Efficacy and Safety of Low-Dose Triple and Quadruple Combination Pills vs Monotherapy, Usual Care, or Placebo for the Initial Management of Hypertension: A Systematic Review and Meta-analysis.
JAMA cardiology
Importance:Low-dose combination (LDC) antihypertensives consisting of 3 or 4 blood pressure (BP)-lowering drugs have emerged as a potentially important therapy for the initial management of hypertension. Objective:To assess the efficacy and safety of LDC therapies for the management of hypertension. Data Sources:PubMed and Medline were searched from date of inception until September 2022. Study Selection:Randomized clinical trials comparing LDC consisting of 3 or 4 BP-lowering drugs compared to either monotherapy, usual care, or placebo. Data Extraction and Synthesis:Data were extracted by 2 independent authors and synthesized using both random and fixed-effects models using risk ratios (RR) for binary outcomes and mean differences for continuous outcomes. Main Outcomes and Measures:The primary outcome was mean reduction in systolic BP (SBP) between LDC and monotherapy, usual care, or placebo. Other outcomes of interest included the proportion of patients achieving BP less than 140/90 mm Hg, rates of adverse effects, and treatment withdrawal. Results:Seven trials with a total of 1918 patients (mean [mean range] age, 59 [50-70] years; 739 [38%] female) were included. Four trials involved triple-component LDC and 3 involved quadruple-component LDC. At 4 to 12 weeks follow-up, LDC was associated with a greater mean reduction in SBP than initial monotherapy or usual care (mean reduction, 7.4 mm Hg; 95% CI, 4.3-10.5) and placebo (mean reduction, 18.0 mm Hg; 95% CI, 15.1-20.8). LDC was associated with a higher proportion of participants achieving BP less than 140/90 mm Hg at 4 to 12 weeks compared to both monotherapy or usual care (66% vs 46%; RR, 1.40; 95% CI, 1.27-1.52) and placebo (54% vs 18%; RR, 3.03; 95% CI, 1.93-4.77). There was no significant heterogeneity between trials enrolling patients with and without baseline BP-lowering therapy. Results from 2 trials indicated LDC remained superior to monotherapy or usual care at 6 to 12 months. LDC was associated with more dizziness (14% vs 11%; RR 1.28, 95% CI 1.00-1.63) but no other adverse effects nor treatment withdrawal. Conclusions and Relevance:The findings in the study showed that LDCs with 3 or 4 antihypertensives were an effective and well-tolerated BP-lowering treatment option for the initial or early management of hypertension.
10.1001/jamacardio.2023.0720
Advances in the Pathogenesis and Treatment of Resistant Hypertension.
International journal of molecular sciences
Hypertension is a prevalent chronic disease associated with an increased risk of cardiovascular (CV) premature death, and its severe form manifests as resistant hypertension (RH). The accurate prevalence of resistant hypertension is difficult to determine due to the discrepancy in data from various populations, but according to recent publications, it ranges from 6% to 18% in hypertensive patients. However, a comprehensive understanding of the pathogenesis and treatment of RH is essential. This review emphasizes the importance of identifying the causes of treatment resistance in antihypertensive therapy and highlights the utilization of appropriate diagnostic methods. We discussed innovative therapies such as autonomic neuromodulation techniques like renal denervation (RDN) and carotid baroreceptor stimulation, along with invasive interventions such as arteriovenous anastomosis as potential approaches to support patients with inadequate medical treatment and enhance outcomes in RH.
10.3390/ijms241612911
[Progress in the treatment of hypertension].
Giornale italiano di cardiologia (2006)
Over the past five decades, we have witnessed significant developments in the management of patients with arterial hypertension and elucidation of basic mechanisms involved in the disease. Many of these progresses resulted from experimental and clinical studies conducted in Italy. Several randomized clinical trials have been carried out worldwide and in Italy according to the best available evidence-based medicine rules, often before the initiation of comparable studies in different cardiovascular areas (acute coronary syndromes, arrhythmias, heart failure). Because of these progresses, we currently dispose of a huge therapeutic armamentarium of effective and generally well tolerated antihypertensive drugs. Ablation of renal nerves is a procedure which is re-gaining attention. We are also learning how to correctly measure blood pressure not only in the hospital setting, but also during normal daily activities using 24 h ambulatory blood pressure monitoring and self-measured home blood pressure. Out-of-office blood pressure proved to be superior to office blood pressure in its relationship with hypertensive organ damage and risk of major cardiovascular complications and mortality. Currently, we should improve our understanding of out-of-office blood pressure measurements and the clinical use of several available drug combinations according to their efficacy and tolerability in the single patients. We should also learn more about optimal blood pressure targets to be achieved in the general hypertensive population is specific subgroups at different cardiovascular risk.
10.1714/3574.35569
Novel approaches to management of hypertension.
Current opinion in nephrology and hypertension
PURPOSE OF REVIEW:Of the roughly 1.4 billion people with hypertension worldwide, only about one in seven has their blood pressure (BP) successfully treated and adequately controlled. This review will focus on new therapeutic approaches of hypertension. RECENT FINDINGS:Several recent clinical studies and guidelines have favoured the assessment of target organ damage and cardiovascular risk scores for the diagnosis and treatment approach of hypertension. Paradigm shifts recommended in the guidelines are the initiation of antihypertensive treatment with combination (not mono) therapy and the recommendation of single-pill combinations (SPC), which improve adherence and result in rapid and effective BP control. In clinical trials with optimized design and renal denervation (RDN) technology, the biological proof of concept has been established. Consistent, durable ambulatory and office BP reductions without procedure associated serious adverse events have been documented. The challenges are now to identify patients who respond best to interventional treatment. SUMMARY:Major key points in the treatment strategy for hypertension are: individualization of the therapy according to total cardiovascular risk, combination therapy as initial step, recommendation of SPC and RDN as promising interventional therapy.
10.1097/MNH.0000000000000668
Managing Hypertension Using Combination Therapy.
Smith Dustin K,Lennon Robert P,Carlsgaard Peter B
American family physician
More than 70% of adults treated for primary hypertension will eventually require at least two antihypertensive agents, either initially as combination therapy or as add-on therapy if monotherapy and lifestyle modifications do not achieve adequate blood pressure control. Four main classes of medications are used in combination therapy for the treatment of hypertension: thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). ACEIs and ARBs should not be used simultaneously. In black patients, at least one agent should be a thiazide diuretic or a calcium channel blocker. Patients with heart failure with reduced ejection fraction should be treated initially with a beta blocker and an ACEI or ARB (or an angiotensin receptor-neprilysin inhibitor), followed by add-on therapy with a mineralocorticoid receptor antagonist and a diuretic based on volume status. Treatment for patients with chronic kidney disease and proteinuria should include an ACEI or ARB plus a thiazide diuretic or a calcium channel blocker. Patients with diabetes mellitus should be treated similarly to those without diabetes unless proteinuria is present, in which case combination therapy should include an ACEI or ARB.
Emerging Drug Classes and Their Potential Use in Hypertension.
Azizi Michel,Rossignol Patrick,Hulot Jean-Sébastien
Hypertension (Dallas, Tex. : 1979)
Despite the availability of multiple antihypertensive drugs targeting the different pathways implicated in its pathophysiology, hypertension remains poorly controlled worldwide, and its prevalence is increasing because of the aging of the population and the obesity epidemic. Although nonadherence to treatment contributes to uncontrolled hypertension, it is likely that not all the pathophysiological mechanisms are neutralized by the various classes of antihypertensive treatment currently available, and, the counter-regulatory mechanisms triggered by these treatments may decrease their blood pressure-lowering effect. The development of new antihypertensive drugs acting on new targets, with different modes of action, therefore, remains essential, to improve blood pressure control and reduce the residual burden of cardiovascular risks further. However, the difficulties encountered in the conception, development, costs, and delivery to the market of new classes of antihypertensive agents highlights the hurdles that must be overcome to release and to evaluate their long-term safety and efficacy for hypertension only, especially because of the market pressure of cheap generic drugs. New chemical entities with blood pressure-lowering efficacy are thus being developed more for heart failure or diabetic kidney disease, 2 diseases pathophysiologically associated with hypertension. These include dual angiotensin II receptor-neprilysin inhibitors, soluble guanylate cyclase stimulators, nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists, as well as sodium-glucose cotransporter 2 inhibitors. However, centrally acting aminopeptidase A inhibitors and endothelin receptor antagonists have a dedicated program of development for hypertension. All these emergent drug classes and their potential use in hypertension are reviewed here.
