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Beta-Blockers: Current State of Knowledge and Perspectives
Abstract
It has been over half a century since propranolol, the first beta-blocker, was developed for medical treatment. Since that time a large number of compounds from this group have been synthesised and many are now in clinical use. The structure, function, pharmacokinetics, and mechanism of beta-blockers have been established. The possibilities for their use in treating different conditions continue to evolve. Since the discovery of later generation beta-blockers, such as carvedilol and nebivolol, the search for new compounds continues, and may include known substances with beta-blocking properties which could extend their therapeutic potential.
... Propranolol was used for treatment firstly in the 1960s. 1 After the serendipitous finding that propranolol accelerated the healing of IHs by the French team, 2,3 more researches proved the efficacy and propranolol is now recognized as the first-line medication for IHs. 4 In the beginning, oral propranolol starts from 1 mg/kg/day to 2-3 mg/kg/day for at least 6-12 months. 4 For further examination, 1.5-2.0 ...
... Catecholamine works through the forming of a hydrogen bond between the hydroxyl group and the receptors. 1 However, propranolol is lack of hydroxyl group, unable to activate the receptors and hold the relative β-adrenergic activity. Propranolol also possess a membrane stabilizing quality by blocking the sodium and calcium channels. ...
... Propranolol also possess a membrane stabilizing quality by blocking the sodium and calcium channels. 1 But the phenomenon only happens in the extremely high dose, and has no clinical meanings. ...
Propranolol, as the first generation of β-blocker family, was initially introduced in the clinical application for tachycardia and hypertension in the 1960s. However, the occasional discovery of propranolol in the involution of infantile hemangiomas (IHs) brought us a new perspective. IHs are the most common infantile tumor, affecting 4–10% newborns. So far, oral propranolol is the first-line medication for IHs treatment. At the same time, local injection and topical propranolol are developing. Despite the worldwide application, the precise mechanism of propranolol of IHs has not been completely studied. In this article, we reviewed and summarized the current information on pharmacology, mechanism, efficacy, and adverse effects of propranolol. Novel design of biomaterials and bioactive molecules are needed for new treatment and ideal pathway to attain the minimal effective treatment concentration and eliminate the adverse effects.
... Although CVD drugs have, for the most part, been tested in clinical trials that were underpowered for sex-specific analyses, experience in using these drugs to treat chronic conditions indicates sex differences (Table 6). 78,[105][106][107][108][109][110][111][112][113][114][115][116] Interventional, Surgical, and Device Therapy ...
... • Despite the beneficial effect of b blockers on cardiac workload and myocardial oxygen demand, 110 women are less likely to receive treatment with b blockers than men. 111,112 • b Blockers are among list of first-line antihypertensive monotherapies for use during pregnancy. ...
... Beta blokerler, hipertansiyon, konjestif kalp yetersizliği, kardiyak aritmiler ve angina pektoris gibi kardiyovasküler hastalıkların tedavisinde önemli bir yer tutarlar. [1][2][3] Beta blokerler genel olarak 3 gruba ayrılırlar. İlk grup, klasik beta blokerler olarak adlandırılan birinci nesil non-selektif ilaçlardır (propranolol, sotalol). ...
... Bu ilaçlar kalpte β-AR'lerin etkinliğini azalttıkları veya bloke ettikleri için, inhibitör etki (negatif inotrop, negatif kronotrop, negatif dromotrop etki) meydana getirirler. [1] Beta blokerlerin farmakolojik özellikleri Beta blokerlerin temel farmakolojik özellikleri arasında, selektiflik (seçicilik), intrinsik sempatomimetik etkinlik (İSE), ters agonizma, lipofilikliğin derecesi ve buna bağlı farmakokinetik farklar, membran stabilizasyonu ve melez (hibrid) etkinlik bulunmaktadır. [13] 1. Selektiflik (seçicilik) Tedavide kullanılan beta blokerlerin çoğu, β1 ve β2 AR'lere karşı aynı derecede yüksek affinite gösterirler ve bunların her ikisini de aynı derecede bloke ederler; bunlara "selektif-olmayan"(non-selektif) ilaçlar adı verilmektedir. ...
... Introduction β blockers are commonly used in the clinical therapy of cardiovascular diseases, such as hypertension, heart failure, coronary heart disease, arrhythmia, etc. [1,2]. Metoprolol is a selective β blocker that can lower blood pressure and reduce decreased sinus rhythm, which makes it widely used in the treatment of hypertension, angina pectoris, myocardial infarction, aortic dissection, arrhythmia, and relieve the symptoms like palpitations and tachycardia [3,4]. ...
... Phenylboronic acid 17 is known to exhibit a similar acidity as the corresponding hemiketals providing a promis-ing starting point for pursuing this ring-opening attempt [41]. We hypothesized that this approach would allow the synthesis of 3-amino-1,2-diols, a motif commonly found in pharmaceuticals such as, e.g., β-blockers [42]. Our envisioned one-pot protocol features protonation of the azetidine from boronic monoester (18 → 19) followed by ring opening, in accordance to the hemiketal reactions. ...
α-Aminoacetophenones are identified as promising building blocks for the synthesis of highly substituted dioxolanes. The presented strategy is founded on the build and release of molecular strain and achieves a formal transposition of a methyl group. During light irradiation, 3-phenylazetidinols are forged as reaction intermediates, which readily undergo ring opening upon the addition of electron-deficient ketones or boronic acids. Key to the successful development of this two-step process is the identification of a benzhydryl-protecting group, which orchestrates the photochemical Norrish–Yang cyclization and facilitates the subsequent ring opening.
... Other systemic treatments have been used for treatment of CSC without consistent data present in literature. Betablockers decrease heart rate and contractility by blocking beta-adrenergic receptors, reducing cardiac output and lowering blood pressure, thus alleviating cardiac stress and workload [116]. Several studies have demonstrated that oral betablockers, Nadolol or Metoprolol, exhibit inconsistent efficacy in the treatment of chronic or acute CSC when compared to placebo [117,118]. ...
... A similar outcome was noted for microscopic infarcts, observed in 37% of subjects in the ninth decade compared to 20% observed in the seventh decade. Since 1960, subjects with high blood pressure have been treated with various medications, including β-blockers, and hypertension is one of the strongest modifiable cardiovascular risk factors [45,46]. In a country like Sweden with a governmental healthcare system, a large proportion of subjects with cardiovascular diseases have been treated. ...
Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to the morgue of Uppsala University Hospital during a 15-year-long period. Among the 1630 subjects, 1610 were ≥41 years of age (range 41 to 102 years). Overall, hyperphosphorylated (HP) τ was observed in the brains of 98% of the 1610 subjects, and amyloid β-protein (Aβ) in the brains of 64%. The most common alteration observed was Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) in 26% of the subjects. In 16% of the subjects, HPτ was limited to the locus coeruleus. In 14 subjects (<1%), no altered proteins were observed. In 3 subjects, only Aβ was observed, and in 17, HPτ was observed in a distribution other than that seen in ADNC/PART. The transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant age-related TDP encephalopathy (LATE) was observed in 565 (35%) subjects and α-synuclein (αS) pathology, i.e., Lewy body disease (LBD) or multi system atrophy (MSA) was observed in the brains of 21% of the subjects. A total of 39% of subjects with ADNC, 59% of subjects with PART, and 81% of subjects with HPτ limited to the locus coeruleus lacked concomitant pathologies, i.e., LATE-NC or LBD-NC. Of the 293 (18% of the 1610 subjects) subjects with dementia, 81% exhibited a high or intermediate level of ADNC. In 84% of all individuals with dementia, various degrees of concomitant alterations were observed; i.e., MIXED-NC was a common cause of dementia. A high or intermediate level of PART was observed in 10 subjects with dementia (3%), i.e., tangle-predominant dementia. No subjects exhibited only vascular NC (VNC), but in 17 subjects, severe VNC might have contributed to cognitive decline. Age-related tau astrogliopathy (ARTAG) was observed in 37% of the 1610 subjects and in 53% of those with dementia.
... Propranolol, a non-selective β-blocker [10], was selected as a historical interest compound in the β-blocker class. The selective action of second-generation β1-blockers is directed towards β1 receptors located in the heart [11]. With a strong affinity for the β1-adrenergic receptor, atenolol is one of the medications from the latter group that is still frequently used in pharmacotherapy today [12,13]. ...
4-Nitro and 7-nitro propranolol have been recently synthesized and characterized by us. (±)-4-NO2-propranolol has been shown to act as a selective antagonist of 6-nitrodopamine (6-ND) receptors in the right atrium of rats. As part of our follow-up to this study, herein, we describe the first synthesis of (±)-3-nitroatenolol as a probe to evaluate the potential nitration of atenolol by endothelium. Chiral chromatography was used to produce pure enantiomers. By using Riguera’s method, which is based on the sign distribution of ΔδH, the absolute configuration of the secondary alcohol was determined.
... Moreover, the majority of studies have focused on naMD, and not on Ga and early aMD. according to their selectivity for β-ar, the BBs used in clinical practice are divided into two main categories: Selective and non-selective BBs (20). the majority of research focuses on non-selective BBs. the association between the development of aMD and the use of selective BBs has not been reported to date, at least to the best of our knowledge. ...
Although age-related macular degeneration (AMD) is the leading cause of legal blindness, the treatment methods for AMD are limited. The aim of the present study was to examine the association between oral β-blockers (BBs) and the risk of developing AMD among hypertensive patients. For this purpose, a total of 3,311 hypertensive patients from the National Health and Nutrition Examination Survey were included in the study. The use of BBs and treatment duration data were collected using a self-reported questionnaire. AMD was diagnosed by gradable retinal images. Multivariate-adjusted survey-weighted univariate logistic regression was used to confirm the association between the use of BBs and the risk of developing AMD. The results revealed that the use of BBs exerted a beneficial effect (odds ratio (OR), 0.34; 95% confidence interval (95% CI, 0.13-0.92; P=0.04) in late-stage AMD in the multivariate adjusted model. When the BBs were classified into non-selective BBs and selective BBs, the protective effect in late-stage AMD was still observed in the non-selective BBs (OR, 0.20; 95% CI, 0.07-0.61; P<0.001). After accounting for treatment duration, long-term treatment with BBs (>6 years) was also found to reduce the risk of late-stage AMD (OR, 0.13; 95% CI, 0.03-0.63; P=0.01). In late-stage AMD, the long-term use of BBs was beneficial for geographic atrophy (OR, 0.07; 95% CI, 0.02-0.28; P<0.001). On the whole, the present study demonstrates that the use of non-selective BBs exerted a beneficial effect against the risk of late-stage AMD among hypertensive patients. Long-term treatment with BBs was also associated with lower risk of developing AMD. These findings may provide novel strategies for the management and treatment of AMD.
