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PubMed1980

Effects of vasodilator drugs, alkaline phosphatase, and cyclic AMP-dependent protein kinase on the 45calcium uptake of sarcolemmal microsomes from human umbilical arteries.

1 A microsomal fraction was prepared from human umbilical arteries by differential centrifugation. The preparation was capable of an oxalate-stimulated Ca2+ uptake at a mean rate of 0.74 nmol Ca2+ mg-1 protein min-1 which could be inhibited by a Ca2+ ionophore, A 23 187, and by Tween 80. 2 The rate of Ca2+ uptake in the fraction obtained by density gradient fractionation paralleled 5'-nucleotidase activity suggesting that vesicles of predominantly sarcolemmal origin were responsible for the microsomal Ca2+ uptake. 3 Cyclic adenosine 3',5'-monophosphate-dependent protein kinase enhanced membrane phosphorylation but did not affect Ca2+ uptake. Preincubation with alkaline phosphatase reduced membrane phosphorylation to a greater extent than Ca2+ uptake. These data are not in favour of a close correlation between Ca2+ uptake and phosphorylation. 4 None of 15 vasodilator drugs (bencyclane, carbocromen, diazoxide, dilazep, hydralazine, indapamide, isosorbide dinitrate, methyl-isobutyl-xanthine, minoxidil, naftidrofuryl, nitroglycerine, prenylamine, sodium nitroprusside, tetracaine, and verapamil) had any effect on Ca2+ uptake at 10(-5) M. This suggests that vasodilator drugs do not act by a direct influence on the Ca2+ pumps of vascular smooth muscle cells.

Alkaline Phosphatase↗
PubMed1996

Inhibition of thiazide photohemolysis in vitro by antioxidants and a nitrogen atmosphere.

The diuretics acetazolamide, bemetizide, bendroflumethiazide, benzthiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlorazanile, chlorothiazide, chlortalidone, clopamide, cyclopenthiazide, cyclothiazide, diazoxide, etozoline, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, mefruside, metolazone, piretanide, polythiazide, trichlormethiazide, and xipamide were screened in vitro for phototoxic effects by means of a photohemolysis test. In all, 19 out of the 25 test substances revealed phototoxic hemolytic properties after irradiation with either solar stimulating irradiation, UVA and/or visible light. Addition of the antioxidants ascorbic acid, alpha-tocopherole or superoxide dismutase significantly inhibited the phototoxic hemolysis, as well as did investigations carried out in a nitrogen rich atmosphere, findings which indicate the involvement of reactive oxygen species in the phototoxic process.

Antioxidants↗
PubMed1996

Phototoxicity due to sulphonamide derived oral antidiabetics and diuretics: investigations in a cell culture model.

A number of sulphonamide-derived oral antidiabetics (chlorpropamide, glibenclamide, glipizide, gliquidone, glymidine, tolazamide and tolbutamide) and diuretics (bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chloratalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide and xipamide) were investigated for phototoxicity in a cell culture model. Cell death dependent on ultraviolet A fluence and test substance concentration was observed in the presence of the oral antidiabetics glibenclamide and gliquidone, as well as the diuretics bemetizide, bendroflumethiazide, benzyl-hydrochlorothiazide, bumetanide, butizide, hydrochlorothiazide, hydroflumethiazide, piretanide, polythiazide and trichlormethiazide. Bendroflumethiazide was phototoxic at 5x10(-5) M and higher concentrations, bemetizide, benzylhydrochlorothiazide, bumetanide and hydroflumethiazide were phototoxic at 2.5x10(-4) M and higher concentrations, and the oral antidiabetics glibenclamide and gliquidone as well as the diuretics butizide, hydrochlorothiazide, piretanide, polythiazide and trichlormethiazide were phototoxic at 5(-4) M and higher concentrations. Electron microscopic investigations showed swelling of mitochondria and endoplasmic reticulum as well as aggregation of euchromatin when the cells were irradiated in the presence of photosensitizers.

Administration, Oral↗
PubMed2004

Medical management of urinary stone disease.

