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1.
Trials ; 22(1): 814, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789314

RESUMO

INTRODUCTION: Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For commonly prescribed drugs, even small differences in effectiveness or safety could have significant public health implications. However, conventional clinical trials that randomise individual subjects are costly and unwieldy. Such trials are also often criticised as having low external validity. We describe an approach to rapidly generate externally valid evidence of comparative safety and effectiveness using the example of two widely used diuretics for the management of hypertension. METHODS AND ANALYSIS: The EVIDENCE (Evaluating Diuretics in Normal Care) study has a prospective, cluster-randomised, open-label, blinded end-point design. By randomising prescribing policy in primary care practices, the study compares the safety and effectiveness of commonly used diuretics in treating hypertension. Participating practices are randomised 1:1 to a policy of prescribing either indapamide or bendroflumethiazide when clinically indicated. Suitable patients who are not already taking the policy diuretic are switched accordingly. All patients taking the study medications are written to explaining the rationale for changing the prescribing policy and notifying them they can opt-out of any switch. The prescribing policies' effectiveness and safety will be compared using rates of major adverse cardiovascular events (hospitalisation with myocardial infarction, heart failure or stroke or cardiovascular death), routinely collected in national healthcare administrative datasets. The study will seek to recruit 250 practices to provide a study population of approximately 50,000 individuals with a mean follow-up time of two years. A primary intention-to-treat time-to-event analysis will be used to estimate the relative effect of the two policies. ETHICS AND DISSEMINATION: EVIDENCE has been approved by the East of Scotland Research Ethics Service (17/ES/0016, current approved protocol version 5, 26 August 2021). The results will be disseminated widely in peer reviewed journals, guideline committees, National Health Service (NHS) organisations and patient groups. TRIAL REGISTRATION: ISRCTN 46635087 . Registered on 11 August 2017 (pre-recruitment).


Assuntos
Hipertensão , Inibidores de Simportadores de Cloreto de Sódio , Diuréticos/efeitos adversos , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Políticas , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Medicina Estatal , Tiazidas
2.
Rev Med Suisse ; 17(750): 1556-1559, 2021 Sep 15.
Artigo em Francês | MEDLINE | ID: mdl-34528418

RESUMO

Thiazide diuretics (hydrochlorothiazide) and « thiazide-like ¼ (chlorthalidone, indapamide) are widely prescribed due to their effectiveness in the treatment of arterial hypertension. The use of thiazides may be complicated by hyponatremia that is associated with increased morbidity and mortality. The pathophysiology of thiazide-induced hyponatremia is not yet clear. It is currently difficult to predict who will develop thiazide-induced hyponatremia. Genetic predisposition is considered, and several studies are attempting to clarify it in order to identify patients at risk of developing hyponatremia after taking a thiazide. Their reintroduction to a patient who already presented hyponatremia upon thiazide should be avoided.


Assuntos
Hiponatremia , Indapamida , Anti-Hipertensivos/efeitos adversos , Clortalidona/efeitos adversos , Humanos , Hiponatremia/induzido quimicamente , Tiazidas/efeitos adversos
3.
Pol Merkur Lekarski ; 49(292): 303-305, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34464373

RESUMO

Clinical consequences of hyponatremia might be serious. It is often related to the administration of diuretics, especially thiazide and thiazide-like diuretics. It is known that elderly subjects are prone to thiazide induced hyponatremia (TIH). A CASE REPORT: A 66-year old female patient was admitted to our Department. The aim of the admission was to complete a differential diagnosis of chronic hyponatremia. For about two years the patient had suffered from the following symptoms: severe headaches, fatigue, episodic mental confusions, stomachaches, and diarrhea. Before admission to the hospital, the patient was treated with bisoprolol, amlodipine, telmisartan, indapamide, furosemide, acetylsalicylic acid, thiamazole, and zolpidem. The general clinical picture might suggest that the cause of hyponatremia was the indapamide diuretic therapy. However, only moderate hyponatremia, normokalemia, as well as, an increased antidiuretic hormone serum concentration were observed. These findings are not typical for TIH. Despite those findings, natremia improved after the cessation of indapamide therapy. CONCLUSIONS: This case report described the atypical presentation of TIH resembling SIADH. TIH diagnosis should be primarily based on the improvement of hyponatremia after the termination of thiazide or thiazide-like diuretic treatment.


