Sodium and volume excess is the fundamental risk factor underlying hypertension in chronic kidney disease (CKD) patients, who represent the prototypical population characterized by salt-sensitive hypertension. Low salt diets and diuretics constitute the centrepiece for blood pressure control in CKD. In patients with CKD stage 4, loop diuretics are generally preferred to thiazides. Furthermore, thiazide diuretics have long been held as being of limited efficacy in this population. In this review, by systematically appraising published randomized trials of thiazides in CKD, we show that this class of drugs may be useful even among people with advanced CKD. Thiazides cause a negative sodium balance and reduce body fluids by 1-2 l within the first 2-4 weeks and these effects go along with improvement in hypertension control. The recent CLICK trial has documented the antihypertensive efficacy of chlorthalidone, a long-acting thiazide-like diuretic, in stage 4 CKD patients with poorly controlled hypertension. Overall, chlorthalidone use could be considered in patients with treatment-resistant hypertension when spironolactone cannot be administered or must be withdrawn due to side effects. Hyponatremia, hypokalaemia, volume depletion and acute kidney injury are side effects that demand a vigilant attitude by physicians prescribing these drugs. Well-powered randomized trials assessing hard outcomes are still necessary to more confidently recommend the use of these drugs in advanced CKD.

Thiazide diuretics are an FDA-approved class of drugs that inhibit the reabsorption of 3% to 5% of luminal sodium in the distal convoluted tubule of the nephron. By doing so, thiazide diuretics promote natriuresis and diuresis. Three thiazide diuretics are the most commonly used: hydrochlorothiazide (HCTZ), chlorthalidone, and indapamide. HCTZ and chlorthalidone are FDA-approved for clinical use in the management of primary hypertension. HCTZ and chlorthalidone are also FDA-approved for clinical use in adjunctive therapy in edema that is associated with chronic heart failure (CHF), hepatic cirrhosis, corticosteroids, and estrogen therapy. Indapamide is FDA-approved for the treatment of salt and fluid retention associated with CHF, and in the management of primary hypertension as either the sole treatment or in conjunction with other antihypertensive drugs. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, toxicity, and monitoring, of thiazide diuretics, so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2022 scientific session of the American Heart Association (AHA).

Chlorthalidone is a medication used in the management and treatment of hypertension. It is in the thiazide-like diuretics class of drugs. This activity reviews the indications, action, and contraindications for chlorthalidone as a valuable agent in managing hypertension, edema, and calcium nephrolithiasis. This activity will highlight the mechanism of action, adverse event profile, and pharmacokinetics of chlorthalidone. Identification of these properties is essential for members of the interprofessional team to effectively manage patients with hypertension.

Hypertension is often difficult to control in patients with CKD as manifested by suboptimal control rates in this population. Use of thiazides in CKD patients has been limited as these agents are thought to be ineffective in reducing blood pressure in people with advanced CKD. This review summarizes recent studies impacting indications and safety of use of thiazide in patients with CKD and discusses the mechanism of how thiazides reduce blood pressure.

This study conducted a pairwise comparison of antihypertensive and metabolic effects of hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) at 25 mg/day in the same individuals to address the clinical dilemma on preferred thiazide for hypertension (HTN) management. We included 15 African American (AA) and 35 European American (EA) patients with HTN treated with HCTZ and CTD as part of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, respectively. Mean reduction in systolic/diastolic blood pressure (SBP/DBP) with HCTZ versus CTD was 8/5 versus 16/8 mmHg among EA patients (p < 1.0e-5 SBP, p = 0.002 DBP) and 11/8 versus 20/11 mmHg among AA patients (p = 0.03 SBP, p = 0.22 DBP). While CTD showed clinically meaningful benefit over HCTZ in two-thirds of participants with respect to SBP reduction and half of EA patients with respect to DBP reduction, a majority of AA patients (53%) showed similar DBP reduction with both thiazides. Sixty percent of AA patients and 29% of EA patients attained blood pressure (BP) <140/90 mmHg with both thiazides. Mean potassium (K+) reduction was greater with CTD compared to HCTZ both in EA patients (mean difference = 0.35, p = 0.0002) and AA patients (0.49, p = 0.043). While 31% of AA patients developed severe hypokalemia on CTD, <5% of others developed severe hypokalemia. Although 46% of AA patients on CTD required K+ supplementation, only 6%-11% of others required supplementation. Overall, in the majority of EA patients, CTD was superior to HCTZ, whereas among AA patients, it was superior in a minority, and was associated with significant potassium-related risk, suggesting that guideline preferences for CTD over HCTZ are reasonable in EA patients but may be less reasonable in AA patients, particularly if the target is <140/90 mmHg.