A variety of dietary and metabolic factors may contribute or cause stone formation in idiopathic calcium oxalate nephrolithiasis. Dietary factors include a high intake of animal proteins, oxalate and sodium, and a low intake of fluids and potassium-containing citrus products. Some of the metabolic causes of stones are hypercalciuria, hypocitraturia, gouty diathesis, hyperoxaluria, and hyperuricosuria. Dietary modification, to be applied in all patients with stones includes a high fluid intake, restriction of oxalate and sodium, and balanced diet with animal proteins complemented by adequate intake of fruits and vegetables. When dietary modification is ineffective in controlling stone formation or in the presence of severe metabolic derangements, a pharmacologic intervention may be necessary. In a simple approach, thiazide or indapamide with potassium citrate is recommended for patients with hypercalciuria, and potassium citrate alone for the remaining normocalciuric subjects.

Diet↗
PubMed1992

Defect of the potassium transport process in the kidney of spontaneously hypertensive rats.

We investigated the natriuretic and kaliuretic effect of distal tubular diuretics in saline-loaded spontaneously hypertensive Wistar rats (SHR) from three different sources and normotensive Wistar rats (NWR). Orally administered early distal tubular diuretics (hydrochlorothiazide, chlorthalidone, metolazone, indapamide and cicletanine) caused much less potassium excretion in SHR than in NWR, whereas the magnitude of concurrent natriuresis was similar in both NWR and SHR. The intriguing renal handling of potassium excretion was exemplified by hydrochlorothiazide, for which enhanced kaliuresis was dose dependent in NWR but not in SHR. The doses tested ranged from 1 to 100 mg/kg, p.o. Amiloride, a late distal tubular diuretic, was also evaluated for its effect on sodium and potassium excretion in NWR and SHR. Amiloride produced potassium retention more effectively in NWR than in SHR, although the magnitude of natriuresis was similar. The difference between SHR and NWR with regard to potassium-retaining activity of amiloride was consistent at all doses tested (1-30 mg/kg, p.o.). In conclusion, it was suggested that SHR appear to have a genetic defect in potassium transport in the distal nephron.

Administration, Oral↗
PubMed1994

Pharmacological classification and renal actions of diuretics.

Diuretics may be classified according to their chemical structure, their mechanism and site of action within the nephron, and their diuretic potency. Those agents with primary action in the proximal nephron include the carbonic anhydrase inhibitors, e.g. acetazolamide, a sulfonamide derivative. Other drugs containing the sulfonamido grouping, e.g. furosemide, chlorothiazide and metolazone, also have secondary effects on the proximal nephron. Those drugs which have their major pharmacologic activity within the ascending limb of the loop of Henle, inhibiting the sodium/potassium/2 chloride electroneutral transport system, include the sulfonamide agents furosemide, bumetanide, piretanide and torasemide, and the phenoxyacetic acid derivative, ethacrynic acid. In the early portion of the distal convoluted tubule, sodium chloride reabsorption is impaired by the thiazide group, indapamide and metolazone, as their primary site of action. In the late reaches of the distal convolution and in the collecting duct, agents that inhibit the exchange of sodium for that of hydrogen and potassium have their major sites of activity. These agents, spironolactone, amiloride and triamterene, differ not only chemically but in their mechanisms of action. Diuretics may also be grouped according to potency. The loop of Henle agents are the most powerful, causing the excretion of 20-25% of filtered sodium load. The thiazide group and metolazone are moderately potent, resulting in the excretion of 5-8% of filtered sodium, and the 'potassium-sparing' drugs are only mildly potent, causing the excretion of only 2-3% of filtered sodium.

Diuretics↗
PubMed1997

Endothelial dysfunction and cardiorenal injury in experimental salt-sensitive hypertension: effects of antihypertensive therapy.

