RESUMO
The Na+-Cl- cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Here we determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension, but it remains unknown whether/how phosphorylation transforms the NCC structure to accelerate ion translocation. We show that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation.
Assuntos
Hidroclorotiazida , Inibidores de Simportadores de Cloreto de Sódio , Membro 3 da Família 12 de Carreador de Soluto , Fosforilação , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/química , Humanos , Hidroclorotiazida/farmacologia , Hidroclorotiazida/química , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Animais , Clortalidona/metabolismo , Clortalidona/química , Clortalidona/farmacologia , Proteínas Quinases/metabolismo , Proteínas Quinases/química , Diuréticos/farmacologia , Diuréticos/química , Diuréticos/metabolismo , Tiazidas/farmacologia , Tiazidas/química , Tiazidas/metabolismo , Células HEK293 , Modelos Moleculares , Proteínas Serina-Treonina QuinasesRESUMO
Diuretics have been used for decades in the treatment of hypertension. Its efficacy has been demonstrated in numerous clinical trials. It is well known that the reduction in cardiovascular risk is a consequence of the reduction in blood pressure levels regardless of the drug used, but thiazide diuretics continue to be first-line drugs, especially in low doses and combined with other drugs. The debate on the advantages of using chlorthalidone or hydrochlorothiazide continues, however hydrochlorothiazide is drug most used and for which there is greater availability. The association with potassium-sparing diuretics increases the effectiveness and reduces the adverse reactions of thiazides. A new group of drugs, close to potassium-sparing diuretics, that antagonise aldosterone synthase are showing promising results as antihypertensives. There are no significant differences between men and women regarding the antihypertensive effect of thiazide diuretics.
Assuntos
Anti-Hipertensivos , Diuréticos , Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Diuréticos/efeitos adversos , Diuréticos/administração & dosagem , Diuréticos/uso terapêutico , Diuréticos/farmacologia , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Hidroclorotiazida/efeitos adversos , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/uso terapêutico , Clortalidona/administração & dosagem , Clortalidona/uso terapêutico , Clortalidona/efeitos adversos , Feminino , Masculino , Quimioterapia CombinadaRESUMO
Acne vulgaris is a common chronic dermatological condition characterized by obstruction and inflammation of pilosebaceous units. Recent research on a different dermatologic condition has demonstrated that the use of vasodilatory medications is associated with a decreased relative risk of rosacea. This finding is significant due to the overlapping inflammatory pathways involved in rosacea and acne. Herein, a retrospective cohort study was designed to determine the correlation between vasodilator usage and the risk of developing acne within 5 years, contrasting it with thiazide diuretics, chosen as a control due to its non-vasodilatory antihypertensive mechanism and availability of data. Angiotensin-converting enzyme (ACE) inhibitors (RR, 0.775; 95% CI, 0.727-0.826; P<0.05), angiotensin receptor blockers (ARBs) (RR, 0.739; 95% CI, 0.685-0.797; P<0.05), beta-blockers (BB) (RR, 0.829; 95% CI, 0.777-0.885; P<0.05), and calcium channel blockers (CCB) usage (RR, 0.821, 95% CI, 0.773-0.873; P<0.05) were associated with a significantly lower risk of developing acne within 5 years of initiating therapy compared to thiazide diuretics. It is unclear if thiazide diuretics are more likely to cause acne within the adult population or if vasodilators are protective against the development of acne. Finding mechanisms and therapeutics that lower the risk of developing acne is of significant public health interest, and this study provides a step toward this endeavor. Further research is required to uncover the underlying mechanisms for this reduction in the development of acne. J Drugs Dermatol. 2024;23(6):446-449. doi:10.36849/JDD.8362.
Assuntos
Acne Vulgar , Vasodilatadores , Humanos , Acne Vulgar/tratamento farmacológico , Acne Vulgar/epidemiologia , Estudos Retrospectivos , Masculino , Adulto , Feminino , Vasodilatadores/administração & dosagem , Pessoa de Meia-Idade , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Adulto Jovem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/efeitos adversosRESUMO
SOURCE CITATION: Andersson NW, Wohlfahrt J, Feenstra B, et al. Cumulative incidence of thiazide-induced hyponatremia: a population-based cohort study. Ann Intern Med. 2024;177:1-11. 38109740.
