Page 365 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 20 Drugs Used in Asthma 351

β -selective agonists, ephedrine is now used infrequently in terbutaline are sometimes used to inhibit the uterine contractions
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treating asthma. associated with premature labor.
Isoproterenol is a potent nonselective β and β bronchodila- Long-acting β 2 -selective agonists (LABA), with 12-hour dura-
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tor. When inhaled as a microaerosol from a pressurized canis- tions of action, such as salmeterol and formoterol, were devel-
ter, 80–120 mcg isoproterenol causes maximal bronchodilation oped to facilitate asthma management. These drugs generally
within 5 minutes and has a 60- to 90-minute duration of action. achieve their long duration of bronchodilating action as a result
An increase in asthma mortality in the United Kingdom in the of high lipid solubility. This permits them to dissolve in the
mid-1960s was attributed to cardiac arrhythmias resulting from smooth muscle cell membrane in high concentrations or, possibly,
the use of high doses of inhaled isoproterenol. As a result of the attach to “mooring” molecules in the vicinity of the adrenoceptor.
availability and efficacy of β -selective agonists, these have dis- These drugs appear to interact with inhaled corticosteroids to
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placed the use of isoproterenol for asthma. improve asthma control. Because they have no anti-inflammatory
action, they should not be used as monotherapy for asthma.
Beta -Selective Drugs Ultra-long-acting β agonists, such as indacaterol, olodaterol,
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vilanterol, and bambuterol, need to be taken only once a day,
The β -selective adrenoceptor agonist drugs, particularly albuterol, but because their prolonged bronchodilation masks symptoms of
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are now the most widely used sympathomimetics for the treat- bronchial inflammation, they should be used only in combination
ment of acute bronchoconstriction (Figure 20–4). These agents with an ICS for asthma. However, they may be used as mono-
differ structurally from epinephrine in having a larger substitution therapy for treatment of COPD.
on the amino group and in the position of the hydroxyl groups on
the aromatic ring. They are effective after inhaled or oral admin- Toxicities
istration and have a longer duration of action than epinephrine
or isoproterenol. Concerns over the potential toxicities of acute treatment of asthma
Albuterol, terbutaline, metaproterenol, and pirbuterol are with inhaled sympathomimetic agents—worsened hypoxemia and
available as metered-dose inhalers. Given by inhalation, these cardiac arrhythmia—have been largely put to rest. Although the
agents cause bronchodilation equivalent to that produced by vasodilating action of β -agonist treatment may increase perfu-
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isoproterenol. Bronchodilation is maximal within 15 minutes and sion of poorly ventilated lung units, transiently decreasing arterial
persists for 3–4 hours. All can be diluted in saline for administra- oxygen tension (PaO ), this effect is small, is easily overcome
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tion from a hand-held nebulizer. Because the particles generated by the routine administration of supplemental oxygen, and is
by a nebulizer are much larger than those from a metered-dose made irrelevant after a short period of time by the increase in
inhaler, much higher doses must be given (2.5–5.0 mg vs 100– oxygen tension that follows β-agonist-induced bronchodilation.
400 mcg) but are no more effective. Nebulized therapy should The other concern, precipitation of cardiac arrhythmias, appears
thus be reserved for patients unable to coordinate inhalation from unsubstantiated. In patients presenting for emergency treatment
a metered-dose inhaler. of severe asthma, irregularities in cardiac rhythm improve with the
Most preparations of β -selective drugs are a mixture of R improvements in gas exchange effected by bronchodilator treat-
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(levo) and S (dextro) isomers. Only the R isomer activates the ment and oxygen administration.
β-agonist receptor. Reasoning that the S isomer may promote Another concern about the administration of β-agonists is
inflammation, a purified preparation of the R isomer of albuterol their induction of tachyphylaxis. A reduction in the bronchodila-
has been developed (levalbuterol). Although this purified isomer tor response to low-dose β-agonist treatment can be shown after
is often used in children with asthma, meta-analyses of clinical several days of regular β-agonist use, but maximal bronchodila-
trials have not shown it to have greater efficacy or lower toxicity tion is still achieved well within the range of doses usually given.
than the standard and less expensive racemic mixture of R- and Tachyphylaxis is more clearly reflected by a loss of the protection
S-albuterol in treating exacerbations of asthma or chronic obstruc- afforded by acute treatment with a β agonist against a later chal-
tive pulmonary disease (COPD). lenge by exercise or inhalation of allergen or an airway irritant. It
Albuterol and terbutaline are also available in oral form. One remains to be demonstrated in a clinical trial, however, whether
tablet two or three times daily is the usual regimen; the princi- this loss of bronchoprotective efficacy is associated with adverse
pal adverse effects are skeletal muscle tremor, nervousness, and outcomes.
occasional weakness. This route of administration presents no The demonstration of genetic variations in the β receptor
advantage over inhaled treatment and produces more pronounced raised the possibility that the risks of adverse effects might not be
adverse effects and is thus rarely prescribed. uniformly distributed among asthmatic patients. Attention first
Of these agents, only terbutaline is available for subcutaneous focused on a single nucleotide polymorphism (SNP) that changes
injection (0.25 mg). The indications for this route are similar to the amino acid code at position 16 from glycine to arginine
those for subcutaneous epinephrine—severe asthma requiring (Gly16Arg). Retrospective analyses of studies of regular β-agonist
emergency treatment when aerosolized therapy is not available treatment suggested that asthma control deteriorated among
or has been ineffective—but it should be remembered that ter- patients homozygous for arginine at this locus, prompting specu-
butaline’s longer duration of action means that cumulative effects lation that a genetic variant may underlie the controversial reports
may be seen after repeated injections. Large doses of parenteral of increased asthma mortality in studies of very large numbers