Assuntos
Anti-Hipertensivos , Hiponatremia , Idoso , Anti-Hipertensivos/efeitos adversos , Diuréticos/efeitos adversos , Feminino , Humanos , Hiponatremia/induzido quimicamente , Hiponatremia/diagnóstico , Tiazidas
5.
Am J Hypertens ; 34(10): 1092-1099, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34115112

RESUMO

BACKGROUND: Blood pressure variability (BPV) is associated with adverse events (AEs) independently of hypertension. It has been suggested that calcium channel blockers (CCBs) may reduce BPV, and thus be particularly valuable in hypertensives with high BPV. We sought to investigate how CCB affect BPV progression and whether long-term adverse effects of BPV differ after CCB treatment than after treatment with other antihypertensives. METHODS: We retrospectively analyzed 25,268 US veterans who had been followed for 3 years without hypertensive therapy, started on a single class of antihypertensive agents (thiazides, CCBs, ACE inhibitors, or beta blockers [BBs]), treated for 6 years, and then followed for 3 additional years. BPV was calculated as SD of systolic or diastolic blood pressures from at least 10 measurements over each 3-year period. A combined AE endpoint included hospitalization, coronary artery bypass grafting, carotid endarterectomy, angioplasty, amputation, arteriovenous fistula creation, and mortality was assessed in years 9-12. RESULTS: Post-medication high BPV and BB or thiazide use were associated with increased AE risk. Medication type also affected mean post-medication BPV. The effects of medications except for BBs on AE and mortality was independent of the patient BPV. CONCLUSIONS: The possible deleterious effects of thiazides should be considered within the context of the study population, who were mostly male and received only a single class of hypertensives. While CCB may ameliorate BPV over time, this study does not support choosing CCB over other agents specifically to lessen BPV-associated risk.


Assuntos
Anti-Hipertensivos , Pressão Sanguínea , Hipertensão , Antagonistas Adrenérgicos beta/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/fisiologia , Bloqueadores dos Canais de Cálcio/efeitos adversos , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Masculino , Estudos Retrospectivos , Tiazidas/efeitos adversos , Resultado do Tratamento , Veteranos
6.
PLoS One ; 16(6): e0253608, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34166457

RESUMO

Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human body. Despite their vital functions, they are also responsible for, or implicated in, numerous ailments and diseases such as glaucoma, high altitude sickness, and cancer. Because CA isoforms are highly homologous, clinical drugs designed to inhibit enzymatic activity of a particular isoform, can also bind to others with similar affinity causing toxic side effects. In this study, the affinities of twelve CA isoforms have been determined for nineteen clinically used drugs used to treat hypertension related diseases, i.e. thiazides, indapamide, and metolazone. Their affinities were determined using a fluorescent thermal shift assay. Stopped flow assay and isothermal titration calorimetry were also employed on a subset of compounds and proteins to confirm inhibition of CA enzymatic activity and verify the quantitative agreement between different assays. The findings of this study showed that pharmaceuticals could bind to human CA isoforms with variable affinities and inhibit their catalytic activity, even though the drug was intended to interact with a different (non-CA) protein target. Relatively minor structural changes of the compounds may cause significant changes in affinity and selectivity for a particular CA isoform.


Assuntos
Anidrases Carbônicas/química , Sulfonamidas/química , Tiazidas/química , Domínio Catalítico , Humanos , Isoenzimas/química , Ligação Proteica , Relação Estrutura-Atividade
7.
Br J Dermatol ; 185(2): 343-352, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33609289