Assuntos
Anti-Hipertensivos , Hiponatremia , Inibidores de Simportadores de Cloreto de Sódio , Humanos , Hiponatremia/induzido quimicamente , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Masculino , Feminino , Incidência , Idoso , Hipertensão/tratamento farmacológico , Pessoa de Meia-IdadeRESUMO
Thiazide and thiazide-like diuretics (thiazides) belong to the most frequently prescribed drugs worldwide. By virtue of their natriuretic and vasodilating properties, thiazides effectively lower blood pressure and prevent adverse cardiovascular outcomes. In addition, through their unique characteristic of reducing urine calcium, thiazides are also widely employed for the prevention of kidney stone recurrence and reduction of bone fracture risk. Since their introduction into clinical medicine in the early 1960s, thiazides have been recognized for their association with metabolic side effects, particularly impaired glucose tolerance, and new-onset diabetes mellitus. Numerous hypotheses have been advanced to explain thiazide-induced glucose intolerance, yet underlying mechanisms remain poorly defined. Regrettably, the lack of understanding and unpredictability of these side effects has prompted numerous physicians to refrain from prescribing these effective, inexpensive, and widely accessible drugs. In this review, we outline the pharmacology and mechanism of action of thiazides, highlight recent advances in the understanding of thiazide-induced glucose intolerance, and provide an up-to-date discussion on the role of thiazides in kidney stone prevention.
Assuntos
Cálculos Renais , Tiazidas , Humanos , Cálculos Renais/induzido quimicamente , Cálculos Renais/prevenção & controle , Tiazidas/uso terapêutico , Tiazidas/efeitos adversos , Tiazidas/farmacologia , Animais , Intolerância à Glucose/induzido quimicamente , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Diuréticos/efeitos adversos , Diuréticos/farmacologia , Diuréticos/uso terapêuticoRESUMO
Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to ß-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs. Among hypertensive participants enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, we previously identified 8 metabolites associated with baseline PRA and 4 metabolic clusters (including 39 metabolites) that are different between those with GWAA <45% versus ≥45%. In the current study, using Ingenuity Pathway Analysis (IPA), we integrated these signals. Three overlapping metabolic signals within three significantly enriched pathways were identified as associated with both PRA and %GWAA: ceramide signaling, sphingosine 1- phosphate signaling, and endothelial nitric oxide synthase signaling. Literature indicates that the identified pathways are involved in the regulation of the Rho kinase cascade, production of the vasoactive agents nitric oxide, prostacyclin, thromboxane A2, and endothelin 1; the pathways proposed to underlie TD- and BB-induced vasodilatation. These findings may improve our understanding of the BP-lowering mechanisms of TDs and BBs. This might provide a possible step forward in personalizing antihypertensive therapy by identifying patients expected to have robust BP-lowering effects from these drugs.
Assuntos
Antagonistas Adrenérgicos beta , Pressão Sanguínea , Hipertensão , Metabolômica , Inibidores de Simportadores de Cloreto de Sódio , Humanos , Masculino , Feminino , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Pessoa de Meia-Idade , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/farmacologia , Renina/sangue , Idoso , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Transdução de Sinais/efeitos dos fármacos , AdultoRESUMO
PURPOSE OF REVIEW: Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are commonly prescribed to prevent the recurrence of kidney stones. This review offers a comprehensive up-to-date assessment of the evidence supporting the use of thiazides for kidney stone recurrence prevention, highlights potential harms associated with treatment, and identifies areas of knowledge that require further investigation. RECENT FINDINGS: The clinical routine to prescribe thiazides for kidney stone prevention has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50âmg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of recurrence. Yet, adverse events such as new onset diabetes mellitus and gout were more common in patients receiving hydrochlorothiazide compared to placebo. As demonstrated by a novel meta-analysis presented in this review encompassing all randomized placebo-controlled trials with thiazide monotherapy, current trial evidence does not indicate that thiazide monotherapy is significantly better than placebo in preventing kidney stone recurrence. SUMMARY: Given the limited efficacy and possible adverse effects, we advocate for a restrictive use of thiazides for kidney stone recurrence prevention. Clearly, there remains a high unmet medical need for effective, targeted therapies to prevent recurrence of kidney stones.