... Blocking the release of adrenaline reduces the oxygen demands and lessens stress on the heart, which will dilate the blood vessels, easing the flow of blood. (Ogrodowczyk et al., 2016). Nitrates allow blood to flow more easily, thus exerting their anti-ischemic effect. ...
Background
The field of network pharmacology showed significant development. The concept of network pharmacology has many similarities to the philosophy of traditional Chinese medicine (TCM), making it suitable to understand the action mechanisms of TCM in treating complex diseases, such as ischemic heart diseases (IHDs).
Purpose
This review summarizes the representative applications of network pharmacology in deciphering the mechanism underlying the treatment of IHDs with TCM.
Methods
In this report, we used “ischemic heart disease” OR “coronary heart disease” OR “coronary artery disease” OR “myocardial ischemia” AND (“network pharmacology” OR “systematic pharmacology”) as keywords to search for publications from PubMed, the Web of Science, and Google Scholar databases and then analyzed the representative research reports that summarized and validated the active components and targets network of TCM in improving IHDs to show the advantages and deficiencies of network pharmacology applied in TCM research.
Results
The network pharmacology research indicated that HGF, PGF, MMP3, INSR, PI3K, MAPK1, SRC, VEGF, VEGFR-1, NO, eNOS, NO3, IL-6, TNF-α, and more are the main targets of TCM. Apigenin, 25S-macrostemonoside P, ginsenosides Re, Rb3, Rg3, SheXiang XinTongNing, colchicine, dried ginger-aconite decoction, Suxiao Xintong dropping pills, Ginseng-Danshen drug pair and Shenlian and more are the active ingredients, extracts, and formulations of TCM to ameliorate IHDs. These active compounds, extract, and formulations of TCM treat IHDs by delaying ventricular remodeling, reducing myocardial fibrosis, decreasing reactive oxygen species, regulating myocardial energy metabolism, ameliorating inflammation, mitigating apoptosis, and many other aspects.
Conclusions
The network pharmacology supplies a novel research exemplification for understanding the treatment of IHDs with TCM. However, the application of network pharmacology in TCM studies is still at a superficial level. By rational combining artificial intelligence technology and network pharmacology, molecular biology, metabolomics, and other advanced theories and technologies, and systematically studying the metabolic process and the network among products, targets, and pathways of TCM from the clinical perspective may be a potential development trend in network pharmacology.
... Beta-blockers are antagonists of β-adrenergic receptors (ARs), which play an important role in the regulation of physiological processes such as blood pressure, heart rate, and airway strength or reactivity, as well as metabolic and central nervous system functions [13]. The mechanism of the hypotensive action of beta-blockers is complex and may be the result of a reduction in the frequency of heart contractions and a decrease in cardiac output capacity, inhibition of renin secretion, increased baroreceptor reactivity, and blocking of β 2 receptors in the presynaptic part of the sympathetic nervous system [14]. Tachycardia, hypertension, myocardial infarction, congestive heart failure, cardiac arrhythmias, coronary artery disease, hyperthyroidism, essential tremor, aortic dissection, portal hypertension, glaucoma, migraine prophylaxis, and other illnesses have all been approved by the FDA for treatment by β-blockers. ...
Multiple illness is an increasingly common phenomenon. Its consequence is the need for polytherapy, which is particularly common among people suffering from arterial hypertension. The development of combined preparations (containing at least two API-active pharmaceutical ingredients) dedicated to the treatment of hypertension is a response to increased compliance, especially in elderly patients. In our work, we describe in particular the possibilities of using β-adrenergic receptors blockers and angiotensin-converting enzyme inhibitors in combinations. The combinations of APIs are used as single pills in patients with arterial hypertension with concomitant diseases such as hyperlipidemia; blood coagulation problems and diabetes mellitus were also discussed successively. Pharmacoeconomic analysis for the API combinations shown is also presented. As a final conclusion, numerous benefits of using the combined preparations should be indicated, especially by the elderly and/or in patients with coexistence of other diseases.
... ). Karvedilol'ün hem insanda hem de hayvanlardaki kardiyovasküler yararlarının, geleneksel βblokerden daha fazla olduğu gösterilmiştir. Çeşitli toksinlerle yapılan birçok in vivo ve in vitro çalışmada, Karvedilol'ün kalp koruyucu, böbrek koruyucu ve karaciğer koruyucu etkilerinin olduğu ve bu etkilerinin β-adrenerjik bloker özelliğinden kaynaklandığı gösterilmiştir(18).Akbaş ve ark. yapmış olduğu bir çalışmada arka ekstremite I/R modelinde Karvedilol'ün GSH-Px ve SOD aktivitelerinde önemli fark yarattığını göstermiştir(26). ...
İskemi, doku ve organların arteryel veya venöz kan akımının azalması nedeniyle yetersiz kanlanmasıdır. Sonuçta hücre enerji depolarının boşalması ve toksik maddelerin birikimiyle hücre ve dokuda hasar veya ölüm gerçekleşir. İskemi sonucunda dokularda hipoksi oluşur ve hipoksik doku hasarı ortaya çıkar. Reperfüzyona sekonder oluşan doku hasarında, hücrenin içine oksijen girmesiyle meydana gelen Serbest Oksijen Radikal (SOR) türevleriyle birlikte pekçok mekanizma rol oynamaktadır. Reperfüzyon etkisine en hassas olan hücresel yapılar; membranda bulunan lipitler, proteinler, nükleik asit ve Deoksiribonükleik Asit gibi moleküllerdir. Karvedilol, vazodilatatör etkili üçüncü kuşak β bloker antihipertansif bir ilaçtır ve genellikle kardiovasküler hastalıklarda tedavi amacıyla kullanılır. Bir β-reseptör antagonisti olarak, miligram başına Propanolol’den 2-4 kat daha güçlüdür. Arteryal hipertansiyon ve kalp yetmezliği tedavisi için geliştirilmiştir ve her iki endikasyon için de FDA (Amerikan Gıda ve İlaç Dairesi başkanlığı) onayı alınmıştır. Bugüne kadar Karvedilol farklı deneysel modellerde antioksidan özelliğinden dolayı birçok çalışmalarda kullanılmış fakat testis iskemi reperfüzyonunda kullanılmamıştır. Biz de Karvedilol’ün Testis İskemi Reperfüzyon hasarı modelinde koruyucu etkilerini değerlendirmek amacıyla böyle bir çalışma yapmayı planladık. Bu çalışmada toplam 28 erkek rat kullanıldı. Ratlar 7’ şer hayvandan oluşan dört eşit gruba ayrıldı. Gruplar; kontrol, iskemi reperfüzyon, Karvedilol ve Karvedilol sonrası iskemi reperfüzyon grubu olarak ayrıldı. Kontrol grubundaki ratlara herhangi bir cerrahi müdahale yapılmadı. Karvedilol grubundaki ratlara 30 mg/ kg i.p. Karvedilol uygulandı, 24 saat sonra ratlar sakrifiye edildi. İskemi reperfüzyon grubundaki ratların testislerine 30 dakika iskemi ve sonrasında 30 dakika reperfüzyon uygulandı, sonra ratlar sakrifiye edildi. Karvedilol+ Testis İskemi Reperfüzyon grubuna ise, önce 30 mg/ kg i.p. Karvedilol verildi. 24 saat sonra 30’ar dakika testis I/R uygulandıktan sonra, ratlar sakrifiye edildi. Tüm gruplardan alınan spesmenler histopatolojik incelemer amacıyla H&E boyama ile boyandı. İmmunohistokimyasal değerlendirme için ise TNF- α ile boyandı. H&E boyamada, kontrol ve Karvedilol grubuna ait testis dokularının transversal kesitinlerinin normal görünümde olduğu tespit edildi. İ/R grubunda ise seminifer tübüllerin yapısal bütünlüğünde bozulmalar ve bazal membranda yer yer kırılmalar olduğu, sertoli hücrelerinde dejenerasyon ve piknozisler olduğu görüldü. Ayrıca inflamatuar hücre infiltrasyonuna ek olarak spermatidlerde pozitif TNF-α ekspresyonları izlendi. Karvedilol sonrası iskemi reperfüzyon grubunda ise, İ/R grubuyla kıyaslandığında seminifer tubül yapısında ve bazal membranların yapısında kısmen iyileşmeler görüldü. İmmünhistokimyasal boyamalarda ise, carvedilol+ İ/Rgrubunda, İ/R grubuna oranla kısmen negatif TNF-α ekspersiyonu izlendi. Sonuç olarak yapmış olduğumuz çalışmada güçlü bir antioksidan olan Karvedilol’un testis iskemi reperfüzyonuna karşı kısmen koruyucu olduğu bu konuda yapılacak çalışmaların daha geniş kapsamlı araştırılması gerektiği kanaatine vardık.
... Введение Возможность применения бета-адреноблокаторов (БАБ) в качестве антигипертензивных средств впервые была описана B.N. Prichard и P.M. Gillam более 50 лет назад [1]. Первые сообщения о терапевтическом применении пропранолола для лечения артериальной гипертензии (АГ) были опубликованы в 1964 г. [2,3]. На сегодняшний день 13 представителей группы БАБ могут быть использованы для перорального применения у пациентов с АГ [4]. ...
More than 50 years after Propranolol was introduced to the pharmaceutical market as a drug that can lower the heart rate, beta-blockers (BAB) are still widely used in the pharmacotherapy of cardiovascular diseases. However, the use of BAB has a number of limitations, first of all, due to adverse drug events (AE) that develop during their use. The purpose of our review was to study the features of the BAB AE manifested by injuries of the skin and its appendages. The clinical manifestations of them are the development or exacerbation of psoriasis, lichen planus, contact dermatitis, acrocyanosis, Raynaud's disease, alopecia, hyperhidrosis, vitiligo, anaphylaxis, and allergic skin reactions. True medicinal psoriasis occurs in patients taking BAB with no family or previous history and most often mimics erythrodermic psoriasis and palmar-plantar pustular psoriasis. Systemic use of BAB can also be accompanied by exacerbation of vitiligo. In patients with segmental vitiligo, the results of Doppler flowmetry and iontophoresis showed increased blood flow in vitiligo foci compared with normal skin. The development of anaphylactic reactions against the background of BAB therapy may be due to the modulation of adenylate cyclase, which can affect the release of anaphylactogenic mediators, as well as a decrease in the severity of cardiovascular compensatory changes. The peculiarities of the development of such reactions may be the resistance of patients to traditional treatment, which is due to the development of paradoxical reflex vagotonic effects when using adrenaline. Some of the mentioned AE may pose a potential threat to the life and health of the patient and therefore require additional discussion.
