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

2
Receptor Polymorphisms. Several single nucleotide polymorphisms
and haplotypes of the human 2
adrenergic receptor gene
(ADRβ2), which affect the structure of 2
receptors, have been
described. The common variants are Gly 16 Arg and Gln 27 Glu, which
have in vitro effects on receptor desensitization, but clinical studies
have shown inconsistent effects on the bronchodilator responses to
short- and long-acting 2
agonists (Hawkins et al., 2008). Some studies
have shown that patients with the common homozygous Arg 16 Arg
variant have more frequent adverse effects and a poorer response to
short-acting 2
agonists than heterozygotes or Gly 16 Gly homozygotes,
but overall these differences are small, and there appears to be
no clinical value in measuring ADRβ2 genotype. No differences have
been found with responses to LABA between these genotypes
(Bleecker et al., 2007).
Side Effects. Unwanted effects are dose related and due to stimulation
of extrapulmonary receptors (Table 36–1 and Chapter 12).
Side effects are not common with inhaled therapy but quite common
with oral or intravenous administration.
• Muscle tremor due to stimulation of 2
receptors in skeletal
muscle is the most common side effect. It may be more troublesome
with elderly patients and so is a more frequent problem
in COPD patients.
• Tachycardia and palpitations are due to reflex cardiac stimulation
secondary to peripheral vasodilation, from direct stimulation
of atrial 2
receptors (human heart has a relatively high proportion
of 2
receptors; see Chapter 12), and possibly also from stimulation
of myocardial 1
receptors as the doses of 2
agonist are
increased. These side effects tend to disappear with continued use
of the drug, reflecting the development of tolerance. There can
be a dose-related prolongation of the corrected QT interval (QTc).
• Hypokalemia is a potentially serious side effect. This is due to
2
receptor stimulation of potassium entry into skeletal muscle,
which may be secondary to a rise in insulin secretion.
Hypokalemia might be serious in the presence of hypoxia, as
in acute asthma, when there may be a predisposition to cardiac
arrhythmias (Chapter 29). In practice, however, significant
arrhythmias after nebulized 2
agonists are rarely observed in
acute asthma or COPD patients.
Table 36–1
Side Effects of 2
Agonists
• Muscle tremor (direct effect on skeletal muscle
2
receptors)
• Tachycardia (direct effect on atrial 2
receptors, reflex
effect from increased peripheral vasodilation via
2
receptors)
• Hypokalemia (direct 2
effect on skeletal muscle
uptake of K + )
• Restlessness
• Hypoxemia (increased . V/ . Q mismatch due to reversal of
hypoxic pulmonary vasoconstriction)
• Ventilation-perfusion(V/Q) mismatch due to pulmonary vasodilation
in blood vessels previously constricted by hypoxia,
resulting in the shunting of blood to poorly ventilated areas and
a fall in arterial oxygen tension. Although in practice the effect
of 2
agonists on PaO 2
is usually very small (<5 mm Hg fall),
occasionally in severe COPD it can be large, although it may
be prevented by giving additional inspired oxygen (O 2
).
• Metabolic effects (increase in free fatty acid, insulin, glucose,
pyruvate, and lactate) are usually seen only after large systemic
doses.
Tolerance. Continuous treatment with an agonist often leads to tolerance
(desensitization, subsensitivity), which may be due to downregulation
of the receptor (Chapter 12). For this reason there have been
many studies of bronchial receptor function after prolonged therapy
with 2
agonists. Tolerance of non-airway 2
receptor–mediated
responses, such as tremor and cardiovascular and metabolic responses,
is readily induced in normal and asthmatic subjects. Tolerance of
human airway smooth muscle to 2
agonists in vitro has been demonstrated,
although the concentration of agonist necessary is high and
the degree of desensitization is variable. In normal subjects, bronchodilator
tolerance is not a consistent finding after high-dose inhaled
albuterol. In asthmatic patients tolerance to the bronchodilator effects
of 2
agonists has not usually been found. However, tolerance develops
to the bronchoprotective effects of 2
agonists, and this is more
marked with indirect bronchoconstrictors that activate mast cells (e.g.,
adenosine, allergen, and exercise) than with direct bronchoconstrictors,
such as histamine and methacholine. The reason for the relative
resistance of airway smooth muscle 2
responses to desensitization
remains uncertain but may reflect the large receptor reserve: >90% of
2
receptors may be lost without any reduction in the relaxation
response. The high level of ADRβ2 expression in airway smooth
muscle compared with peripheral lung may also contribute to the
resistance to tolerance because a high rate of receptor synthesis is
likely. In addition, the expression of GRK2, which phosphorylates and
inactivates occupied 2
receptors, is very low in airway smooth
muscle (McGraw and Liggett, 1997). By contrast there is no receptor
reserve in inflammatory cells, GRK2 expression is high, and tolerance
to 2
agonists rapidly develops at these sites.
Experimental studies have shown that corticosteroids prevent
the development of tolerance in airway smooth muscle, and prevent
and reverse the fall in pulmonary receptor density (Mak et al.,
1995). However, ICS fail to prevent the tolerance to the bronchoprotective
effect of inhaled 2
agonists, possibly because they do not
reach airway smooth muscle in a high enough concentration.
Long-Term Safety. Because of a possible relationship between
adrenergic drug therapy and the rise in asthma deaths in several
countries during the early 1960s, doubts were cast on the long-term
safety of agonists. A causal relationship between agonist use
and mortality has never been firmly established, although in retrospective
studies this would not be possible. A particular 2
agonist,
fenoterol, was linked to the rise in asthma deaths in New
Zealand in the early 1990s because significantly more of the fatal
cases were prescribed fenoterol than the case-matched control
patients. An epidemiological study examined the links between
drugs prescribed for asthma and death or near death from asthma
attacks, based on computerized records of prescriptions. There was
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CHAPTER 36
PULMONARY PHARMACOLOGY