Assuntos
Cálculos Renais , Recidiva , Prevenção Secundária , Inibidores de Simportadores de Cloreto de Sódio , Humanos , Cálculos Renais/prevenção & controle , Prevenção Secundária/métodos , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Tiazidas/uso terapêutico , Tiazidas/efeitos adversos , Resultado do Tratamento , Hidroclorotiazida/uso terapêutico , Hidroclorotiazida/efeitos adversosRESUMO
OBJECTIVE: Thiazides are the first-line treatment for hypertension, however, they have been associated with hospitalizations for thiazide-associated hyponatremia (TAH). The aim of this study was to evaluate the risk of TAH and other drug-associated hyponatremia in a Korean population. METHODS: The study used big data from the National Health Insurance Sharing Service of 1,943,345 adults treated for hypertension from January 2014 to December 2016. The participants were divided into two groups based on the use of thiazides. Cox proportional hazard models were used to identify independent risk factors for the occurrence of hyponatremia. RESULTS: The study found that hyponatremia-related hospitalizations were significantly higher in the thiazide group than the control group (2.19% vs. 1.45%). The risk increased further with concurrent use of other diuretics or desmopressin, and thiazide+spironolactone+desmopressin and hospitalization risk further increased (4.0 and 6.9 times). Multivariate analysis showed that hyponatremia occurrence increased with age, diabetes mellitus, depression, and thiazide use (hazard ratio = 1.436, p < 0.001). The thiazide group had better 6-year overall survival than the control group but had more fractures and hyponatremia. CONCLUSIONS: Thiazide use is associated with an increased risk of hyponatremia and related complications. However, the mortality rate decreased in those who received thiazides, suggesting that thiazide use itself is not harmful and may help decrease complications and improve prognosis with proper, cautious use in high-risk patients.
Assuntos
Hipertensão , Hiponatremia , Tiazidas , Humanos , Hiponatremia/induzido quimicamente , Hiponatremia/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Hipertensão/tratamento farmacológico , Idoso , Tiazidas/efeitos adversos , República da Coreia/epidemiologia , Estudos de Coortes , Fatores de Risco , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Hospitalização/estatística & dados numéricos , Adulto , Modelos de Riscos Proporcionais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêuticoRESUMO
Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide-use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self-reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene-environment interaction (GEI) tests on the significant (P < 2.5 × 10-9) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10-3; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10-4) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9-mediated interaction having been previously reported. In conclusion, we used a two-stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide-associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes.
