ion and chloride ion. In clinical use all thiazide diuretic agents are considered to be of equal effectiveness, both as diuretics and as antihypertensive agents.

Although the specific daily dosage will vary for different thiazide compounds and some have a longer half-life than others, and some may cause different levels of chloride ion loss, there is no evidence that these agents differ either in their safety or in their basic mode of action from the prototype compound, chlorothiazide. The adverse effects, especially those involving potassium depletion and patient morbitidy are observed with all of the members of this class.

Diuretic - Wikipedia

It has been proposed that the diuretic potency of the thiazide group, which ranges in activity from chlorothiazide being one and cyclopenthiazide as a thousand, is correlated with lipid-solubility of the respective compound and is inversely related to renal clearance of the agent.

The observation that a thiazide acts on different receptor sites of the kidney to cause specific actions and pharmacologic responses raises the question that these compounds may also act on systemic receptor sites to cause other systemic actions which as yet remain unknown. The current clinical use of these diuretic compounds in the management of hypertension is solely directed toward achieving high urinary output.

It is another object of the present invention to provide for the protection of thiazide compounds against the polarizing influence of gastric acidity by the formation of mixed cationic-anionic resin-thiazide adsorbate complexes, and to provide for the use of such complexes to effect diuretic action with antihypertensive action or to effect antihypertensive action alone without diuresis. It is a further object of the present invention to provide for the protection of thiazide compounds from the ionizing effect of strong acids by the provision of insoluble basic hydroxy metal thiazide salts, and to provide for effecting diuresis therewith, antihypertensive action or antihypertensive action without diuresis.

It is another object of the present invention to provide protection of thiazide compounds from polar excitation due to mineral and other substances by the provision of salts of thiazides with calcium disodium edetate or sodium edetate and also to provide mixtures of thiazides with calcium disodium edetate or disodium edetate for this purpose. The invention still further provides for the use of such salts and mixtures to achieve diuretic action with antihypertension or to achieve antihypertension without diuretic action.

In accordance with a further object of the present invention the ionizing effects of gastric acidity on thiazide compounds is protected by the formation of molecular complexes between thiazides and long chain polymers such as hydroxy alkyl cellulose polymers, carboxy methyl cellulose and polyvinylpyrrolidone.

The invention further comprises the use of such complexes to effect diuretic action with antihypertension and to effect antihypertension without diuretic action.

structure activity relationship of thiazide diuretics and weight

It is still a further object of the present invention to provide augmented antihypertensive action by the administration with a thiazide salt of a beta-adrenergic blocking agent.

It is yet another object of the present invention to provide compounds of thiazides and beta-adrenergic blocking agents and to effect antihypertensive action without diuresis by the administration thereof.

It is still a further object of the present invention to provide salts of thiazides with amiloride which have improved antihypertensive action. Other objects and advantages of the present invention will be apparent from a further reading of the specification and of the appended claims. It was unexpectedly found that a systemic antihypertensive action, which is dissociated from the diuretic action on the kidney, will be obtained after the administration of an amount of a thiazide agent which is substantially below the effective diuretic dose but which can nevertheless effect antihypertensive action and thus to achieve antihypertension without diuresis.

This new approach to treating hypertension results in a more effective and advantageous method since the well-known noxious effects of high potency diuresis are avoided. In this manner, potassium loss is avoided; patient disability and sleep interruption, because of frequent micturition is not encountered, and vitamin and mineral washout avoided. Patient compliance is high and the salutory effects of lowered blood pressure are readily observed.

Such antihypertensive action dissociated from the diuretic action for the thiazide compounds represents a hitherto unkown pharmacologic effect and constitutes an important therapeutic advance since it enables a positive approach to achieve a lowering of blood pressure, without patient detriment. Such dosage was preferably administered at hourly intervals over a period of from 4 to 8 hours to hypertensive patients. In this manner, a favorable clinical manometric response was observed without the occurrence of diuresis and its consequent noxious effects.

Long term clinical usage of these compounds is facilitated since potassium loss may be generally avoided and the occurrence of alkalosis virtually never encountered. Since the absence of diuresis permits uninterrupted sleep and otherwise alleviates morbidity of the patient arising from frequent micturition, better patient compliance with therapy results.

