Bronchodilators

Most of the drugs such as epinephrine and albuterol used to treat asthma attacks are bronchodilators—substances that expand the bronchial passages Newer drugs are designed to either inhibit the enzyme 5 lipoxygenase which acts on arachidomc acid m the first stage of leukotriene biosynthesis or to block leukotriene receptors... 

It has been demonstrated that the P -selectivity is due to the para-substituents of these dmgs (96). In contrast, (-)-erythro-isoetharine (127), a bronchodilator, is 80 times more selective for receptors than for P ceptors. Isoetharine (97) contains an a-alkyl substituent, thus... 

Many 1,2,3,5-benzenetetrol derivatives are used mediciaaHy. For example, khellin [82-02-0] (65), which is a naturally occurring benzopyranone, is used as a coronary vasodilator and bronchodilator (233). Derivatives of khellin are effective local anesthetics and antiarrythmics (234). Similarly, amine derivatives (68) that are prepared from khellinone oxime (66) exhibit hypnotic, sedative, anticonvulsant, antiinflammatory, cardiac analeptic, diuretic, and antiulcerous activity (235) (see Analgesics, antipyretics, and antiinflammatory agents). 

The modern usage of P2" go Asts for the treatment of asthma dates to 1903 when the effect of injected epinephrine [51-43-4] (adrenaline) C2H23NO2, (1 R = CH3) was investigated (see Epinephrine and norepinephrine) (33). As in some other modem treatments, eg, xanthines and anticholinergics, the roots of P2" go Ast therapy for asthma can be found in historical records which document the use of herbal extracts containing ephedrine [299-42-3] C qH NO, (2) as bronchodilators. Epinephrine and ephedrine are stmcturaHy related to the catecholamine norepinephrine [51-41-2] CgH NO, (1, R = H), a neurotransmitter of the adrenergic nervous system (see Neuroregulators). 

Ephedrine, which is not a catecholamine, has weak oral activity as a bronchodilator and although it has some direct action at adrenergic receptors, its predominant mode of action is by displacing norepinephrine from storage vesicules. 2"Agonists which are in use or are under investigation are the result of quests for improved selectivity, retention of potency, oral activity, and longer duration of action. 

The bronchodilating effect of caffeine has been recognized for hundreds of years. In the western world the first description of a caffeine preparation for asthma was made in 1859 (59) by a Scottish physician who recommended strong black coffee as a bronchodilator. In many parts of the world, however, use of xanthines is less frequent than in the United States. 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

Single dose or short-term treatment with aerosolized steroids inhibits both the late asthmatic response and allergen-induced bronchial hyperresponsiveness (45,92). However it does not affect the early asthmatic response nor does it induce bronchodilation (45,92). Long-term treatment with steroids protects against both the early and late asthmatic responses and also reduces bronchial hyperresponsiveness (44,71,86,93). Over time, the airways relax (dilate) and measures of airway function, such as forced expiratory volume in one second (FEV ), gradually return to almost normal levels. 

At this writing anticholinergic agents are not widely used for the symptomatic treatment of asthma, although compounds such as atropine [51 -55-8] C17H23NO3, (18) have been used for centuries (111). Inhalation of the smoke produced by burning herbal mixtures, such as Datura Stramonium provided bronchodilation and rehef from some of the symptoms of asthma. The major active component in these preparations was atropine or other closely related alkaloids (qv). 

Cromakalim. Cromakalim has along half-life (254). Cromakalim at an oral dose of 1.5 mg ia humans significantly lowers blood pressure 19/12 mm Hg (systohc/diastoHc pressure). It iacreases reaal blood flow, PRA, and heart rate. Cromakalim has bronchodilating activity that is beneficial for hypertensive asthmatic patients. Because of some undesirable effects seen ia cardiac papillary muscles of animals oa long-term treatmeat, future clinical trials are to be carried out usiag the active enantiomer, lemakalim (BRL 38227). 

Others. Other choline salts available as commercial products include choline bicarbonate [78-73-9] choline saUcylate [2016-36-6] and the bronchodilator choline theophyllinate [4499-40-5]. 

Safety and efficacy data on a number of antitussives and expectorants have been reviewed by the FDA s Advisory Review Panel on Over-the-Counter (OTC) Cough, Cold, Allergy, Bronchodilator, and Antiasthmatic Products. The conclusions and recommendations regarding the effectiveness, safety, labeling, and suitability for marketing of over-the-counter preparations have been reported (103). After review of these recommendations, FDA has issued final monographs for over-the-counter antitussives (12) and for expectorants (1). LD q data for most of the compounds described have been reported (104,105). 

The action of epinephrine and related agents forms the basis of therapeutic control of smooth muscle contraction. Breathing disorders, including asthma and various allergies, can result from excessive contraction of bronchial smooth muscle tissue. Treatment with epinephrine, whether by tablets or aerosol inhalation, inhibits MLCK and relaxes bronchial muscle tissue. More specific bronchodilators, such as albuterol (see figure), act more selec-... 

Acylation of ami noketone 8 with the acid chloride from p-toluic acid affords the corresponding ester (10) catalytic hydrogenation leads to the bronchodilator bitolerol (11). An analogous scheme starting from the N-methyl ketone (12) and pivaloyl chloride gives ami noalcohol (14). This compound is then resolved to isolate the levorotatory isomer. There is thus obtained the drug dipivefrin. 

Beta adrenergic agonists also exert bronchodilating effects. These drugs are thus often used in conjunction with theophiline in asthma therapy. A drug that combines both moieties, reproterol (40), has interestingly proved... 

Butaprost (82) not only has the typical C-15 hydroxyl of the natural prostaglandins moved to C-16, as do several of the analogues discussed above, but it has a rather interesting gem dialkyl substitution at C-17, presumably for metabolic protection, in the form of a cyclobutyl ring. It is a bronchodilator and is prepared in a manner analogous to that of rioprostil discussed above [17]. 

A derivative of an isomeric azapurine ring system interestingly exhibits bronchodilator activity, possibly indicating interaction with a target for theophylline. The starting pyridazine 97 is available from dichloro compound 96 by sequential replacement of the halogens. Treatment of 97 with formic acid supplies the missing carbon and cyclizes the intermediate formamide with consequent formation of zindotrine (98) [16]. 

---