RESUMO

BACKGROUND: Case-control studies report a dose-dependent increased risk of skin cancer in users of hydrochlorothiazide (HCTZ) vs. nonusers. The degree to which other thiazides and thiazide-like diuretics (TZs) are associated with skin cancer is less certain. OBJECTIVES: To assess the risk of skin cancer in new users of different TZs compared with new users of calcium channel blockers (CCBs). METHODS: We conducted a cohort study using a UK primary-care database (1998-2017), including 271 154 new TZ users [87·6% bendroflumethiazide (BFT), 5·8% indapamide and 3·6% HCTZ] and 275 263 CCB users. The outcomes were basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). We estimated incidence rates (IRs) and IR ratios (IRRs) in short-term (< 20 prescriptions) and long-term (≥ 20 prescriptions) users of TZs and CCBs using negative binomial regression, and calculated rate differences (RDs) for selected results. We used fine stratification on the propensity score (PS) to control for 23 baseline covariates. RESULTS: Long-term use of HCTZ increased absolute and relative risks of SCC [PS-weighted IRR 1·95; 95% confidence interval (CI) 1·87-2·02; RD per 100 000 person-years 87.4], but not of BCC or CMM. Long-term use of indapamide was associated with an increased incidence of CMM (IRR 1·43; 95% CI 1·35-1·50). BFT was not meaningfully associated with the risk of any type of skin cancer. CONCLUSIONS: Our results corroborate the previously reported increased risk of SCC (but not of BCC or CMM) for long-term use of HCTZ. BFT may be a safer alternative for patients at increased risk of skin cancer.


Assuntos
Carcinoma Basocelular , Neoplasias Cutâneas , Carcinoma Basocelular/induzido quimicamente , Carcinoma Basocelular/epidemiologia , Estudos de Coortes , Diuréticos/efeitos adversos , Humanos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/epidemiologia , Tiazidas/efeitos adversos
8.
Am J Med Sci ; 361(1): 106-110, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32709394

RESUMO

Potassium is the most important intracellular cation and the kidneys play a pivotal role in potassium homeostasis. Potassium disorder is a common electrolyte abnormality and it increases the risk of death from any cause, particularly cardiovascular events. Hyperkalemia is a common electrolyte abnormality encountered post organ transplantation. The etiology is multifactorial, and includes drugs such as calcineurin inhibitors. In certain regards, the clinical picture of post-transplantation hyperkalemia and hypertension resembles that of Gordon syndrome or familial hyperkalemic hypertension, a disorder characterized by over activity of thiazide-sensitive sodium chloride cotransporter. Effective and safe management of chronic hyperkalemia can be challenging in this special patient population. Despite the significant short-term and long-term side effects, fludrocortisone (a potent synthetic oral mineralocorticoid receptor agonist) has emerged as the default drug of choice for treatment of refractory hyperkalemia in many organ transplant recipients. However, the long-term efficacy and safety of fludrocortisone for management of hyperkalemia in organ transplant recipients remains unknown. This review discusses potassium homeostasis, including the role of the kidneys, and focuses on calcineurin inhibitor-induced hyperkalemia and on the under-appreciated role of thiazide-type diuretic use in management of hyperkalemia and hypertension. We present an illustrative case of post-transplantation hyperkalemia and hypertension with relevant literature.


Assuntos
Inibidores de Calcineurina/metabolismo , Diuréticos/uso terapêutico , Hiperpotassemia/terapia , Hipertensão/terapia , Potássio/fisiologia , Tiazidas/uso terapêutico , Transplantes/fisiopatologia , Homeostase , Hiperpotassemia/etiologia , Hipertensão/etiologia , Rim/fisiologia
9.
Environ Res ; 192: 110316, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065070

RESUMO

OBJECTIVE: Phthalates are non-persistent pollutants related to impaired metabolism and high cardiovascular risk. Their toxic metabolites are eliminated through urine and feces. Prevention policies are considered by the governments, although no therapeutic strategy to facilitate their elimination from the human body has been proposed so far. Aim of the present study was to verify, for the first time in humans, whether diuretics might be able to enhance phthalates' toxic metabolites urinary output. DESIGN AND METHODS: We conducted a two-armed, parallel-design, randomized clinical trial. Thirty patients with type 2 diabetes and hypertension received a four week-treatment with Dapagliflozin 10 mg or Hydrochlorothiazide 12.5 mg. 24-hours urine were collected to measure urinary excretion of three major 2-ethylhexyl-phthalate (DEHP) metabolites, i.e. mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) and mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP). RESULTS: 24-h urinary excretion of DEHP and MEHP was increased (+44%, p = 0.036; +49%, p = 0.0016) while MEOHP e MEHHP showed only a positive trend (+25%, p = 0.016; +36%, p = 0.062). Irrespective of the specific treatment, induced variations of daily urinary eliminations of MEHP metabolites were related with the 24-h urinary sodium (r = 0.42, p = 0.0226) and potassium (r = 0.54, p = 0.0026) excretion. Also, DEHP and MEOHP were related to sodium (r = 0·43, p = 0.0205; r = 0·44, p = 0.0168 respectively) but not to potassium. CONCLUSIONS: Urinary phthalates excretion seems to occur mainly through sodium- and potassium-related mechanisms, apparently independent from the different diuretic effect. Both thiazide diuretics and SLGT2 inhibitors are effective into the removal of phthalates metabolites from the human body, reducing the human tissues' exposure to their toxicity.


