Antidiuretic Effect Of Hydrochlorothiazide In Lithium-induced Nephrogenic Diabetes Insipidus Is Associated With Upregulation Of Aquaporin-2, Na-cl Co-transporter, And Epithelial Sodium Channel
Specific pathogen-free male Sprague-Dawley rats (SLC Inc., Shizuoka, Japan) that weighed 180 to 220 g were used to produce Li-induced NDI animals and to treat with HCTZ. Initially, the rats were randomly allocated to normal controls (n = 4) and Li-induced NDI rats (n = 7). For Li administration, Li chloride was added to the rat diet to give a concentration of 40 mmol Li/kg dry food as described previously ( 2,12 ). Normal controls were given the same amount of food without Li, and all rats were allowed free access to water. After 3 wk of Li administration, NDI induction was confirmed by measurements of urine output and urine osmolality. Then, after an additional week of Li administration to ensure the induction of NDI, Li-induced NDI rats were randomly divided into vehicle-treated rats (n = 4) and HCTZ-treated rats (n = 3). For chronic HCTZ treatment for 7 d, osmotic minipumps (model 2ML1; Alzet, Palo Alto, CA) were implanted subcutaneously to deliver 3.75 mg/d HCTZ (YuHan Corp., Seoul, Korea) as described previously ( 13 ). HCTZ was dissolved in a 1.7% ethanolamine solution, and the minipumps that contained vehicle (ethanolamine) alone were implanted in vehicle-treated rats. Li-containing food was offered continuously to both groups throughout the study period. Considering the role of sodium depletion in the antidiuretic effect of thiazides in NDI ( 14,15 ), no salt was added to the drinking fluid. Serum samples were collected at the time each rat was killed for determination of the serum Li concentration by a colorimetric method (VITROS 250 Chemistry System; Shanghai Golden-Grand Medical Instruments Co., Ltd., Shanghai, China) ( 16 ). After the whole-animal experiments, the rats were killed by decapitation, and kidneys were rapidly removed and placed in chilled isola Continue reading >>
Hydrochlorothiazide - Wikipedia
Primarily kidney (>95% as unchanged drug) Potential side effects include poor kidney function, electrolyte imbalances especially low blood potassium and less commonly low blood sodium , gout , high blood sugar , and feeling faint initially upon standing up . [2] While allergies to HCTZ are reported to occur more often in those with allergies to sulfa drugs , this association is not well supported. [2] It may be used during pregnancy but is not a first line medication in this group. [2] It is in the thiazide medication class and acts by decreasing the kidneys ' ability to retain water. [2] This initially reduces blood volume, decreasing blood return to the heart and thus cardiac output . [4] Long term, however, it is believed to lower peripheral vascular resistance . [4] Two companies, Merck and Ciba , state they discovered the medication which became commercially available in 1959. [5] It is on the World Health Organization's List of Essential Medicines , the most effective and safe medicines needed in a health system . [6] In 2008 it was the second most commonly used blood pressure medication in the United States. [4] It is available as a generic drug [2] and is relatively affordable. [7] Hydrochlorothiazide is frequently used for the treatment of hypertension , congestive heart failure , symptomatic edema , diabetes insipidus , renal tubular acidosis . [2] It is also used for the prevention of kidney stones in those who have high levels of calcium in their urine. [2] Most of the research supporting the use of thiazide diuretics in hypertension was done using chlorthalidone , a different medication in the same class. Some more recent studies have suggested that chlorthalidone might be the more effective thiazide diuretic. [8] It is also sometimes used for treatment of Continue reading >>
Diuretic-related Side Effects: Development And Treatment
