DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

294 agonist that has twice the potency of racemic formoterol.
It is FDA-approved for the long-term treatment
of bronchoconstriction in patients with COPD, including
chronic bronchitis and emphysema (Matera and
Cazzola, 2007). It is the first long-acting β 2
agonist
developed as inhalational therapy to use with a nebulizer
(Abdelghany, 2007). Like other β 2
agonists, arformoterol
activates the cyclic AMP pathway, thereby
relaxing bronchial smooth muscle and inhibiting release
of mast cell mediators (e.g., histamine and leukotrienes).
SECTION II
NEUROPHARMACOLOGY
A substantial portion of systemic exposure to arformoterol is
due to pulmonary absorption with plasma levels reaching peak levels
in 0.25-1 hour. Plasma protein binding is 52-65%. It is primarily
metabolized by direct conjugation to glucuronide or sulfate conjugates
and secondarily by O-demethylation by CYP2D6 and
CYP2C19. It does not inhibit any of the common CYPs. The drug is
well tolerated and the most common side effects are skeletal muscle
tremor and cramps, insomnia, tachycardia, decreases in plasma
potassium, and increases in plasma glucose. As mentioned previously,
a black-box warning has been instituted in response to findings
of the SMART trials (Fanta, 2009; Lipworth, 2007).
Carmoterol. Carmoterol is a pure (R,R)-isomer and a non-catechol
with a p-methoxyphenyl group on the carbostyril aromatic ring. It
is a potent and selective β 2
adrenergic agonist with a selectivity for
β 2
over β 1
receptors of 53. It is claimed to be 5 times more selective
for the β 2
adrenergic receptor in tracheal preparations than
those in the right atrium. Carmoterol has a rapid onset and long
duration of action and shows a bronchodilator effect over 24 hours
with once a day dosing. Indications for carmoterol include asthma
and COPD (Cazzola and Matera, 2008; Matera and Cazzola, 2007).
Indacaterol. Indacaterol is a once-daily long-acting β adrenergic
agonist in development for asthma and COPD. It has a fast onset of
action, appears well tolerated, and has been shown to be effective in
both asthma and COPD with little tachyphalaxis upon continued use.
Indacaterol behaves as a potent β 2
agonist with high intrinsic efficacy,
which, in contrast to salmeterol, does not antagonize the bronchorelaxant
effect of short-acting β 2
adrenergic agonists. Evidence
indicates that indacaterol has a longer duration of action than salmeterol
and formoterol.
Both indacaterol and carmoterol are currently in Phase III
clinical trials in the U.S. (Cazzola and Matera, 2008; Matera and
Cazzola, 2007).
Ritodrine. Ritodrine is a β 2
-selective agonist that was developed
specifically for use as a uterine relaxant. Nevertheless, its pharmacological
properties closely resemble those of the other agents in
this group.
Ritodrine is rapidly but incompletely (30%) absorbed following
oral administration, and 90% of the drug is excreted in the urine
as inactive conjugates; ~50% of ritodrine is excreted unchanged
after intravenous administration. The pharmacokinetic properties of
ritodrine are complex and incompletely defined, especially in pregnant
women.
Ritodrine may be administered intravenously to selected
patients to arrest premature labor. Ritodrine and related drugs can
prolong pregnancy. However, β 2
-selective agonists may not have
clinically significant benefits on perinatal mortality and may actually
increase maternal morbidity. Ritodrine is not available in the U.S.
See Chapter 66 for the pharmacology of tocolytic agents.
Adverse Effects of β 2
-Selective Agonists. The major
adverse effects of β receptor agonists occur as a result
of excessive activation of β receptors. Patients with
underlying cardiovascular disease are particularly at
risk for significant reactions. However, the likelihood
of adverse effects can be greatly decreased in patients
with lung disease by administering the drug by inhalation
rather than orally or parenterally.
Tremor is a relatively common adverse effect of the β 2
-selective
receptor agonists. Tolerance generally develops to this effect; it is not
clear whether tolerance reflects desensitization of the β 2
receptors of
skeletal muscle or adaptation within the CNS. This adverse effect can
be minimized by starting oral therapy with a low dose of drug and progressively
increasing the dose as tolerance to the tremor develops.
Feelings of restlessness, apprehension, and anxiety may limit therapy
with these drugs, particularly oral or parenteral administration.
Tachycardia is a common adverse effect of systemically
administered β receptor agonists. Stimulation of heart rate occurs
primarily by means of β 1
receptors. It is uncertain to what extent the
increase in heart rate also is due to activation of cardiac β 2
receptors
or to reflex effects that stem from β 2
receptor–mediated peripheral
vasodilation. However, β 2
receptors are also present in the human
myocardium and all β 2
adrenergic agonists have the potential to produce
cardiac stimulation. During a severe asthma attack, heart rate
actually may decrease during therapy with a β agonist, presumably
because of improvement in pulmonary function with consequent
reduction in endogenous cardiac sympathetic stimulation. In patients
without cardiac disease, β agonists rarely cause significant arrhythmias
or myocardial ischemia; however, patients with underlying
coronary artery disease or preexisting arrhythmias are at greater risk.
The risk of adverse cardiovascular effects also is increased in
patients who are receiving MAO inhibitors. In general, at least
2 weeks should elapse between the use of MAO inhibitors and
administration of β 2
agonists or other sympathomimetics.
Large doses of β receptor agonists cause myocardial necrosis
in laboratory animals. When given parenterally, these drugs also may
increase the concentrations of glucose, lactate, and free fatty acids in
plasma and decrease the concentration of K + . The decrease in K + concentration
may be especially important in patients with cardiac disease,
particularly those taking digoxin and diuretics. In some diabetic
patients, hyperglycemia may be worsened by these drugs, and higher
doses of insulin may be required. All these adverse effects are far less
likely with inhalation therapy than with parenteral or oral therapy.
α 1
-SELECTIVE ADRENERGIC
RECEPTOR AGONISTS
The major clinical effects of a number of sympathomimetic
drugs are due to activation of α adrenergic
receptors in vascular smooth muscle. As a result, peripheral