10.1161/HYPERTENSIONAHA.119.12676
K and the renin-angiotensin-aldosterone system: new insights into their role in blood pressure control and hypertension treatment.
Poulsen Søren B,Fenton Robert A
The Journal of physiology
Approximately 25% of the adult population is diagnosed with hypertension and it is therefore one of the biggest challenges for the health sector. The renin-angiotensin-aldosterone system (RAAS) adjusts effective circulating volume and ultimately blood pressure (BP). Accordingly, antihypertensive drugs targeting the RAAS have been a major focus in modern medical treatment. Low and high dietary K intakes are associated with increased or decreased BP and risk of cardiac failure, respectively, suggesting that dietary K augmentation has the potential to supplement or replace conventional anti-hypertensive drugs. Animal studies have indicated that the beneficial effects of high dietary K may be linked to a dominant regulatory role of plasma K on key renal transport proteins controlled by the RAAS. However, only a limited number of studies have investigated whether the reported mechanisms in animal models apply to humans. Furthermore, hypertension is often treated with so-called 'K sparing' drugs, thus complicating co-treatment with K supplementation. In this review, we revisit old concepts of RAAS effects in the kidney, relate them to effects of dietary K manipulation, and finally consider the clinical potential of treating hypertension with K supplementation alone or in combination with RAAS inhibitors. Collectively, a wealth of data suggest that increased dietary K intake may have beneficial effects on BP in the general population, but underlying medical conditions or current treatment regimens need to be carefully considered before implementing K supplementation in patients.
10.1113/JP276844
The NEW-HOPE study and emerging therapies for difficult-to-control and resistant hypertension.
Ferdinand Keith C,Harrison Daniel,Johnson Adedoyin
Progress in cardiovascular diseases
Despite the availability of numerous approved antihypertensive drugs, difficult-to-control and resistant hypertension are persistent and are major risk factors for cardiovascular disease. Emerging and investigational treatments that are currently being explored to target hypertension include firibrastat, empagliflozin and interventional procedures, including improved approaches to renal artery denervation and a novel baroreceptor device implantation. Firibrastat is an investigational drug that specifically and selectively inhibits aminopeptidase A leading to decreased formation of angiotensin III in the brain, resulting in decreased blood pressure. Sodium-glucose cotransporter-2 inhibitors, such as empagliflozin used to treat type 2 diabetes, may be beneficial as antihypertensive agents. Empagliflozin in a recent study demonstrated significant reductions in high blood pressure in an African American population. Advances in renal artery denervation and an investigational baroreceptor device implantation also show promise as potential interventions in patients with difficult-to-control and resistant hypertension.
10.1016/j.pcad.2019.12.008
New and developing pharmacotherapies for hypertension.
Expert review of cardiovascular therapy
INTRODUCTION:Despite the significant contribution of hypertension to the global burden of disease, disease control remains poor worldwide. Considering this unmet clinical need, several new antihypertensive drugs with novel mechanisms of action are under development. AREAS COVERED:The present review summarizes the recent advances in the development of emerging pharmacological agents for the management of hypertension. The latest technological innovations in the design of optimized formulations of available antihypertensive drugs and the potential role of the modification of intestinal microbiota to improve blood pressure (BP) control are also covered. EXPERT OPINION:Significant efforts have been made to develop new antihypertensive agents with novel actions that target the main mechanisms involved in resistant hypertension. Sacubitril/valsartan may emerge as a potential first-line drug due to its superiority over renin angiotensin system inhibitors, and SGLT2 inhibitors can reduce BP in difficult-to-control hypertensive patients with type 2 diabetes. In addition, firibastat and aprocitentan may expand the therapeutic options for resistant hypertension by novel mechanism of actions. Since gut dysbiosis not only leads to hypertension but also causes direct target organ damage, prebiotics and probiotics could represent a potential strategy to prevent or reduce the development of hypertension and to contribute to BP control.
10.1080/14779072.2022.2105204
New drug targets for hypertension: A literature review.
Gao Qiannan,Xu Li,Cai Jun
Biochimica et biophysica acta. Molecular basis of disease
Hypertension is one of the most prevalent cardiovascular diseases worldwide. However, in the population of resistant hypertension, blood pressure is difficult to control effectively. Moreover, antihypertensive drugs may have adverse effect currently. Hence, new therapeutic targets and treatments are needed to uncovered and exploited to control hypertension and its comorbidities. In the past, classical drug targets, such as the aldosterone receptor, aldosterone synthase, and ACE2/angiotensin 1-7/Mas receptor axis, have been investigated. Recently, vaccines and drugs targeting the gastrointestinal microbiome, which represent drug classes, have also been investigated for the management of blood pressure. In this review, we summarized current knowledge on classical and new drug targets and discussed the potential utility of new drugs in the treatment of hypertension.
10.1016/j.bbadis.2020.166037
Antihypertensive drugs.
Laurent Stéphane
Pharmacological research
Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators.
10.1016/j.phrs.2017.07.026
Sex differences in spontaneous reports on adverse drug events for common antihypertensive drugs.
Rydberg Diana M,Mejyr Stefan,Loikas Desirée,Schenck-Gustafsson Karin,von Euler Mia,Malmström Rickard E
European journal of clinical pharmacology
PURPOSE:To explore sex differences in spontaneously reported adverse drug events (ADEs) for antihypertensives in routine care. METHODS:A cross sectional analysis combining number of reports from the national pharmacovigilance database with data from the Swedish Prescribed Drug Register, from 2005 to 2012 for ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARB), with or without thiazide, diuretics (thiazides, potassium-sparing agents, sulfonamides, aldosterone antagonists), selective betablockers, and dihydropyridine calcium-channel-blockers (DHPs). The total number of reports was adjusted to exposed patients and dispensed DDDs among women and men. Dose exposures, co-medications, and co-prescriptions were also analyzed. RESULTS:In women, a higher prevalence of ADE-reports was seen in ACE-I (odds ratio, OR 1.21; 95% CI 1.09-1.35), ACE-I-combinations (OR 1.61; 1.44-1.79), ARB-combinations (OR 2.12; 1.47-3.06), thiazides (OR 1.78; 1.33-2.39), diuretics and potassium-sparing agents (OR 1.62; 1.22-2.17), and DHPs (OR 1.40; 1.17-1.67), with a potential linkage to dose exposure. For aldosterone antagonists, we observed a higher prevalence of ADE reports in men (OR 0.75; 0.59-0.97) but without any sex difference in dose exposure. CONCLUSIONS:This ecological study of reported ADEs showed a higher prevalence of reports in women in six out of ten groups of antihypertensive drugs, and this may potentially be linked to dose exposure. Aldosterone antagonists was the only group with a higher prevalence of ADE-reports in men with a similar dose exposure between women and men.
10.1007/s00228-018-2480-y
[Severe and rare adverse reaction to hydrochlorothiazide].
