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Ailments and Diseases
Published in James Sherifi, General Practice Under the NHS, 2023
Salbutamol was good but had a short half-life. Salmeterol, a long-acting beta-adrenergic agonist (LABA), available from 1990, provided a useful adjunct in both the treatment of acute wheeze and the prevention of bronchospasm. Inhaled corticosteroids (ICS) were marketed and shown to be useful in both the prevention of and pulmonary destruction from chronic asthma. Inhalers combining a LABA and ICS, such as Seretide, were widely prescribed, overcoming the profession’s antipathy to their high cost and drug combinations in general. GPs were inundated with a host of inhaler devices. Spacer devices and peak flow meters were issued to patients with asthma, and they were encouraged to keep a peak flow diary that was periodically reviewed by a clinician, increasingly a nurse. A step-by-step hierarchy of drug treatment was introduced. Patients were allowed to keep rescue courses of steroids and antibiotics at home for severe exacerbations.
The Development of Beta Receptor Agonist Drugs
Published in Richard Beasley, Neil E. Pearce, The Role of Beta Receptor Agonist Therapy in Asthma Mortality, 2020
Mast cell mediators can undoubtedly contribute not only to acute bron-chospasm but to inflammatory events in the airways, e.g., bronchial microvascular leakage and plasma exudation119,120 and infiltration of airway tissue with proinflammatory cells.121 Beta2 agonists have been shown to attenuate the microvascular leakage effects of mediators in the tracheobronchial airways in animal models,122,123 but more studies are needed to clarify their effects on proinflammatory cells, such as eosinophils. Also, the relevance of these observations in animals to clinical asthma has not yet been established. Thus, the recent promotion of salmeterol as a bronchodilator with anti-inflammatory properties when used in asthmatics, the latter being based on the ability of the drug to stabilize mast cells, inhibit eosinophil infiltration, and attenuate microvascular leakage in the airways in animal models, has been criticized.124
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Peter A. Crooks, Narsimha R. Penthala, Abeer M. Al-Ghananeem
Examples of drugs that exhibit improved affinity for exoreceptor binding in the lung have been reported. The drug salmeterol (6) was developed from molecular modification of salbutamol (4) (Ullman and Svedmyr 1988) and represents a β2-receptor stimulant with high exoreceptor affinity in order to persist in the vicinity of the β2-receptors in the respiratory tract. Salmeterol given by inhalation has a markedly prolonged bronchodilatory effect compared to salbutamol, exhibiting sustained bronchodilation over a 12-hour period, with no tachyphylaxis after 9 days of treatment (Bradshaw et al. 1987).
State-of-the-art beta-adrenoreceptor agonists for the treatment of asthma
Published in Expert Opinion on Pharmacotherapy, 2022
W. Tatiana Garzon-Siatoya, Ismael Carrillo-Martin, Sergio E Chiarella, Alexei Gonzalez-Estrada
Salmeterol is a derivative of phenylethanolamine (Figure 3), created using the head group of albuterol, taking advantage of this molecule’s β2-agonist properties and minimal adverse effect profile. The aliphatic side chain was extended to interact with a theoretical exosite inside or outside of the β2-receptor to lengthen the action of salmeterol by profoundly augmenting the lipophilicity of the molecule [40]. As a result, salmeterol partitions rapidly (within 1 min) into the outer phospholipid monolayer of any cell membrane in its vicinity and then diffuses laterally to approach the active site of the β2-AR. Nevertheless, to reach the bronchial smooth muscle, salmeterol must first diffuse from one cell to another and from the epithelium to the smooth muscle through the submucosa. Because most salmeterol molecules remain in cell membranes, the diffusion process is considerably slower than that of formoterol, which explains why salmeterol has a slower onset of action [41]. Salmeterol’s slower onset of action can be further explained by its relatively weaker interaction with β2-receptors in the interstitium than other drugs in its class [36]. Clinically, it takes salmeterol approximately 30 minutes to achieve maximum effect after inhalation. Compared to this, medications such as formoterol, albuterol, and terbutaline can achieve impactful effects in as little as 3 minutes and near maximum effects within 10 to 15 minutes [36].
Impact of chronic medications in the perioperative period: mechanisms of action and adverse drug effects (Part I)
Published in Postgraduate Medicine, 2021
Ofelia Loani Elvir-Lazo, Paul F White, Hillenn Cruz Eng, Firuz Yumul, Raissa Chua, Roya Yumul
Beta agonists exert their clinical effects by mimicking effects of the endogenous catecholamines (e.g. norepinephrine, epinephrine, and dopamine) on adrenergic receptors. As inhaled agents, they have greater selectivity for β2-adrenergic receptors located on the airway of smooth muscles. The activation of these receptors leads to a cascade of intracellular signaling, resulting in the inhibition of myosin light-chain phosphorylation producing bronchodilation and airway smooth muscle dilation [36]. Inhaled beta agonists are mainstays for the treatment of respiratory disorders, including asthma and COPD. Salmeterol is metabolized by cytochrome P450 CYP3A4, and formoterol CYP2D6, 2C9, and 2C19. Salmeterol should be used with caution in patients taking strong 3A4 inhibitors. Formoterol should be used with caution when combined with drugs that prolonged the QT interval [37].
Recent progress in the development of β2 adrenergic receptor agonists: a patent review (2015-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Gang Xing, Ce Yi, Peiyuan Dou, Zhengxing Zhi, Bin Lin, Maosheng Cheng
Many β2AR agonists have been developed over the years. They induce relaxation of the airway smooth muscles, and accordingly they find applications in the treatment of various respiratory diseases especially asthma and chronic obstructive pulmonary disease (COPD). Based on the duration of these agonists, they are broadly classified into the short-acting, the long-acting, and the ultra-long-acting types. Short-acting β2AR agonists, such as salbutamol (1), have a rapid onset of action and produce symptom relief for 3–6 h. The inhaled long-acting agents include salmeterol (2) and formoterol (3). The ultra-long-acting β2AR agonists include indacaterol (4) [31] and olodaterol (5) [32,33]. Other compounds under development include Pfizer’s PF-610,355 (6) [34], Chiesi’s carmoterol (7) [35], and Theravance’s milveterol (8) [36] (Figure 1).