... Beta-blocker selectively binds to beta-adrenergic receptors, so as to antagonize the activation of beta receptor by neurotransmitter and catecholamine (Ogrodowczyk et al., 2016). A number of clinical trials assessed in the previous meta-analysis showed beneficial results for beta-blocker usage in the patients with sepsis (Lee et al., 2019). ...
This meta-analysis is to systematically evaluate the efficacy and safety of beta-blockers in the treatment of sepsis. A total of 17 articles that met the inclusion criteria were included, and 10,385 cases were obtained. The meta-analysis results showed that patients with sepsis with beta-blocker usage had a significantly lower 28-day mortality. The heart rate decreased over time in patients with sepsis using beta-blocker. Moreover, central venous blood oxygen saturation increased after 24, 48, 72 hours of treatment; lactic acid and cardiac troponin I decreased after 48, 72 hours of treatment; and tumor necrosis factor-α, interleukin-1β levels decreased significantly after 12, 24, 48, 72 hours of treatment (p<0.05). In conclusion, beta-blockers reduce 28-day mortality and heart rate.
... With this case, we want to present our experience regarding the feasibility of ECMO support in a patient suffering from cardiogenic shock after severe mix intoxication consisting of cardio-depressant drugs. Beta blockers, one very important group of cardio-depressant drugs, exert their effect through competitive blockade of beta-adrenoreceptors [11]. Furthermore, calcium antagonists and ace inhibitors are important substances for the management of arterial hypertension [12], either acting on the renin angiotensin aldosterone system in the course of ACE inhibitors [13], or on calcium channels that can be found on vascular smooth muscle cells [14] in the course of dihydropyridine calcium channel antagonists. ...
... Adrenoceptor blockers can be divided into non-selective blockers for β1 and β2 receptors and β1-selective blockers, which have higher selective affinity for β1 receptors than for β2 receptors (114). The latter mainly slow down HR and decrease myocardial contractility when the sympathetic nervous system is activated but have a relatively small effect on the heart at rest (115). ...
Postural tachycardia syndrome (POTS), characterized by chronic (≥6 months) orthostatic intolerance symptoms with a sustained and excessive heart rate increase while standing without postural hypotension, is common in children and adolescents. Despite the unclear pathogenesis of POTS, the present opinion is that POTS is a heterogeneous and multifactorial disorder that includes altered central blood volume, abnormal autonomic reflexes, “hyperadrenergic” status, damaged skeletal muscle pump activity, abnormal local vascular tension and vasoactive factor release, mast cell activation, iron insufficiency, and autoimmune dysfunction. A number of pediatric POTS patients are affected by more than one of these pathophysiological mechanisms. Therefore, individualized treatment strategies are initiated in the management of POTS, including basal non-pharmacological approaches (e.g., health education, the avoidance of triggers, exercise, or supplementation with water and salt) and special pharmacological therapies (e.g., oral rehydration salts, midodrine hydrochloride, and metoprolol). As such, the recent progress in the pathogenesis, management strategies, and therapeutic response predictors of pediatric POTS are reviewed here.
... Beta-blockers are categorized as selective β 1 blockers, selective β 2 blockers, and non-selective blockers on the basis of their receptor binding capacity [18,19]. When adrenaline is administered to patients taking non-selective beta-blockers, the vasodilative effect due to stimulation of the beta receptors is not expressed, and abnormal elevation of blood pressure may occur due to vasoconstriction as a result of alpha receptor stimulation. ...
Administration of local anesthetics with adrenaline can cause tachycardia and hypertension. This study assessed whether combined administration of landiolol with adrenaline and lidocaine would induce local anesthesia without causing hemodynamic changes. Normal saline (NS), lidocaine with adrenaline (LA), and lidocaine with adrenaline and landiolol (LLA) were injected into Wistar Kyoto (WKY/Izm) or spontaneously hypertensive (SHR/Izm) rats, followed by measurement of the pulse rate (PR), and the systolic, diastolic and mean blood pressures (SBP, DBP and MBP). In the LLA group, the increase in PR was significantly suppressed in both SHR/Izm and WKY/Izm rats relative to those in the LA group. Although SBP was significantly reduced in WKY/Izm rats given LLA, relative to those given NS or LA, it was elevated in SHR/Izm rats given LLA. Landiolol-induced changes in PR may be due to blockade of adrenaline-induced β1 receptor stimulation, which suppresses cardiac hyperactivity, whereas the early surge of blood pressure in SHR/Izm rats given LLA may be due to the dominant alpha-adrenergic effects of β1 receptor inhibition. The anti-adrenergic effects of LLA were safe and effective in WKY/Izm rats, although the unexpected early hypertensive surge in SHR/Izm rats indicates the need for caution.
... A meta-analysis of 23 studies showed that the mean decrease in headache days per month was −0.94 days (CI, −1.4 to −0.46) with metoprolol and −1.3 days (CI, −2 to −0.62) with propranolol (Jackson 2015). The mechanism of β-blockers in migraine is unclear but likely involves inhibition of arterial vasodilation and blocking post-synaptic serotonin synthesis (Ogrodowczyk 2016). pathophysiology of episodic and chronic migraine may differ (Aurora 2006). ...
To effectively care for patients who are at risk of opioid-related mortality and morbidity, clinical pharmacists must consider the following:
• People who inject opioids are at extremely high risk of mortality and morbidity, and identification of their use should result in expanded care delivery rather than punitive
action.
• Supply reduction interventions that decrease the availability of prescription opioids for misuse result in increased use of more dangerous illegal substances; thus, they should be paired with harm reduction interventions to maximize public health benefit.
• Opioid intoxication may lead to fatal poisoning by inducing severe respiratory depression and hypoxia. Risk of overdose increases over time and with escalating doses.
• Naloxone is a potent opioid antagonist that can rapidly reverse opioid-induced respiratory depression. Many formulations of naloxone are available for layperson administration. None of these formulations has been proven more effective than another.
• The evidence base supporting expanded access to naloxone through pharmacies, primary care clinics, hospitals, and community organizations is substantial. Pharmacists can play a key role in overdose prevention across all of these settings.
• Syringe services programs are endorsed by the CDC for prevention of injection-related infections and associated morbidity, however they remain illegal in 15 states. Effective pharmacy-based syringe access can fill this gap.
• Fentanyl cannot cause an overdose through passive exposure, and it is not resistant to naloxone. However, it is extremely potent and increasingly found in the illegal drug supply. Fentanyl test strips can help patients identify it and modify their drug use behaviors.
• Typical naloxone doses can effectively reverse the effects of fentanyl and fentanyl analogs. However, naloxone may need to be administered more quickly in the case of a fentanyl overdose, given the rapid onset of effect.
... Plasma half-life of propranolol is 3-6 h. [11,12] A long-acting preparation of propranolol has also been developed with a half-life of [8][9][10][11] h. This sustained-release preparation provides the advantage of once-daily dose with similar efficacy and better patient compliance. ...
Propranolol is a beta-adrenergic receptor antagonist that was developed by the British scientist Sir James Black primarily for the treatment of angina pectoris, more than 50 years ago. It was not long before several other cardiovascular as well as noncardiovascular therapeutic uses of propranolol were discovered. Propranolol soon became a powerful tool for physicians in the treatment of numerous conditions such as hypertension, cardiac arrhythmias, myocardial infarction, migraine, portal hypertension, anxiety, essential tremors, hyperthyroidism, and pheochromocytoma. Owing to its action at multiple receptor sites, propranolol exerts several central and peripheral effects and is therefore useful in various conditions. Right from reduction in postmyocardial mortality to control of anxiety in performers, propranolol plays an important role in a plethora of medical conditions. Interestingly, even today, newer indications of this age-old drug are being discovered. Moreover, propranolol treatment has been found to be cost-effective when compared to other corresponding treatment options for individual indications. In this article, we attempt to recount the journey of propranolol right from its inception to the present day.
... CVL blocks sympathetic neural activation via antagonism of β1-, β2-, and α1-adrenoreceptors and has shown greater cardiovascular benefits than traditional β-blockers in both humans and animals. Several in vivo and in vitro studies have demonstrated the cardioprotective, nephroprotective and hepatoprotective effects of CVL against various toxicant-induced preclinical models, and these effects are independent of its β-adrenergic blocking properties (1). Versatile anti-inflammatory effects of CVL were observed in both in vitro and in vivo studies. ...
The NLRP3 inflammasome is a multiprotein complex that plays a key role in the innate immune system, and aberrant activation of this complex is involved in the pathogenesis of inflammatory diseases. Carvedilol (CVL) is an α-, β-blocker used to treat high blood pressure and congestive heart failure; however, some benefits beyond decreased blood pressure were observed clinically, suggesting the potential anti-inflammatory activity of CVL. In this report, the inhibitory potential of CVL toward the NLRP3 inflammasome and the possible underlying molecular mechanisms were studied. Our results showed that CVL attenuated NLRP3 inflammasome activation and pyroptosis in mouse macrophages, without affecting activation of the AIM2, NLRC4 and non-canonical inflammasomes. Mechanistic analysis revealed that CVL prevented lysosomal and mitochondrial damage and reduced ASC oligomerization. Additionally, CVL caused autophagic induction through a Sirt1-dependent pathway, which inhibited the NLRP3 inflammasome. In the in vivo mouse model of NLRP3-associated peritonitis, oral administration of CVL reduced (1) peritoneal recruitment of neutrophils; (2) the levels of IL-1β, IL-18, active caspase-1, ASC, IL-6, TNF-α, MCP-1, and CXCL1 in the lavage fluids; and (3) the levels of NLRP3 and HO-1 in the peritoneal cells. Our results indicated that CVL is a novel autophagy inducer that inhibits the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.