Assuntos
Hiperglicemia , Hiperuricemia , Polimorfismo de Nucleotídeo Único , Inibidores de Simportadores de Cloreto de Sódio , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores/urina , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Hiperglicemia/genética , Hiperglicemia/induzido quimicamente , Hiperglicemia/urina , Hiperglicemia/epidemiologia , Hipertensão/genética , Hipertensão/induzido quimicamente , Hiperuricemia/genética , Hiperuricemia/urina , Hiperuricemia/induzido quimicamente , Potássio/urina , Potássio/sangue , Locos de Características Quantitativas , Sódio/urina , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Biobanco do Reino Unido , Reino Unido/epidemiologia , Ácido Úrico/urina , Ácido Úrico/sangueRESUMO
RATIONALE & OBJECTIVE: Data supporting the efficacy of preventive pharmacological therapy (PPT) to reduce urolithiasis recurrence are based on clinical trials with composite outcomes that incorporate imaging findings and have uncertain clinical significance. This study evaluated whether the use of PPT leads to fewer symptomatic stone events. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare enrollees with urolithiasis who completed 24-hour urine collections that revealed hypercalciuria, hypocitraturia, low urine pH, or hyperuricosuria. EXPOSURE: PPT (thiazide diuretics for hypercalciuria, alkali for hypocitraturia or low urine pH, or uric acid lowering drugs for hyperuricosuria) categorized as (1) adherent to guideline-concordant PPT, (2) nonadherent to guideline-concordant PPT, or (3) untreated. OUTCOME: Symptomatic stone event occurrence (emergency department [ED] visit or hospitalization for urolithiasis or stone-directed surgery). ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: Among 13,942 patients, 31.0% were prescribed PPT. Compared with no treatment, concordant/adherent PPT use was associated with a significantly lower hazard of symptomatic stone events for patients with hypercalciuria (HR, 0.736 [95% CI, 0.593-0.915]) and low urine pH (HR, 0.804 [95% CI, 0.650-0.996]) but not for patients with hypocitraturia or hyperuricosuria. These associations were largely driven by significantly lower rates of ED visits after initiating PPT among the concordant/adherent group versus untreated patients. Patients with hypercalciuria had adjusted 2-year predicted probabilities of a visit of 3.8% [95% CI, 2.5%-5.2%%] and 6.9% [95% CI, 6.0%-7.7%] for the concordant/adherent PPT and no-treatment groups, respectively. Among patients with low urine pH, these probabilities were 4.3% (95% CI, 2.9%-5.7%) and 7.3% (95% CI, 6.5%-8.0%) for the concordant/adherent PPT and no-treatment groups, respectively. LIMITATIONS: Potential bias from the possibility that patients prescribed PPT had more severe disease than untreated patients. CONCLUSIONS: Patients with urolithiasis and hypercalciuria who were adherent to treatment with thiazide diuretics as well as those with low urine pH adherent to prescribed alkali therapy had fewer symptomatic stone events than untreated patients. PLAIN-LANGUAGE SUMMARY: Despite multiple clinical trials demonstrating the efficacy of thiazide diuretics and alkali for secondary prevention of kidney stones, they are infrequently prescribed due in part to a lack of data about their effectiveness in real-world settings. We analyzed medical claims from older adults with kidney stones for whom urine chemistry data were available. We found that patients who took prescribed thiazide diuretics for elevated urine calcium levels or alkali for low urinary pH were less likely to experience symptomatic stone recurrences than untreated patients. This benefit was expressed as lower rates of emergency department visits after initiating therapy. Our findings should inform the prescription of and adherence to treatment with thiazide diuretics and alkali for the prevention of recurrent kidney stones.
Assuntos
Urolitíase , Humanos , Estudos Retrospectivos , Feminino , Masculino , Idoso , Urolitíase/prevenção & controle , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Estudos de Coortes , Prevenção Secundária/métodos , Hipercalciúria/prevenção & controle , Resultado do Tratamento , Estados Unidos/epidemiologia , Idoso de 80 Anos ou mais , MedicareRESUMO
Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.