Núñez-Acevedo Beatriz,Domínguez-Ortega Javier,Rodríguez-Jiménez Beatriz,Kindelan-Recarte Cristina,Pérez-Fernández Manuel Arturo
Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993)
BACKGROUND:The immune mechanism involved in the reaction to hydrochlorothiazide, which is widely used to control hypertension, is unknown. The short latency period between the take of the drug and the onset of symptoms suggests immediate hypersensitivity. CASE REPORT:63-year-old woman with arterial hypertension who, on three occasions, experienced nausea, vomiting, general malaise, shivering, arthralgias, dysthermic sensation, back pain of mechanical characteristics and mild non-productive cough, as well as fever and chest tightness with increased dyspnea and desaturation of up to 88 %, after taking hydrochlorothiazide. CONCLUSIONS:Clinical presentation in the patient was similar to a septic shock, which is a rare allergic reaction. The diagnosis has to be clinical. This type of reaction might be due to type III hypersensitivity owing to the formation of immune complexes. Avoiding of the culprit drug is key to a good evolution.
10.29262/ram.v65i4.363
Phototoxic Reactions Inducted by Hydrochlorothiazide and Furosemide in Normal Skin Cells-In Vitro Studies on Melanocytes and Fibroblasts.
International journal of molecular sciences
Hypertension is known to be a multifactorial disease associated with abnormalities in neuroendocrine, metabolic, and hemodynamic systems. Poorly controlled hypertension causes more than one in eight premature deaths worldwide. Hydrochlorothiazide (HCT) and furosemide (FUR), being first-line drugs in the treatment of hypertension, are among others the most frequently prescribed drugs in the world. Currently, many pharmacoepidemiological data associate the use of these diuretics with an increased risk of adverse phototoxic reactions that may induce the development of melanoma and non-melanoma skin cancers. In this study, the cytotoxic and phototoxic potential of HCT and FUR against skin cells varied by melanin pigment content was assessed for the first time. The results showed that both drugs reduced the number of metabolically active normal skin cells in a dose-dependent manner. UVA irradiation significantly increased the cytotoxicity of HCT towards fibroblasts by approximately 40% and melanocytes by almost 20% compared to unirradiated cells. In the case of skin cells exposed to FUR and UVA radiation, an increase in cytotoxicity by approximately 30% for fibroblasts and 10% for melanocytes was observed. Simultaneous exposure of melanocytes and fibroblasts to HCT or FUR and UVAR caused a decrease in cell viability, and number, which was confirmed by microscopic assessment of morphology. The phototoxic effect of HCT and FUR was associated with the disturbance of redox homeostasis confirming the oxidative stress as a mechanism of phototoxic reaction. UVA-irradiated drugs increased the generation of ROS by 10-150%, and oxidized intracellular thiols. A reduction in mitochondrial potential of almost 80% in melanocytes exposed to HCT and UVAR and 60% in fibroblasts was found due to oxidative stress occurrence. In addition, HCT and FUR have been shown to disrupt the cell cycle of normal skin cells. Finally, it can be concluded that HCT is the drug with a stronger phototoxic effect, and fibroblasts turn out to be more sensitive cells to the phototoxic effect of tested drugs.
10.3390/ijms25031432
Hydrochlorothiazide-Induced Exfoliative Rash and Sepsis.
Cureus
Hydrochlorothiazide is a diuretic agent commonly used to treat hypertension, chronic edema from congestive heart failure or cirrhosis, and nephrogenic diabetes insipidus. Diuretics work by increasing urine output and are classified based on the specific renal segments they act on. As with all medications, they are not without their side effects. The most significant and serious include hypovolemia and electrolyte disturbances. Other more rare adverse effects include dermatitis and hypersensitivity reactions. We discuss an 86-year-old male who presented to the emergency room with complaints of lightheadedness and progressive exfoliating rash that began shortly after starting hydrochlorothiazide in an outpatient setting.
10.7759/cureus.63655
Hydrochlorothiazide use and risk of non-melanoma skin cancer in Spain: A case/non-case study.
Lecaros-Astorga Darío A,Molina-Guarneros Juan A,Rodríguez-Jiménez Pedro,Martin-Arias Luis H,Sainz-Gil María
International journal of clinical pharmacology and therapeutics
OBJECTIVE:In 2018, the Pharmacological Risk Assessment Committee alerted to a potential relationship between accumulated hydrochlorothiazide dosage and the risk of non-melanoma skin cancer. To study this relationship we used data from the Spanish Pharmacovigilance System for Medicinal Products of Human Use. MATERIALS AND METHODS:Following a case search for every thiazide potentially associated with (SMQ/MedDRA) "Malignant Skin Neoplasms and not Otherwise Specified Skin Neoplasms", a series of disproportionality analyses were conducted by estimating the reporting odds ratio (95% confidence interval). Registered adverse drug reactions and disproportionality through the reported odds ratio were the main outcome measures. RESULTS:For basal cell carcinoma, reporting odds ratio was 4.8 (2.2 - 10.7); squamous cell carcinoma 3.2 (0.9 - 10.5); malignant melanoma, 0.8 (0.2 - 3.5). We found both disproportionality and association between hydrochlorothiazide and basal cell carcinoma, but none of these were found regarding malignant skin melanoma. In the case of squamous cell carcinoma, the lower confidence interval limit was below 1, thus the disproportionality value was not statistically significant. The accumulated hydrochlorothiazide dose was 36,714 mg for basal cell carcinoma; 98,288 mg for squamous cell carcinoma; and 38,444 mg for malignant melanoma. CONCLUSION:The results in Spain, where sun exposure is significant, are consistent with the data in the Pharmacological Risk Assessment Committee's alert, which were obtained in Denmark for both basal cell carcinoma and malignant melanoma. However, the results for squamous cell carcinoma did not reach statistical significance, although the reporting odds ratio value suggested a potential relationship between hydrochlorothiazide and squamous cell carcinoma.
10.5414/CP203769
Hydrochlorothiazide use is associated with the risk of cutaneous and lip squamous cell carcinoma: A systematic review and meta-analysis.
European journal of clinical pharmacology
PURPOSE:The aim of this study is to investigate the association between hydrochlorothiazide (HCTZ) use and the risk of cutaneous and lip squamous cell carcinoma development. METHODOLOGY:We performed a systematic review and meta-analysis of case-control studies. We searched the Cochrane Library, PubMed, Scopus, Web of Science and LILACS. This study was registered in PROSPERO under protocol CRD42019129710. The meta-analysis was performed using the software Stata (version 12.0). RESULTS:A total of 2181 published studies referring to the theme were identified, from which six were included in this systematic review. Men were more frequently affected by cutaneous and lip squamous cell carcinoma than women, with a 1.42:1 ratio. The mean age for cutaneous and lip squamous cell carcinoma development was 73.7 years. This meta-analysis demonstrated a chance of developing cutaneous and lip squamous cell carcinoma in any region of the body in hydrochlorothiazide users of 1.76-fold higher than in non-users. In addition, a risk factor of 1.80 higher (CI 95% = 1.71-1.89) of cutaneous squamous cell carcinoma in the head and neck region was observed in HCTZ users. Moreover, in the analysis of the dose used, the chance of developing squamous cell carcinoma was 3.37-fold lower when the concentration of HCTZ used was less than 50,000 mg. CONCLUSIONS:Our results confirm the association between the use of hydrochlorothiazide and the cutaneous and lip squamous cell carcinoma development.
10.1007/s00228-022-03299-x
Genetic Determinants of Thiazide-Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances - A Genome-Wide Evaluation of the UK Biobank.
Clinical pharmacology and therapeutics
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) 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; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10) 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.
10.1002/cpt.3229
Cutaneous effects of antihypertensive drugs.