Assuntos
Diabetes Mellitus Tipo 2 , Dietilexilftalato , Ácidos Ftálicos , Inibidores do Transportador 2 de Sódio-Glicose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exposição Ambiental , Humanos , Tiazidas
10.
J Bras Nefrol ; 43(1): 103-109, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33179717

RESUMO

Thiazide and thiazide-like diuretics are widely used for the management of hypercalciuria among stone-forming patients. Although the effects of different thiazides should be relatively similar in terms of prevention of stone recurrence, their potency and side effects may differ. However, there is scarce data concerning the metabolic and bone effects of these agents among recurrent nephrolithiasis patients with hypercalciuria. The aim of this update article was to compare our experience in the use of thiazide and thiazide- like diuretics with that of the current literature, concerning their anticalciuric properties and consequent reduction of recurrent stone formation. Their impact on bone mass and potential side effects were also discussed.


Assuntos
Cálculos Renais , Nefrolitíase , Diuréticos/uso terapêutico , Humanos , Nefrolitíase/tratamento farmacológico , Recidiva , Tiazidas/uso terapêutico
11.
Expert Opin Drug Saf ; 19(12): 1577-1583, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33047990

RESUMO

INTRODUCTION: ACE-inhibitors (ACEI) and diuretics are the typical first-line antihypertensive drugs with complementary mechanisms of action. The present paper is summarizing the evidence supporting the efficacy of their combination in a broad range of hypertensive patients. AREAS COVERED: This source of data is different trials investigating the use of ACEI and diuretics in different populations of patients. The available evidence supports some advantage for thiazide-type compounds (chlortalidone-CHT and indapamide-IND) in the prevention of major CV complications. In terms of safety, hydrochlorothiazide (HCTZ) and indapamide are associated with a lesser rate of hypokalemia and abnormalities of metabolic profile (glucose control, uric acid levels, serum potassium levels). As far as the results of clinical trials, the most relevant studies are involving the combination of benazepril or perindopril with HCTZ (benazepril) or IND (Perindopril) respectively. All these studies have resulted in a favorable clinical outcome. In terms of safety profile, the combination of ACEi and diuretic is safe and comparable with that of ACEi and calcium channel blockers with no differences in the rate of major adverse events (cough or angioedema) and a lower rate of ankle edema. EXPERT OPINION: The combination of ACEi and diuretic is safe and well-tolerated and should be considered among the first-line treatments in most of the patients with hypertension.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Tiazidas/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Diuréticos/administração & dosagem , Diuréticos/efeitos adversos , Quimioterapia Combinada , Humanos , Hipertensão/tratamento farmacológico , Tiazidas/efeitos adversos
14.
Hypertension ; 76(2): 432-441, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32639892