Assuntos
Angiotensina II , Hipertensão , Natriurese , Trocador 3 de Sódio-Hidrogênio , Animais , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Feminino , Trocador 3 de Sódio-Hidrogênio/metabolismo , Natriurese/efeitos dos fármacos , Diuréticos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fatores Sexuais , Simulação por Computador , Sódio/metabolismo , Ratos , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Caracteres Sexuais , Modelos Animais de Doenças , Diurese/efeitos dos fármacos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologiaRESUMO
Prescribing cascade is a significant clinical problem but is often overlooked. We explore the incidence of the prescribing cascades of antigout medications related to thiazide treatment in gout-naïve hypertensive adults newly exposed to the pharmacological treatment. This population-based, retrospective cohort study used the Taiwan National Health Insurance Registry Database. Gout-naïve hypertensive adults who were newly dispensed first-line antihypertensive drugs between January 1, 2000, and December 31, 2016, were enrolled. Patients were divided into the thiazide group (n = 4192) and the non-thiazide group (n = 81,083). The non-thiazide group included patients who received an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blocker, or beta-blocker. The study utilized propensity score matching and multivariable Cox regression models to investigate the prescribing cascade of antigout agents following antihypertensive treatment, adjusting for factors like age, sex, comorbidities, and concurrent medications. After propensity score matching, each group consisted of 4045 patients, with the thiazide group exhibiting a higher risk of being prescribed antigout medications across different time intervals post-treatment initiation. Specifically, adjusted hazard ratios (aHRs) for the thiazide group were 2.23, 2.07, and 2.41 for < 30 days, 31-180 days, and > 180 days, respectively, indicating a sustained and significant risk over time. Comparative analyses revealed thiazide diuretics were associated with a higher risk of antigout medication prescriptions compared to other antihypertensive classes, particularly evident after 180 days. Subgroup analyses across various demographics and comorbidities consistently showed an increased risk in the thiazide cohort. Gout-naïve hypertensive adults newly dispensed thiazide had a higher risk of subsequently adding antigout agents than those taking other first-line antihypertensive medications. The awareness and interruption of these prescribing cascades are critical to improving patient safety.
Assuntos
Gota , Hipertensão , Adulto , Humanos , Anti-Hipertensivos/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Estudos Retrospectivos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/induzido quimicamente , Bloqueadores dos Canais de Cálcio/uso terapêutico , Tiazidas/uso terapêutico , Gota/tratamento farmacológico , Gota/complicações , Supressores da Gota/uso terapêutico , Diuréticos/uso terapêuticoRESUMO
Previous work comparing safety and effectiveness outcomes for new initiators of angiotensin converting-enzyme inhibitors (ACEi) and thiazides demonstrated more favorable outcomes for thiazides, although cohort definitions allowed for addition of a second antihypertensive medication after a week of monotherapy. Here, we modify the monotherapy definition, imposing exit from cohorts upon addition of another antihypertensive medication. We determine hazard ratios (HR) for 55 safety and effectiveness outcomes over six databases and compare results to earlier findings. We find, for all primary outcomes, statistically significant differences in effectiveness between ACEi and thiazides were not replicated (HRs: 1.11, 1.06, 1.12 for acute myocardial infarction, hospitalization with heart failure and stroke, respectively). While statistical significance is similarly lost for several safety outcomes, the safety profile of thiazides remains more favorable. Our results indicate a less striking difference in effectiveness of thiazides compared to ACEi and reflect some sensitivity to the monotherapy cohort definition modification.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Hipertensão , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Diuréticos/efeitos adversos , Hipertensão/tratamento farmacológico , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Tiazidas/efeitos adversosRESUMO
BACKGROUND: Urinary stone disease is a prevalent condition associated with a high recurrence risk. Preventive pharmacological therapy has been proposed to reduce recurrent stone episodes. However, limited evidence exists regarding its effectiveness, contributing to its underutilization by physicians. This study aimed to evaluate the association between preventive pharmacological therapy (thiazide diuretics, alkali therapy, and uric acid-lowering medications) and clinically significant urinary stone disease recurrence. METHODS: Using data from the Veterans Health Administration, adults with an index episode of urinary stone disease from 2012 through 2019 and at least one urinary abnormality (hypercalciuria, hypocitraturia, or hyperuricosuria) on 24-hour urine collection were included. The primary outcome was a composite variable representing recurrent stone events that resulted in emergency department visits, hospitalizations, or surgery for urinary stone disease. Cox proportional hazards regression was performed to estimate the association between preventive pharmacological therapy use and recurrent urinary stone disease while adjusting for relevant baseline patient characteristics. RESULTS: Among the cohort of patients with urinary abnormalities ( n =5637), treatment with preventive pharmacological therapy was associated with a significant 19% lower risk of recurrent urinary stone disease during the 12-36-month period after the initial urine collection (hazard ratio, 0.81; 95% confidence interval, 0.65 to 1.00; P = 0.0496). However, the effectiveness of preventive pharmacological therapy diminished over longer follow-up periods (12-48 and 12-60 months after the urine collection) and did not reach statistical significance. When examining specific urinary abnormalities, only alkali therapy for hypocitraturia was associated with a significant 26% lower recurrence risk within the 12-36-month timeframe (hazard ratio, 0.74; 95% confidence interval, 0.56 to 0.97; P = 0.03). CONCLUSIONS: When considering all urinary abnormalities together, this study demonstrates that the use of preventive pharmacological therapy is associated with a lower risk of clinically significant recurrent episodes of urinary stone disease in the 12-36 month timeframe after urine collection, although only the association with the use of alkali therapy for hypocitraturia was significant when individual abnormalities were examined.