BACKGROUND: Pharmacological control of hypertension has contributed to a significant decrease in cardiovascular morbidity and mortality, although the beneficial effect on cardiac and renal diseases has been far more modest than the reduction in stroke. The endothelium plays a crucial homeostatic role in the regulation of vascular tone thrombogenesis and vascular remodeling. We studied the relationship between endothelial dysfunction and cardiorenal injury in hypertensive rats and evaluated the effects of two classes of antihypertensive agents commonly used in the clinical setting, a diuretic (DIU) and an ACE inhibitor (CEI). METHODS AND RESULTS: Dahl salt-sensitive rats (DS) given high dietary salt (4% NaCl) developed hypertension (systolic blood pressure [SBP], 218+/-9 versus 147+/-3 mm Hg in DS given 0.5% NaCl; P<.001), which was associated with impaired endothelium-dependent relaxations (EDRs) in aortic rings (ED50, 5.44+/-.18 versus 7.51+/-.10; P<.05) and mesenteric vessels (area under the curve, 299+/-11 versus 217+/-11 arbitrary units; P<.05). Hypertensive DS also demonstrated depressed nitric oxide synthase activity in the aorta (0.76+/-.15 versus 2.83+/-.17 nmol x min(-1) x g protein(-1); P<.05), left ventricular hypertrophy (0.43+/-.02 versus 0.29+/-.02 g ventricular weight/100 g body weight; P<.05), glomerular injury (histological injury score: 151+/-8 versus 11+/-2; P<.05), and increased urinary protein excretion (95+/-21 versus 25+/-5 mg/24 hours; P<.05). Treatment of DS rats with the CEI perindopril (4.56 mg x kg(-1) x d(-1)) did not affect SBP (225+/-6 mm Hg) but modestly improved EDR (ED50: 6.07+/-.37; P<.05 versus hypertensive DS) as well as proteinuria and glomerular histology. Addition of the DIU indapamide (1.44 mg x kg(-1) x d(-1)) normalized SBP (151+/-2 mm Hg; P<.05), EDR (ED50, 7.33+/-.08; P<.05), left ventricular hypertrophy (0.27+/-.01 g/100 g body weight; P<.05), and proteinuria (31+/-4 mg/24 hours; P<.05) and prevented glomerular injury (injury score: 30+/-2; P<.05). Monotherapy with DIU reduced SBP (175+/-3 mm Hg; P<.05) and normalized EDR and left ventricular hypertrophy but did not provide effective renal protection. In hypertensive DS, impaired EDR and left ventricular hypertrophy were positively correlated with SBP. In addition, we found a significant correlation between cardiac hypertrophy and endothelial dysfunction. Indeed, a hierarchical regression analysis revealed that impaired aortic EDR, and therefore decreased aortic compliance, positively contributed to left ventricular hypertrophy in addition to but independently of SBP [F(2,37)=6.29; P=.004]. CONCLUSIONS: These studies suggest a dissociation of the endothelial, cardiac, and renal effects of antihypertensive therapy in hypertension and may explain the variable success of antihypertensive regimens in treating hypertension while preventing cardiac and renal damage.

Acetylcholine↗
PubMed2004

Management of hypertension in the very elderly patient.

This Hypertension Grand Rounds discusses pharmacological treatment of hypertension in individuals who have survived 9 decades on earth. This rapidly growing group of relatively active and healthy elderly people is at high risk for hypertension, its treatment, and its adverse consequences, including stroke and heart failure. In this age group, the most common abnormality is elevated systolic blood pressure, which is much more predictive of stroke and heart disease death after 53 years of age. With the possible exception of the Antihypertensive and Lipid Lowering to prevent Heart Attack Trial (ALLHAT), recent clinical trials have emphasized the overriding importance of lowering blood pressure rather than the specific agent chosen to begin therapy. In 1999, a metaanalysis of 7 clinical trials that enrolled 1670 subjects >80 years of age indicated that active antihypertensive drug therapy significantly reduced stroke by 34% and heart failure by 39% but was associated with a nonsignificant 6% increase in mortality. The HYpertension in the Very Elderly Trial (HYVET) will enroll 2100 patients >80 years of age and will compare 2 groups randomized to indapamide+/-perindopril versus placebo+/-placebo for incident stroke during 5 years of follow-up. This study should answer lingering questions about whether active antihypertensive therapy is associated with a major and significant reduction in cardiovascular morbidity and mortality in this age group as it clearly does in younger hypertensives. Its choice of a diuretic as initial therapy is consistent with other trials, but chlorthalidone is the drug with the most compelling evidence in large US trials that included very elderly patients.

Aged↗
PubMed1997

The link among nitric oxide synthase activity, endothelial function, and aortic and ventricular hypertrophy in hypertension.