RESUMO

The SPRINT (Systolic Blood Pressure Intervention Trial) study reported that intensive blood pressure (BP) treatment with a systolic BP target of <120 mm Hg decreased the risks of cardiovascular events. However, it remains unknown whether specific medications can further improve cardiovascular outcome in patients receiving intensive BP treatment. This study examined whether thiazide use improves cardiovascular outcome in patients receiving intensive BP treatment. We used data of nondiabetic patients receiving intensive BP treatment in the SPRINT study. The primary outcome was a composite end point of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. We analyzed hazard ratios for outcomes with 95% CIs in patients taking thiazides compared with those not taking thiazides using Cox proportional hazard models. This study included 2847 patients and the mean follow-up period was 3.3 years. The risk of primary outcome events was significantly lower in patients taking thiazides than in those not taking thiazides in both entire and propensity score-matched cohorts. Particularly, heart failure risk was significantly lower in those taking thiazides. These associations were also observed in various subgroups. In addition, thiazide use was associated with decreased risk of all-cause mortality. Hypokalemia occurred more frequently in patients taking thiazides than in those not taking thiazides. Thiazide use decreased risk of cardiovascular events, particularly heart failure, in nondiabetic high-risk patients receiving intensive BP treatment.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Insuficiência Cardíaca/epidemiologia , Hipertensão/tratamento farmacológico , Tiazidas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/farmacologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Tiazidas/farmacologia
15.
J Am Soc Nephrol ; 31(6): 1226-1242, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32295826

RESUMO

BACKGROUND: The potassium channel Kir4.1 forms the Kir4.1/Kir5.1 heterotetramer in the basolateral membrane of the distal convoluted tubule (DCT) and plays an important role in the regulation of the thiazide-sensitive NaCl cotransporter (NCC). Kidney-specific deletion of the ubiquitin ligase Nedd4-2 increases expression of NCC, and coexpression of Nedd4-2 inhibits Kir4.1/Kir5.1 in vitro. Whether Nedd4-2 regulates NCC expression in part by regulating Kir4.1/Kir5.1 channel activity in the DCT is unknown. METHODS: We used electrophysiology studies, immunoblotting, immunostaining, and renal clearance to examine Kir4.1/Kir5.1 activity in the DCT and NCC expression/activity in wild-type mice and mice with kidney-specific knockout of Nedd4-2, Kir4.1, or both. RESULTS: Deletion of Nedd4-2 increased the activity/expression of Kir4.1 in the DCT and also, hyperpolarized the DCT membrane. Expression of phosphorylated NCC/total NCC and thiazide-induced natriuresis were significantly increased in the Nedd4-2 knockout mice, but these mice were normokalemic. Double-knockout mice lacking both Kir4.1/Kir5.1 and Nedd4-2 in the kidney exhibited increased expression of the epithelial sodium channel α-subunit, largely abolished basolateral potassium ion conductance (to a degree similar to that of kidney-specific Kir4.1 knockout mice), and depolarization of the DCT membrane. Compared with wild-type mice, the double-knockout mice displayed inhibited expression of phosphorylated NCC and total NCC and had significantly blunted thiazide-induced natriuresis as well as renal potassium wasting and hypokalemia. However, NCC expression/activity was higher in the double-knockout mice than in Kir4.1 knockout mice. CONCLUSIONS: Nedd4-2 regulates Kir4.1/Kir5.1 expression/activity in the DCT and modulates NCC expression by Kir4.1-dependent and Kir4.1-independent mechanisms. Basolateral Kir4.1/Kir5.1 activity in the DCT partially accounts for the stimulation of NCC activity/expression induced by deletion of Nedd4-2.


Assuntos
Túbulos Renais Distais/metabolismo , Ubiquitina-Proteína Ligases Nedd4/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Simportadores de Cloreto de Sódio/fisiologia , Tiazidas/farmacologia , Animais , Canais Epiteliais de Sódio/fisiologia , Camundongos , Camundongos Knockout
16.
Clin Ther ; 42(4): 583-591, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32229030