Baccino Danilo,Merlo Giulia,Cozzani Emanuele,Rosa Gian M,Tini Giacomo,Burlando Martina,Parodi Aurora
Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia
INTRODUCTION:Treatment with antihypertensive drugs may be associated with different dermatological adverse reactions. EVIDENCE ACQUISITION:We systematically reviewed the literature available on the MEDLINE (PubMED) databases, up to July 2018. We searched for the terms "calcium-channel blockers" or "angiotensin-converting enzyme inhibitors" or "angiotensin II receptors blockers" or "diuretics" or "beta blockers" AND "dermatological effects" or "skin disease." EVIDENCE SYNTHESIS:The most important cutaneous events occurring during treatment with calcium-channel blockers are represented by pedal edema and photosensitivity with consequent increased risk of skin cancer. Moreover, other adverse reactions are eczematous and psoriasiform dermatitis, subacute cutaneous lupus erythematosus, and rarely toxic epidermal necrolysis. In patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptors blockers, angioedema, psoriasis and pemphigus can be exacerbated. Furthermore, some authors associated the use of these medications with the onset of skin neoplasms. As for diuretics, the most relevant cutaneous reactions are represented by subacute cutaneous lupus erythematosus and leukocytoclastic vasculitis. Photosensitivity is another important event related to diuretics use. Eventually, itching is often related to the use of thiazides, particularly in elderly patients. With regards to beta blockers, we should remember a significant association with psoriasis, lichen planus, subacute cutaneous lupus erythematosus, and an increased risk of skin cancer. CONCLUSIONS:During antihypertensive treatment, several dermatological reactions may occur. Clinicians should inform their patients of the increased risk of cutaneous lesions associated with the use of these drugs, and perform periodic examination of the skin.
10.23736/S0392-0488.19.06360-0
Hydrochlorothiazide-induced systemic capillary leak.
Vadas Peter
The American journal of emergency medicine
Hypersensitivity reactions to drugs may cause very rapid physiologic derangements that can be fatal in the absence of adequate compensatory mechanisms or definitive treatment. For the most part, adverse drug reactions that progress over the course of minutes are mediated either by mast cell or complement activation. If a patient survives the acute event, appropriate long-term management requires the identification and future avoidance of the inciting drug. Here, we describe a patient who experienced two life-threatening multisystem reactions with cardiopulmonary compromise minutes after taking hydrochlorothiazide (HCTZ). The reactions were associated with systemic vascular leak resulting in hypotension and non-cardiogenic pulmonary edema.
10.1016/j.ajem.2020.02.029
First-line drugs for hypertension.
The Cochrane database of systematic reviews
BACKGROUND:This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical question: What class of drug to use first-line? This review attempted to answer that question. OBJECTIVES:To quantify the mortality and morbidity effects from different first-line antihypertensive drug classes: thiazides (low-dose and high-dose), beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers (ARB), and alpha-blockers, compared to placebo or no treatment.Secondary objectives: when different antihypertensive drug classes are used as the first-line drug, to quantify the blood pressure lowering effect and the rate of withdrawal due to adverse drug effects, compared to placebo or no treatment. SEARCH METHODS:The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA:Randomized trials (RCT) of at least one year duration, comparing one of six major drug classes with a placebo or no treatment, in adult patients with blood pressure over 140/90 mmHg at baseline. The majority (over 70%) of the patients in the treatment group were taking the drug class of interest after one year. We included trials with both hypertensive and normotensive patients in this review if the majority (over 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure. DATA COLLECTION AND ANALYSIS:The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. We used a fixed-effect model to to combine dichotomous outcomes across trials and calculate risk ratio (RR) with 95% confidence interval (CI). We presented blood pressure data as mean difference (MD) with 99% CI. MAIN RESULTS:The 2017 updated search failed to identify any new trials. The original review identified 24 trials with 28 active treatment arms, including 58,040 patients. We found no RCTs for ARBs or alpha-blockers. These results are mostly applicable to adult patients with moderate to severe primary hypertension. The mean age of participants was 56 years, and mean duration of follow-up was three to five years.High-quality evidence showed that first-line low-dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84).Low- to moderate-quality evidence showed that first-line high-dose thiazides reduced stroke (1.9% with control versus 0.9% with treatment; RR 0.47, 95% CI 0.37 to 0.61) and total CVS (5.1% with control versus 3.7% with treatment; RR 0.72, 95% CI 0.63 to 0.82), but did not reduce mortality (3.1% with control versus 2.8% with treatment; RR 0.90, 95% CI 0.76 to 1.05), or coronary heart disease (2.7% with control versus 2.7% with treatment; RR 1.01, 95% CI 0.85 to 1.20).Low- to moderate-quality evidence showed that first-line beta-blockers did not reduce mortality (6.2% with control versus 6.0% with treatment; RR 0.96, 95% CI 0.86 to 1.07) or coronary heart disease (4.4% with control versus 3.9% with treatment; RR 0.90, 95% CI 0.78 to 1.03), but reduced stroke (3.4% with control versus 2.8% with treatment; RR 0.83, 95% CI 0.72 to 0.97) and total CVS (7.6% with control versus 6.8% with treatment; RR 0.89, 95% CI 0.81 to 0.98).Low- to moderate-quality evidence showed that first-line ACE inhibitors reduced mortality (13.6% with control versus 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95), stroke (6.0% with control versus 3.9% with treatment; RR 0.65, 95% CI 0.52 to 0.82), coronary heart disease (13.5% with control versus 11.0% with treatment; RR 0.81, 95% CI 0.70 to 0.94), and total CVS (20.1% with control versus 15.3% with treatment; RR 0.76, 95% CI 0.67 to 0.85).Low-quality evidence showed that first-line calcium channel blockers reduced stroke (3.4% with control versus 1.9% with treatment; RR 0.58, 95% CI 0.41 to 0.84) and total CVS (8.0% with control versus 5.7% with treatment; RR 0.71, 95% CI 0.57 to 0.87), but not coronary heart disease (3.1% with control versus 2.4% with treatment; RR 0.77, 95% CI 0.55 to 1.09), or mortality (6.0% with control versus 5.1% with treatment; RR 0.86, 95% CI 0.68 to 1.09).There was low-quality evidence that withdrawals due to adverse effects were increased with first-line low-dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high-dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24), and beta-blockers (3.1% with control versus 14.4% with treatment; RR 4.59, 95% CI 4.11 to 5.13). No data for these outcomes were available for first-line ACE inhibitors or calcium channel blockers. The blood pressure data were not used to assess the effect of the different classes of drugs as the data were heterogeneous, and the number of drugs used in the trials differed. AUTHORS' CONCLUSIONS:First-line low-dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First-line ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality. First-line high-dose thiazides and first-line beta-blockers were inferior to first-line low-dose thiazides.
10.1002/14651858.CD001841.pub3
β blockers switched to first-line therapy in hypertension.
Lancet (London, England)
In their recent guidelines, the European Society of Hypertension upgraded β blockers, putting them on equal footing with thiazide diuretics, renin-angiotensin system blockers (eg, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and calcium channel blockers. The reason offered for upgrading β blockers was the observation that they are often used for many other clinical conditions commonly encountered with hypertension. This upgrade would allow for the treatment of two conditions with a single drug (a so-called twofer). In most current national and international hypertension guidelines, β blockers are only considered to be an alternative when there are specific indications. Compared with the other first-line antihypertensive drug classes, β blockers are significantly less effective in preventing stroke and cardiovascular mortality. To relegate β blockers to an inferiority status as previous guidelines have done was based on the evidence in aggregate, and still stands. No new evidence supports the switch of β blockers back to first-line therapy. We are concerned that this move might lead to widespread harm because of inferior stroke protection.
10.1016/S0140-6736(23)01733-6
The Efficacy and Safety of Bisoprolol in the Treatment of Myocardial Infarction with Cardiac Insufficiency.