... To date the best example is provided by beta adrenergic receptors and the targeting by the beta-blockers. Beta-blockers, such as propranolol are antagonist of beta adrenergic receptors that therefore prevent the stimulatory activity of noradrenalin and other catecholamines; they are primarily used to treat cardiovascular disorders, migraine and anxiety (41). Interestingly, epidemiological studies have suggested that individuals undergoing treatment with beta-blockers have an improved survival in relation to prostate (15), breast (42) and ovarian (43) and cholinergic signaling and they should now be tested for their potential anti-tumor activities at nerve dependent cancers. ...
Recent breakthrough discoveries have highlighted the stimulatory role of nerves in cancer initiation and progression, through the release of neurotransmitters and growth factors by nerve terminals in the tumor microenvironment. Intriguingly, neuroproteins such as neuronal membrane proteins, synaptic proteins, neurotransmitters and neurotrophic growth factors as well as their corresponding receptors, to name only a few, are frequently found in proteomic analyses of cancer tissues external to the brain and central nervous system. While the usual explanation was that neuroproteins were actually not specific of the nervous system and were therefore also expressed in cancer cells, it now appears that the presence of neuroproteins in cancer is largely due to the infiltration of nerves in the tumor microenvironment. Given the newly identified function of nerves as promoters of cancer growth and metastasis, neuroproteins should be considered with great attention because they may actually represent innovative biomarkers and therapeutic targets in oncology.
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Purpose
This study aimed to investigate the prescription of beta‐blockers (β‐blockers) for patients with asthma.
Methods
In this retrospective cross‐sectional study using the National Patient Sample (NPS) of the Health Insurance Review and Assessment Service (HIRA) of South Korea, β‐blockers and asthma medications were investigated using generic name codes provided by HIRA. Concomitant administration was identified when a β‐blocker and an asthma medication were co‐prescribed in one billing statement or when separate β‐blocker and asthma prescriptions had overlapping dates of use.
Results
In the 1027 patients with asthma who were prescribed non‐selective β‐blockers (non‐SBs), 3087 non‐SB prescriptions were identified, of which 62.3% and 37.3% were for carvedilol and propranolol, respectively. Of the 906 patients with asthma prescribed selective β‐blockers (SBs), 2942 SB prescriptions were identified, of which 48.5%, 28.3%, and 20.3% were for bisoprolol, atenolol, and nebivolol, respectively. Overall, 2149 non‐SB and 2124 SB prescriptions with overlapping use dates with asthma medications were identified, which were prescribed to 726 and 657 patients, accounting for 70.7% and 72.5% of the patients receiving non‐SBs and SBs, respectively. β2‐agonists accounted for 39.9% of the concomitant asthma medications with overlapping dates of use with non‐SBs. Co‐prescribing of bronchodilators occurred at a rate of 38.7% and 45.1% for the 3087 non‐SB prescriptions and 2942 SB prescriptions, respectively.
Conclusions
Carvedilol and propranolol accounted for half of all β‐blockers prescribed to asthma patients. Prescribing β‐blockers to patients with asthma requires caution to prevent exacerbation of asthma and drug interactions between β‐blockers and co‐prescribed asthma medications.
Introduction:
Beta-blockers involve a group of drugs widely used nowadays. Propranolol was the first beta-blocker available in the market. It is the most prescribed first-generation betablocker and is commonly used. Beta-blocker allergy is extremely unusual. Only an isolated case of an urticaria reaction to propranolol has been published in 1975.
Case presentation:
We present a 44-year-old man. In 2016, he was treated with a daily dose of 5 mg of propranolol prescribed for a diagnosis of essential tremor. On the third day of medical treatment, he experienced an episode of generalized urticaria directly related to the administration of propranolol. He continued with his habitual treatment and he had no other urticaria episodes. A drug provocation test was carried out with gradually increasing doses of the culprit drug. Thirty minutes after a total cumulative dose of 5 mg, the patient had several hives on the chest, abdominal region and arms. Two weeks later, a new drug provocation test was performed to bisoprolol as an alternative beta-blocker, with good tolerance.
Conclusion:
We describe a new case of urticaria secondary to propranolol, presenting as an immediate hypersensitivity reaction. Bisoprolol has been succesfully proved to be a safe option. Bisoprolol is a second-generation beta-blocker, it is available and commercialized worldwide, which makes it a good alternative.
G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β1 and β2 adrenergic receptors (β1AR and β2AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β2AR over the β1AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β2AR, as well as a less stable binding pocket for constrained epinephrine in the β1AR. The differences in the amino acid sequence of the extracellular vestibule of the β1AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β2AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.
A detailed revision on natural and synthetic glycosylated quinolines, spanning the last 20 years, is presented. Exhaustive descriptions about the state of the art of the synthesis and relevant applications of these glyco‐heterocycles are provided. In addition, an account of the natural products containing this motif and their associated bioactivity data are also outlined. For the sake of consistency, quinolones are also covered as well as hybrid compounds, embodied with linkers between the heterocyclic ring and the carbohydrate fragment.
Chitosan is a valued excipient due to its biocompatibility properties and increasing solubility of poorly water-soluble drugs. The research presented in this paper concerns the preparation of binary combinations of chitosan (deacetylated chitin) with carvedilol (beta-blocker) to develop a formulation with a modified carvedilol release profile. As part of the research, six physical mixtures of chitosan with carvedilol were obtained and identified by spectral (PXRD, FT-IR, and Raman), thermal (DSC), and microscopic (SEM) methods. The next stage of the research estimated the profile changes and the dissolution rate for carvedilol in the obtained drug delivery systems; the reference sample was pure carvedilol. The studies were conducted at pH = 1.2 and 6.8, simulating the gastrointestinal tract conditions. Quantitative changes of carvedilol were determined using the developed isocratic UHPLC-DAD method. Established apparent permeability coefficients proved the changes in carvedilol’s permeability after introducing a drug delivery system through membranes simulating the gastrointestinal tract and skin walls. A bioadhesive potential of carvedilol–chitosan systems was confirmed using the in vitro model. The conducted research and the obtained results indicate a significant potential of using chitosan as an excipient in modern oral or epidermal drug delivery systems of carvedilol.
Despite a myriad of available pharmacotherapies for the treatment of type 2 diabetes (T2D), challenges still exist in achieving glycemic control. Several novel glucose-lowering strategies are currently under clinical investigation, highlighting the need for more robust treatments. Previously, we have shown that suppressing peroxisome proliferator-activated receptor gamma coactivator 1-alpha activity with a small molecule (SR18292, 16) can reduce glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Despite structural similarities in 16 to known β-blockers, detailed structure-activity relationship studies described herein have led to the identification of analogues lacking β-adrenergic activity that still maintain the ability to suppress glucagon-induced glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Hence, these compounds exert their biological effects in a mechanism that does not include adrenergic signaling. These probe molecules may lead to a new therapeutic approach to treat T2D either as a single agent or in combination therapy.
Many hospitals use β-blockers in adult patients, however, their use in children has not yet been determined. The objective: to collect data on the use of β-blockers in children in intensive care units (ICU). Methods: an anonymous survey containing 17 questions regarding the use of β-blockers was distributed through social networks, messengers and email. The answers were compared with published data. Results. 48 respondents provided their replies. The survey has shown that 66.7% of them use β-blockers in children while 33.3% do not. Differences in the use of β-blockers in general and pediatric ICUs are statistically insignificant. Most clinics (50%) use β-blockers in patients with congenital heart defects, followed by sepsis (18.5%). Esmolol (34.4%) is the first-line drug, followed by propranolol (31.3%). The doses ranges vary significantly (excluding esmolol). Basic monitoring and echocardiography (40.6%) are most often used to monitor the use of β-blockers. Conclusion: The survey results have shown that in Russia, the use of β-blockers in children in ICU is very limited. It is necessary to conduct big randomized, multicenter, placebo-controlled studies that will determine the effectiveness of β-blockers in children in various clinical conditions.
The family of GPCRs represents the most important class of pharmaceutical drug targets. In this chapter, we describe such receptors and pathways that are targets for well-known plant-derived drugs and toxins. These include adrenergic receptors, the muscarinic acetylcholine receptor (MAchR), adenosine receptors, cannabinoid receptors, dopamine- and serotonin (5HT) receptors/transporters and opiate receptors. They are targets for compounds such as cannabis, muscarine and atropine, caffeine, cocaine, morphine and hallucinogenic drugs, among others.
We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the β-adrenoreceptor antagonists (-)-(S)-carazolol (5) and (-)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.
Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.
Systematic literature review.
No significant increase in the number of patients requiring rescue oral corticosteroid for an exacerbation of asthma has been observed after initiation of β-blocker treatment. Patients with mild to moderate reactive airway disease, probably both asthma and chronic obstructive pulmonary disease, may have a limited fall in forced expiratory volume in 1 second (FEV1) following single-dose administration of β-blocker, whereas no change in FEV1 has been reported following long-term administration. In a murine model of asthma, long-term administration of β-blockers resulted in a decrease in airway hyperresponsiveness, suggesting an anti-inflammatory effect. In keeping with this, long-term administration of a nonselective β-blocker to steroid-naïve asthma patients has shown a dose-dependent improvement in airway hyperresponsiveness, and either an asymptomatic fall in FEV1 or no significant change in FEV1. Furthermore, available studies show that bronchoconstriction induced by inhaled methacholine is reversed by salbutamol in patients on regular therapy with a β-blocker. On the other hand, a recent placebo-controlled trial of propranolol and tiotropium bromide added to inhaled corticosteroids revealed no effect on airway hyperresponsiveness and a small, not statistically significant, fall in FEV1 in patients classified as having mild to moderate asthma.
The available, although limited, evidence suggests that a dose-escalating model of β-blocker therapy to patients with asthma is well tolerated, does not induce acute bronchoconstriction, and, not least, may have beneficial effects on airway inflammation and airway hyperresponsiveness in some patients with asthma. Further studies addressing the potential role of β-blocker therapy for asthma are clearly needed, but careful selection of the target population is warranted.
Objective:
β-adrenergic antagonists (β-blockers) are often used to attenuate the hyperadrenergic symptoms of Graves' disease (GD), including palpitation. Although β-blockers reduce the heart rate, cardiac output and oxygen consumption, no firm evidence exists regarding the effects of combined therapy with β-blockers and anti-thyroid drugs. The objective is to elucidate the effects of β-blockers on anti-thyroid drug therapy in GD.
Methods:
Patients newly diagnosed with mild GD were randomly assigned to receive methimazole with or without β-blockers in a prospective multi-center survey. The heart rate and thyroid function were measured and the quality of life was assessed using original and SF-36 questionnaires at 0 and 4 weeks.