RESUMO

PURPOSE: Hypertension occurs in >50% of US nursing home (NH) residents, but it is unclear which antihypertensive classes offer the best balance of benefits and risks in this population. The objectives of this study were to describe the patterns of antihypertensive medication treatment in this population, focusing on thiazide diuretics, and to determine the association between thiazide diuretics (DIURs) and outcomes important to NH patients. METHODS: This observational cohort study was conducted in long-term NH residents treated for hypertension in the second quarter (Q2) of 2013, from all US NHs. The primary exposure was the frequency of use of antihypertensive treatment class (DIURs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers [ARBs], calcium channel blockers, and ß-blockers) according to Medicare Part D dispensing data. Because DIUR-related urinary symptoms were a focus, residents receiving nonthiazide diuretics were excluded. We ascertained continued medication use by class from Q2 to Q4 of 2013, and ascertained 6-month incontinence and hospitalization using data from Medicare claims and the Minimum Data Set. FINDINGS: Of 152,902 NH residents treated for hypertension, 52.2% were treated with ß-blockers (22% as a single agent), 39.7% with calcium channel blockers (14% as a single agent), 38.8% with angiotensin-converting enzyme inhibitors (14% as a single agent), 14.2% with DIURs (2% as a single agent), and 13.2% with ARBs (4% as a single agent). Overall, 55.1% were treated with 1 drug; 33.2%, with 2 drugs; and 11.8%, with 3 or more drugs. From Q2 to Q4, DIURs were more likely to have been discontinued than any other class (19.4% vs 14.1%-16.1% for each of the other 4 classes; all, p < 0.05) and less likely to have been started than any other class except ARBs (1.4% vs 3.8%-5.3% for each of the other 3 classes). Urinary incontinence occurred in 76.6% of the sample. In a multivariate logistic regression model, new DIUR use from Q2 to Q4 of 2013 was not significantly associated with urinary incontinence in Q4, and none of the antihypertensive drug classes were associated with 6-month hospitalization. IMPLICATIONS: In 2013, long-term NH residents treated for hypertension were least likely to receive, more likely to discontinue, and less likely to start a new DIUR than any other first-line antihypertensive medication. DIURs were not associated with increased incontinence or hospitalization, so in the absence of indications for other drugs, DIURs may be a reasonable first-line choice for hypertension treatment in this population.


Assuntos
Anti-Hipertensivos/uso terapêutico , Diuréticos/uso terapêutico , Tiazidas/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Casas de Saúde , Resultado do Tratamento
17.
Kidney Int ; 97(6): 1208-1218, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32299681

RESUMO

The basolateral potassium channel KCNJ10 (Kir4.1), is expressed in the renal distal convoluted tubule and controls the activity of the thiazide-sensitive sodium chloride cotransporter. Loss-of-function mutations of KCNJ10 cause EAST/SeSAME syndrome with salt wasting and severe hypokalemia. KCNJ10 is also expressed in the principal cells of the collecting system. However, its pathophysiological role in this segment has not been studied in detail. To address this, we generated the mouse model AQP2cre:Kcnj10flox/flox with a deletion of Kcnj10 specifically in the collecting system (collecting system-Kcnj10-knockout). Collecting system-Kcnj10-knockout mice responded normally to standard and high potassium diet. However, this knockout exhibited a higher kaliuresis and lower plasma potassium than control mice when treated with thiazide diuretics. Likewise, collecting systemKcnj10-knockout displayed an inadequately high kaliuresis and renal sodium retention upon dietary potassium restriction. In this condition, these knockout mice became hypokalemic due to insufficient downregulation of the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK) in the collecting system. Consistently, the phenotype of collecting system-Kcnj10-knockout was fully abrogated by ENaC inhibition with amiloride and ameliorated by genetic inactivation of ROMK in the collecting system. Thus, KCNJ10 in the collecting system contributes to the renal control of potassium homeostasis by regulating ENaC and ROMK. Hence, impaired KCNJ10 function in the collecting system predisposes for thiazide and low potassium diet-induced hypokalemia and likely contributes to the pathophysiology of renal potassium loss in EAST/SeSAME syndrome.


Assuntos
Hipopotassemia , Canais de Potássio Corretores do Fluxo de Internalização , Animais , Dieta , Canais Epiteliais de Sódio , Hipopotassemia/induzido quimicamente , Hipopotassemia/genética , Camundongos , Camundongos Knockout , Potássio , Canais de Potássio Corretores do Fluxo de Internalização/genética , Tiazidas
18.
Hypertension ; 75(4): 966-972, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114850