Hypertension is a major public health challenge in low- and middle-income countries (LMICs) and calls for large-scale effective hypertension control programs. Adoption of drug and dose-specific treatment protocols recommended by the World Health Organization-HEARTS Initiative is key for hypertension control programs in LMICs. We estimated the annual medication cost per patient using three such protocols (protocol-1 and protocol-2 with Amlodipine, Telmisartan, using add-on doses and different drug orders, adding Chlorthalidone; protocol-3 with a single-pill combination (SPC) of Amlodipine/Telmisartan with dose up-titration, and addition of Chlorthalidone, if required) in India. The medication cost was simulated with different hypertension control assumptions for each protocol and calculated based on prices in the public and private sectors in India. The estimated annual medication cost per patient for protocol-1 and protocol-2 was $33.88-58.44 and $51.57-68.83 for protocol-3 in the private sector. The medication cost was lower in the generic stores ($5.78-9.57 for protocol-1 and protocol-2, and $7.35-9.89 for protocol-3). The medication cost for patients was the lowest ($2.05-3.89 for protocol-1 and protocol-2, and $2.94-3.98 for protocol-3) in the public sector. At less than $4 per patient per annum, scaling up a hypertension control program with specific treatment protocols is a potentially cost-effective public health intervention. Expanding low-cost generic retail networks would extend affordability in the private sector. The cost of treatment with SPC is comparable with non-SPC protocols and can be adopted in a public health program considering the advantage of simplified logistics, reduced pill burden, improved treatment adherence, and blood pressure control.

We investigated whether diabetes mellitus (DM) affects the efficacy of a low-dose triple combination pill and usual care among people with mild-moderate hypertension. TRIUMPH (TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension) was a randomised controlled open-label trial of patients requiring initiation or escalation of antihypertensive therapy. Patients were randomised to a once-daily low-dose triple combination polypill (telmisartan-20mg/amlodipine-2.5 mg/chlorthalidone-12.5 mg) or usual care. This analysis compared BP reduction in people with and without DM, both in the intervention and control groups over 24-week follow-up. Predicted efficacy of prescribed therapy was calculated (estimation methods of Law et al.). The trial randomised 700 patients (56 ± 11 yrs, 31% DM). There was no difference in the number of drugs prescribed or predicted efficacy of therapy between people with DM and without DM. However, the observed BP reduction from baseline to week 24 was lower in those with DM compared to non-diabetics in both the triple pill (25/11 vs 31/15 mmHg, p ≤ 0.01) and usual care (17/7 vs 22/11 mmHg, p ≤ 0.01) groups, and these differences remained after multivariable adjustment. DM was a negative predictor of change in BP (β-coefficient -0.08, p = 0.02). In conclusion, patients with DM experienced reduced efficacy of BP lowering therapies as compared to patients without DM, irrespective of the type of BP lowering therapy received.

Analyzing a drug based on its overlapping spectra requires the use of sophisticated equipment and more hazardous solvents, which is detrimental to ecological sustainability. There is a critical need to create a simple, unique, and cost-effective approach for detecting a mixture of compounds in a safer environment. The aim was to develop an eco-friendly, stability-indicating assay method to determine Chlorthalidone (CLD) and Cilnidipine (CIL) in bulk and tablet dosage form using four different Ultra-Violet (UV) spectrophotometric methods. The ratio difference method showed absorbance peaks at 256.01 nm, 220.87 nm, first ratio difference spectra at 267.21 nm, 288.03 nm, and second ratio difference spectra at 309.2 nm, 280.03 nm. The area under curve techniques showed an absorbance range of around 224-232 nm for CIL and 218-227 nm for CLD. Further, the spectral changes have been assessed at various conditions like acid, base, oxidation, and UV radiation, and it has been found that CLD tends to lose its spectral property by more than 45%. The method developed for two drugs has obeyed Beers law with the selected concentration range of 7-13 μg/mL for CLD and 8.75-16.25 μg/mL for CIL. The developed method was finally evaluated using four tools, and the results showed green pictographically representation in the GAPI and score near to 100 for AES and closer to 1 for AGREE indicated that the method was found to be most eco-friendly. The findings were easy to replicate, adoptive with major regulatory requirements, environmentally friendly, fast, and inexpensive to perform. This approach does not require any specific expensive equipment, and it might be inexpensive to use in the future to assess laboratory and commercial mixtures.