Results:
A total of 28 patients were enrolled in the study. Fourteen patients (one man, 13 women) were randomly assigned to the group treated with β-blockers and 14 patients (one man, 13 women) were randomly assigned to the group not treated with β-blockers. Although no significant differences in the improvement of thyroid function were observed between the two groups, the heart rates improved more significantly in the group treated with β-blockers. Specific symptoms, such as easy fatigability and shortness of breath, also improved more significantly with the β-blocker treatment. In addition, 'physical functioning' assessed with the SF-36 questionnaires significantly improved only in the group treated with β-blockers.
Conclusion:
Although β-blockers may not reinforce the effects of anti-thyroid drugs on thyroid function, at least during the course of one month, they are effective in reducing heart rates and ameliorating specific symptoms in patients with mild GD.
Sir James Black developed β-blockers, one of the most useful groups of drugs in use today. Not only are they being used for their original purpose to treat angina and cardiac arrhythmias, but they are also effective therapeutics for hypertension, cardiac failure, glaucoma, migraine and anxiety. Recent studies suggest that they might also prove useful in diseases as diverse as osteoporosis, cancer and malaria. They have also provided some of the most useful tools for pharmacological research that have underpinned the development of concepts such as receptor subtype selectivity, agonism and inverse agonism, and ligand-directed signalling bias. This article examines how β-blockers have evolved and indicates how they might be used in the future.
Glaucoma is a preventable cause of blindness if timely effective and successful treatment is provided. Patient adherence to the medication is a constant challenge that is now recognized as an essential component to treatment. Several studies have demonstrated that patients are more likely to be adherent to their medication if they understand the disease and the rationale for treatment and if their treatment regimen is simplified. Additionally, using eye drops has its own set of challenges that must be recognized and addressed at the clinical level. Although numerous socioeconomic factors are associated with poor adherence, these factors must be addressed at the societal level. Maximizing patient adherence to medication has the potential to reduce the number of surgical interventions required to treat glaucoma, prevent unnecessary vision loss, and save the overall healthcare system money in the long run.
The synthesis of (2R,S)-1-(6-methoxy-4-(methoxymethyl)-1H-indol-5-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and (2R,S)-1-(4-methoxy-6-(methoxymethyl)-1H-indol-5-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol is described. The compounds were tested for electrographic, antiarrhythmic, hypotensive, and spasmolytic activity, as well as for alpha(1)-, alpha(2)- and beta(1)-adrenoceptor binding affinity.
Purpose
Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response.
Patients and Methods
Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m ² every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers.
Results
Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03).
Conclusion
Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.
The synthesis of (2RS)-1-(5-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and (2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and its enantiomers, analogs of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol ((RS)-9) is described. Compounds were tested for electrographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for alpha(1)-, alpha(2)- and beta(1)-adrenoceptors binding affinities. The antagonist potency of the new compounds was compared with carvedilol and (RS)-9.
The occurrence of migraine in women is influenced by hormonal changes throughout the lifecycle. A beneficial effect of pregnancy on migraine, mainly during the last 2 trimesters, has been observed in 55 to 90% of women who are pregnant, irrespective of the type of migraine. A higher percentage of women with menstrual migraine find that their condition improves when they are pregnant. However, in rare cases migraine may appear for the first time during pregnancy.
The positive effects of pregnancy on migraine and the possible worsening post partum are probably related to the uniformly high and stable estrogen levels during pregnancy and the rapid fall-off thereafter.
Nondrug therapies (relaxation, sleep, massage, ice packs, biofeedback) should be tried first to treat migraine in women who are pregnant.
For treatment of acute migraine attacks 1000mg of paracetamol (acetaminophen) preferably as a suppository is considered the first choice drug treatment. The risks associated with use of aspirin (acetylsalicylic acid) and ibuprofen are considered to be small when the agents are taken episodically and if they are avoided during the last trimester of pregnancy.
The ‘triptans’ (sumatriptan, zolmitriptan, naratriptan), dihydroergotamine and ergotamine tartrate are contraindicated in women who are pregnant. Prochlorperazine for treatment of nausea is unlikely to be harmful during pregnancy. Metoclopramide is probably acceptable to use during the second and third trimester.
Prophylactic treatment is rarely indicated and the only agents that can be given during pregnancy are the β-blockers metoprolol and propranolol.
These practice guidelines are intended to assist physicians in clinical decision making by describing a range of generally acceptable approaches for the diagnosis and management of supraventricular arrhythmias. These guidelines attempt to define practices that meet the needs of most patients in most
The synthesis and spectroscopic characterization (UV–Vis, IR, EPR) of a new copper complex with a beta-blocker propranolol (1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol) are presented. Besides, the X-ray crystal structure of [Cu(propranolol)2]·2H2O is determined, showing two different copper ions, one coordinated through two S propranolol isomers and the other through two R isomers. The effect on the heart contraction force and on the heart rate plus the block of response to adrenaline of the complex and the free ligand, were studied. The effect of [Cu(propranolol)2]·2H2O on contractility was very similar to that of the free propranolol while the reduction on the heart rate is approximately 30% of the reduction obtained with the free ligand. This is an encouraging result since the search of new beta-blocker drugs that have lesser effect on heart rate is one of the important topics in cardiac pharmacology. The block of the response to adrenaline is at least similar for both ligand and complex.
A series of vanilloid-type β-adrenoceptor blockers derived from antioxidant traditional Chinese herbal medicines were synthesized and tested for their antioxidant and adrenoceptor antagonistic activities. They all possessed significant β-adrenoceptor blocking activities under in vitro experiments and radioligand binding assays. In addition, some compounds were further examined in in vivo tests and produced antagonist effects matching that of propranolol and labetalol by measurements of antagonism toward (−)isoproterenol-induced tachycardia and (−)phenylephrine-induced pressor responses in anesthetized rats. Furthermore, all of the compounds had antioxidant effects inherited from their original structures. In conclusion, compound 11 had the most potent β-adrenoceptors blocking activity, 12 and 13 possessed high cardioselectivity, whereas 14, 15 and 16 possessed additional α-adrenoceptor blocking activity and 15 is the most effective antioxidant of all. The antioxidant activity may be due to their α and β unsaturated side chain at position 1 and ortho-substituted methoxy moiety on 4-phenoxyethylamine.
The aim of this survey was to provide insight into current practice regarding the use of antiarrhythmic drugs for atrial fibrillation (AF) among members of the European Heart Rhythm Association research network. Thirty-seven centres responded. Rhythm control was preferred in patients with significant AF-related symptoms by 73% of centres, in all patients after a first detected episode by 59%, and in young patients even if AF was well tolerated by 49% of centres. The most common strategy after successful conversion of the first AF episode was a 'wait-and-see' approach without initiation of antiarrhythmic drugs (49%). Conventional β-blockers were always or sometimes used as first-choice drugs for AF prevention by 76% of centres. Only 11% used dronedarone regularly as a first-choice drug. The diagnostic work-up for exclusion of heart disease prior to initiation of class IC antiarrhythmic drugs was limited. Markers monitored for proarrhythmia risk were QRS duration for class IC drugs (68%) and the QT interval for sotalol and amiodarone (65%). In conclusion, rhythm control is more widely employed than expected. Beta-blockers are widely used for AF prevention in contrast to the limited use of the new drug dronedarone.
Glaucoma is the second major cause of blindness in the world after cataract. Glaucoma management through eye drops that reduce the intra ocular pressure (IOP) has major deficiencies including low patient compliance and low bioavailability. Extended wear contact lenses that deliver glaucoma drugs for extended periods could increase patient compliance, while also increasing the bioavailability. To develop extended wear contact lenses that can also provide extended glaucoma therapy, we disperse nanoparticles of PGT (propoxylated glyceryl triacylate) that contain a glaucoma drug timolol. The particles can also be loaded into prefabricated lenses by soaking the lenses in a solution of particles in ethanol. The particle loaded gels can release timolol in phosphate buffered saline (PBS) for about a month at room temperature. The most likely rate controlling mechanism is hydrolysis of the ester bond that links timolol to the PGT matrix, but other mechanisms such as water and drug diffusion, drug dissolution, drug-polymer chain cleavage, time-dependent drug permeability within the polymeric matrix, etc. may also be important. Nanoparticle incorporation in the silicone hydrogels results in reduction in ion and oxygen permeabilities, and an increase in modulus, and the impact on each of these properties is proportional to the particle loading. A gel with 5% particle loading can deliver timolol at therapeutic doses for about a month at room temperature, with a minimal impact on critical lens properties. Preliminary animal studies in Beagle dogs conducted with lenses in which particles are loaded by soaking the lenses in ethanol show a reduction in IOP.
The introduction of β-adrenergic-blocking drugs into clinical medicine in the early 1960s represented a major advance in pharmacotherapy. The use of these drugs highlighted the importance of the sympathetic nervous system in contributing to the pathophysiology of a wide variety of cardiovascular and noncardiovascular disorders. This article summarizes the history of β-blocking agents and reviews the applications of this therapeutic class. These drugs may be useful as primary protection against cardiovascular morbidity and mortality in hypertensive patients and have proved to be beneficial in other cardiovascular conditions. Not all β-blockers have the same mechanism of action and, among them, there are pharmacologic differences that may be of clinical importance.
Migraine is one of the most frequent neurological disorders affecting up to 15% of the general population. Many patients require not only management of individual migraine episodes but also prophylactic treatment. β-adrenoceptor blockers, flunarizine and valproic acid have been established as first-line agents for the prophylaxis of migraine attacks. Among the β-adrenoceptor blockers propranolol and metoprolol are best documented and hence deserve preferential use. On the other hand, it appears that other β-adrenoceptor blockers, perhaps with the exception of those with intrinsic sympathomimetic activity, can be equally effective. Uncertainties regarding the relative merits of various treatment modalities are largely caused by lack of adherence to specific requirements for clinical trials on migraine prophylaxis. Therefore, this article reviews internationally recommended conditions for reliable studies on migraine prophylaxis and appraises individual agents in the light of these criteria.