Please confirm that you would like to log out of Medscape.If you log out, you will be required to enter your username and password the next time you visit. Log out Cancel Diuretic-Related Side Effects: Development and Treatment Prolonged thiazide diuretic therapy can lead to glucose intolerance and may occasionally precipitate diabetes mellitus.[ 4 , 5 , 54 , 55 ] Short-term metabolic studies, epidemiologic studies, and a variety of clinical trials suggest a connection between ongoing thiazide diuretic use and the development of type 2 diabetes. However, it should be noted that interpretation of these studies is confounded by multiple factors including: differing definitions of new-onset diabetes, small numbers of patients, inadequate comparison groups, relatively limited periods of follow-up, selection criteria that limited the generalizability of the findings, and study designs that prohibited valid comparisons among antihypertensive drug classes.[ 56 ] Moreover, in a review of all the placebo-controlled hypertension trials with diuretics, there was only an approximate 1% increase in new-onset diabetes compared with placebo.[ 57 ] Hyperglycemia and carbohydrate intolerance have been linked to diuretic-induced hypokalemia. K+ deficiency is known to inhibit insulin secretion by cells; however, diuretic-induced changes in glucose metabolism are not conclusively related to altered K+ homeostasis, and impaired glucose tolerance occurs even when thiazide-type diuretics in relatively low doses are combined with K+ -sparing agents. The glucose intolerance seen with diuretic therapy can deteriorate further with an increase in sympathetic nervous system activity, which also decreases peripheral glucose utilization. Diuretic-associated glucose intolerance appears to be dose-rel Continue reading >>
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The principal new finding in this study is that we can show experimentally that correcting the serum K and uric acid abnormalities in F-induced MS in rats can largely prevent the metabolic abnormalities that are associated with thiazides. The beneficial effects of these treatments were associated with an increase in urine nitrite/nitrates, suggesting the involvement of endothelial dysfunction on the development of MS with thiazide usage. Hypokalemia occurs in 6.5 to 50% of patients receiving diuretics, 28 30 with the average reduction of serum K from thiazides reported at approximately 0.3 to 1.1 mEq/L. 6 , 31 , 32 Previous studies suggested that hypokalemia may be a factor causing hyperglycemia, hyperinsulinemia, and insulin resistance in patients receiving thiazides, because these features can be improved with K supplements. 13 , 33 It also has been shown that K depletion, even without frank hypokalemia, can cause insulin resistance. 34 In our experiments, HCTZ produced a significant reduction in serum K (0.3 mEq/L), although this did not reach the criteria of hypokalemia (serum K <3.5 mEq/L). Our important finding is that this mild K depletion was significantly associated with exacerbation of hyperglycemia, insulin resistance, and a reduction of urine NO excretion, all of which were corrected by K supplementation. The observation that K supplements prevented the reduction of urine NO in F-fed rats receiving HCTZ is consistent with an improvement in endothelial function. K supplementation has been shown to act as an endothelium-derived hyperpolarizing factor 35 and release NO to preserve endothelial function, 36 whereas K depletion was found to attenuate endothelial-dependent vasorelaxation. 37 In turn, an inhibition of endothelial NO is known to cause insulin resist Continue reading >>
Thiazide Induced Dysglycemia It's Time To Take Notice
Thiazide Induced Dysglycemia It's Time To Take Notice Rhonda M. Cooper-DeHoff, Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, Florida. Address for correspondence: Rhonda M. Cooper-DeHoff, PharmD, MS, FAHA, Research Associate Professor, University of Florida College of Medicine, PO Box 100277, Gainesville, FL 32610-0277; Tel: 352-273-8470; FAX: 352-371-0370; ude.lfu.enicidem@mrfohed The publisher's final edited version of this article is available at Expert Rev Cardiovasc Ther See other articles in PMC that cite the published article. Almost a half century ago, Wolff et al wrote, During the course of studies of hypertensive patients, including a double blind study, observations were made concerning the diabetogenic activity of