While the exact mechanism of the clinically advantageous dissociated antihypertensive effect observed in the absence of a diuretic action when the low dose thiazide compositions are administered has not been fully defined, it may be postulated that the observed lowering of blood pressure reflects a hitherto unkown systemic vascular response of the thiazide, apart from the kidney, and involves a modification of systemic vasomotor tone.

This is consistent with the evolving knowledge of the pharmacologic activity of the thiazide compounds to indicate that these agents act upon systemic receptor sites to result in specific actions and that these may be obscured by high diuretic potency.

Thus, for example, it has been shown that the administration of a thiazide compound will depress sexual function, an action apart from the kidney.

The antihypertensive action that we have found to be dissociated from the diuretic activity of the thiazides, has not been earlier observed because the potent diuresis causes a washout of the drug thereby depleting the plasma blood level to interrupt or prevent its action at the systemic receptor site affecting vasomotor tone.

In the absence of the diuretic effect, this novel pharmacologic response becomes dominant.

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However, because of the normal excretion of the thiazides, together with metabolic inactivation and the short half-life of the thiazide compounds, thiazide supplementation is required to maintain steady-state saturation levels. Frequent administration of the sub-diuretic dose of the thiazide compound is necessary to enable tissue receptor site saturation to achieve the desired modification of vasomotor tone with its consequent lowering of blood pressure.

It is known that the half-life duration of activity for the separate thiazide compounds ranges from 3 hours to 6 hours after administration of a single dose, with the half-life peak effect occurring within 1. This half-life period is dependent upon the metabolic inactivation of the particular thiazide compound together with its rate of excretion through the kidney and other routes.

structure activity relationship of thiazide diuretics and weight

The metabolic inactivation and excretory loss of the compound depletes the plasma blood level of the active ingredient thereby effecting the steady state concentration of active substance at the vasomotor receptor site.

Ordinarily such plasma drug loss is compensated for by the administration of dose overage. However, since a critical fractional low dosage range is required to achieve the antihypertensive effect dissociated from diuresis, then compensation for the metabolic inactivation and systemic excretion of the compound cannot be corrected by dose elevation.

It was found that the metabolic inactivation and systemic excretion may be satisfactorily overcome by administering repeat doses at hourly intervals for a period of from 4 to 8 hours until receptor site saturation occurs.

This hourly dose supplementation assures the maintenance of a steady state plasma level without exceeding the critical diuretic threshold to achieve the desired antihypertensive effect. The particular amount of the respective thiazide compound used to manufacture the unit dose is further influenced by certain chemical and physiologic forces which modify its absorption pattern as well as the individual patient's level of sensitivity of the systemic receptor site to a particular thiazide compound.

Further improvement in the use of thiazide compounds by the protection thereof from the actions of substances in the gastrointestinal tract are desirable. The thiazide compounds behave as non-ionized acids and are preferentially absorbed in their free, lipid-soluble, non-ionized acid form.

Thus, salt-forming and polar ionizing moieties encountered in the gastrointestinal tract will increase the polarity of a thiazide compound to change its ionizing characteristics to modify its absorption pattern. The dynamic equilibrium formed under the changing conditions encountered physiologically causes a proton- electron transfer between the non-ionic lipid-soluble free form and the weakly charged acid ionized form of the thiazide compound.

The proportion of the ionized thiazide form that is present will impact on the absorption potential of the thiazide molecule across the gastrointestinal tract with the lipid-soluble non-ionized form being preferentially absorbed. The amount absorbed and its steady-state blood level will be reflected in the response at the systemic vasomotor receptor site.

It was found that certain measures could be taken to preferentially shift the equilibrium in the direction to preserve the non-polarized, free-acid, lipid-soluble form of the thiazide against polarizing forces. Protection of the thiazide compound may be obtained by forming an adsorbate compound, comprising a high capacity, mixed cation-anion exchange resin, as for example, the Amberlite ion exchange resins available as an article of commerce from the Rohm and Haas Company, Philadelphia, Pa.

Such compounds are obtained by precipitating the free acid form of the thiazide, e. This adsorbate may be used directly or preferably mixed with one part by weight of a high capacity cationic Amberlite resin, to reinforce the protective action against ionization arising from salts in the gastrointestinal tract.

Under certain conditions, the mixed high potency cationic-anionic Amberlite resin may be used directly to form the adsorbate thiazide compound. The mixture is then treated as a single absorption resin when used to prepare the resin thiazide adsorbate salt and the same proportions are used.

The mixed cationic-anionic resin-thiazide adsorbate salt provides protection against the polarizing influence of the gastric acidity. Since hydrochloride acid is a stronger acid than the thiazide compound, it is capable of displacing the absorbed weaker thiazide acid form form the resin. The displaced thiazide would then have an increased polarity to modify the absorption pattern of the thiazide released from the unit dose.

An alternate means to protect the lipid-soluble acid thiazide compound from the ionizing effect of stronger acids and salt forming moieties in the gastric pouch is to administer the respective thiazide compound in the form of the insoluble basic hydroxy metallic salt.

Such a compound preferentially buffers the immediate acid environment surrounding the thiazide salt by maintaining a protective pH mantle at a level wherein the polar stimulation of the thiazide is suppressed.

Insoluble basic hydroxy metal thiazide salts my be formed through the reaction of the selected thiazide compound with a suitable metallic oxide, hydroxide, or carbonate and bicarbonate salt selected from the group of metals consisting of aluminum, calcium and magnesium in suitable molar proportions. The formed compound is recovered, dried and used to prepare the unit dosage form, in a sufficient amount based upon the respective thiazide content.

Ethylene diaminetetraacetic acid or edetic acid, calcium disodium edetate, and disodium edetate have the ability to form water soluble complexes with alkaline earth ions and basic substances which involve a coordinate linkage between metal ions, carboxyl groups and nitrogen.

This complexing action of the salts of edetic acid prevent precipitation and activation by basic ions of the free acid thiazide, thereby preserving its non-polar lipid-soluble-form.

While the formation of the calcium disodium edetate salt of the appropriate thiazide compound is a preferred means to protect the compound from polar excitation by diverse mineral and other substances in physiologic fluids, a similar effect was found when the disodium thiazide edetate salt is used. A satisfactory protective effect was also observed when these agents are used in admixture with the appropriate thiazide compound, although the formed complex salt remains a preferred protective compound.

Still another method to avoid the ionizing effects of gastric acidity on the selected thiazide compound so that it retains its lipid-soluble, non-polar characteristics is to form a molecular complex between a long chain polymer as for example, a hydroxyalkylcellulose polymer, a carboxymethylcellulose or polyvinylpyrrolidone.

These polymeric substances are capable of forming protective molecular complexes with the respective thiazide compound, which complexes resist acid polarizing activity. The formed complexes are reversed in the lower intestinal tract where the more alkaline pH favors the absorption of the lipid-soluble, non-polar thiazide form.

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Removal of excessive fluid is usually achieved by a combination of salt restriction and loop diuretics, but in some cases congestion persists despite adequate diuretic therapy. This has been termed diuretic resistance. The prevalence of diuretic resistance in the HF population is unknown due to the heterogeneity of the populations studied, the frequent comorbidity, the different treatment regimens, as well as to the different definitions used in various clinical trials.

HF shifts the dose-response curve for loop diuretics downward and to the right. Thus a higher starting dose of loop diuretics is needed in order to achieve the same level of sodium excretion.

In a seminal study on rats by Kaissling, furosemide treatment was associated with cell hypertrophy at the distal convoluted tubule, the connecting tubule and the cortical collecting duct. This may result in renal function deteriorating and development of cardiorenal syndrome. Probably the single most used and reproducible marker of cardiovascular congestion is body weight. As a result, HF guidelines advocate daily body weight monitoring in order to detect the pre-symptomatic phase in patients at risk to develop acute decompensated HF.

It showed a significant correlation with relevant clinical variables and also highlighted a correlation with adverse events. In another study, Testani et al. For patients refractory to escalating doses of intravenous diuretics, options include use of continuous infusion rather than intermittent boluses.

This strategy was tested in the DOSE study,28 but no significant difference was noted between the two treatment groups. Another approach is to administer two classes of diuretics together, a loop diuretic combined with a thiazide-like diuretic, thus performing a sequential nephron blockade. Indeed, inhibiting NaCl transport along the distal tubule counteracts the reabsorption due to hyper-functioning cells in the distal tubule.

In addition, they markedly increase the fractional sodium excretion, which is needed to achieve a neutral or negative sodium balance if the GFR is depressed. It has been suggested that metolazone is superior to other thiazide-like diuretics in patients with advanced kidney disease, but other thiazide-like diuretics also increased the response to loop diuretics, even in patients with advanced renal failure.

More recently, a small, retrospective, single-centre cohort study compared two of the most commonly used thiazide-like diuretics oral metolazone and intravenous chlorothiazide as add-on therapy to loop diuretics and no statistically significant differences in efficacy or safety were found. Moreover, head-to- head studies comparing these for treating hypertension described an increased risk of hyponatraemia with chorthalidone.

The main problem when using sequential nephron blockage is the excessive depletion of water and electrolytes. Chronic thiazide diuretics use is a predictor of worsening renal function in chronic HF and this is of concern, given the adverse prognosis associated with worsening renal function in these patients. Impaired renal function with diuretic therapy can result from direct alterations in glomerular haemodynamics due to neurohormonal and intrarenal feedback mechanisms or from overt volume depletion.

As a result of the above considerations, nowadays it is not easy to apply sequential nephron blockage to outpatient settings. Conversely, because of their lower natriuretic effect, thiazide diuretics are used infrequently and are limited to cases where there is diuretic resistance.

The same is true for potassium-sparing diuretics, which are only used in cases of refractory oedema or concomitant hypokalaemia. One of the major concerns of clinicians is the effect of excessive diuretic therapy on the intra-arterial volume and, consequently, on the possible deleterious effects on renal function.

Several studies have, indeed, demonstrated that there is a correlation between doses of diuretics and the worsening of the prognosis in patients with acute decompensated HF. It is, indeed, virtually impossible to distinguish between the multiple confounding factors, because sicker patients present often with greater congestion and therefore receive higher doses of diuretics.

The pathophysiological basis of many of these concerns is that these drugs, which cause intravascular volume depletion, could increase the hyperactivation of the neuroendocrine system with resulting detrimental consequences. It remains unclear what the preferred loop diuretic should be, what should be the appropriate combination, what is the optimal dosage and what should be the clinical goal. This is because of the progression of the disease or the worsening of the renal function. Other solutions have been tested in addition to the aforementioned combination therapy sequential nephron blockade.

Some trials demonstrated the positive effects of incorporating hypertonic saline solution HSS with standard loop diuretic therapy. The thiazides and potassium-sparing diuretics are considered to be calcium-sparing diuretics. They work primarily by expanding extracellular fluid and plasma volume, therefore increasing blood flow to the kidneyparticularly the peritubular capillaries.

structure activity relationship of thiazide diuretics and weight

This reduces medullary osmolality and thus impairs the concentration of urine in the loop of Henle which usually uses the high osmotic and solute gradient to transport solutes and water. Furthermore, the limited tubular epithelial cell permeability increases osmolality and thus water retention in the filtrate.

Thus their presence leads to an increase in the osmolarity of the filtrate and to maintain osmotic balance, water is retained in the urine.

Glucoselike mannitol, is a sugar that can behave as an osmotic diuretic. Unlike mannitol, glucose is commonly found in the blood. However, in certain conditions, such as diabetes mellitusthe concentration of glucose in the blood hyperglycemia exceeds the maximum reabsorption capacity of the kidney. When this happens, glucose remains in the filtrate, leading to the osmotic retention of water in the urine.

Use of some drugsespecially stimulantsmay also increase blood glucose and thus increase urination. Certain classes of diuretic are in this category, such as the thiazides. First, they effectively reduce blood pressure.