Carvedilol (CAR) is a vasodilating β-blocker which also has antioxidant properties. CAR produces dose-related reduction in mortality in patients with congestive heart failure. In the present study, we tested the hypothesis that CAR protects against doxorubicin (DOX)-induced cardiomyopathy in rats. Sprague-Dawley rats were treated with DOX, CAR, CAR+DOX, or atenolol (ATN)+DOX. DOX (cumulative dose, 15 ) was administered intraperitoneally, and CAR (30 daily) or ATN (150 daily) was administered orally. Three weeks after the completion of these treatments, cardiac performance and myocardial lipid peroxidation were assessed. Mortality was observed in the DOX (25%) and ATN+DOX (12.5%) groups. Compared with control rats, DOX significantly decreased systolic blood pressure (104 ± 4 vs. 120 ± 4 mmHg, P < 0.05) and left ventricular fractional shortening (38.8 ± 3.1 vs. 55.4 ± 1.3%, P < 0.01), and resulted in a significant accumulation of ascites (14.4 ± 4.9 vs. 0 ml, P < 0.01). CAR significantly prevented the cardiomyopathic changes caused by DOX, while ATN did not. The myocardial thiobarbituric acid reactive substances (TBARS) content was significantly higher in DOX-treated rats than in control rats (80.4 ± 7.1 vs. 51.5 ± 1.2 heart, p < 0.01). CAR prevented the increase in TBARS content (48.8 ± 3.0 heart, P < 0.01 vs. DOX group), whereas ATN had no significant effect (74.3 ± 5.2 heart). CAR also significantly prevented the increase in both myocardial and plasma cholesterol concentrations caused by DOX. These data indicate that CAR protects against DOX-induced cardiomyopathy and that this effect may be attributed to the antioxidant and lipid-lowering properties of CAR, not to its β-blocking property.
Objectives:
We evaluated the use and effectiveness of beta-blocker therapy after acute myocardial infarction (AMI) for elderly patients with chronic obstructive pulmonary disease (COPD) or asthma.
Background:
Because patients with COPD and asthma have largely been excluded from clinical trials of beta-blocker therapy for AMI, the extent to which these patients would benefit from beta-blocker therapy after AMI is not well defined.
Methods:
Using data from the Cooperative Cardiovascular Project, we examined the relationship between discharge use of beta-blockers and one-year mortality in patients with COPD or asthma who were not using beta-agonists, patients with COPD or asthma who were concurrently using beta-agonists and patients with evidence of severe disease (use of prednisone or previous hospitalization for COPD or asthma) compared with patients without COPD or asthma.
Results:
Of 54,962 patients without contraindications to beta-blockers, patients with COPD or asthma (20%) were significantly less likely to be prescribed beta-blockers at discharge after AMI. After adjusting for demographic and clinical factors, we found that beta-blockers were associated with lower one-year mortality in patients with COPD or asthma who were not on beta-agonist therapy (relative risk [RR] = 0.85, 95% confidence interval [CI] 0.73 to 1.00), similar to patients without COPD or asthma (RR = 0.86, 95% CI 0.81 to 0.92). A survival benefit for beta-blockers was not found among patients concurrently using beta-agonists or with severe COPD or asthma.
Conclusions:
Beta-blocker therapy after AMI may be beneficial for COPD or asthma patients with mild disease. A survival benefit was not found for elderly AMI patients with more severe pulmonary disease.
The purpose of the study was to examine (1) how patient adherence and eye drop technique were associated with visual field defect severity and (2) how general glaucoma adherence self-efficacy and eye drop technique self-efficacy were related to visual field defect severity.
Cross-sectional study conducted at a single private practice site.
Patients using eye drops for their glaucoma.
Subject adherence to glaucoma medications through Medication Events Monitoring System (MEMS) devices were measured, and eye drop instillation technique was assessed by video recording. General glaucoma medication adherence self-efficacy was measured using a 10-item scale, and eye drop technique self-efficacy was measured using a 6-item scale. Multivariate logistic regression was used to analyze the data.
Visual field defect severity.
Patients who were less than 80% adherent according to the MEMS devices were significantly more likely to have worse defect severity. Patients with lower scores on the general glaucoma medication adherence self-efficacy scale also were significantly more likely to have worse defect severity. Eye drop technique and eye drop technique self-efficacy were not related significantly to visual field defect severity.
Eye care providers need to assess patient adherence and to work with those patients with poor adherence to find ways to improve their ability and self-efficacy in using their glaucoma medications.
Proprietary or commercial disclosure may be found after the references.
Introduction:
In the last decades, the therapy of glaucoma has largely shifted from surgery to medical treatment thanks to the introduction of strongly effective formulations, that is, prostaglandin analogs and fixed combinations. This clinical scenario may dramatically change in the future thanks to the progresses in biochemistry, genetics and drug delivery technology.
Areas covered:
This review covers the strategies currently used to achieve effective medical reduction of intraocular pressure in clinical practice; treatments that are currently been experimented in humans and that may be clinically available in the next few years; treatments at preclinical stages; and future goals of glaucoma treatment (gene therapy, ocular implants and neuroprotection).
Expert opinion:
Apart from an adequate reduction of intraocular pressure, effective glaucoma treatments should guarantee other characteristics: good tolerability, low problems of adherence and, possibly, multiple ways of action. From this viewpoint, a crucial clinical role may be played by drugs remodeling the trabecular meshwork (i.e., ROCK inhibitors, metalloproteinases). Other strategies such as the use of ocular implants for drug delivery, neuroprotection or gene therapy could renew glaucoma management in the future, but need long-term rigorous verification of safety and efficacy.
James Black has many claims to pharmacological fame as the creator of two new classes of drugs (beta-blockers and H2 antihistamines) and as a tireless innovator in drug discovery strategies and analytical procedures. The latter attributes in particular assisted Black in the invention of the prototypes for the two major classes of drugs for which he is best known, propranolol and cimetidine. The clinical impact of these drugs on both morbidity and mortality has been profound. In addition, the application of his analytical approach to drug discovery and pharmacology led others in the field to create many other new classes of drugs. Shortly before he died in 2010, Black wrote a retrospective review of his research career that provides insight into his innovative thinking and career success. This overview affords readers a very personal picture of the man, his ideas and his contributions.
The introduction of beta-blockers in the treatment of cardiovascular diseases was a milestone and one of the most important contributions to clinical medicine in the 20th century. For many years, beta-blockers were considered contraindicated in patients with chronic heart failure owing to the negative inotropic action of these substances. With increasing evidence of neurohormonal activation in heart failure patients, there was a focus on the potential role of beta-blockers in the treatment of chronic heart failure. Several large randomized placebo- controlled clinical trials have shown favorable effects of beta-blockers on mortality and morbidity in heart failure patients with impaired systolic function. Beneficial effects in patients with preserved left ventricular systolic function are less clear. A reduction in heart rate is one of several mechanisms by which beta-blockers exert beneficial effects in chronic heart failure. In this article we present results from major clinical trials examining beta-blocker treatment in chronic heart failure patients and discuss heart rate as a therapeutic target in these patients.
Beta blockers have been used in the treatment of cardiovascular conditions for decades. Despite a long history and status as a guideline-recommended treatment option for hypertension, recent meta-analyses have brought into question whether β blockers are still an appropriate therapy given outcomes data from other antihypertensive drug classes. However, β blockers are a heterogenous class of agents with diverse pharmacologic and physiologic properties. Much of the unfavorable data revealed in the recent meta-analyses were gleaned from studies involving nonvasodilating, traditional β blockers, such as atenolol. However, findings with traditional β blockers may not be extrapolated to other members of the class, particularly those agents with vasodilatory activity. Vasodilatory β blockers (i.e., carvedilol and nebivolol) reduce blood pressure in large part through reducing systemic vascular resistance rather than by decreasing cardiac output, as is observed with traditional β blockers. Vasodilating ability may also ameliorate some of the concerns associated with traditional β blockade, such as the adverse effects on metabolic and lipid parameters, including an increased risk for new-onset diabetes. Furthermore, vasodilating ability is physiologically relevant and important in treating a condition with common co-morbidities involving metabolic and lipid abnormalities such as hypertension. In patients with hypertension and diabetes or coronary artery disease, vasodilating β blockers provide effective blood pressure control with neutral or beneficial effects on important parameters for the co-morbid disease. In conclusion, it is time for a reexamination of the clinical evidence for the use of β blockers in hypertension, recognizing that there are patients for whom β blockers, particularly those with vasodilatory actions, are an appropriate treatment option.
A: Yes. Treatment with beta-adrenergic receptor blockers decreases the mortality rate in patients with coronary artery disease or heart failure, as well as during the perioperative period in selected patients (eg, those with a history of myocardial infarction, a positive stress test, or current chest pain due to myocardial ischemia). The current evidence supports giving beta-blockers to patients with coronary artery disease and chronic obstructive pulmonary disease (COPD) or asthma, which lowers the 1-year mortality rate to a degree similar to that in patients without COPD or asthma, and without worsening respiratory function. 1 However, many clinicians still hesitate to start patients with COPD or asthma on a beta-blocker due to the fear of bronchoconstriction. 2 .
Headache is a common complaint in childhood with up to 75% of children reporting a notable headache by the age of 15 years. Paediatric migraine is the most frequent recurrent headache, occurring in up to 28% of older teenagers. Migraine can have a substantial effect on the life of the child, as well as their family, leading to lost school days and withdrawal from social interactions. Early recognition can lead to successful treatment, improved outcome, and reduced disability. The treatment strategy needs to be multipronged and can include acute therapy (which can vary depending on the severity of the headache), preventive therapy (when the headaches are frequent or causing substantial disability), and biobehavioural therapy (to assist with coping with recurrent headaches). Additional factors can contribute to exacerbations of headaches, including comorbid disorders and pubertal changes, which might lead to the development of menstrual migraine. When all these factors are effectively managed, there should be an improvement in long-term outcome and prevention of disease progression.
Glaucoma is a slow progressive degeneration of the retinal ganglion cells (RGCs) and the optic nerve axons, leading to irreversible blindness if left undiagnosed and untreated. Although increased intraocular pressure is a major risk factor of glaucoma, other factors include increased glutamate levels, alterations in nitric oxide (NO) metabolism, vascular alterations and oxidative damage caused by reactive oxygen species. Glaucoma is the second leading cause of blindness globally, accounting for 12.3% of the total blindness. Glaucoma has been broadly classified as primary or secondary open-angle or angle-closure glaucoma. The primary goal in management of glaucoma is to prevent the risk factor, especially elevated intraocular pressure (IOP), using medications, laser therapy or conventional surgery. The first-line treatment of glaucoma usually begins with the use of a topical selective or nonselective blocker or a prostaglandin analog. Second-line drugs of choice include alpha-agonists and topical carbonic anhydrase inhibitors. Cholinergic agonists are considered third-line treatment options. When a single therapy is not sufficient to lower the IOP, a combination therapy is indicated. To enhance the patient compliance, drug delivery systems like electronic devices, ocular inserts, tansdermal and mechanical drug delivery systems have been developed. Use of viscoelastic agents in ophthalmic formulations, emulsions and soluble ophthalmic drug inserts (SODI) enhance patience compliance and ocular drug delivery in patients in long-term glaucoma therapy. For patients who do not respond to antiglaucoma medications, laser trabeculoplasty and incisional surgery are recommended. Several nutrients and botanicals hold promise for the treatment of glaucoma, but most studies are preliminary, and larger, controlled studies are required. Future directions for the development of a novel therapy glaucoma may target glutamate inhibition, NMDA receptor blockade, exogenously applied neurotrophins, open channel blockers, antioxidants, protease inhibitors and gene therapy.
