Hazard
A poison by inhalation.
Description
Salmeterol is a long-acting β2-
agonist for patients with chronic asthma, useful
also in controlling persistent nocturnal asthma.
Definition
ChEBI: A phenol having a hydroxymethyl group at C-2 and a 1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl group at C-4; derivative of phenylethanolamine.
General Description
Salmeterol (89365-50-4) has an N-phenylbutoxyhexyl substituent incombination with a β-OH group and a salicyl phenyl ring foroptimal direct-acting β2-receptor selectivity and potency. Ithas a potency similar to that of ISO. This drug associateswith the β2-receptor slowly resulting in slow onset of actionand dissociates from the receptor at an even slower rate. It is resistant to both MAO and COMT and highly lipophilic(log P=3.88). It is thus very long acting (12 hours), aneffect also attributed to the highly lipophilic phenylalkylsubstituent on the nitrogen atom, which is believed to interactwith a site outside but adjacent to the active site.
Biological Activity
Potent and selective β 2 -adrenoceptor agonist (EC 50 = 5.3 nM); bronchodilator. Unlike other β 2 agonists, binds to exo-site domain of β 2 receptors, producing a slow onset of action and prolonged activation. Also available as part of the β -Adrenoceptor Agonist Tocriset™ .
Mechanism of action
A β2-agonist with a slow onset and extended duration of action is salmeterol. Salmeterol has the same phenyl ring substitution R3
as albuterol but also an unusually
long and lipophilic group R1
on the nitrogen. The octanol–water partition coefficient, log P, for salmeterol is 3.88, compared with 0.66 for albuterol. Salmeterol is
approximately 50-fold more selective than albuterol for the β2-receptor. Substantial evidence indicates that its long duration of action results from a specific binding
interaction (“anchoring”) of the phenyl group at the end of the extended lipophilic side chain with a specific region of the β2-receptor, affording salmeterol a unique
binding mechanism.
Pharmacokinetics
Salmeterol is 94 to 98% bound to human plasma proteins, both albumin and α1-acid glycoprotein, in vitro over the concentration range of 8 to 7722μg of base/L, much higher concentrations than those achieved following therapeutic doses of this drug. When salmeterol is inhaled, plasma concentrations of the drug often cannot be detected, even 30 minutes after administration of therapeutic doses. Larger inhaled doses give approximately proportionally increased blood concentrations. Plasma salmeterol concentrations of 0.1 to 0.2 and 1 to 2 μg/L were attained in healthy volunteers about 5 to 15 minutes after inhalation of single doses of 50 and 400μg, respectively. These concentrations were most probably related to the drug passing rapidly through the alveolar-capillary interface and probably into mucosal and submucosal vessels. In patients who inhaled salmeterol 50μg twice a day for 10 months, a second Cmax of 0.07 to 0.2 μg/L occurred 45 to 90 minutes after inhalation, probably due to gastrointestinal absorption of the swallowed drug (most of the dose delivered by a metered-dose inhaler is swallowed). Oral administration of 1mg of radiolabelled [14C]salmeterol (as salmeterol xinafoate) to two healthy individuals gave peak plasma salmeterol concentrations of about 650 μg/L at about 45 minutes. In another volunteer, t1 ?2β was about 5.5 hours. The dose-normalised Cmax values in comparative animal studies suggest that the systemic absorption and bioavailability in humans is greater (about 15 times greater) than that in rodents, being more closely related to that in dogs. Absorption may be high in humans, and first-pass metabolism less than in animals[1].
Clinical Use
Salmeterol usually is prescribed for severe persistent asthma following previous treatment with a short-acting β-agonist, such as albuterol. The noticeable differences
between salmeterol and albuterol are the onset of action and their duration of action (Table 13.6). When used regularly every day as prescribed, inhaled albuterol
decreases the number and severity of asthma attacks. It is not used, however, for relieving an asthma attack that has already started.
Side effects
Hoarseness, throat irritation, headache, rapid heartbeat, nervousness, cough, dry mouth/throat, or upset stomach may occur. To relieve dry mouth, suck on (sugarless) hard candy or ice chips, chew (sugarless) gum, drink water, or use a saliva substitute.
This medication may raise your blood pressure. Rarely, this medication may cause sudden breathing problems/asthma right after you use it. If this occurs, use your quick-relief inhaler and get medical help right away.
Drug interactions
Many drugs besides salmeterol may affect the heart rhythm (QT prolongation), including amiodarone, dofetilide, pimozide, procainamide, quinidine, sotalol, macrolide antibiotics (such as erythromycin), among others. Before using salmeterol, report all medications you are currently using to your doctor or pharmacist.Other medications can affect the removal of salmeterol from your body, which may affect how salmeterol works. Examples include cobicistat, nefazodone, ritonavir, telithromycin, azole antifungals (such as ketoconazole, itraconazole), macrolide antibiotics (such as clarithromycin), HIV protease inhibitors (such as saquinavir), among others.
Metabolism
Salmeterol is metabolized predominantly through CYP3A4, an isoform of cytochrome P450. CYP3A4 is responsible for the aliphatic oxidation of the salmeterol base. Salmeterol is extensively metabolized by hydroxylation into alpha-hydroxy-salmeterol and subsequently eliminated through feces and urine. Salmeterol is 57.4% eliminated in the feces and 23% in the urine. At recommended doses, systemic concentrations of salmeterol are low or undetectable. Only at very high doses are blood concentrations increased.
References
[1] M. Cazzola, M. Matera, R. Testi. “Clinical Pharmacokinetics of Salmeterol.” Clinical Pharmacokinetics 41 1 (2002): 19–30.