The adaptive changes that occur in the left ventricle (LV) and vessels in response to hypertension, namely, muscle hypertrophy/hyperplasia, endothelial dysfunction, and extracellular matrix increase, do not depend solely on blood pressure elevation. These changes are in fact, maladaptive since they are forerunners of cardiac failure, stroke, and renal failure. Nitric oxide, an endogenous vasodilator and inhibitor of vascular smooth muscle cell growth, is synthesized in the endothelium by constitutive nitric oxide synthase (cNOS). We investigated the relationships among LV and aortic cNOS activity (conversion of [14C] L-arginine to [14C] L-citrulline), with LV hypertrophy (LV weight/body weight), and (2) aortic hypertrophy (aortic weight/ length) in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats matched for blood pressure (219 +/- 12 versus 211 +/- 7 mm Hg, P = NS) and age. Compared with their normotensive counterparts, aortic cNOS activity was increased 106% in SHR but reduced by 73% in DS rats. The correlation between blood pressure and aortic cNOS activity was positive (r = .74, P < .01) in SHR and negative (r = -.82, P < .01) in DS rats, LV cNOS activity was increased 73% in SHR compared with normotensive Wistar-Kyoto rats (P < .01). On the other hand, LV cNOS activity was not increased in hypertensive DS rats compared with normotensive DS rats. In SHR, aortic hypertrophy did not increase significantly and LV hypertrophy increased only 15%, whereas in hypertensive DS rats the aorta and LV hypertrophied 36% and 88%, respectively (both P < .01). Moreover, in DS rats there was a negative correlation between cNOS activity and aortic hypertrophy (r = -.70, P < .01). In DS rats, antihypertensive therapy consisting of an angiotensin-converting enzyme inhibitor, perindopril, and a diuretic, indapamide, normalized blood pressure, aortic cNOS activity, and LV hypertrophy and reduced aortic hypertrophy. Our studies imply that upregulation of vascular cNOS activity has a protective cardiovascular homeostatic role in hypertension. Clinically, the variable end-organ disease observed in individuals with similar severity of hypertension may be explained, at least in part, by genetically conditioned differences in vascular cNOS activity in response to hypertension.

Animals↗
PubMedDate not supplied

Effects of antihypertensive therapy on serum lipoproteins.

Several drugs used for standard antihypertensive therapy may also interact with the lipoprotein metabolism. The following has been observed after 1 to 12 months of treatment. Various thiazide-type diuretics may significantly increase the potentially atherogenic serum low-density-lipoprotein cholesterol (LDL-C) and/or very-LDL-C-fractions, while the antiatherogenic high-density-lipoprotein cholesterol (HDL-C) is largely unchanged. Certain loop-diuretics also increase the LDL-C/HDL-C ratio and both types of diuretics elevated serum triglycerides (Tg) in some but not all studies. LDL-C was increased in diuretic-treated men and in chlorthalidone-treated postmenopausal women, but not in chlorthalidone-treated premenopausal women. The latter may be protected from this effect. Only two diuretics evaluated, namely indapamide and spironolactone, had no apparent influence on lipoproteins. Beta-blocker monotherapy may often increase Tg and slightly decrease HDL-C. The magnitude of these changes did not distinctly differ between highly cardioselective and nonselective beta-blockers, but it was less pronounced on beta-blockers than on those without intrinsic sympatholytic activity. Other sympatholytics such as reserpine, methyldopa, clonidine, debrisoquine, the alpha-beta-blocker labetalol, or the postsynaptic alpha-blocker, prazosin, did not affect or even slightly decrease Tg or total C, LDL-C, and very-LDL-C values. With combinations, a tendency for increased Tg and lower HDL-C was also apparent during thiazide-type diuretic-beta-blocker therapy. However, diuretic-induced increases in LDL-C were prevented or reversed by concomitant beta-blockade, but not by reserpine, methyldopa, or clonidine. Monotherapy with the potent direct vasodilator, carprazidil, improved blood pressure and significantly increased HDL-C. Prospective long-term studies are needed to clarify the course and the pathogenic and prognostic relevance of lipoprotein changes induced by certain diuretics or beta-blockers.

Adrenergic beta-Antagonists↗
PubMed2006

Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial.