Glaucoma, the most common optic neuropathy (GON) is characterised by the loss of retinal ganglion cells and their axons, as well as tissue remodelling of both the retina and the optic nerve head with corresponding visual field defects. Elevated intraocular pressure (IOP) is generally regarded as the major risk factor for glaucoma and its reduction is the most common target for therapy of GON. There are indications that the greater the IOP reduction, the better is the visual field prognosis. This article investigates, on the basis of two beta-blockers, betaxolol and timolol, whether the amount of IOP reduction is truly a good surrogate for successful glaucoma therapy with respect to visual field outcome. Contrary to what is generally expected, our analysis of the literature exemplifies that despite a smaller IOP reduction, patients treated with betaxolol had a smaller rate of visual field deterioration than patients treated with timolol. Based on the dissociation of IOP reduction and visual field prognosis, we postulate that for successful treatment in glaucoma not only the amount of IOP reduction is relevant but also the drug by which the reduction is achieved. This seeming paradox phenomenon highlights that ocular hypotensive drugs have relevant effects on GON other than IOP-related. Some of these effects on retinal ganglion cells (neuroprotection) or on ocular blood flow are mediated by calcium- and sodium channels. Future studies on glaucoma treatment should focus on their effect on visual field function, and not just on IOP. This should particularly be considered when comparing drugs from different classes.
The 2005 American Heart Association/American College of Cardiology heart failure (HF) guidelines contributed to a renewed focus on "at-risk" patients and emphasized HF as a progressive disease. Patient categorization by stages focused attention on customization of therapy to achieve optimal, evidence-based treatments across the HF continuum. Therapy for risk factors that predispose patients to left ventricular dysfunction or other symptoms may help reduce HF development. beta-Blockers are valuable for treatment of HF; however, the class is heterogeneous, and proper beta-blocker selection for each HF stage is important. beta-Blockers have been used routinely to treat patients with stage A HF with hypertension. Recent controversy regarding the detrimental effects that some beta-blockers have on metabolic parameters has raised inappropriate concerns about the use of any beta-blocker for diabetes. beta-Blockade is standard therapy for the patient with stage B HF who has had a myocardial infarction, but few data are available concerning use in asymptomatic patients with left ventricular dysfunction. Additionally, beta-blockers are part of the core therapy for stage C HF and selected patients with stage D HF. This review examines the role and use of beta-blockers in each HF stage through an evidence-based approach to provide better understanding of their importance in this progressive disease. PubMed searches (1980-2008) identified large clinical trials that evaluated cardiovascular events and outcomes in any HF stage or hypertension. Search terms were heart failure, hypertension, beta-blocker, ACEI, ARB, and calcium channel blocker AND blood pressure coronary artery disease, diabetes, efficacy, left ventricular dysfunction, metabolism, mortality, myocardial infarction, or stroke.
A novel class of timolol derivatives with nitric oxide (NO)-donating moieties achieved chemical stability yet under physiologically relevant conditions released timolol and NO. Hindered esters A were designed and synthesized, whose 'triggered' release relied on enzymatic hydrolysis of the nitrate ester in A to B, that in turn cyclized to liberate timolol.
PP-24 is a newly synthesized putative beta-adrenoceptor antagonist. The objective of the study was to the evaluate beta-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg(-1)) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 microg kg(-1)) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 microg kg(-1)). The pA(2) of PP-24 to beta(1)-, beta(2)- and beta(3)-adrenoceptors was 7.72 +/- 0.082, 7.40 +/- 0.082 and 6.39 +/- 0.16, respectively. The beta(1)/beta(2) selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses beta-adrenoceptor blockade activity but with non-specific affinity for beta(1)- and beta(2)-adrenoceptor subtypes. The rank order of potency of the antagonists for beta(1)-adrenoceptors was atenolol > PP-24 > propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of beta-adrenoceptors.
In the twenty years since beta-blockers were proposed for treatment of glaucoma, use of topical timolol has increased to account for 70% of all glaucoma medications used. The objective of this article is to review the "newer" beta-blockers, and to address the generalization that "all ophthalmic beta-blockers are the same." The review concentrates on agents that have been studied as topical treatments for patients with elevated intraocular pressure. Sections on pharmacology and design of clinical trials are included to aid the ophthalmologist in evaluating the new drugs and published clinical reports. The major questions to consider in evaluating the therapeutic potential of a new beta-blocker for the treatment of glaucoma involve efficacy and safety: Is the drug as effective as timolol? Does it have a duration of action at least as long as timolol? Does it have ocular toxicity? Is it comfortable? What are its systemic effects?
CLASSIFICATION of receptor systems which are activated by sympathomimetic amines has engaged the attention of many investigators. Ahlquist1-3 has suggested the convenient designations of alpha (alpha) and beta (beta) to distinguish major differences in the responses elicited in various organ systems. Our investigations have provided results which cannot be explained easily on the assumption that the beta-type designates a single receptor population4-6. We now report additional studies which show that two distinct receptor types are at present included within this group.
We examined the time course of ventricular functional improvement in patients with dilated cardiomyopathy who received beta-blockade and the long-term effects of beta-blockade on ventricular mass and geometry in these patients.
Previous studies have shown that beta-adrenergic blocking agents when administered long term improve ventricular function in patients with heart failure. However, the time course of improvement in ventricular function and the long-term effects of beta-blockade on ventricular mass and geometry are not known.
Twenty-six men with dilated cardiomyopathy underwent serial echocardiography on days 0 and 1 and months 1 and 3 of either metoprolol (n = 16) or standard therapy (n = 10). At 3 months all patients on standard therapy were crossed over to metoprolol, and late echocardiograms were obtained after 18 +/- 5 (mean +/- SD) months of metoprolol therapy. All echocardiograms were read in blinded manner.
Patients treated with metoprolol had an initial decline (day 1 vs. day 0) in ventricular function (increase in end-systolic volume and decrease in ejection fraction). Ventricular function improved between months 1 and 3 (p = 0.013, metoprolol vs. standard therapy). Left ventricular mass regressed at 18 months (333 +/- 85 to 275 +/- 53 g, p = 0.011) but not at 3 months. Left ventricular shape became less spherical and assumed a more normal elliptical shape by 18 months (major/minor axis ratio 1.5 +/- 0.2 to 1.7 +/- 0.2, p = 0.0001).
Patients with heart failure treated with metoprolol do not demonstrate an improvement in systolic performance until after 1 month of therapy and may have a mild reduction in function initially. Long-term therapy with metoprolol results in a reversal of maladaptive remodeling with reduction in left ventricular volumes, regression of left ventricular mass and improved ventricular geometry by 18 months.
Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction < 0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p < 0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.
The objective was to determine the dosing, efficacy, and side effects of the nonselective beta-blocker carvedilol for the management of heart failure in children.
Carvedilol use in addition to standard medical therapy for pediatric heart failure was reviewed at 6 centers.
Children with dilated cardiomyopathy (80%) and congenital heart disease (20%), age 3 months to 19 years (n = 46), were treated with carvedilol. The average initial dose was 0.08 mg/kg, uptitrated over a mean of 11.3 weeks to an average maintenance dose of 0.46 mg/kg. After 3 months on carvedilol, there were improvements in modified New York Heart Association class in 67% of patients (P =.0005, chi2 analysis) and improvement in mean shortening fraction from 16.2% to 19.0% (P =.005, paired t test). Side effects, mainly dizziness, hypotension, and headache, occurred in 54% of patients but were well tolerated. Adverse outcomes (death, cardiac transplantation, and ventricular-assist device placement) occurred in 30% of patients.
Carvedilol as an adjunct to standard therapy for pediatric heart failure improves symptoms and left ventricular function. Side effects are common but well tolerated. Further prospective study is required to determine the effect of carvedilol on survival and to clearly define its role in pediatric heart failure therapy.
Recent data suggest that beta-blockers can be beneficial in subgroups of patients with chronic heart failure (CHF). For metoprolol and carvedilol, an increase in ejection fraction has been shown and favorable effects on the myocardial remodeling process have been reported in some studies. We examined the effects of bisoprolol fumarate on exercise capacity and left ventricular volume with magnetic resonance imaging (MRI) and applied a novel high-resolution MRI tagging technique to determine myocardial rotation and relaxation velocity.
Twenty-eight patients (mean age, 57 +/- 11 years; mean ejection fraction, 26 +/- 6%) were randomized to bisoprolol fumarate (n = 13) or to placebo therapy (n = 15). The dosage of the drugs was titrated to match that of the the Cardiac Insufficiency Bisoprolol Study protocol. Hemodynamic and gas exchange responses to exercise, MRI measurements of left ventricular end-systolic and end-diastolic volumes and ejection fraction, and left ventricular rotation and relaxation velocities were measured before the administration of the drug and 6 and 12 months later.
After 1 year, heart rate was reduced in the bisoprolol fumarate group both at rest (81 +/- 12 before therapy versus 61 +/- 11 after therapy; P <.01) and peak exercise (144 +/- 20 before therapy versus 127 +/- 17 after therapy; P <.01), which indicated a reduction in sympathetic drive. No differences were observed in heart rate responses in the placebo group. No differences were observed within or between groups in peak oxygen uptake, although work rate achieved was higher (117.9 +/- 36 watts versus 146.1 +/- 33 watts; P <.05) and exercise time tended to be higher (9.1 +/- 1.7 minutes versus 11.4 +/- 2.8 minutes; P =.06) in the bisoprolol fumarate group. A trend for a reduction in left ventricular end-diastolic volume (-54 mL) and left ventricular end-systolic volume (-62 mL) in the bisoprolol fumarate group occurred after 1 year. Ejection fraction was higher in the bisoprolol fumarate group (25.0 +/- 7 versus 36.2 +/- 9%; P <.05), and the placebo group remained unchanged. Most changes in volume and ejection fraction occurred during the latter 6 months of treatment. With myocardial tagging, insignificant reductions in left ventricular rotation velocity were observed in both groups, whereas relaxation velocity was reduced only after bisoprolol fumarate therapy (by 39%; P <.05).