Computational and mathematical methods in medicine
Background:Bisoprolol is commonly used to treat moderate or severe chronic stable heart failure, coronary heart disease, and hypertension. This study is aimed at analyzing the efficacy of bisoprolol in the treatment of myocardial infarction with cardiac insufficiency and its effect on cardiac function, Hcy, and CRP through meta-analysis. Methods:A total of 120 patients with myocardial infarction and cardiac insufficiency from February 2020 to February 2021 were selected and randomly divided into two groups (control and the observation, = 60) according to the random number table method. The control group was given conventional treatment. The observation group was given bisoprolol on the basis of control group. The clinical efficacy, systolic blood pressure, diastolic blood pressure, heart rate, cardiac function indexes, homocysteine (Hcy), and C-reactive protein (CRP) levels were compared between the two groups before and after treatment through data analysis. Adverse reactions were observed during treatment. Results:Compared with the control group, the total effective rate of the observation group was significantly increased ( < 0.05). After treatment, the levels of heart rate, left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) and serum Hcy and CRP levels in the observation group were significantly lower than those in the control group ( < 0.05). Meanwhile, left ventricular ejection fraction (LVEF) level in the observation group after treatment was higher than that of the control group ( < 0.05). Conclusion:Bisoprolol combined with conventional treatment can reduce serum Hcy and CRP levels in patients with myocardial infarction and cardiac insufficiency and improve cardiac function. Moreover, there are no obvious adverse reactions during the treatment.
10.1155/2022/3098726
Diuretics use in the management of hypertension.
Hipertension y riesgo vascular
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.
10.1016/j.hipert.2024.03.004
Considering Adverse Effects of Common Antihypertensive Medications in the ED.
Current hypertension reports
PURPOSE OF REVIEW:To evaluate the adverse effects of common antihypertensive agents utilized or encountered in the Emergency Department. RECENT FINDINGS:All categories of antihypertensive agents may manifest adverse effects, inclusive of adverse drug reactions (ADRs), drug-to-drug interactions, or accidental overdose. Adverse effects, and specifically ADRs, may be stratified into the organ systems affected, might require specific time-sensitive interventions, could pose particular risks to vulnerable populations, and may result in significant morbidity, and potential mortality. Adverse effects of common antihypertensive agents may be encountered in the ED, necessitating that ED systems of care are poised to prevent, recognize, and intervene when adverse effects arise.
10.1007/s11906-024-01304-5
Efficacy and Safety of a Single-Pill Triple Combination of Olmesartan, Amlodipine, and Rosuvastatin in Hypertensive Patients with Low-to-Moderate Cardiovascular Risk: A Multicenter, Randomized, Open-Label, Active-Control, Phase IV Clinical Trial.
Journal of cardiovascular pharmacology and therapeutics
INTRODUCTION:This study evaluated the efficacy and safety of a single-pill triple-combination of olmesartan/amlodipine/rosuvastatin (Olme/Amlo/Rosu) in comparison with a single-pill dual-combination of olmesartan/amlodipine (Olme/Amlo) in hypertensive patients with low-to-moderate cardiovascular risk. METHODS:This multicenter, active-control, randomized study included 106 hypertensive patients at low-to-moderate cardiovascular risk who were randomly assigned to receive either Olme/Amlo/Rosu 20/5/5 mg (Treatment 1), Olme/Amlo/Rosu 20/5/10 mg (Treatment 2), or Amlo/Olme 20/5 mg (Control) once daily for 8 weeks. The primary endpoint was the difference of the percent change in low-density lipoprotein cholesterol (LDL-C) level at 8 weeks from baseline in the 3 groups. RESULTS:The difference in the least square mean percent change (standard deviation) of LDL-C in the Treatment 1 and 2 groups compared with the Control group at 8 weeks was -32.6 (3.7) % and -45.9 (3.3) %, respectively ( < .001). The achievement rates of LDL-C level <100 mg/dL at 8 weeks were significantly different between the 3 groups (65.8%, 86.7%, and 6.3% for Treatment 1, 2, and Control groups, respectively, < .001). The results of total cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein B, and apolipoprotein B/apolipoprotein A1 were superior in the Treatment 1 and 2 groups compared with the Control group. Serious adverse drug reaction did not occur in the 3 groups. Medication adherence rates were excellent in the 3 groups (98.0% for Treatment 1 group, 99.7% for Treatment 2 group, and 96.3% for the Control group, > .05). CONCLUSION:Single-pill triple-combination of olmesartan/amlodipine/rosuvastatin was superior to the single-pill dual-combination of amlodipine/olmesartan in LDLC-lowering effects, with excellent safety profiles and adherence rates, in hypertensive patients at low-to-moderate cardiovascular risk. CLinicalTrials.gov identifier NCT04120753.
10.1177/10742484231205204
Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects.
Circulation
BACKGROUND:Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide. METHODS:Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank. RESULTS:Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32). CONCLUSIONS:Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.
10.1161/CIRCULATIONAHA.118.038814
Efficacy and toxicity of antihypertensive pharmacotherapy relative to effective dose 50.
Dimmitt Simon B,Stampfer Hans G,Martin Jennifer H,Ferner Robin E
British journal of clinical pharmacology
Antihypertensive drugs have usually been approved at doses near the top of their respective dose-response curves. Efficacy plateaus but adverse drug reactions (ADRs), such as falls, cerebral or renal ischaemia, increase as dose is increased, especially in older patients with comorbidities. ADRs reduce adherence and may be difficult to ascertain reliably. Higher doses have generally not been shown to reduce total mortality, which provides a summary of efficacy and safety. Weight loss and other lifestyle measures are essential and may be sufficient treatment in many young and low risk patients. Most antihypertensive drug lower systolic blood pressure by around 10 mmHg, which reduces stroke and heart failure by about a quarter. Clinical trials have not been designed to demonstrate specific blood pressure treatment thresholds and targets, which are mostly extrapolated from epidemiology. Mean population oral effective dose 50 may be the most appropriate dose at which to commence antihypertensive drugs. The dose can then be titrated up if greater efficacy is demonstrated, or lowered if ADRs develop. Lower dose combination therapy may best balance benefit and harms with fewer ADRs and additive, potentially synergistic, efficacy.
10.1111/bcp.14033
Drug-Induced Ototoxicity: A Comprehensive Review and Reference Guide.
Rizk Habib G,Lee Joshua A,Liu Yuan F,Endriukaitis Lauren,Isaac Julianne L,Bullington Wendy M
Pharmacotherapy
OBJECTIVE:In an era of increasing polypharmacy, adverse drug effects such as ototoxicity have significant public health implications. Despite the availability of evidence, many health care professionals may not know the risk of ototoxicity in common medications. Therefore, the aim of this review is to provide a comprehensive, easy to use, ototoxic profile of medications with an assessment of supporting evidence. METHODS:Medications of interest were identified through adverse drug reaction reports derived from Micromedex (IBM), Lexicomp (Wolters Kluwer), and the textbook, Drug Induced Diseases: Prevention, Detection, and Management. Additional evidence was identified though a query of PubMed and the Cochrane database. Evidence of causality was graded according to the following: A (randomized, controlled clinical trials), B (nonrandomized clinical trials, prospective observational studies, cohort studies, retrospective studies, case-controlled studies, and/or postmarketing surveillance studies), and C (case reports/case series). RESULTS:A total of 194 systemically administered medications associated with ototoxicity were identified, most commonly antimicrobials (53), psychotropics (21), antihypertensive/antiarrhythmics (19), nonsteroidal antiinflammatory drugs (18), and antineoplastics (16). There was evidence of cochleotoxicity in 165 medications (evidence grading A [22], B [77], C [69]), vestibulotoxicity in 100 medications (evidence grading A [23], B [47], and C [30]), and dizziness in 142 medications (evidence grading A [50], B [76], and C [16]). In addition, a review of the evidence of ototoxicity in ototopical medications is also reviewed. CONCLUSION:The effect and severity of ototoxicity can vary immensely depending on pharmacological and individual patient risk factors. The intent of this comprehensive review was to help health care providers of all sectors obtain a deeper knowledge of drug-induced ototoxicity to make more informed management decisions for their patients.
