Asthma airway resistance

One of the most convincing demonstrations of the effect of placebos on asthma was conducted by a research team led by Thomas Luparello, a psychiatrist at the State University of New York.41 Luparello s team asked 40 asthmatic patients to inhale what they presented as irritants or allergens previously identified by the subjects as triggers for their asthmatic attacks. In fact, the substance they inhaled was an inert saline solution - simple table salt dissolved in water. Nineteen of the 40 asthmatic patients reacted with a significant increase in airway resistance, and 12 of them developed full-blown bronchospasm attacks. These asthma attacks were then reversed by the administration of a placebo presented as an asthma medication. 

An MRL of 0.07 ppm has been derived for acute-duration inhalation exposure to hydrogen sulfide. This MRL is based on a LOAEL of 2 ppm for respiratory effects—bronchial obstruction (30% change in airway resistance) in 2/10 persons with asthma reported in the Jappinen et al. 1990 study (Table 2-1 LSE 16). An uncertainty factor of 30 was applied,... 

Based on a LOAEL of 2 ppm for respiratory effects—bronchial obstruction (30% change in airway resistance) in 2/10 persons with asthma in the Jappinen et al. (1990) study, an acute inhalation MRL of 0.07 ppm was derived. An uncertainty factor of 30 was applied to the LOAEL 10 for the use of a LOAEL and 3 for human variability. Since persons with severe asthma were excluded from the study, an uncertainty factor of 3 is needed to protect all sensitive individuals including children. Further details on the derivation of this MRL can be found in the MRL worksheets in Appendix A of this profile. Based on aNOAEL of 30.5 ppm for respiratory effects in mice observed in the CUT (1983a) study, an intermediated MRL of 0.03 ppm was derived. The NOAEL is adjusted for intermittent exposure and the NOAEL[hec] is calculated. An uncertainty factor of 30 is then applied 3 for extrapolating from animals to humans and 10 for human variability. Further details on this MRL can be found in the MRL worksheets in Appendix A of this profile. 

Bronchodilation can be achieved by the use of ipratropium in conditions of increased airway resistance (chronic obstructive bronchitis, bronchial asthma). When administered by inhalation, this quaternary compound has Uttle effect on other organs because of its low rate of systemic absorption. 

Bronchodilators. Narrowing of bronchioles raises airway resistance, e.g in bronchial or bronchitic asthma Several substances that are employed as bronchodilators are described elsewhere in more detail P2-sympathomimetics (p. 84, given by pulmonary, parenteral, or oral route), the methylxanthine theophylline (p. 326, given parenterally or orally), as well as the parasympatholytic ipratropium (pp. 104, 107, given by inhalation). 

Four nurses who were sterilizing endoscopes with glutaraldehyde developed symptoms of asthma and rhinitis temporally related to exposures to glutaraldehyde. Three of the four nurses, however, had a prior history of mild seasonal asthma." On specific provocation testing, one patient had an increase in nasal airway resistance, with a dual immediate and late response pattern. Another patient had a delayed 22% decline in FEVi 80 minutes after the final exposure to glutaraldehyde. The occurrence of late reactions suggested that the underlying mechanism involved sensitization rather than an irritant effect." ... 

Studies of individuals with mild asthma have demonstrated much greater sensitivity to low levels of sulfur dioxide exposure, particularly during exercise. Exposures to concentrations of 0.5-0.Ippm during exercise resulted in signiflcant increases in airway resistance in these subjects. At rest, exposures to Ippm resulted in significant increases in airway resistance in mild asthmatics. ... 

Epidural/Intrathecal administration Limit epidural or intrathecal administration of preservative-free morphine and sufentanil to the lumbar area. Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use. Asthma and other respiratory conditions The use of bisulfites is contraindicated in asthmatic patients. Bisulfites and morphine may potentiate each other, preventing use by causing severe adverse reactions. Use with extreme caution in patients having an acute asthmatic attack, bronchial asthma, chronic obstructive pulmonary disease or cor pulmonale, a substantially decreased respiratory reserve, and preexisting respiratory depression, hypoxia, or hypercapnia. Even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Reserve use for those whose conditions require endotracheal intubation and respiratory support or control of ventilation. In these patients, consider alternative nonopioid analgesics, and employ only under careful medical supervision at the lowest effective dose. 

Pulmonary disease Pilocarpine has been reported to increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. Administer with caution and under close medical supervision in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease. 

Adrenaline but not noradrenaline is useful in the therapy of bronchial asthma since the dilatory effects on the smooth muscle in this area are mediated via /82-adrenoceptors. Furthermore, a swelling of the mucosa, which might considerably contribute to the airway resistance, is reduced by /82-adrenoceptor activation. In this indication selective /82-mimetics are useful due to less circulatory side effects. 

Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer s disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. 

When nonselective beta blockers are used, some antagonism of beta-2 receptors also occurs.2,31 The antagonism of beta-2 receptors on bronchiole smooth muscle often leads to some degree of bronchoconstric-tion and an increase in airway resistance. Although this event is usually not a problem in individuals with normal pulmonary function, patients with respiratory problems such as asthma, bronchitis, and emphysema may be adversely affected by nonselective beta antagonists. In these patients, one of the beta-1-selective drugs should be administered. 