benzothiadiazine derivatives. This activity was observed to occur in nonobese patients without a family history of diabetes as well as in obese hypertensives with such a family history. These observations suggest that benzothiadiazines should not be given to young or middle-aged hypertensives in whom there is a lengthy life expectancy and for whom alternative hypotensive therapy is feasible. [ 1 ] Despite these insightful recommendations, benzothiadiazine derivatives (most often hydrochlorothiazide [HCTZ]) are the first line recommended therapy for hypertension regardless of glycemic status [ 2 ]. Epidemiologic data as well as data from randomized controlled trials have associated a new diagnosis of diabetes with hypertension treatment that contains a thiazide diuretic, including chlorthalidone [ 3 , 4 ], HCTZ [ 5 , 6 ] and bendroflumethiazide [ 7 ]. There is controversy over the long-term significance of diuretic-induced diabetes [ 8 ], primarily related to the benefit of BP lowering vs. the hazard o Continue reading >>
Hydrochlorothiazide Dosage And Administration
Hydrochlorothiazide is a diuretic and antihypertensive. It is the 3,4-dihydro derivative of chlorothiazide. It is chemically designated as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide and it has the following structural formula: Hydrochlorothiazide USP is a white, or practically white, crystalline powder which is slightly soluble in water, but freely soluble in sodium hydroxide solution. Each tablet for oral administration contains 25 mg or 50 mg Hydrochlorothiazide USP. In addition, each tablet contains the following inactive ingredients: dibasic calcium phosphate, lactose monohydrate, pregelatinized starch, FD&C yellow No.6 lake, corn starch, colloidal silicon dioxide, and magnesium stearate. Hydrochlorothiazide - Clinical Pharmacology The mechanism of the antihypertensive effect of thiazides is unknown.Hydrochlorothiazide does not usually affect normal blood pressure. Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. Indications and Usage for Continue reading >>
Treatment Of Nephrogenic Diabetes Insipidus
INTRODUCTION Nephrogenic diabetes insipidus (nephrogenic DI) results from partial or complete resistance of the kidney to the effects of antidiuretic hormone (ADH). As a result, patients with this disorder are not likely to have a good response to hormone administration (as desmopressin [dDAVP]) or to drugs that increase either the renal response to ADH or ADH secretion. Nephrogenic DI can be hereditary or acquired. In adults, a concentrating defect severe enough to produce polyuria due to nephrogenic DI is most often due to chronic lithium use or hypercalcemia and less frequently to other conditions that impair tubular function, such as Sjögren's syndrome [1]. Release of ureteral obstruction is often associated with a diuresis, but this is short lived and does not require specific therapy other than maintenance fluids. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus" and "Clinical manifestations and diagnosis of urinary tract obstruction and hydronephrosis", section on 'Prognosis and recovery of renal function'.) Hereditary nephrogenic DI, which is largely an X-linked disease, may also be seen by internists since early recognition and treatment in infancy has led to survival to adulthood [2,3]. In addition, affected women may be carriers with few or no symptoms until pregnancy or other stress. In infants with hereditary nephrogenic DI, treatment is aimed at minimizing the polyuria and avoiding hypernatremia and volume depletion. In adults, therapy is usually aimed at correcting the underlying disorder or discontinuing an offending drug. In hypercalcemic patients, for example, normalization of the plasma calcium concentration usually leads to amelioration of polyuria. By contrast, lithium-induced nephrogenic DI may be irreversible if the pati Continue reading >>
Drugs That Can Worsen Diabetes Control