RESUMO

Little is known about the occurrence of hypokalemia due to combination therapy for hypertension. Using data from Danish administrative registries, we investigated the association between different combinations of antihypertensive therapy and risk of developing hypokalemia. Using incidence density matching, 2 patients without hypokalemia were matched to a patient with hypokalemia (K, <3.5 mmol/L) on age, sex, renal function, and time between index date and date of potassium measurement. Combination therapies were subdivided into 10 groups including ß-blockers (BB)+thiazides (BB+thiazides), calcium channel blockers (CCB)+renin angiotensin system inhibitors (RASi)+thiazides (CCB+RASi+Thiazides), calcium channel blockers+thiazides (CCB+thiazides), and ß-blockers+renin angiotensin system inhibitors+thiazides (BB+RASi+thiazides). We used conditional logistic regression to estimate the odds of developing hypokalemia for different combinations of antihypertensive drugs within 90 days of combination therapy initiation. We matched 463 patients with hypokalemia to 926 patients with normal potassium concentrations. The multivariable analysis showed 5.82× increased odds of developing hypokalemia if administered CCB+thiazides (95% CI, 3.06-11.08) compared with CCB+RASi. Other combinations significantly associated with increased hypokalemia odds were BB+thiazides (odds ratio, 3.34 [95% CI, 1.67-6.66]), CCB+RASi+thiazides (odds ratio, 3.07 [95% CI, 1.72-5.46]), and BB+RASi+thiazides (odds ratio, 2.78 [95% CI, 1.41-5.47]). Combinations of thiazides with CCB, RASi, or BB were strongly associated with increased hypokalemia risk within 90 days of treatment initiation.


Assuntos
Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Hipertensão/tratamento farmacológico , Hipopotassemia/epidemiologia , Tiazidas/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Dinamarca/epidemiologia , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Hipopotassemia/induzido quimicamente , Incidência , Masculino , Sistema de Registros , Risco , Tiazidas/uso terapêutico
19.
Hypertension ; 75(3): e2-e5, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32008437

RESUMO

A recently published analysis in Hypertension suggests that thiazide use, versus nonuse, is associated with excess risk of adverse cardiovascular outcomes in patients with diabetes mellitus enrolled in the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes). Here, we replicate these findings using the same publicly available datasets and following their reported methods. We further show that possible misclassification of thiazide exposure exists in the original analysis. We perform alternative analyses that correct for this misclassification to highlight the impact that misclassification can have on observed associations between an exposure (eg, thiazides) and outcomes (eg, stroke and major adverse cardiovascular events).


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensão , Pressão Sanguínea , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Fatores de Risco , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Tiazidas/efeitos adversos
20.
J Clin Pharm Ther ; 45(5): 997-1005, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32012317

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Hyponatremia is a common side effect of thiazide diuretics that can lead to increased mortality and hospitalization. A rapid and accurate screening tool is needed for rapid and appropriate management. In this study, we report on the development of a simple clinical screening tool for hyponatremia using thiazide diuretics. METHODS: This nested case-control study was performed by collecting data from 1 January 2015 to 30 June 2017. Univariable and multivariable logistic regressions were used to identify potential risk factors. The regression coefficients were converted into item scores by dividing each regression coefficient with the minimum coefficient in the model and rounding to the nearest integer. This value was then summed to the total score. The prediction power of the model was determined by the area under the receiver operating characteristic curve (AuROC). RESULTS AND DISCUSSION: Six clinical risk factors, namely age ≥65 years, benzodiazepine use, history of a cerebrovascular accident, dose of hydrochlorothiazide ≥25 mg, female sex and statin use, were included in our ABCDF-S score. The model showed good power of prediction (AuROC 81.53%, 95% confidence interval [CI]: 78%-84%) and good calibration (Hosmer-Lemeshow X2  = 23.20; P = .39). The positive likelihood ratios of hyponatremia in patients with low risk (score ≤ 6) and high risk (score ≥ 8) were 0.26 (95% CI: 0.21-0.32) and 3.89 (95% CI: 3.11-4.86), respectively. WHAT IS NEW AND CONCLUSION: The screening tool with six risk predictors provided a useful prediction index for thiazide-associated hyponatremia. However, further validation of the tool is warranted prior to its utilization in routine clinical practice.


Assuntos
Diuréticos/efeitos adversos , Hipertensão/tratamento farmacológico , Hiponatremia/induzido quimicamente , Tiazidas/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diuréticos/administração & dosagem , Feminino , Humanos , Hiponatremia/diagnóstico , Hiponatremia/epidemiologia , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Tiazidas/administração & dosagem
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