10.1002/phar.2478
Antidepressant Drugs Effects on Blood Pressure.
Frontiers in cardiovascular medicine
Individuals suffering from depressive disorders display a greater incidence of hypertension compared with the general population, despite reports of the association between depression and hypotension. This phenomenon may depend, at least in part, on the use of antidepressant drugs, which may influence blood pressure through different effects on adrenergic and serotoninergic pathways, as well as on histaminergic, dopaminergic, and cholinergic systems. This review summarizes extant literature on the effect of antidepressant drugs on blood pressure. Selective serotonin reuptake inhibitors are characterized by limited effects on autonomic system activity and a lower impact on blood pressure. Thus, they represent the safest class-particularly among elderly and cardiovascular patients. Serotonin-norepinephrine reuptake inhibitors, particularly venlafaxine, carry a greater risk of hypertension, possibly related to greater effects on the sympathetic nervous system. The norepinephrine reuptake inhibitor reboxetine is considered a safe option because of its neutral effects on blood pressure in long-term studies, even if both hypotensive and hypertensive effects are reported. The dopamine-norepinephrine reuptake inhibitor bupropion can lead to blood pressure increases, usually at high doses, but may also cause orthostatic hypotension, especially in patients with cardiovascular diseases. The norepinephrine-serotonin modulators, mirtazapine and mianserin, have minimal effects on blood pressure but may rarely lead to orthostatic hypotension and falls. These adverse effects are also observed with the serotonin-reuptake modulators, nefazodone and trazodone, but seldomly with vortioxetine and vilazodone. Agomelatine, the only melatonergic antidepressant drug, may also have limited effects on blood pressure. Tricyclic antidepressants have been associated with increases in blood pressure, as well as orthostatic hypotension, particularly imipramine. Oral monoamine-oxidase inhibitors, less frequently skin patch formulations, have been associated with orthostatic hypotension or, conversely, with hypertensive crisis due to ingestion of tyramine-containing food (i.e., cheese reaction). Lastly, a hypertensive crisis may complicate antidepressant treatment as a part of the serotonin syndrome, also including neuromuscular, cognitive, and autonomic dysfunctions. Clinicians treating depressive patients should carefully consider their blood pressure status and cardiovascular comorbidities because of the effects of antidepressant drugs on blood pressure profiles and potential interactions with antihypertensive treatments.
10.3389/fcvm.2021.704281
Pharmacogenomics of Hypertension Treatment.
Rysz Jacek,Franczyk Beata,Rysz-Górzyńska Magdalena,Gluba-Brzózka Anna
International journal of molecular sciences
Hypertension is one of the strongest modifiable cardiovascular risk factors, affecting an increasing number of people worldwide. Apart from poor medication adherence, the low efficacy of some therapies could also be related to inter-individual genetic variability. Genetic studies of families revealed that heritability accounts for 30% to 50% of inter-individual variation in blood pressure (BP). Genetic factors not only affect blood pressure (BP) elevation but also contribute to inter-individual variability in response to antihypertensive treatment. This article reviews the recent pharmacogenomics literature concerning the key classes of antihypertensive drugs currently in use (i.e., diuretics, β-blockers, ACE inhibitors, ARB, and CCB). Due to the numerous studies on this topic and the sometimes-contradictory results within them, the presented data are limited to several selected SNPs that alter drug response. Genetic polymorphisms can influence drug responses through genes engaged in the pathogenesis of hypertension that are able to modify the effects of drugs, modifications in drug-gene mechanistic interactions, polymorphisms within drug-metabolizing enzymes, genes related to drug transporters, and genes participating in complex cascades and metabolic reactions. The results of numerous studies confirm that genotype-based antihypertension therapies are the most effective and may help to avoid the occurrence of major adverse events, as well as decrease the costs of treatment. However, the genetic heritability of drug response phenotypes seems to remain hidden in multigenic and multifactorial complex traits. Therefore, further studies are required to analyze all associations and formulate final genome-based treatment recommendations.
10.3390/ijms21134709
Clevidipine : a state-of-the-art antihypertensive drug under the scope.
Espina Ilse M,Varon Joseph
Expert opinion on pharmacotherapy
INTRODUCTION:Clevidipine butyrate is the first intravenous antihypertensive drug to be approved by the FDA over the last decade. This medication is approved for use in the USA, Australia and New Zealand, but is still pending for approval in Europe. It is a new agent that might change the current management for severe acute hypertension in the critical care, emergency and perioperative areas. AREAS COVERED:This systematic review summarizes the pharmacological and clinical characteristics of this third-generation dihydropyridine intravenous calcium channel blocker, and was done using the literature available from the first publication in 1999 up until now, including the pivotal trials that led to its approval. EXPERT OPINION:This agent is arterially selective, has an ultrashort half-life, with no CYP-mediated interactions with other medications and is easily titratable. These characteristics place it in a unique category compared with other commonly used antihypertensives. Clevidipine butyrate reaches target systolic blood pressure in more than 90% of patients, within 30 min. It has a low incidence of adverse reactions and is generally well tolerated. The main goal of this review is to provide healthcare providers with a comprehensive appraisal of this promising medication.
10.1517/14656566.2012.651126
Antihypertensive medications: relative effectiveness and adverse reactions.
Moser M
Journal of hypertension. Supplement : official journal of the International Society of Hypertension
Thiazide diuretics may be more effective as antihypertensive agents in many subsets of patients than other medications, especially in reducing systolic blood pressure. Angiotensin converting enzyme (ACE) inhibitors and beta-blockers are less effective than calcium blockers or diuretics in black hypertensives and beta-blockers may be less effective in the elderly. Calcium blockers are equally effective in blacks, whites and the elderly but may not be as efficacious as diuretics. When used as initial monotherapy, most available antihypertensive drugs produce significant adverse subjective effects in about 8-10% of patients; centrally acting drugs, however, may produce annoying side effects in 20-30% of patients. Usually, some medication can be found that lowers blood pressure and is acceptable to the patient. Adverse metabolic effects are probably of limited long-term clinical significance except in a few patients. An approach to therapy that will prove effective in a majority of patients is outlined. Any one of the four classes of agents may appropriately be used as initial monotherapy (diuretics, beta-blockers, ACE inhibitors, calcium blockers). Diuretics are recommended as the second drug of choice if one of the other agents is used first. With this approach approximately 80% or more of patients can be controlled at normotensive levels on one or at most two drugs.
10.1097/00004872-199006002-00003
Adverse psychiatric reactions to modern medication.
Whitlock F A
The Australian and New Zealand journal of psychiatry
From this survey it will be apparent that many psychiatric reactions to drugs are largely caused by their direct toxic actions or from combinations of drugs. As such, they are often dose related, although age and slow speed of detoxification will increase the risk of patients developing delirium, hallucinations, sleep disturbances, anxiety etc. Similar toxic reactions can also occur when drugs to which a patient has developed some measure of tolerance are abruptly withdrawn. In this context the effects of drugs upon patterns of sleep may be important determinants of adverse withdrawal symptoms. In contrast are the reactions which resemble one or other of the functional psychoses. In these patients it appears that a past history of an affective or schizophrenic psychosis is the best predictor of a similar illness being precipitated by a particular drug. Nonetheless, with substances like reserpine and cycloserine there is good reason for thinking that, given a sufficient quantity, practically any patient can develop an adverse psychiatric reaction.
10.3109/00048678109159417
Antihypertensive drugs: adverse reactions and metabolic effects in elderly patients.
Gifford R W
Geriatrics
Symptomatic and metabolic side effects seen in the treatment of elderly hypertensive patients are an area of concern for physicians. Of the four drug classes used as Step 1 antihypertensive agents--diuretics, beta-blockers, ACE inhibitors, and calcium-entry blocking agents--only diuretics have been studied as monotherapy for the elderly in placebo-controlled, long-term clinical trials. These studies have shown diuretics to be well tolerated in this patient population, producing only mild, infrequent side effects.