Blockade of the 2 receptors in bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. Betai-receptor antagonists such as metoprolol or atenolol may have some advantage over nonselective antagonists when blockade of Bi receptors in the heart is desired and -receptor blockade is undesirable. However, no currently available i-selective antagonist is sufficiently specific to completely avoid interactions with 62 adrenoceptors. Consequently, these drugs should generally be avoided in patients with asthma. On the other hand, some patients with chronic obstructive pulmonary disease (COPD) may tolerate these drugs quite well. 

Several diseases with established oscillatory rhythm in their pathogenesis have been identified. In the case of asthma, chronotherapy has been extensively studied [9, 10]. Airway resistance increases progressively at night in asthmatic patients [11], Circadian changes are seen in normal lung function, which reaches a low point in the early morning hours. This dip is particularly pronounced in people with asthma. 

Jappinen et al. (1990) exposed 10 subjects who had asthma to 2 ppm hydrogen sulfide for 30 min. On average, airway resistance was increased by 26.3% and specific airway conductance was decreased by 8.4% in the exposed subjects compared with control subjects. Although the changes were not statistically significant, 2 subjects showed changes of more than 30% in airway resistance and specific airway conductance, which indicate bronchial obstruction (Jappinen et al. 1990). 

Table 9-2 summarizes exposure studies that used controlled exposures to sulfur dioxide. Mild irritation, bronchoconstriction, and decreased lung function, as assessed by measurements of specific airway resistance or decreases in forced expiratory volume or expiratory flow, are produced after exposure of healthy individuals to low concentrations of sulfur dioxide. People with asthma are more susceptible. Exercise, cold air, and airborne participates appear to exacerbate the toxic effects (Gong et al. 1995 Roger et al. 1985 Schachter et al. 1984 Stacy et al. 1981). Concentration seems to be more important than duration as a determinant of health effects. Initial atmospheric exposure to sulfur dioxide can result in immediate discomfort, irritation, and coughing that abate after gradual acclimation to increasing concentrations (Andersen et al. 1974). Health effects reported by healthy volunteers are summarized in Table 9-3. 

A 37-year-old man who had taken lithium and sulpiride for 14 years and who was a long-time smoker without respiratory symptoms or a history of asthma had lithium withdrawn because of an asymptomatic bradycardia (44 beats/minute) (125). Six weeks later, he developed symptoms of asthma, including nocturnal cough, exertional wheezing, increased airway resistance, and a low FEV1, attributed to lithium withdrawal. 

A number of patients who have persistent airflow obstruction exhibit considerable variation in airways resistance and hence in their benefit from bronchodilators drugs for asthma. It is important to recognise the coexistence of asthma with chronic obstructive pulmonary disease in some patients, and to assess their responses to bronchodilators or glucocorticoids over a period of time (as formal tests of respiratory function may not reliably predict clinical response in this setting). 

Partial agonists, such as acebutolol, oxprenolol, pindolol, practolol, and xamoterol, produce less resting bradycardia. It has also been claimed that such agents cause a smaller increase in airways resistance in asthmatics, less reduction in cardiac output (and consequently a lower risk of congestive heart failure), and fewer adverse effects in patients with cold hands, Raynaud s phenomenon, or intermittent claudication. However, none of these advantages has been convincingly demonstrated in practice, and patients with bronchial asthma or incipient heart failure must be considered at risk with this type of compound. 

Labetalol is less likely to increase airways resistance in patients with bronchial asthma or to reduce peripheral blood flow. However, it can produce postural hypotension (SEDA-3, 166-7), and paresthesia of the scalp (1,2) and perioral numbness (3) have been described. 

Although tachykinins are important in the airway response to certain interventions, there appears to be little or no tachykinin tone in the absence of intervention. In non-asthmatic or stable asthmatic human airways, neither the NEP inhibitor thiorphan (Cheung et /., 1992, 1993) nor the combined Nkl/Nk2 receptor antagonist FK224 (Ichinose et al., 1992) has any effect on baseline specific airways resistance. Likewise, alterations in NEP activity do not contribute to the enhanced bronchoconstrictive responses to NkA observed in patients with mild asthma. Asthmatic patients respond to inhaled thiorphan with an increase in NkA-induced bronchoconstriction similar in magnitude to that documented in non-asthmatic subjects (Cheung et al., 1992, 1993). 

Asthma is defined clinically by recurrent episodes of airway obstruction that reverse either spontaneously or with bronchodilator therapy. The airway obstruction is accompanied by increase in airway resistance due to bronchospasm, inflammation, and excessive mucus production. Bronchoconstriction, airway closure, and gas trapping may eventually lead to respiratory failure. Hyperresponsiveness is considered a hallmark of asthma, making these individuals uniquely sensitive to exposure to airborne chemicals such as isocyanates. 

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