One of the main goals of any diabetes control regimen is keeping blood glucose levels in the near-normal range. The cornerstones of most plans to achieve that goal include following a healthy diet, getting regular exercise, and taking insulin or other medicines as necessary. However, it’s not uncommon for people with diabetes to have other medical conditions that also require taking medicines, and sometimes these drugs can interfere with efforts to control blood glucose. A few medicines, including some commonly prescribed to treat high blood pressure and heart disease, have even been implicated as the cause of some cases of diabetes. This article lists some of the medicines that can worsen blood glucose control, the reasons they have that effect, the usual magnitude of the blood glucose changes, as well as the pros and cons of using these drugs in people who have diabetes. Where the problems occur To understand how various medicines can worsen blood glucose control, it helps to understand how insulin, the hormone responsible for lowering blood glucose, works in the body. Insulin is released from the beta cells of the pancreas in response to rising levels of glucose in the bloodstream, rising levels of a hormone called GLP-1 (which is released from the intestines in response to glucose), and signals from the nerve connections to the pancreas. The secretion of insulin occurs in two phases: a rapid first phase and a delayed second phase. Both of these phases are dependent on levels of potassium and calcium in the pancreas. Insulin acts on three major organs: the liver, the muscles, and fat tissue. In the liver, insulin enhances the uptake of glucose and prevents the liver from forming new glucose, which it normally does to maintain fasting glucose levels. In muscle and f Continue reading >>
Drug Induced Diabetes
Tweet A number of medications have side effects which include the raising of blood glucose levels. Drug induced diabetes is when use of a specific medication has lead to the development of diabetes. In some cases the development of diabetes may be reversible if use of the medication is discontinued, but in other cases drug-induced diabetes may be permanent. Drug induced diabetes is a form of secondary diabetes, in other words diabetes that is a consequence of having another health condition. Which drugs can induce diabetes? A number of drugs have been linked with an increased risk development of type 2 diabetes. Corticosteroids Thiazide diuretics Beta-blockers Antipsychotics Is diabetes permanent? Diabetes may not be permanent but this can depend on other health factors. With some medications, blood glucose levels may return back to normal once the medication is stopped but, in some cases, the development of diabetes may be permanent. Managing drug induced diabetes If you need to continue taking the medication that has brought on diabetes, it may make your diabetes more difficult to control than would otherwise be the case. If you are able to stop the course of medication, you may find your blood glucose levels become slightly easier to manage. Following a healthy diet and meeting the recommended exercise guidelines will help to improve your chances of managing your blood glucose levels. Can drug induced diabetes be prevented? It may be possible to reduce the risk of developing diabetes by ensuring you to keep to a healthy lifestyle whilst you are on the medication. Being on smaller doses of the medication or shorter periods of time may help to reduce the likelihood of developing high blood sugar levels and diabetes. Doctors will usually try to put you on the smallest e Continue reading >>
Chlorothiazide-induced Gout And Diabetestheir Sequential Occurrence In The Same Patient
Introduction Chlorothiazide has been a drug of undisputed value both as a nonmercurial diuretic1 and as an adjunct in the treatment of systemic hypertension.2 Side-effects, though uncommon, should nevertheless be recognized in view of the frequent use of this agent and in view of the impression that its use is relatively free of untoward sequelae. In the past few years reported complications of chlorothiazide administration have included thrombocytopenia,3 agranulocytosis,4 jaundice,5 photosensitivity,6 yellow vision,7 skin eruptions,8 hypokalemia,9,10 pancreatitis,11, 12A,12B pancreatic atrophy,13 and hyperpyruvicacidemia.14 Of particular interest have been two additional complications: ( 1 ) hyperuricemia15,16alone or with clinical manifestations of gout,17-20 and (2) hyperglycemiaeither in previously nondiabetic subjects or in otherwise well-stabilized diabetics.21-28 We have recently had an opportunity to observe a patient who, after receiving chlorothiazide continually for four years, developed, in sequence, hyperuricemia with acute Continue reading >>
Diuretics May Increase Diabetes Risk By Lowering Blood Potassium Levels
Diuretics may increase diabetes risk by lowering blood potassium levels Posted on Nov 25, 2008, 6 a.m. By Rich Hurd New research suggests that depleted blood potassium levels could help to explain why people prescribed diuretics for the treatment of high blood pressure are at increased risk of type 2 diabetes. New research suggests that depleted blood potassium levels could help to explain why people prescribed diuretics for the treatment of high blood pressure are at increased risk of type 2 diabetes. Tariq Shafi and colleagues examined data from 3,790 non-diabetic participants in the Systolic Hypertension in Elderly Program (SHEP), a study designed to determine the risk versus benefit of treating people age 60 years or older with the thiazide diuretic chlorthalidone. Previous research has shown that treatment with thiazide diuretics causes potassium levels to drop and increases patients' risk of developing type 2 diabetes by as much as 50%, although whether the drop in blood potassium was linked to the increased risk of diabetes was uncertain. Results of this study suggest that the increased risk of type 2 diabetes associated with thiazide diuretics is indeed linked to their action on blood potassium levels. In fact, results showed that for each 0.5 milliequivalent-per-liter (MEq/L) decrease in serum potassium, there was a 45% increased risk of diabetes . Thiazides are effective at treating high blood pressure and are inexpensive, however their association with diabetes has led many doctors to prescribe other, more expensive, drugs. However, according to Dr Shafi, the study findings suggest that thiazides can be used safely as long as doctors monitor and regulate blood potassium levels. The authors speculate that potassium supplement may prevent thiazide-induced diab Continue reading >>
Diuretic-induced Hyperglycemia Is A Determinant Of Diabetes Epidemic | 4340
Volume 2 Issue 5 - 37International Conference and Exhibition onNephrology & TherapeuticsAugust 20-22, 2012 Hilton Chicago/Northbrook, USAJ Nephrol TherapeutISSN: 2161-0959 JNT, an open access journalNephro-2012August 20-22, 2012Anil K. Mandal et al.,J Nephrol Therapeut 2012, 2:5blood glucose level (or hyperglycemia) above laboratory range of normal values (70-99 mg/dL or 3.8 ? 5.5 mmol/L) isa common laboratory finding in patients treated with a diuretic. Among all the diuretics, thiazide diuretics are most notablefor increasing blood glucose levels. Thiazide diuretics such as hydrochlorothiazide (HCTZ) or chlorthalidone are widely used tocontrol blood pressure in hypertensive subjects. Blood glucose is elevated in some individuals more than others. However, thiselevated glucose level or hyperglycemia produces no symptoms of polyuria, polydipsia or rapid weight loss which are commonin established diabetes.A question has been raised about the risk of hyperglycemia induced by diuretic therapy. Although controversies exist, thereis a general consensus that diuretic-induced hyperglycemia is a reversible condition caused by volume depletion and decreasedserum potassium level. Correction of volume and serum potassium reduces blood glucose level even if diuretics are to becontinued.Patients with diuretic-induced hyperglycemia are often labeled as Type 2 diabetics and prescribed oral antidiabetic agents.Since hypertension is more prevalent than diabetes, and because of the use of thiazide diuretic to treat hypertension, thiazide-induced hyperglycemia or diabetes is very common. Thus thiazide-induced diabetes has become synonymous with Type 2diabetes giving rise to epidemic of diabetes which is unreal.Thiazide diuretic is a cheap and effective blood pressure lowering agent and l Continue reading >>
Is Diuretic-induced Hyperglycemia Reversible And Inconsequential?
