P2-Adrenoceptor agonists

Fig. 2.13 Structures of salbutamol and salmeterol, rapid and slow offset p2-adrenoceptor agonists.

Tocolysis. The uterine relaxant effect of P2-adrenoceptor agonists, such as terbutaline or fenoterol, can be used to prevent premature labor. Vasodilation Ltillmann, Color Atlas of Pharmacology (... 

Isoproterenol and epinephrine are potent P2-adrenoceptor agonists norepinephrine is a relatively weak P2-adrenoceptor agonist. Isoproterenol and epinephrine produce vasodilation in skeletal muscle, but norepinephrine does not rather it produces vasoconstriction through the aj-adrenoceptors. Isoproterenol,... 

The effect of a given adrenomimetic drug on a particular type of effector cell depends on the receptor selectivity of the drug, the response characteristics of the effector cells, and the predominant type of adrenoceptor found on the cells. For example, the smooth muscle cells of many blood vessels have only or predominantly a-adrenoceptors. The interaction of compounds with these adrenoceptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for a-adrenoceptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains p2-adrenoceptors, the response in this tissue elicited by the action of p2-adrenoceptor agonists is relaxation of smooth muscle cells. Epinephrine and isoproterenol, which have high affinities for p2-adrenoceptors, cause relaxation of bronchial smooth muscle. Norepinephrine has a lower affinity for p2-adrenoceptors and has relatively weak bronchiolar relaxing properties. 

Selective p2-adrenoceptor agonists Albuterol Proventil Ventolin Oral... 

Ipratropium bromide (Atrovent) is a quaternary amine derivative that is used via inhalation in the treatment of chronic obstructive pulmonary disease and to a lesser extent, asthma. Ipratropium has a slower onset of action (1-2 hours for peak activity) than Pz-adrenoceptor agonists and thus may be more suitable for prophylactic use. Compared with p2-adrenoceptor agonists, ipratropium is generally at least as effective in chronic obstructive pulmonary disease but less effective in asthma. 

Terbutaline (Brethine, Bricanyl) is a relatively specific P2-adrenoceptor agonist (see Chapters 10 and 39). Terbutaline can prevent premature labor, especially in individuals who are more than 20 weeks into gestation and have no indication of ruptured fetal membranes or in whom labor is not far advanced. Its effectiveness in premature labor after 33 weeks of gestation is much less clear. Terbutaline can decrease the frequency, intensity, and duration of uterine contractions through its ability to directly stimulate Pj-adrenoceptors. While it appears to be especially selective for P2-receptor activation, terbutaUne does have some Pi activity as well. 

After infusion of the P2 adrenoceptor agonist terbutaline, a profound decrease in esophageal peristaltic amplitude was reported. Peristaltic velocity in the distal part of the esophagus was decreased by 2 adrenoceptor stimulation. Clenbuterol, which is used commonly in horses, caused relaxation of rat esophageal smooth muscle (de Boer et al 1993), but it is not known whether drugs such as clenbuterol or terbutaline will similarly affect the equine esophagus. 

Clenbuterol, a P2 adrenoceptor agonist, is sometimes used in pregnant mares with lower airway disease for its bronchodilatory effects. This drug has been found to have minimal effects on fetal heart rate when administered i.v. to mares in the last trimester of pregnancy. The effects on fetal health have not been established. 

Coleman. R.A. et al. (19%) Exosites their current status, and their relevance to the duration of action of long-acting P2 adrenoceptor agonists. Trends Pharmacoi Sci, 17.324-330. 

The cAMP/Gs protein-coupled pathway stimulates adenylate (also known as adenylyl) cyclase, which catalyzes the formation of cAMP (Fig. 29.2). In VSM, unlike the heart, an increase in intracellular cAMP concentrations stimulated by a P2-adrenoceptor agonist, such as epinephrine or isoproterenol, binding to the p-receptor inhibits myosin light-chain phosphorylation, causing VSM relaxation. Therefore, drugs that increase cAMP (e.g., p2-adrenoceptor agonists, PDE3 phosphodiesterase inhibitors) cause vasodilation. On the other hand, stimulation of Gi protein inhibits adenylyl cyclase. 

Figure 7 Structure of the selective P2-adrenoceptor agonist formoterol.

Stereoselectivity in the pharmacodynamics of p2-agonists has been extensively studied at both the receptor and the end-clinical response levels [82-95]. Except for trimethoquinol, the bronchodilator action of all p2-agonists is predominantly due to the R enantiomer. Using excised tissues from various animals and humans, it has been shown that p2-adrenoceptor agonist activity resides mainly with the R or (R,R) isomers of racemic albuterol, terbutaline, formoterol, and clenbuterol (Table 5) [82-95]. 

Nix et al. (1990) found the protective effect of formoterol against methacholine-induced broncho-constriction in 12 asthmatic patients lasting for at least 5 h. The rapid pulmonary absorption of inhaled formoterol and its slow elimination from plasma are in agreement with the fast onset and the long duration, respectively, of bronchodilation of inhaled formoterol fumarate in clinical trials (Le-CAiLLON et al. 1997). There was no indication that formoterol produced a more pronounced tachyphylaxis to P2-adrenoceptor stimulation in the bronchial muscle of asthmatics than the P2-adrenoceptor agonists normally used, e.g. salbutamol (Larsson et al. 1988, Arvidsson et al. 1989). Formoterol powder is as potent as solution (Clauzel et al. 1991). 

Respiratory A 25-year-old woman developed symptoms of rhinoconjunctivitis and asthma, attributed to an allergy to cyanoacrylate in a fingernail adhesive gel, which as a manicurist she had used for 6 months [41 ]. Skin prick tests were positive with dog and cat dander and grass pollens. Patch tests were positive with nickel, cadmium, and silver salts. An inhalation challenge with cyanoacrylate for 30 minutes elicited a late asthmatic response, with a 24% fall in FEVi, with rhinorrhea and asthma that worsened progressively until she received short-acting P2-adrenoceptor agonists. 

Various aspects of airway response may be used in different ways to predict the effects of both relievers or controllers on asthma. For example, the ability of relievers to inhibit EAR seems to be correlated with their efficacy in treating intercurrent asthma symptoms. In this regard, P2-adrenoceptor agonists are the most powerful agents and the best choice for their rapid onset of action. 

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