Assuntos
Recidiva , Inibidores de Simportadores de Cloreto de Sódio , Cálculos Urinários , Humanos , Cálculos Urinários/prevenção & controle , Cálculos Urinários/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Ácido Úrico/urina , Prevenção Secundária , Adulto , Fatores de Risco , Álcalis , Uricosúricos/uso terapêuticoRESUMO
Thiazide diuretics are an essential part of the treatment of hypertension, which affects nearly a third of the world's population. Hydrochlorothiazide is the most widely used member of this class, due to its long availability on the market and the many combinations available with other substances. Other analogues of this class exist, with notable advantages from a clinical point of view, recognized under the name of thiazide-like. This article reviews some of the considerations in clinical practice concerning the different types of thiazides currently available in Switzerland.
Les diurétiques thiazidiques font partie des traitements de premier choix dans la prise en charge de l'hypertension artérielle, touchant près d'un tiers de la population mondiale. L'hydrochlorothiazide est le représentant de cette classe médicamenteuse le plus utilisé dans les combinaisons antihypertensives en Suisse. D'autres analogues de cette classe existent sur le marché, avec des avantages notables du point de vue clinique, reconnus sous la dénomination de thiazides-like. Le choix de l'utilisation d'un diurétique thiazidique repose avant tout sur les indications et les contre-indications relatives à cette classe. Cet article propose une revue de quelques considérations en pratique clinique sur les différents types de thiazides actuellement disponibles en Suisse.
Assuntos
Diuréticos , Hipertensão , Humanos , Diuréticos/uso terapêutico , Hipertensão/tratamento farmacológico , Tiazidas/uso terapêutico , Hidroclorotiazida/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Anti-Hipertensivos/uso terapêuticoRESUMO
BACKGROUND: Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response. METHODS AND RESULTS: We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5-fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide-treated European Americans, chlorthalidone-treated European Americans, and hydrochlorothiazide-treated Black individuals. Different blood pressure phenotypes including categorical (responder versus nonresponder) and continuous diastolic blood pressure and systolic blood pressure were tested for association with the candidate miRNA expression using multivariate regression analyses adjusting for age, sex, and baseline blood pressure. After quality control, 74 miRNAs were available for screening, 19 of which were considered for validation. In the validation cohort, miR-193b-3p and 30d-5p showed significant associations with continuous SBP or diastolic blood pressure response or both, to hydrochlorothiazide in European Americans at Benjamini-Hochberg adjusted P<0.05. In the combined analysis of validation cohorts, let-7g (odds ratio, 0.6 [95% CI, 0.4-0.8]), miR-142-3p (odds ratio, 1.1 [95% CI, 1.0, 1.2]), and miR-423-5p (odds ratio, 0.7 [95% CI, 0.5-0.9]) associated with categorical diastolic blood pressure response at Benjamini-Hochberg adjusted P<0.05. Predicted target genes of the 5 miRNAs were mapped to key hypertension pathways: lysine degradation, fatty acid biosynthesis, and metabolism. CONCLUSIONS: The above identified circulating miRNAs may have a potential for clinical use as biomarkers for thiazide diuretic selection in hypertension. REGISTRATION: URL: ClinicalTrials.gov. Unique identifiers: NCT00246519, NCT01203852, NCT00005520.