BACKGROUND AND PURPOSE: The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)-lowering. METHODS: Subsidiary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial that established the benefits of BP-lowering in 6105 patients (mean age 64 years, 30% female) with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, plus indapamide in those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s). RESULTS: Stroke subtypes and coronary events were associated with 1.5- to 6.6-fold greater risk of recurrence of the same event (hazard ratios, 1.51 to 6.64; P=0.1 for large artery infarction, P<0.0001 for other events). However, 46% to 92% of further vascular outcomes were not of the same type. Active treatment produced comparable reductions in the risk of vascular outcomes among patients with a broad range of vascular events at entry (relative risk reduction, 25%; P<0.0001 for ischemic stroke; 42%, P=0.0006 for hemorrhagic stroke; 17%, P=0.3 for coronary events; P homogeneity=0.4). CONCLUSIONS: Patients with previous vascular events are at high risk of recurrences of the same event. However, because they are also at risk of other vascular outcomes, a broad range of secondary prevention strategies is necessary for their treatment. BP-lowering is likely to be one of the most effective and generalizable strategies across a variety of major vascular events including stroke and myocardial infarction.

Aged↗
PubMed2005

Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy.

BACKGROUND: The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease. METHODS AND RESULTS: The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI -7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001). CONCLUSIONS: These results indicate that an active blood pressure-lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease.

Aged↗
PubMed2004

Effects of antihypertensive and hypolipidemic drugs on plasma and high-density lipoprotein-associated platelet activating factor-acetylhydrolase activity.

BACKGROUND: Human plasma platelet activating factor acetylhydrolase (PAF-AH) is a phospholipase A2 primarily associated with low-density lipoprotein (LDL). PAF-AH activity has also been found on high-density lipoprotein (HDL). Most of the clinical studies that have investigated the plasma levels of PAF-AH activity in cardiovascular disease have involved patients who were under treatment with various drugs, such as antihypertensive or hypolipidemic agents. However, the influence of these drugs on the enzyme activity has not been adequately studied. MATERIAL AND METHODS: We evaluated the effects of representative antihypertensive and hypolipidemic drugs on the total plasma, as well as on the HDL-associated PAF-AH activity, in 121 patients with essential hypertension and in 90 patients with dyslipidemias of type IIA or type IIB. Serum lipids and enzymatic activities were determined at baseline and after 3 months of treatment. RESULTS: The administration of lacidipine (4 mg, n = 21), valsartan (80 mg, n = 26), indapamide (2.5 mg, n = 20), benazepril (20 mg, n = 20), or atenolol (50 mg, n = 34) did not affect either the total plasma- or the HDL-associated PAF-AH activity. In contrast, treatment with fluvastatin (40 mg, n = 50) or ciprofibrate (100 mg, n = 40) reduced by 25% plasma PAF-AH activity (P <.001) associated with a decrease in serum levels of total cholesterol and LDL-cholesterol (P <.001). Furthermore, ciprofibrate induced an increase by 26% in HDL-associated PAF-AH activity (P =.004) along with an increase in serum HDL-cholesterol levels (P =.02). CONCLUSIONS: Among all types of drugs studied, only those that significantly affect lipid metabolism, such as statins and fibrates, significantly influence PAF-AH activity in human plasma.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1996

Chemoprophylaxis of diabetic nephropathy in the elderly.

Renal disease in elderly diabetic patients is costly in terms of morbidity, mortality and medical payments. Therefore, prevention of diabetic nephropathy has become a prominent goal in the treatment of diabetic patients. Preventive treatment should begin not later than at the stage of persistent microalbuminuria, and regular screening for microalbuminuria is recommended for both elderly and younger diabetic patients. Improved metabolic control, through diet and hypoglycaemic therapy, has been demonstrated to lower urinary albumin excretion. The target level of glycated haemoglobin is < 8%, or < 2% higher than the upper limit of normal in nondiabetic people. Insulin therapy has no adverse effects on renal indices, unless it increases bodyweight and consequently raises blood pressure. To preserve renal function in elderly diabetic patients, blood pressure should be kept well below 140/90 mm Hg. Treatment with ACE inhibitors may be the 'gold standard' intervention, and should be initiated at the lowest possible dosage and then titrated until the maximum tolerated dosage has been reached. Nonchronotropic calcium antagonists have been shown to be as effective as ACE inhibitors with regard to their effects on blood pressure, renal haemodynamics and urinary albumin excretion. Most dihydropyridines have been found to increase or to have no effect on urinary albumin excretion despite significant blood pressure reduction. A renoprotective action of diuretics is generally unlikely, with the possible exception of indapamide. Although beta-blockers are effective antihypertensive agents, they may not adequately preserve kidney function in diabetic patients. Because beta-blocker treatment may mask the symptoms of hypoglycaemia, they should be reserved for patients with coronary artery disease or arrhythmias.