Management of hypertension.
Kaplan N M
Disease-a-month : DM
To provide maximal protection against the cardiovascular complications that accompany hypertension, the disease must be managed in ways to minimize the total cardiovascular risk burden. These involve five major steps: (1) careful monitoring of the blood pressure in response to appropriate therapy; (2) assessment of concomitant cardiovascular risk factors; (3) institution of life-style modifications needed to control both hypertension and other risk factors; (4) use of antihypertensive drugs, chosen to best manage the individual patient's overall risk burden and provided in a manner that will lower the pressure gently while avoiding adverse reactions; and (5) identifying and reaching the goal of therapy: levels of blood pressure that are neither too high to avoid increased risks for cerebral and renal damage nor too low to avoid increased risks for coronary ischemia. This monograph builds on the 30-year experience of one of the leading clinical investigators in the field to translate the multiple advances made in the management of hypertension into practical guidelines for improved care of the many millions of patients with this disease. Particular emphasis is directed toward certain therapeutic challenges, including the elderly, diabetic patients, and resistant hypertensive patients.
The evolution of antihypertensive therapy.
Perry H M
The American journal of cardiology
Beginning in the early 1950s, when a ganglioplegic agent and a vasodilator were used in combination to provide long-term control of severe hypertension, which neither drug alone could control, much has been learned about the management of hypertension from the use of new antihypertensive agents in man and from clinical trials of antihypertensive regimens. Some of this information includes: the unexpected yet very real hazards as well as benefits associated with the long-term use of powerful drugs, in particular the original description of hydralazine-induced lupus, its relation to genetic markers and its association with control of hypertension; the apparently decreasing need for antihypertensive drugs in subjects with well-controlled severe and moderate hypertension; the identification of risk factors for the complications of hypertension and the quantitation of their effects; the decrease in the incidence of hypertensive complications associated with the pharmacologic treatment of severe, moderate and, at least, the upper ranges of mild hypertension; the possibility of designing a chemical to block a specific reaction and the realization that it would have broader than expected effects; and the primary prevention of myocardial infarction in very high risk subjects.
10.1016/0002-9149(85)90548-x
Adverse reactions to antihypertensive drugs in pregnancy.
Schoenfeld A,Segal J,Friedman S,Hirsch M,Ovadia J
Obstetrical & gynecological survey
In conclusion from a clinical pharmacological point of view it is stressed that side effects from antihypertensive therapy in part is related to dosage. Increased knowledge should make it possible to reduce the rate of side effects. In the individual case the physician always has to compare a number of factors: general condition of the patient, age, adherence to the prescribed therapy, side effects, and other factors in addition to blood pressure values. With all these limitations in mind there is agreement that the benefit of antihypertensive therapy far out-weigh the negative aspects of such treatment.
10.1097/00006254-198602000-00001
Antihypertensives in dermatology Part II - Cutaneous adverse reactions to antihypertensives.
Ranugha P S S,Betkerur Jayadev B
Indian journal of dermatology, venereology and leprology
Antihypertensive drugs are prescribed frequently and can cause cutaneous adverse reactions. The exact incidence and frequency of these reactions are unknown. Multiple antihypertensive drug consumption has contributed to a substantial increase in the number of cutaneous adverse reactions to them. Thus, there is a need for dermatologists and physicians to be aware of the wide range of available antihypertensives and the type of reactions that can be expected. This review article focuses on the various clinical presentations that have been implicated or associated with them. The diagnosis and management have been discussed in brief.
10.4103/ijdvl.IJDVL_992_16
An update on the pharmacogenetics of treating hypertension.
Fontana V,Luizon M R,Sandrim V C
Journal of human hypertension
Hypertension is a leading cause of cardiovascular mortality, but only one third of patients achieve blood pressure goals despite antihypertensive therapy. Genetic polymorphisms may partially account for the interindividual variability and abnormal response to antihypertensive drugs. Candidate gene and genome-wide approaches have identified common genetic variants associated with response to antihypertensive drugs. However, there is no currently available pharmacogenetic test to guide hypertension treatment in clinical practice. In this review, we aimed to summarize the recent findings on pharmacogenetics of the most commonly used antihypertensive drugs in clinical practice, including diuretics, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, beta-blockers and calcium channel blockers. Notably, only a small percentage of the genetic variability on response to antihypertensive drugs has been explained, and the vast majority of the genetic variants associated with antihypertensives efficacy and toxicity remains to be identified. Despite some genetic variants with evidence of association with the variable response related to these most commonly used antihypertensive drug classes, further replication is needed to confirm these associations in different populations. Further studies on epigenetics and regulatory pathways involved in the responsiveness to antihypertensive drugs might provide a deeper understanding of the physiology of hypertension, which may favor the identification of new targets for hypertension treatment and genetic predictors of antihypertensive response.
10.1038/jhh.2014.76
Relative efficacy of, and some adverse reactions to, different antihypertensive regimens.
Moser M
The American journal of cardiology
Although it is a common belief that all antihypertensive agents are equally effective in reducing blood pressure, there is some evidence to the contrary, both in the general population and when specific patient demographics are considered. In black patients, beta blockers and angiotensin-converting enzyme (ACE) inhibitors have been shown to be less effective at reducing blood pressure than the thiazide diuretics. After age 60, the percentage of responders to beta blockers is less than with calcium antagonists, and a higher percentage of elderly patients also achieve normotensive blood pressure levels with diuretic therapy than with beta blockers. When a thiazide diuretic is added to an ACE inhibitor, beta blocker or calcium antagonist, the number of normotensive responders increases significantly. Combinations of some other agents (i.e., an ACE inhibitor plus a beta blocker) may not, however, improve efficacy. Diuretics, beta blockers and ACE inhibitors are all generally well tolerated, with a 9 to 10% incidence of subjective side effects. The use of calcium antagonists and especially the centrally acting adrenergic inhibitors may result in more frequent adverse effects. Data from long-term, diuretic-based clinical trials do not support the statement that diuretic therapy results in sustained elevations in lipid levels. These trials have shown cholesterol levels to be at or below baseline after long-term diuretic therapy. The use of beta blockers, on the other hand, may result in long-term elevation of triglyceride levels and a slight decrease in high-density lipoprotein cholesterol. Calcium antagonists and ACE inhibitors do not affect lipid levels, and alpha blockers may actually lower cholesterol levels and increase high-density lipoprotein levels.(ABSTRACT TRUNCATED AT 250 WORDS)
10.1016/0002-9149(89)90931-4
A practical guide to monitoring for adverse drug reactions during antihypertensive drug therapy.
McDowell Sarah E,Thomas Sarah K,Coleman Jamie J,Aronson Jeffrey K,Ferner Robin E
Journal of the Royal Society of Medicine
Monitoring of patients taking antihypertensive treatment can identify potential adverse drug reactions (ADRs). However, published guidelines give divergent or incomplete recommendations on monitoring for ADRs. Using a predetermined strategy, we undertook a systematic review to identify hypertension guidelines published from January 2001 to October 2011 with recommendations for monitoring for ADRs. We screened 88 abstracts and 187 web-based guidelines, and identified 19 published guidelines on monitoring the biochemical effects of antihypertensive drug therapy. We then produced a set of practical clinical guidelines, synthesized from those recommendations. Our recommendations are designed to provide efficient monitoring. They reduce the number of tests to a minimum consistent with safe practice and align monitoring schedules, so that creatinine, potassium and sodium concentrations are measured at the same times in all cases. The instructions for biochemical monitoring in current guidelines differ greatly, both in the extent of advice and in the detail provided. The current lack of consistent and workable instructions poses serious difficulties for practitioners. The recommendations distilled from this systematic review should help practitioners when they monitor therapy with antihypertensive drugs.
