Structure activity relationship of thiazide diuretics hypercalcemia

structure activity relationship of thiazide diuretics hypercalcemia

Diuretics. Metadisulfamoylbenzene derivatives SAR. Maximal diuretic activity is SITE 2 Diuretics, High ceiling or loop diuretics Uses: Edema,; Hypertension,; Hypercalciuria (i.e., an elevated urinary concentration of calcium) are prone to. Loop diuretics: furosemide, bumetanide, torasemide, ethacrynic acid. IV. Thiazides Calcium nephrolithiasis (thiazides to decrease Ca2+ excretion into urine). - Osteoporosis (thiazides to . (CF = loss-of-function mutation of an ATP- driven Cl-. Thiazide is a type of molecule and a class of diuretics often used to treat hypertension (high Benzothiadiazine, the parent structure of this class of molecules . Thiazide diuretics also increase calcium reabsorption at the distal tubule. thiazides indirectly increase the activity of the basolateral Na/Ca antiporter to maintain.

Conversely, loop diuretics induce natriuresis by inhibiting the Na-K-2Cl transporter in the thick ascending limb of the loop of Henle, causing increased urinary calcium losses and increased PTH 58. The epidemiology of thiazide-associated hypercalcemia is poorly understood. Based on prospective health screening measurements in the early s in Sweden, Christensson et al 9 suggested that the prevalence of hypercalcemia in 20 to 63 year olds on thiazide diuretics was 1.

A second study from Sweden evaluating hypercalcemia after the introduction of automated chemistry panels in a single county hospital estimated that the prevalence of hypercalcemia in thiazide-treated adults was 0. However, when this study was conducted, chemistry panels were primarily performed on hospitalized patients, rather than the much larger ambulatory population.

Since the early s, only one study has evaluated the epidemiology of thiazide-associated hypercalcemia From tothe overall age and sex-adjusted annual incidence of thiazide-associated hypercalcemia was 7. The incidence increased afterpeaking at The purpose of this study was to update our understanding of the incidence of thiazide-induced hypercalcemia in an era of routine calcium measurement, now spanning over two decades.

In addition, we wanted to gain better understanding of its clinical features and relationship to PHPT. Finally, given the unique record system in this community 12we hoped to provide guidance to clinicians in the evaluation and management of this disorder based on its natural history among unselected patients in the general population. Patients and Methods Most endocrinological care in this community is provided by the Mayo Clinic, which has maintained a common medical record with its two hospitals for over years.

The diagnoses and surgical procedures in these records are indexed, as are the medical records of other providers who serve the local population After approval from the Institutional Review Boards of Mayo Clinic and the Olmsted Medical Center, we used this comprehensive medical records-linkage system the Rochester Epidemiology Project to identify all Olmsted County, Minnesota, residents with hypercalcemia from throughincluding all patients with PHPT as described previously In addition, all Olmsted County residents with serum calcium levels exceeding For each potential case, the complete inpatient and outpatient community medical record was reviewed by one of the investigators M.

Mayo Clinic records contain details of every inpatient hospitalization, outpatient clinic visit, emergency department and nursing home care, as well as all radiographic and pathology reports, including autopsies This information was supplemented by that available from other providers for local residents, most notably the Olmsted Medical Center Patients were accepted as having thiazide-associated hypercalcemia if they met the following criteria: Patients with hypercalcemia before thiazide initiation were excluded.

structure activity relationship of thiazide diuretics hypercalcemia

Although the methods used to measure serum calcium levels changed over time, the normal range remained unchanged because instrumentation was calibrated against atomic absorption spectrophotometry according to certified references from the National Bureau of Standards.

The date of diagnosis of thiazide-induced hypercalcemia was the date of the first elevated calcium level while on thiazides, consistent with prior criteria Patients with thiazide-associated hypercalcemia who subsequently had biochemically proven PHPT must have met the inclusion criteria consistent with previous studies 3 months or longer after thiazide discontinuation Serum intact PTH was measured by two-site immunochemiluminometric assay, which changed throughout the course of the study with normal ranges as follows: To qualify for the study, patients must have been residents of Olmsted County on the date the first elevated serum calcium was discovered.

In addition, to assure comparability with our previous study 11we established residency in Olmsted County for at least 1 year before the diagnosis of thiazide-associated hypercalcemia. The updated cohort from — was combined with the previously identified Olmsted County thiazide-associated hypercalcemia cases from through Incidence rates were based on the date of the initial elevated serum calcium level, consistent with previous studies Person-years were estimated by decennial census data for the Olmsted County population with interpolation for intercensal years.

CV Pharmacology | Diuretics

The rates from our study, including previous reports, were directly age- and sex-adjusted to the U. The reason for this is that one nephron segment can compensate for altered sodium reabsorption at another nephron segment; therefore, blocking multiple nephron sites significantly enhances efficacy.

Loop diuretics inhibit the sodium-potassium-chloride cotransporter in the thick ascending limb see above figure. This altered handling of sodium and water leads to both diuresis increased water loss and natriuresis increased sodium loss. By acting on the thick ascending limb, which handles a significant fraction of sodium reabsorption, loop diuretics are very powerful diuretics. These drugs also induce renal synthesis of prostaglandins, which contributes to their renal action including the increase in renal blood flow and redistribution of renal cortical blood flow.

Thiazide diuretics, which are the most commonly used diuretic, inhibit the sodium-chloride transporter in the distal tubule.

structure activity relationship of thiazide diuretics hypercalcemia

Nevertheless, they are sufficiently powerful to satisfy many therapeutic needs requiring a diuretic. Their mechanism depends on renal prostaglandin production. Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this increases potassium loss potentially causing hypokalemia because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine.

The increased hydrogen ion loss can lead to metabolic alkalosis. Part of the loss of potassium and hydrogen ion by loop and thiazide diuretics results from activation of the renin-angiotensin-aldosterone system that occurs because of reduced blood volume and arterial pressure. Increased aldosterone stimulates sodium reabsorption and increases potassium and hydrogen ion excretion into the urine.

index-art.infoy-Thiazide Diuretics

There is a third class of diuretic that is referred to as potassium-sparing diuretics. Unlike loop and thiazide diuretics, some of these drugs do not act directly on sodium transport. Some drugs in this class antagonize the actions of aldosterone aldosterone receptor antagonists at the distal segment of the distal tubule.

structure activity relationship of thiazide diuretics hypercalcemia

This causes more sodium and water to pass into the collecting duct and be excreted in the urine. The reason for this is that by inhibiting aldosterone-sensitive sodium reabsorption, less potassium and hydrogen ion are exchanged for sodium by this transporter and therefore less potassium and hydrogen are lost to the urine.

Other potassium-sparing diuretics directly inhibit sodium channels associated with the aldosterone-sensitive sodium pump, and therefore have similar effects on potassium and hydrogen ion as the aldosterone antagonists. Because this class of diuretic has relatively weak effects on overall sodium balance, they are often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia. Carbonic anhydrase inhibitors inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium, which leads to less sodium reabsorption at this site and therefore greater sodium, bicarbonate and water loss in the urine.

These are the weakest of the diuretics and seldom used in cardiovascular disease. Their main use is in the treatment of glaucoma. This decreases cardiac filling preload and, by the Frank-Starling mechanismdecreases ventricular stroke volume and cardiac outputwhich leads to a fall in arterial pressure.

structure activity relationship of thiazide diuretics hypercalcemia

The decrease in venous pressure reduces capillary hydrostatic pressurewhich decreases capillary fluid filtration and promotes capillary fluid reabsorption, thereby reducing edema if present. There is some evidence that loop diuretics cause venodilation, which can contribute to the lowering of venous pressure. Long-term use of diuretics results in a fall in systemic vascular resistance by unknown mechanisms that helps to sustain the reduction in arterial pressure.

Antihypertensive therapy with diuretics is particularly effective when coupled with reduced dietary sodium intake.

Thiazide - Wikipedia

The efficacy of these drugs is derived from their ability to reduce blood volume, cardiac output, and with long-term therapy, systemic vascular resistance. Thiazide diuretics, particularly chlorthalidone, are considered "first-line therapy" for stage 1 hypertension. Potassium-sparing, aldosterone-blocking diuretics e. Heart failure Heart failure leads to activation of the renin-angiotensin-aldosterone system, which causes increased sodium and water retention by the kidneys.

This in turn increases blood volume and contributes to the elevated venous pressures associated with heart failure, which can lead to pulmonary and systemic edema. Long-term treatment with diuretics may also reduce the afterload on the heart by promoting systemic vasodilation, which can lead to improved ventricular ejection.

When treating heart failure with diuretics, care must be taken to not unload too much volume because this can depress cardiac output. For example, if pulmonary capillary wedge pressure is 25 mmHg point A in figure and pulmonary congestion is present, a diuretic can safely reduce that elevated pressure to a level e.