In human airways, bronchoconstrictor responses are countered by epinephrine, which is released from storage sites within the supra renal glands. Interestingly, endogenous epinephrine is a pure single isomer (R)-epinephrine which binds specifically to the b 2 -adrenoceptor protein. However, almost all the b 2 -agonist class of drugs including salbutamol, which were developed based upon the structure of epinephrine are racemates (50: 50 mixture of two non-superimposable mirror-image isomers).

It has long been recognized that multiple points of attachment between drug molecules and receptor sites provides a basis for specificity of drug-receptor interaction and herein stereochemistry plays a major role. High-affinity binding for (R)-epinephrine requires a particular three-dimensional conformation of the b 2 -adrenoceptor protein. The orientation of the benzylic b 2 -hydroxyl group in case of (R)-epinephrine, ensures close interaction between (R)-epinephrine and b 2 -adrenoceptors, an equivalent interaction between that group and (S)-epinephrine is automatically precluded, leaving only two of the three points of attachment available for (S)-epinephrine. Analogous considerations apply to other synthetic sympathomimetics, including racemic salbutamol. The biological consequence of this restriction is a high eudismic ratio for b 2 -sympathomimetics. (ie., biological activities of (R)-or (R,R)-enantiomers exceeding those of (S)- or (S,S)-enantiomers
by > 100-fold).

 

 

Salbutamol has one asymmetric (chiral) carbon atom (Fig.1) and therefore it exists as a pair of enantiomers. Only the (R)-enantiomer (also known as (-) or levosalbutamol is a potent b 2 -adrenoceptor stimulant whereas the (S)-enantiomer (also known as (+) or dextrosalbutamol (Fig.2), shows no adrenoceptor activity and has no therapeutic activity. The entire bronchodilatory activity of racemic salbutamol is attributable entirely to (R)-salbutamol.

In vitro studies have shown that (R)-salbutamol exhibits greater affinity (90 to 100-fold) than does (S)-salbutamol for b 2 -adrenoceptors, also it increases intracellular cAMP to an extent (23-fold) that is indistinguishable from the racemate (24-fold) and demonstrates a degree of intrinsic activity (45%) that is indistinguishable from the racemate (46%). From these observations, it can be predicted that activation of b 2 -adrenoceptors is entirely determined by (R)-salbutamol.

 

In a randomized, double-blind, placebo controlled crossover study, mild asthmatic patients received cumulative doses of (R)-salbutamol, (S)-salbutamol, racemic salbutamol or placebo and FEV 1 was measured 20 minutes after each dose. Both (R)- and racemic salbutamol produced significant and dose-dependent increases in FEV1 (Fig. 3) However, S-salbutamol did not show any effect on FEV 1 confirming that it is inactive as a bronchodilator.

 

In a placebo-controlled study, the effects of (R) or (S)- salbutamol (100 m g each) and racemic salbutamol (200 m g) on bronchial reactivity in patients with stable asthma were determined before and 20 and 180 minutes after drug treatment. Analyses of the PD 20 data revealed statistically significant differences between groups, such that (R)- and racemic salbutamol significantly protected against methacholine challenge at 20 min, whereas (S)-salbutamol had no effect (Fig 4).

In addition, while prolonged bronchoprotection remained at 180 minutes for the (R)-salbutamol group, the PD 20 value for the (S)-salbutamol treated group (158 ± 54 m g/ml methacholine) fell below the baseline value (243 ± 99), indicating that less methacholine was needed to produce the 20% decrease in FEV 1 . This difference was statistically significant and substantiated the reports of hyperresponsiveness induced by (S)-salbutamol in guinea pigs. This capacity of (S)-salbutamol to induce hyperresponsiveness may account for loss of protective effect of salbutamol, which limits its clinical efficacy .

 

Studies have suggested two concerns regarding inhaled beta 2 -agonists. The first is the wide spread use of these potent symptom relieving agents which, has probably resulted in their overuse. There are a number of reports of the association between the use of beta 2 -agonists and increased risk of mortality and morbidity. This is most likely due to the tendency towards over reliance on these excellent symptom relievers, resulting in under appreciation of asthma severity and consequent under treatment with anti-inflammatory agents. The second concern is the increased hyperresposiveness of asthmatic airways to non-allergic and allergic stimuli, development of tolerance and reduced protection against provoking stimuli on regular use of these beta- 2 agonists particularly in the absence of inhaled corticosteroids. This might lead to exaggerated responses on exposure to spasmogens, leading to potentially worsening asthma control. A number of studies have suggested that the ‘S' enantiomer in the absence of (R)- salbutamol has the potential to cause bronchoconstriction and airway hyperresponsiveness.