10.1258/jrsm.2012.120137
Psychiatric side effects of antihypertensive drugs other than reserpine.
Paykel E S,Fleminger R,Watson J P
Journal of clinical psychopharmacology
The psychiatric side effects of the major antihypertensive drugs other than reserpine are reviewed, including centrally acting drugs such as methyldopa and clonidine, peripheral adrenergic drugs such as guanethidine, beta-adrenoceptor blockers such as propranolol, and diuretics. Problems with differential diagnosis and with the interpretation of case reports make assessment of psychiatric side effects difficult. Sedation and sleep disturbances are the most common side effects, occurring with methyldopa, clonidine, and propranolol. Only methyldopa is clearly associated with depression. Other reported effects are toxic confusional states and psychotic reactions. These are rare, however, and no clear patterns of development have been recognized.
The renaissance of centrally acting antihypertensive drugs.
van Zwieten P A
Journal of hypertension. Supplement : official journal of the International Society of Hypertension
Classic centrally acting antihypertensive drugs such as clonidine, guanfacine and alpha-methyl-dioxyphenylalanine (alpha-methyl-DOPA) (via its active metabolite alpha-methyl-noradrenaline) are assumed to induce peripheral sympathoinhibition and a reduction in (elevated) blood pressure as a result of the stimulation of alpha2-adrenoceptors in the pons-medulla region in the brain. Their antihypertensive efficacy is beyond doubt, but their profile of adverse reactions is considered unfavourable when compared with most other antihypertensive drugs currently used, such as low-dose diuretics, beta-blockers, angiotensin-converting enzymes (ACE)-inhibitors, calcium antagonists, peripheral alpha1-adrenoceptor antagonists, and angiotensin II-receptor antagonists. More recently, central imidazoline (I1)-receptors have been recognized to be another target of centrally acting antihypertensive drugs. Clonidine is considered at present to be a mixed agonist that stimulates both alpha2- and I1-receptors. Moxonidine and rilmenidine are considered to be moderately selective I1-receptor stimulants, although it still remains unknown whether these agents act directly on the receptor as genuine agonists. The imidazoline (I1)-agonists also cause peripheral sympathoinhibition, triggered at the level of central nervous imidazoline receptors, predominantly in the rostral ventrolateral medulla. The imidazoline receptor stimulants are effective antihypertensives with a mode of action and haemodynamic profile which seems attractive from a pathophysiological point of view. Moxonidine and rilmenidine are considered preferable over the classic alpha2-adrenoceptor stimulants because of their pattern of side-effects, which may be explained on the basis of absent or weak affinity for the alpha2-adrenoceptor.
Antihypertensive drugs and risk of skin cancer.
Cassano Nicoletta,Di Stefani Alessandro,Vena Gino A,Peris Ketty
Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia
The potential carcinogenic risk of antihypertensive drugs has been examined in several studies that reported controversial results. The association between treatment with antihypertensives and risk of skin cancer has also been questioned, considering the long-term administration of such drugs and the ability of some agents to cause photosensitive reactions. In fact, experimental and epidemiologic findings suggest a link between drug-induced photosensitivity and skin cancer, possibly through the induction of DNA damage in predisposed individuals. Antihypertensive medications might influence skin homeostasis through additional mechanisms. For instance, some antihypertensive drugs can affect epidermal differentiation by interfering with calcium or sodium channels in the skin. Mediators in the renin-angiotensin system (RAS) are also involved in the modulation of cellular proliferation and angiogenesis. Of note, the existence of RAS has been recognized in many organs and tissues, including the skin. The available data regarding the relationship between use of different types of antihypertensives and skin cancer risk do not allow to draw definite conclusions at present. The aim of this article is to summarize the current evidence about the association of antihypertensive use with risk of non-melanoma skin cancer, melanoma, lip cancer and cutaneous lymphoma. A brief mention of the role of beta-blockers in melanoma progression has also been added.
10.23736/S0392-0488.18.05870-4
Adverse effects of antihypertensive drugs.
Husserl F E,Messerli F H
Drugs
Early essential hypertension is asymptomatic and should remain so throughout treatment. In view of the increasing number of available antihypertensive agents, clinicians need to become familiar with the potential side effects of these drugs. By placing more emphasis on non-pharmacological treatment (sodium restriction, weight loss, exercise) and thoroughly evaluating each case in particular, the pharmacological regimen can be optimally tailored to the patient's needs. Potential side effects should be predicted and can often be avoided; if they become clinically significant they should be rapidly recognised and corrected. These side effects can be easily remembered in most instances, as they fall into 3 broad categories: (a) those caused by an exaggerated therapeutic effect; (b) those due to a non-therapeutic pharmacological effect; and (c) those caused by a non-therapeutic, non-pharmacological effect probably representing idiosyncratic reactions. This review focuses mainly on adverse effects of the second and third kind. Each group of drugs in general shares the common side effects of the first two categories, while each individual drug has its own idiosyncratic side effects.
10.2165/00003495-198122030-00002
Pharmacological Research Progress of Novel Antihypertensive Drugs.
Discovery medicine
Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely β-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.
10.24976/Discov.Med.202436184.83
Adverse reactions to antihypertensive therapy.
Aellig W H
Cardiovascular drugs and therapy
A large number of antihypertensive agents are available today. They belong to different drug classes and permit the treating physician to choose the drug he deems best suited for the treatment of an individual patient. Because hypertension is usually asymptomatic yet requires long-term therapy, consideration of potential undesirable effects of drugs used for its treatment is important for making the appropriate choice. In this context, a precise understanding of the typical adverse reaction profiles of the different drugs is essential. This article provides a short review of the adverse reaction profiles of the main classes of antihypertensive drugs and refers to topics such as the recent controversy regarding calcium channel blockers and comparative investigations between different antihypertensive agents. Furthermore, the effects of antihypertensives on metabolic parameters, differences between their effects in subgroups of patients and in patients with different concomitant diseases, and the potential of antihypertensives for interactions with other drugs are briefly discussed. Even with a good knowledge of all of these aspects, however, no fixed plan for drug treatment of hypertension suitable for every patient can be established. A high percentage of adverse drug reactions can, however, be avoided by appropriate drug selection and dosage, carried out after careful consideration of the known adverse reaction profiles as well as the known spectrum of pharmacological actions of the different compounds. Low doses are often effective and well tolerated. Instead of increasing the dose, it is usually preferable to add a low dose of a second agent with a different mode of action if one drug given alone does not sufficiently lower blood pressure. This procedure avoids many adverse drug reactions attributable to an exaggerated pharmacological response, and, if chosen carefully, this combination may also reduce counterregulatory reactions secondary to the fall in blood pressure.
Adverse reactions and interactions limiting the use of antihypertensive drugs.
Nies A S
The American journal of medicine
One major problem in the management of hypertensive patients is their lack of compliance with therapeutic regimens. Some of the problem with compliance is due to side effects of the drugs being used. Additionally, drug resistance may be related to interactions of antihypertensive drugs with other prescription and nonprescription drugs. By classifying drugs into common modes of action, common side effects can be predicted. However, each drug has its own spectrum of other side effects which can be dose-limiting. Most of the side effects are extensions of the pharmacologic actions of these drugs, and only relatively rarely is an allergic reaction a problem. Drug interactions can be important in explaining some side effects or drug resistance. A knowledge of the pharmacology of the antihypertensive drugs allows the physician to predict, in many cases, the possibility of an interaction and, indeed, can allow the use of interactions to advantage as with combinations of vasodilators and beta adrenergic blocking drugs. Until such time as the perfect antihypertensive drug is discovered, most patients can be managed satisfactorily with minimal side effects by judicious combination of available drugs and avoiding drugs which interact to cause more side effects or decrease the antihypertensive effects.
10.1016/0002-9343(75)90122-9