Isoproterenol (Isuprel) is a nonselective and prototypical S-agonist (S2/j1 = 1). After oral administration, the absorption of ISO is rather erratic and undependable. The principal reason for its poor absorption characteristics and relatively short DOA is its facile metabolism by sulfate and glucuronide conjugation of the phenolic OH groups and o-methylation by COMT. Because it is a catechol, it is sensitive to light and air. Aqueous solutions become pink on standing. Unlike E and NE, ISO does not appear to
Di-OH groups result in: sensitive to air and light metabolized by COMT, sulfate and glucuronide conjugation poor absorption and short DOA
Isopropyl goup results in: T (3 activity, virtually no a activity resistant to MAO -»
undergo oxidative deamination by MAO. The drug has DOA of 1 to 3 hours after inhalation.
Because of an isopropyl substitution on the nitrogen atom, it has virtually no ^-activity. However, it does act on both fS 1- and jS 2-receptors. It thus can produce an increase in cardiac output by stimulating cardiac ^-receptors and can bring about bronchodilation through stimulation of jS2-receptors in the respiratory tract. In fact, it is one of the most potent bronchodilators available and is available for use by inhalation and injection. Cardiac stimulation is an occasionally dangerous adverse effect. This effect of ISO on the heart is sometimes used in the treatment of heart block.
The cardiac stimulation caused by its jS ractivity and its lack of oral activity have led to its diminished use in favor of more selective jS-agonists. The problems have been overcome at least partially by the design and development of several noncatechol selective jS2-agonists. These agents relax smooth muscle of the bronchi, uterus, and skeletal muscle vascular supply. They find their primary use as bron-chodilators in the treatment of acute and chronic bronchial asthma and other obstructive pulmonary diseases.
Metaproterenol (Alupent), terbutaline (Bricanyl, Brethine), and fenoterol (an investigational drugs)
belong to the structural class of resorcinol bronchodilators that have 3',5'-diOH groups of the phenyl ring (rather than 3',4'-diOH groups as in catechols). 3',5'-diOH groups confer jS 2-receptor selectivity on compounds with large amino substituents. For example, metaproterenol (a resorcinol analog of ISO), terbutaline (an N-f-butyl analog of metaproterenol), and other similar compounds are resorcinol jS 2-selective agonists. They relax the bronchial musculature in patients with asthma but cause less direct cardiac stimulation than do the nonselective jS-agonists. Because metaproterenol has a jS-directing N-isopropyl group and it is less jS2 selective than either terbutaline or albuterol (both have jS2-directing f-butyl groups), and hence is more prone to cause cardiac stimulation. Although these agents are more selective for jS2-receptors, they have a lower affinity for jS2-receptors than ISO. However, they are much more effective when given orally, and they have a longer DOA. This is because they are resistant to the metabolism by either COMT or MAO. Instead, their metabolism primarily involves glucuronide conjugation. Although both metaproterenol and terbutaline exhibit significant jS2-receptor selectivity, the common cardiovascular effects associated with other adrenergic agents can also be seen with these drugs when high doses are used.
Albuterol (Proventil, Ventolin), pirbuterol (Maxair), and salmeterol (Serevent) are examples of selective jS2-agonists whose selectivity results from replacement of the mefa-OH group of the aromatic ring with a hydroxymethyl moiety. Pirbuterol is closely related structurally to albuterol (SS = 60); the only difference between the two is that pirbuterol contains a pyridine ring instead of a benzene ring. As in the case of metaproterenol and terbutaline, these drugs are not metabolized by either COMT or MAO. Instead, they are conjugated with sulfate. They are thus orally active, and exhibit a longer DOA than ISO. The DOA of terbutaline, albuterol, and pirbuterol is in the range of 3 to 6 hours. (s)-albuterol enhances bronchial muscle contraction, and this undesirable effect is completely avoided by using the pure (r)-albuterol, levalbuterol (Xopenex). Therefore, the efficacy is achieved at one-fourth dose of racemic albuterol with markedly reduced adverse effects.
Salmeterol has an n-phenylbutoxyhexyl substituent in combination with a jS-OH group and a salicyl phenyl ring for optimal direct-acting jS2-receptor selectivity and potency. It has a potency similar to that of ISO. This drug associates with the jS2-receptor slowly resulting in slow onset of action and dissociates from the receptor at an even slower rate.51 It
is resistant to both MAO and COMT and highly lipophilic (log P = 3.88). It is thus very long acting (12 hours), an effect also attributed to the highly lipophilic phenylalkyl substituent on the nitrogen atom, which is believed to interact with a site outside but adjacent to the active site.
Formoterol and Levalbuterol. Formoterol (Foradil) is also a lipophilic (log P = 1.6) and long-acting ¡2-agonist. It has 3'-formylamino (¡-directing) and 4'OH groups on one phenyl ring and a lipophilic ¡-directing N-isopropyl-^-methoxyphenyl group on the nitrogen atom. Its long DOA (12 hours), which is comparable to that of salmeterol, has been suggested to result from its association with the membrane lipid bilayer,52 from which it gradually diffuses to provide prolonged stimulation of ¡2 receptors and its resistance to MAO and COMT. Formoterol has a much faster onset of action than does salmeterol as result of its lower lipophilic-ity. Both of these long-acting drugs are used by inhalation and are recommended for maintenance treatment of asthma, usually in conjunction with an inhaled corticosteroid.
All of the previously mentioned ¡2-agonists possess at least one chiral center and are used as racemic mixtures. Formoterol possesses two chiral centers and is used as the racemic mixture of the (R,R) and (S,S) enantiomers. As mentioned previously, it is the (R) isomer of the phenylethanolamines that possesses the pharmacological activity. There is no clinical advantage for using (R,R)-formoterol as bronchodilators compared with the racemic mixture because of its high potency and low dose. However, concerns have been raised about the use of racemic mixtures under the belief that the inactive isomer may be responsible for some of the adverse effects. Levalbuterol (Xopenex), the pure (R) isomer of racemic albuterol, represents the first attempt to address this issue as mentioned earlier.
Isoetharine. (a-ethyl ISO) was the first ¡2-selective drug widely used for the treatment of airway obstruction. However, its degree of selectivity and activity for ¡2-receptors may not approach that of some of the other agents such as terbutaline, albuterol, or even ISO. Because of the presence of the ¡2-directing a-ethyl group and ¡-directing isopropyl group, isoetharine is a ¡2-agonist and is resistant to MAO. However, because it contains the catechol ring system, it is metabolized by COMT and O-sulfated quite effectively. Consequently, it has a short DOA similar to that of ISO and is used only by inhalation for the treatment of acute episodes of bronchoconstriction.
Bitolterol (Tornalate, a Prodrug). Colterol (active metabolite of bitolterol) differs from ISO by replacing the ¡-directing N-isopropyl to ¡2-directing N-tert-butyl group, which results in the increased ¡2-selectivity. Bitolterol (Tornalate) is a prodrug of colterol (a ¡2-selective agonist) in which the catechol OH groups have been converted to di-p-toluate esters, providing increased lipid solubility caused by the presence of the two lipophilic di-p-toluate esters in bitolterol. The presence of the bulky di-ester and bulky N-tert-butyl groups also prolong the DOA (8 hours) because it is resistant to COMT and MAO metabolism. Bitolterol is administered by inhalation for bronchial asthma and reversible bronchospasm. The highly bulky p-toluoyl groups apparently inhibit the efficiency of the esterases. After absorption, it is hydrolyzed by esterases slowly enough in the
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