Clinical Pharmacology of the LABAs

Posted by James

LABAs differ from short-acting inhaled beta-2 agonists principally in having large side chains, increasing their lipophilicity. The greater water solubility of short-acting inhaled beta-2 agonists, such as albuterol, leads them to diffuse away from the beta-2-adrenergic receptors, limiting their duration of action. The greater lipophilicity of formoterol and salmeterol facilitates their partitioning and retention in the phospholipid region of the cell membrane lipid bilayer, prolonging the duration of action.

A single inhaled dose of either LABA causes clinically significant bronchodilation for 12 hours and measurable activity for up to 24 hours. In addition to their longer duration, both LABAs exhibit greater potency and selectivity for the beta-2-adren-ergic receptor than albuterol, but these particular properties are unlikely to be clinically significant. Both formoterol and salmeterol have demonstrated inhibitory effects on various inflammatory cells in vitro, but the contribution of these actions to their therapeutic efficacy is unproven. The ability of LABAs to inhibit the late asthmatic response to allergen appears to be due to functional antagonism (i.e., prevention of smooth muscle contraction) and not to an antiinflammatory effect.
cialis professional canada

Formoterol and salmeterol differ somewhat in pharmacologic properties. Formoterol is approximately fourfold more potent than salmeterol, but this difference in potency is simply overcome by adjusting the dose delivered. Formoterol has greater efficacy than salmeterol (i.e., salmeterol is a partial agonist). This property is more easily demonstrated through study of the bronchoprotec-tive activity of the agents, in which their efficacy in inhibiting the bronchoconstrictor response to a provocative stimulus (e.g., methacholine, adenosine, exercise) is analyzed. In these studies, salmeterol is found to have a relatively flat dose-response curve compared to formoterol. Formoterol is less lipophilic than salmeterol, attaches to the beta-adrenergic receptor more rapidly and has an onset of action as rapid as albuterol. Although both the efficacy and onset differences can be demonstrated with appropriate laboratory studies, their clinical relevance to the customary use of these agents as long-term controllers is unknown.

Partial agonists produce less tolerance or down-regulation of the beta-2-adrenergic receptor and theoretically should produce less beta-2-agonist-mediated adverse effects, such as tremor, tachycardia, prolonged QTc interval, fall in serum potassium and rise in serum glucose. In normal volunteers naive to beta-2 agonists, formoterol and salmeterol have a similar therapeutic ratio, with the single dose required to produce significant cardiovascular and metabolic effects being at least four times the recommended dose. In asthma patients receiving chronic beta-2-agonist therapy, a single dose of formoterol five times the recommended dose produced a significantly greater drop in serum potassium than a comparable dose of salmeterol. Thus, both drugs have an excellent therapeutic ratio, with clinically significant aberrations of the cardiovascular system occurring only at doses 4-5 times those recommended.

Both salmeterol and formoterol produce tolerance when taken chronically. This tolerance is more easily detected as a reduction in bronchoprotective activity rather than of bronchodilating activity, probably because of the enormous surplus of beta-2-adren-ergic receptors on bronchial smooth muscle. The clinical significance of the tolerance from chronic administration of LABAs appears minimal, except in their probable use in preventing exercise-induced bronchospasm. The slight decrease in response to short-acting beta-2 agonists produced by formoterol and salmeterol can be overcome by administering a single additional dose of a short-acting beta-2 agonist. In addition, bolus doses of either a systemic corticosteroid or an inhaled corticosteroid partially reverses the tolerance. Lastly, long-term clinical trials with the LABAs have not demonstrated a diminution in clinical efficacy over time.

More recently, the issue of whether chronic administration of inhaled beta-2 agonists might worsen asthma severity, thereby increasing morbidity and the risk of dying from asthma, again has been raised. Pharma-cogenetic studies and a recent prospective population surveillance study have once again brought this issue to the forefront. Two large, well-controlled trials (BAGS and TRUST) demonstrated no worsening of asthma with regular administration of albuterol compared to as needed administration. However, a retrospective evaluation of single-nucleotide polymorphisms of the beta-2-adrenergic receptor in patients enrolled in the BAGs trial suggested that patients who were homozygous for arginine at locus 16 of the receptor (Arg/Arg 16) experienced a significant decline in lung function during regular albuterol administration compared to heterozygotes or those homozygous for glycine (Gly/Gly 16). In a follow-up prospective, placebo-controlled, crossover trial stratified by genotype, this same group reported significantly lower lung function and increased symptoms in Arg/Arg 16 patients receiving regular albuterol, compared to those receiving placebo with both groups receiving ipratropium bromide for rescue as needed. Although they did not find the same decrease in lung function in the Arg/Arg 16 group as previously reported, the patients demonstrated significant improvement while on placebo, which produced the difference in lung function and symptoms. Patients who were Gly/Gly 16 exhibited a significant improvement in lung function and symptoms during regular albuterol administration. As Arg/Arg 16 patients make up only about one-sixth of the population, that may explain why the full population studies failed to demonstrate an adverse effect.

What impact the Arg/Arg 16 genotype may have on the response to LABAs is unclear. The LABAs have not been found to produce the rebound increase in bronchial hyperresponsiveness that has been observed after chronic treatment with short-acting beta-2 agonists. Nor does monotherapy with LABAs appear to increase biomarkers of airway inflammation over placebo. A retrospective genotype study of a randomized comparison of regular albuterol, salmeterol or placebo reported an increase in asthma exacerbations in Arg/Arg 16 patients receiving regular albuterol but not regular salmeterol. Although the total number of exacerbations was reduced with the salmeterol treatment (0.64/patient/year) compared to placebo (1.91/ patient/year) and albuterol (3.57/patient/year), this difference was not significant. More recently, it has been reported that the Arg/Arg 16 and Arg/Gly 16 patients had greater bronchoprotective subsensitivity in patients treated with LABAs than homozygous Gly/Gly 16 patients, suggesting greater agonist-induced tolerance in these groups.
You can afford your pills. Levitra professional