The aim of this clinical trial was to assess the efficacy and safety of low-dose triple combinations of amlodipine, telmisartan, and chlorthalidone in patients with essential hypertension. After a 2-week placebo run-in period, 176 patients were randomized to seven treatment groups (placebo, quarter-dose combination, third-dose combination, half-dose combination, amlodipine 5 mg, amlodipine 10 mg, and telmisartan 80 mg) and administered the assigned study drug orally for 8 weeks. The primary efficacy endpoint was the change in the mean sitting systolic blood pressure (BP) (MSSBP) at Week 8. The MSSBP and mean sitting diastolic BP in the quarter-dose and half-dose groups were significantly lower compared to the placebo and amlodipine 5 mg groups, with similar BP-lowering effects observed compared to the amlodipine 10 mg and telmisartan 80 mg groups. However, the third-dose group showed significant BP improvement only compared to the placebo group. A similar pattern was observed for the control rate of hypertension and response rates. Additional analysis was conducted after correcting for gender and age effects, and, as a result, the third-dose group showed similar results with regard to the BP-lowering effect as the quarter-dose and half-dose groups. In terms of safety, no special adverse events and clinically significant results were noted, and all dose groups of the triple combination are considered safe for use in essential hypertension patients. The current findings indicated that low-dose triple combination of amlodipine, telmisartan, and chlorthalidone over 8 weeks effectively improved the BP-lowering effect in patients with essential hypertension without any safety concerns.

Chlorthalidone (CTD) may be superior to hydrochlorothiazide (HCTZ) in the reduction of adverse cardiovascular events in hypertensive patients. The mechanism of the potential benefit of CTD could be related to antiplatelet effects. The objective of this study was to determine if CTD or HCTZ have antiplatelet effects. This study was a prospective, double-blind, randomized, three-way crossover comparison evaluating the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers. The effects of these treatments on platelet activation and aggregation were assessed using a well-established method with five standard platelet agonists. Thirty-four patients completed the three-way crossover comparing pre- and post-treatment changes in platelet activation and aggregation studies. There were statistically significant antiplatelet effects with ASA but not with CTD or HCTZ. Hypokalemia occurred in 0 (0%), 10 (30%), and 6 (18%) of the ASA, CTD, and HCTZ patients, respectively. The results of our study suggest that the benefits of CTD and HCTZ in reducing adverse cardiovascular events in patients with hypertension is not a result of an antiplatelet effect. In our study, hypokalemia with CTD was more prevalent than that reported in a large outcome trial in patients with hypertension. The clinical relevance of this finding is uncertain.

Hypertension is the leading single preventable risk factor for cardiovascular disease. The India Hypertension Control Initiative (IHCI) project was designed to improve hypertension control in public sector clinics. The project was launched in 2018-2019 in 26 districts across five states: Punjab (5), Madhya Pradesh (3), Kerala (4), Maharashtra (4), and Telangana (10), with five core strategies: standard treatment protocol, reliable supply of free antihypertensive drugs, team-based care, patient-centered care, and an information system to track individual patient treatment and blood pressure control. All states implemented simple treatment protocols with three drugs: a long-acting dihydropyridine calcium channel blocker (amlodipine), angiotensin receptor blocker (telmisartan), and thiazide or a thiazide-like diuretic (hydrochlorothiazide or chlorthalidone). Medication supplies were adequate to support at least one month of treatment. Overall, 570,365 hypertensives were enrolled in 2018-2019; 11% did not have follow-up visits in the most recent 12 months. Clinic-level blood pressure control averaged 43% (range 22-79%) by Jan-March, 2020. The proportion of the estimated people with hypertension who had it controlled and documented in public clinics increased three-fold, albeit from very low levels (1.4-5.0%). The IHCI demonstrated the feasibility of implementing protocol-based hypertension treatment and control supported by a reliable drug supply and accurate information systems at scale in Indian primary health care facilities. Lessons from the IHCI's initial phase will inform plans to improve screening in health care facilities, increase retention in care, and ensure a sustained supply of drugs as part of a nationwide hypertension control program.