Aged↗
PubMed2003

Prevention and treatment of diabetic nephropathy in older patients.

Renal disease in older diabetic patients is costly in terms of morbidity, mortality and expenditure. Therefore, prevention and treatment of diabetic nephropathy has become a prominent goal in the treatment of patients with diabetes mellitus. Preventive treatment should begin no later than at the stage of microalbuminuria, and regular screening for microalbuminuria is recommended for all patients with diabetes, irrespective of age. Improved metabolic control has been demonstrated to lower urinary albumin excretion. Target glycosylated haemoglobin levels should be below 7%, or 1% above the upper limit of normal of non-diabetic subjects. The use of an intensified treatment regimen is recommended. Insulin therapy has no adverse effects on renal indexes. To preserve renal function in older diabetic patients, blood pressure should be kept at or below 130/80 mm Hg. Treatment with ACE inhibitors or angiotensin II receptor antagonists (angiotensin II receptor blockers; ARBs) is superior to other pharmacological therapy, and should be initiated as first-line treatment. Most of the calcium channel antagonists have been found to increase or to have no effect on microalbuminuria despite blood pressure reduction. Moreover, there is substantial controversy as to whether they may be associated with increased cardiovascular morbidity. Non-dihydropyridine derivatives and calcium channel antagonists, such as nitrendipine, may be nephroprotective and have favourable effects on patients outcomes. A renoprotective action of diuretics may be confined to indapamide. Although beta-adrenoreceptor blockers are effective antihypertensive agents, they may not adequately preserve kidney function in older diabetic patients. However, as add-on treatment to ACE inhibitors or ARBs, they are particularly beneficial in nephropathic patients at risk of cardiovascular disease or with arrhythmias, in whom they may prove life-saving.

Aged↗
PubMed2006

A substudy protocol of the hypertension in the Very Elderly Trial assessing cognitive decline and dementia incidence (HYVET-COG) : An ongoing randomised, double-blind, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Randomised, controlled trials and population studies have suggested a link between hypertension and the development of dementia (vascular dementia and Alzheimer's disease) although the results are not conclusive. The very elderly are at highest risk for both hypertension and dementia but have been underrepresented in studies to date. The Hypertension in the Very Elderly Trial (HYVET), an international, randomised, double-blind, placebo-controlled trial of antihypertensive medication for those > or =80 years of age, is currently underway. The protocol for the assessment of cognitive decline and detection of incident dementia cases is described in this article. The objective of this protocol is to determine whether treatment of hypertension in this very elderly group affects the incidence of dementia and decline in cognitive function during the period of the HYVET trial. METHODS: Cognitive function in all HYVET trial participants is assessed at baseline and annually thereafter using the Mini-Mental State Examination (MMSE). An MMSE score that decreases more than three points per year or decreases to <24 prompts further investigation for possible incident dementia. This includes use of the Diagnostic and Statistical Manual-IV criteria, the modified Hachinski scale and CT scanning. In cases where a CT scan cannot be obtained the full Hachinski scale is used. Additional information is provided when available from the clock drawing test and Geriatric Depression Scale. Data are also gathered from all trial participants with regard to education, blood pressure, alcohol use, co-morbidities and concomitant treatments. At the end of the trial, changes in cognitive function and incident dementia cases will be compared in those receiving active treatment (indapamide slow-release +/- perindopril) and those receiving matching placebo. RESULTS: The protocol has been applied successfully and the data collection phase is underway. DISCUSSION: Previous population studies have been unable to study antihypertensive use in a controlled manner and randomised, controlled trials suggest a positive or mixed picture regarding an association between use of antihypertensive therapy and reduction in incident cognitive decline and/or dementia. No such trial has yet been performed exclusively in subjects > or =80 years of age with hypertension. The HYVET trial is placebo controlled and while investigating the cardiovascular effect of treatment also assesses cognitive function and quality of life in both the placebo and actively treated arms of the trial. The HYVET cognitive substudy trial (HYVET-COG) design has been successfully applied and the instruments chosen appear to be appropriate, valid and pragmatic. CONCLUSION: HYVET-COG provides the first opportunity to examine the effect of antihypertensive treatment on incident dementia in a high-risk very elderly population.

Aged, 80 and over↗
PubMed1987

Clinical pharmacokinetics of some newer diuretics.

Several new diuretics have recently been developed. This review summarises the published knowledge about some of them. Azosemide is a loop diuretic. The bioavailability is about 15% and it has a half-life of 2 to 3 hours. Renal and non-renal clearance are 1.32 and 5.4 L/h, respectively. Etozolin is also a loop diuretic. It is rapidly metabolised to the active metabolite, ozolinone. The gastrointestinal uptake of etozolin is almost complete. The plasma half-life of etozolin and ozolinone are 2 and 10 hours, respectively. The compounds are mainly eliminated as metabolites. Renal and liver impairment do not seem to change the pharmacokinetics. Fenquizone has properties similar to the thiazides. The plasma half-life is approximately 17 hours. Apparent volume of distribution averaged 686 L and renal clearance is 7.2 L/h. Indapamide acts predominantly on the proximal segment of the distal tubule and also has direct vasodilatory effects. Gastrointestinal uptake is at least 80%. The drug binds highly to carbonic anhydrases of red blood cells. Protein binding is about 80%, while terminal plasma half-life is 15 hours and the apparent volume of distribution 25 L. Renal clearance is 0.3 L/h and non-renal clearance 0.9 L/h. Several metabolites have been described, of which one major metabolite is pharmacologically active. Muzolimine is a loop diuretic. Its uptake is almost complete, but decreased substantially by food. The protein binding is about 65%, the apparent volume of distribution is about 1 L/kg and average terminal half-life 10 to 20 hours. Elimination is mainly non-renal, and non-renal clearance ranges between 0.5 and 1.32 L/h. The pharmacokinetics of the drug do not seem to be changed in cardiac failure. Terminal plasma half-life is essentially unchanged in patients with renal failure, except in those with very severe reduction of glomerular filtration rate. Piretanide is a loop diuretic which is about 6 times as potent as frusemide (furosemide). Its bioavailability is most likely complete in healthy subjects and in renal patients. Protein binding in healthy subjects is about 95%. The plasma half-life of the drug is about 1 hour and apparent volume of distribution averages about 17 L. Renal and non-renal clearance are about 6 L/h, although renal clearance is decreased in renal failure: this decrease is correlated with glomerular filtration rate. Non-renal clearance is unchanged in renal failure, as is the apparent volume of distribution.(ABSTRACT TRUNCATED AT 400 WORDS)

Diuretics↗
PubMed1986

The effects of antihypertensive drugs on serum lipids and lipoproteins, I. Diuretics.

Potassium-losing diuretic drugs, when used in the treatment of hypertension, cause unfavourable short term alterations in blood lipid and lipoprotein concentrations. The disturbance is characterised by increases in total cholesterol of 4 to 13%, in low density lipoprotein (LDL) cholesterol of 7 to 29%, in very-low density lipoprotein (VLDL) cholesterol of 7 to 56%, and in total triglyceride of 14 to 37%. The disturbance is variable among patients and over time in individual patients; it is absent in some. In long term treatment the data are fragmentary, but total cholesterol and triglycerides usually return to baseline values or below. The variability of the lipid response to diuretics has several consequences: firstly, it necessitates a sizeable study population (minimum of 30 patients) in order to document convincingly its presence or absence; secondly, lipoprotein fractions must be examined to define the pattern of the disturbance; and thirdly, the subsidence of the diuretic-induced lipid effects in long term treatment may be more apparent than real because even larger decreases have been noted in untreated groups in the few studies that wisely included these important controls for comparison. While the cause of the lipid-lipoprotein aberration is unclear, existing data suggest that certain attributes of the study population influence the response, i.e. age, habitual diet, hormonal milieu (gender), baseline cholesterol concentrations, and induced glucose intolerance. The apparent absence of lipid alterations with indapamide needs to be substantiated and compared with low doses of a standard thiazide-type drug. The lipid-lipoprotein effects of diuretics seem inconsequentially small, but they may contribute to the disappointing failure of diuretic-based regimens to lower the incidence of coronary heart disease in hypertensive patients. Nevertheless, diuretic-based treatment remains the only therapeutic regimen of proven benefit to congestive heart failure in patients with hypertension, and it is superior to beta-blockade in preventing stroke. Hence, alternative antihypertensive drug regimens must be compared prospectively with diuretics in order to verify any theoretic superiority.

Antihypertensive Agents↗