One year of bisoprolol fumarate therapy resulted in an improvement in exercise capacity, showed trends for reductions in end-diastolic and end-systolic volumes, increased ejection fraction, and significantly reduced relaxation velocity. Although these results generally confirm the beneficial effects of beta-blockade in patients with chronic heart failure, they show differential effects on systolic and diastolic function.
Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy.
We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mRNA) for contractility-regulating genes (those encoding beta1- and beta2-adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and alpha- and beta-myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of beta-adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography.
Twenty-six of 32 beta-blocker-treated patients (those with complete mRNA measurements) had an improvement in left ventricular ejection fraction of at least 5 ejection-fraction (EF) units (mean [+/-SE] increase, 18.8+/-1.8). As compared with the six beta-blocker-treated patients who did not have a response (mean change, a decrease of 2.5+/-1.8 EF units), those who did have a response had an increase in sarcoplasmic-reticulum calcium ATPase mRNA and alpha-myosin heavy chain mRNA and a decrease in beta-myosin heavy chain mRNA. The change in sarcoplasmic-reticulum calcium ATPase was not present in the patients in the placebo group who had a spontaneous response. There were no differences between those who had a response and those who did not in terms of the change in mRNA or protein expression of beta-adrenergic receptors.
In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.
Our purpose was to evaluate the clinical effect of carvedilol among pediatric patients with congestive heart failure (CHF) who did not respond to standard therapy and to assess the pharmacokinetics of carvedilol among these children.
In this prospective, open intervention trial with blinded interpretation of selected end points, patients with CHF who did not improve on standard therapy, including digoxin, angiotensin-converting enzyme inhibitors, and diuretics, were treated with oral carvedilol in a ramped dosing scheme. Clinical parameters (ejection fraction, fractional shortening, and modified Ross score) were assessed before initiation of treatment and monthly for 6 months. Pharmacokinetic profiles of carvedilol were determined over the first 12-hour period after the initial dose in study patients, and for comparison, in 9 healthy adult volunteers.
Fifteen patients (aged 6 weeks to 19 years) were enrolled in the study, including 10 patients with dilated cardiomyopathy and 5 with CHF secondary to congenital heart disease. All 15 patients tolerated carvedilol for the duration of the trial, and all achieved maximum target dosing. After 6 months of carvedilol therapy, ejection fraction increased (36% vs 54%; P <.05) and modified Ross Score improved (5 +/- 2 vs 3 +/- 3; P <.05). Elimination half-life was about 50% shorter in pediatric CHF patients compared with healthy adult volunteers (2.9 vs 5.2 hours; P <.05).
Pediatric patients with CHF not responding to standard therapy may benefit from oral carvedilol treatment. The observed increased elimination of carvedilol in children suggests that optimal dosing strategies need to be further defined among the pediatric population.
To determine tolerability and symptom changes associated with the introduction of bisoprolol treatment in older patients with heart failure.
Prospective observational cohort study.
Geriatric medicine outpatient department of a university hospital.
51 patients (mean age 78 years, range 70-89 years) with stable symptomatic heart failure caused by left ventricular systolic dysfunction.
Bisoprolol tablets, 1.25-10.0 mg.
Tolerability; changes in symptoms and exercise tolerance.
69% of patients tolerated bisoprolol. Mean tolerated dose was 7.6 mg. There was no change in symptoms or exercise capacity in those who tolerated bisoprolol. Perceived health status and symptoms of anxiety and depression improved during the titration period.
The rate of withdrawal from bisoprolol treatment in older patients with congestive heart failure was twice that previously reported in younger patients. The mean tolerated dose was similar to that found in trials reporting clinical efficacy. There was no evidence of a negative impact on symptoms or exercise capacity in patients who tolerated bisoprolol.
Sodium bicarbonate is well recognised in the treatment of tricyclic overdose. But its use in the treatment of massive β blocker (propanol) overdose has not been previously reported.
A 24 year old woman presented to the accident and emergency department with a history of overdose, taking 92 propanolol LA 80 mg, 45 paroxetine 30 mg, and 28 diazepam 5 mg tablets, two hours before admission. NPIS advised us to give activated charcoal every four hours and monitor vital signs closely …
Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome.
In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat.
The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups.
Our results suggest that carvedilol extends survival compared with metoprolol.
To study the efficacy and tolerability of beta-blockade in elderly patients with heart failure in the MERIT-HF study.
Cox proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). Risk reduction was defined as (1-HR). In patients > or = 65 years total mortality was reduced by 37% (95% CI 17% to 52%; p=0.0008), sudden death by 43% (95% CI 17% to 61%; p=0.0032), and death from worsening heart failure by 61% (95% CI 32% to 77%; p=0.0005). Hospitalisations for worsening heart failure was reduced by 36% (p=0.0006). Elderly patients with severe heart failure (NYHA class III/IV with ejection fraction < 0.25; n=425, and patients above 75 years (n=490) showed similar risk reductions. Metoprolol CR/XL was safe and well tolerated both during initiating therapy and during long-term follow-up.
Metoprolol CR/XL was easily instituted, safe and well tolerated in elderly patients with systolic heart failure. The data suggest that these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalisations avoided. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of elderly patients with heart failure in need of this therapy.
Beta-adrenergic blockers are one of the most frequently prescribed cardiovascular drugs. Numerous beta-blockers are available for clinical use. Although these agents differ substantially, it is not clear whether (and which) differences are clinically relevant. Most of the important differences among agents reflect the relative specificity for beta1-, beta2-, and alpha-adrenergic receptors. Selection of a particular agent and target dose is probably best guided by available trial data, even though data are limited. Nonselective agents (with or without alpha-blocking properties) devoid of intrinsic sympathetic activity (ISA) are most appropriate postinfarction. Evidence exists demonstrating a mortality benefit postinfarction for propranolol, timolol, metoprolol, and, in the presence of left ventricular dysfunction, carvedilol. In the setting of heart failure, the selective agents metoprolol and bisoprolol as well as the nonselective agent carvedilol (which possesses alpha-blocking properties) have a demonstrated mortality benefit. Not all tolerated beta-blockers are associated with a survival benefit and it is probably not advisable to extrapolate benefits to all drugs with similar (although probably not identical) properties. Carvedilol may possess advantages over other beta-blockers and a possible survival advantage, suggested by the recent Carvedilol or Metoprolol European Trial (COMET), although these findings are not universally accepted. Ultimately, selection of a specific agent avoids obvious contraindications and uses trial data to guide selection and dose as long as side effects are absent or tolerable.
Whether beta-blockers reduce atrial arrhythmias and, when added to an angiotensin-converting enzyme (ACE) inhibitor, ventricular arrhythmia is unknown.
Ventricular and atrial arrhythmias are common after acute myocardial infarction (AMI) and are associated with a poor prognosis. Angiotensin-converting enzyme inhibitors reduce the incidence of both types of arrhythmia.
The antiarrhythmic effect of carvedilol was examined in a placebo-controlled multicenter trial, the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study, which enrolled 1,959 patients with reduced left ventricular systolic function after AMI, 98% of whom were treated with an ACE inhibitor.
The incidence of atrial fibrillation/flutter was 53 to 984 (5.4%) in the placebo group and 22 to 975 (2.3%) in the carvedilol group, giving a carvedilol/placebo hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.25 to 0.68; p = 0.0003). The corresponding rates of ventricular tachycardia/flutter/fibrillation were 38 to 984 (3.9%) and 9 to 975 (0.9%) (HR 0.24, 95% CI 0.11 to 0.49; p < 0.0001).
Carvedilol has a powerful antiarrhythmic effect after AMI, even in patients already treated with an ACE inhibitor. Carvedilol suppresses atrial as well as ventricular arrhythmias in these patients.
To estimate the intraocular pressure (IOP) reduction achieved by the most frequently prescribed glaucoma drugs and a placebo in a meta-analysis of randomized clinical trials.
Meta-analysis of randomized clinical trials.
Twenty-seven articles reporting on 28 randomized clinical trials. These articles reported 6953 participants for the trough and 6841 for the peak.
Articles published up to December 2003 were identified in the following data sources: Medline, Embase, and the Cochrane Controlled Trials Register, and references from relevant articles. Over 85% of the patients had to be diagnosed with primary open-angle glaucoma (POAG) or ocular hypertension (OH), and articles had to be written in English, German, French, or Dutch. Quality of trials was assessed by a Delphi list with additions. The pooled 1-month IOP-lowering effect from baseline at peak and trough was calculated by performing meta-analysis using the random effects model.
Absolute and relative change in IOP from baseline, for peak and trough moments.
Relative IOP reductions from baseline [mean (95% confidence interval)] were -23% (-25% to -22%) for a peak and -20% (-23% to -17%) for a trough for 0.5% betaxolol; peak, -27% (-29% to -25%), and trough, -26% (-28% to -25%), for 0.5% timolol; peak, -22% (-24% to -20%), and trough, -17% (-19% to -15%), for 2.0% dorzolamide; peak, -17% (-19% to -15%), and trough, -17% (-19% to -15%) for 1.0% brinzolamide; peak, -25% (-28% to -22%), and trough, -18% (-21% to -14%) for 0.2% brimonidine; peak, -31% (-33% to -29%), and trough, -28% (-30% to -26%) for 0.005% latanoprost; peak, -31% (-32% to -29%), and trough, -29% (-32% to -25%) for 0.004% travoprost; peak, -33% (-35% to -31%), and trough, -28% (-29% to -27%) for 0.03% bimatoprost; and peak, -5% (-9% to -1%), and trough, -5% (-10% to -0%) for the placebo. The difference in absolute IOP reduction from baseline between timolol and prostaglandin analogs or prostamide varied from -0.4 to 0.1 mmHg at trough and from 1.0 to 1.5 mmHg at peak. Quality scores of included studies were generally high, a mean of 14.2 on a scale from 0 to 20 (interquartile range, 13-16).
This meta-analysis suggests that bimatoprost, travoprost, latanoprost, and timolol are the most effective intraocular pressure-reducing agents in POAG and OH patients.