Short report *Corresponding author: Anil K Mandal [email protected] 1. Mandal Diabetes Research Foundation, St. Augustine, Florida and University of Florida, Gainesville,Florida, USA. © 2012 Mandal et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Antihypertensive drugs including thiazide diuretics, beta blockers (BB), calcium channel blockers (CCB), reninangiotensin inhibitors or vasodilators produce elevated blood glucose (hyperglycemia) (>70-99 mg/dL). Hyperglycemia is more common and severe with thiazide diuretics than with BB, CCB, ACEI or ARB drugs. Questions have been raised about the mechanism and risk of drug-induced hyperglycemia. Method: We present here four patients treated with diuretics who developed hyperglycemia - fasting blood glucose (FBG) > 126 mg/ dL (7 mmol/L) diagnostic of diabetes. Three patients had hypertension and one, congestive heart failure (CHF). Three patients had no diabetes, one gave 8 to 10 year history of diabetes. One patient received no diuretic therapy and his glucose level was normal with insulin and oral hypoglycemic agent treatment. Subsequently, he became hypertensive and was treated with a thiazide diuretic but no antidiabetic agents. He then developed new-onset diabetes. Results: All patients showed hyperglycemia above FBG criteria for diabetes. 2-hour postprandial blood glucose (2hPPG) was not diagnostic of diabetes in three patients. Two patients were prescribed antidiabetic therapy which was stopped with no worsening of hyperglycemia although diuretic therapy continued. In two patien Continue reading >>
Paradoxical Antidiuretic Effect Of Thiazides In Diabetes Insipidus: Another Piece In The Puzzle
Diabetes insipidus (DI) is a temporary or chronic disorder characterized by the excretion of excessive quantities of very dilute, but otherwise normal urine. The disease results either from impaired synthesis and secretion of antidiuretic hormone (ADH, vasopressin) by the hypothalamus and posterior pituitary, respectively (central DI), or from an unresponsiveness of the kidneys to the hormone itself (nephrogenic DI) (1–3⇓⇓). The renal water transport defect is located in the collecting system (i.e. the connecting tubule – CNT and the collecting duct – CD) in which vasopressin normally controls the expression and cell surface targeting of the apical water channel aquaporin-2 (AQP2) (4). The CNT and CD are also the site of amiloride-sensitive sodium reabsorption via the epithelial sodium channel (ENaC) (5). Sodium transport across ENaC may osmotically drive transepithelial water reabsorption. Consistently, both AQP2 and ENaC are regulated by vasopressin via V2-receptor-dependent cAMP production (4,5⇓). While exogenous application of vasopressin efficiently corrects the reduced AQP2 expression and the urinary concentration defect in central DI (4), the treatment of nephrogenic DI is usually less obvious and may include different approaches such as dietary sodium restriction, prostaglandin synthesis inhibitors, potassium-sparing diuretics and/or thiazide diuretics (3,6⇓). The use of diuretics for the treatment of a polyuric disease appears paradoxical, but the beneficial effect of thiazides has now been proven for more than 45 yr. In 1959, Crawford and Kennedy showed in a seminal paper that thiazides reduce polyuria and increase urine osmolality in DI (7). Since then, thiazides have become an important component in the therapeutic repertoire for treatment of D Continue reading >>
Hydrochlorothiazide & Blood Glucose
Roseanne Omalacy became a published author and freelance writer in 2006. She is the author of several novels and has been published with Literary Partners Group, Alyson Publishing and "Scarlet Magazine." She is a Pittsburgh health and relationships columnist, holds a bachelor's degree in nursing from Pennsylvania State University and has over 15 years of nursing experience. A man is filling a syringe with insulin.Photo Credit: Images_By_Kenny/iStock/Getty Images Hydrochlorothiazide is a diuretic that treats water retention by reducing the amount of salt absorbed by the body. This is especially important in patients with high blood pressure, kidney disorders and diabetes. Diabetes is a metabolic disease characterized by high levels of sugar in the bloodstream. Diabetes increases your risk of heart disease, blindness and stroke. Combining certain medications with diabetes can cause adverse reactions, so you must know how hydrochlorothiazide affects your blood sugar. Insulin is a hormone produced by the pancreas that changes food into energy. When your cells become resistant to insulin or your pancreas quits making insulin, diabetes can develop. There are two kinds of diabetes, but diabetes type 2 is the most common form of the disease. As of 2011, more than 25 million Americans have diabetes, according to the American Diabetes Association. Symptoms of diabetes include increased thirst, vision changes, hunger and increased urination. Diabetes increases your risk of stroke, heart disease, blindness and kidney disease. Physicians treat diabetes with dietary changes, oral medications and insulin injections. Diuretics are a family of drugs used to treat fluid retention associated with kidney disease, heart disease, diabetes and other disorders. Diuretics are sometimes called Continue reading >>
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