According to the green chemistry approach, the usage of carcinogenic and teratogenic organic solvents should be minimized in the development of the analytical method for the safety of the environment and analysts. According to the literature review, no high-performance thin-layer chromatographic (HPTLC) method has been reported yet for concomitant analysis of azilsartan medoxomil (AZM), chlorthalidone (CTD) and cilnidipine (CDP) in human plasma. Hence, a robust and accurate HPTLC method has been developed using safe and non-toxic organic solvents for the concomitant analysis of AZM, CTD and CDP in human plasma, fixed-dose combinations (FDCs) and laboratory mixtures. The HPTLC method was developed by the implementation of the analytical quality by design approach using principles of quality risk management and design of experiments (DoE) for regulatory compliance. The principal component analysis was applied for the risk assessment and analysis of potential method variables in the method development. The principle of DoE was used for the response surface modeling to link identified critical method risk parameters with critical method performance attributes using full factorial design (FFD). The method operable design region and analytical control space were navigated for the optimization of the method as per quality target analytical profile. The developed method was also applied for concomitant analysis of AZM, CTD and CDP in their FDCs and laboratory mixture and results were found in good agreement with the labeled amount of the respective drug.

Despite broad treatment recommendations, there are limited published reports comparing the efficacy of different antihypertensive agents in patients with isolated systolic hypertension or isolated diastolic hypertension. This study was a secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. We compared the use of chlorthalidone, amlodipine, or lisinopril on the primary outcome of combined coronary heart disease, stroke, or all-cause mortality in patients with isolated systolic hypertension or isolated diastolic hypertension.

Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD.

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component. Utilizing data from 4297 AA participants randomized to chlorthalidone from the Genetics of Hypertension Associated Treatments (GenHAT) study, we aimed to identify variants associated with the efficacy of chlorthalidone. An additional aim was to find variants that contributed to changes in fasting glucose (FG) in these individuals. We performed genome-wide association analyses on the change of systolic and diastolic BP (SBP and DBP) over six months and FG levels over 24 months of treatment. We sought replication in the International Consortia of Pharmacogenomics Studies. We identified eight variants statistically associated with BP response and nine variants associated with FG response. One suggestive LINC02211-CDH9 intergenic variant was marginally replicated with the same direction of effect. Given the impact of hypertension in AAs, this study implies that understanding the genetic background for BP control and glucose changes during chlorthalidone treatment may help prevent adverse cardiovascular events in this population.

A sensitive and selective UPLC-MS/MS method was developed for the synchronized determination of four drugs used in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), namely, azithromycin, apixaban, dexamethasone, and favipiravir in rat plasma. using a Poroshell 120 EC-C18 column (50 mm × 4.6 mm, 2.7 m) with a high-resolution ESI tandem mass spectrometer detection with multiple reaction monitoring. We used an Agilent Poroshell column, which is characterized by a stationary phase based on non-porous core particles. With a remarkable improvement in the number of theoretical plates and low column backpressure. In addition, the developed method was employed in studying the potential food-drug interaction of grapefruit juice (GFJ) with the selected drugs which affects their pharmacokinetics in rats. The LC-MS/MS operated in positive and negative ionization mode using two internal standards: moxifloxacin and chlorthalidone, respectively. Liquid- liquid extraction of the cited drugs from rat plasma was accomplished using diethyl ether: dichloromethane (70:30, v/v). The analytes were separated using methanol: 0.1 % formic acid in water (95: 5, v/v) as a mobile phase in isocratic mode of elution pumped at a flow rate of 0.3 mL/min. A detailed validation of the bio-analytical method was performed in accordance with US-FDA and EMA guidelines. Concerning the in vivo pharmacokinetic study, the statistical significance between the results of the test groups receiving GFJ along with the cited drugs and the control group was assessed demonstrating that GFJ increased the plasma concentration of azithromycin, apixaban, and dexamethasone. Accordingly, this food-drug interaction requires cautious ingestion of GFJ in patients using (SARS-CoV-2) medications as it can produce negative effects in the safety of the drug therapy. A potential drug-drug interaction is also suggested between those medications requiring a suitable dose adjustment.

High blood pressure (BP) is the world's leading risk factor for cardiovascular disease (CVD) and death. This review highlights findings during the past 18 months that apply to the management of high BP in adults in the context of the 2017 American College of Cardiology/American Heart Association (AHA) BP guideline.

The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD).