Asthma Inhalers - Bronchodilatation and Ventolin Inhalers in Asthma Treatment
Inhaled bronchodilators reduce airway resistance and increase maximum expiratory flow by relaxing bronchial smooth muscle. Two classes of inhaled bronchodilators are beta-adrenergic agents and anticholinergic agents. Barnes et al have recently shown that the density of cholinergic receptors is maximum in large airways and decreases in the more peripheral airways, while the opposite is true for beta-adrenergic receptors. The site of action of an inhaled broncho-dilator depends on where in the tracheobronchial tree it is deposited and on the density of receptors for that particular agent at the site of deposition. Previous studies using density dependence of maximal expiratory flow (Vmax) have produced conflicting results. Ingram et al found a decrease in density dependence after atropine and an increase after isoproterenol suggesting predominant large and small airway dilatation respectively. In another study, Hensley et al supported these observations with measurements of dead space and closing volume. On the other hand, MacNee et al found no preferential site of action following inhaled ipratropium-bromide and salbutamol employing changes in density dependence of Vmax as the method to determine site of action.
In the present study, we examined whether a selective beta-adrenergic agonist, fenoterol, or the newly developed anticholinergic agent, ipratropium bromide, would have a measurable difference in their site of action when administered in the usual manner by a metered dose inhaler. We measured the site of action of these bronchodilators by changes in the density dependence of Vmax as well as changes in the density dependence of pulmonary resistance (Rl). We took advantage of a computer averaging technique to measure Rl, which allowed more accurate and reproducible estimates by eliminating errors induced by cardiac artifacts.
Material and Methods
Hie subjects for these experiments were eight normal laboratory personnel, six men and two women, with a mean age of 33 (± 4.2 SD) years. Anthropometric data are shown in Table 1. All subjects were nonsmokers with normal pulmonary function. Each subject was studied on two separate days in a double-blind cross-over manner.
All studies were performed in an air-conditioned, pressure-compensated, volume displacement plethysmograph. Flow was measured with a pneumotachometer (Fleisch No. 3) coupled to a differentia pressure transducer (Sanborn 270), volume was measured with a spirometer (Krogh) coupled to a linear displacement transducer (Type 33 HR: Shaevitz). The plethysmograph was pressure-compensated so that input was in phase with output to 8 Hz and there was a flat amplitude vs frequency response to 8 Hz. Do you know where to buy asthma ventolin inhalers? The answer is given if you will go to the page using the link.
Flow and volume signals were digitized to an accuracy of 0.5 percent using a computer (Apple lie) programmed to calculate forced expiratory volume in one second (FEV), forced vital capacity (FVC), maximum expiratory flow at 50 percent (VmaxSO) and 25 percent (Vmax25) of vital capacity. The pneumotachometer was calibrated separately for air and for the helium/oxygen mixture.
Functional residual capacity (FRC) was measured by Boyles Law technique. Transpulmonary pressure was monitored with an esophageal balloon catheter which was positioned 10 cm from the gastroesophageal junction in the middle third of the esophagus where cardiac oscillations were minimal, and inflated with 1 ml of air. Pressure was measured with a differential pressure transducer (Validyne MP45-2± 100 cmHaO). Volume, flow, and transpulmonary pressure were charted on a Hewlett Packard recorder (HP 7754A).
The Rl was measured by the method of Mead and Whitten-berger. Subjects inhaled to total lung capacity (TLC), after exhaling to FRC, breathed at a fixed respiratory rate of 30 breaths per minute, achieved by the use of a metronome. Tidal volume was controlled by displaying a signal proportional to volume in view of the subject: volume was set at 1 L. Transpulmonary pressure and flow signals were displayed on a storage oscilloscope (Tektronix), and the pressure flow loop was closed by subtracting a signal in phase with tidal volume from the transpulmonary pressure. It was frequently impossible to close both the inspiratory and expiratory limbs of the pressure flow curve, and under such circumstances, a closed inspiratory limb and a single point at zero flow was accepted as a satisfactory recording. Once closed, the signals were channelled to the computer, configured to act as a data averaging circuit at a sampling rate of 100 Hz. The computer averaged the pressure and flow signals in a cumulative fashion over a minimum of ten breaths to decrease the artifact induced by cardiac oscillations. Figure 1 shows a representative pressure flow curve. The averaged curves were stored on diskette for later analysis.
Fenoterol (400 μg) and ipratropium bromide (40 μg) were administered in a double-blind, crossover design on separate study days by metered dose inhaler from residual volume (RV). The patients were instructed to activate the inhaler at the onset of inspiration and inhale to near TLC.
The protocols for the two study days were identical except for the actual bronchodilator inhaled. After measurement of FRC, at least three forced expiratory maneuvers were performed on compressed air which had a similar humidity to the helium/oxygen mixture. Subjects then inspired to TLC, and while still breathing compressed air at FRC, maintained a tidal volume of 1 L at a frequency of 30 breaths per minute as outlined previously. During this time, the pressure flow curve was closed, averaged, and stored on diskette. When a satisfactory air pressure flow curve had been recorded, the inhaled gas mixture was changed to 80 percent helium and 20 percent oxygen (He-O2), which the subject breathed until equilibration, defined as an end-tidal nitrogen concentration of less than 5 percent. Pulmonary resistance was again measured, and the subjects then performed three forced expiratory maneuvers before leaving the body plethysmograph. The predetermined bronchodilator was inhaled and the subject rested quietly for 45 minutes before re-entering the body plethysmograph. The above protocol was repeated in total. At the end of the study, the subjects performed three additional forced expiratory maneuvers on compressed air to assess the possibility of continuing bronchodilatation and ventolin inhalers.
The subdivisions of lung volume consisted of FRC, TLC, and FVC. Measurements of flow included the FEV1, Vmax50, and Vmax25. Two criteria were used to select air flow volume curves for analysis. The forced expiratory maneuver with the largest sum of FEV1 and FVC was selected unless the FVC was greater than 5 percent larger than the largest He-02 curve. Under these circumstances, the air curve with the largest sum of FEV1 and FVC which was within 5 percent of the best helium/oxygen curve was chosen.
The Rl was measured by digitizing the stored, averaged pressure flow-curves. The change in pressure at inspiratory flow rates of 1.0, and 1.5 Us was calculated and resistance defined as the change in pressure divided by flow. Since satisfactory closure of the expiratory pressure flow curves was not achieved in all subjects, the analysis was confined to the inspiratory limb. We have recently studied the reproducibility of measurement of Rl by this method in our laboratory. Ten normal subjects were studied on four separate days and the coefficient of variation of Rl in inspiration (RlI) at 1 L/sec between days was 15 ± 7.3 percent and that for the density dependence of RlI was 20±10.3 percent.
Density dependence was defined as the ratio of flow or resistance during He-Oa breathing to that on compressed air. The average difference between air and He-Oa FVC was 1.23 ± 1.12 SD percent, and the largest difference was 4.0 percent. The curves were matched so that half the volume difference occurred at TLC and half at RV. Density dependence of flow at 50 percent and 25 percent of VC and density dependence of Rl at 1.0 and 1.5 Us were calculated.
Comparisons of baseline measurements on the two study days and of measurements before and after bronchodilator were made with a paired Students f-test.
Table 1—Anthropometric Data and Baseline Lung Function
Figure 1. Pressure (in cmHtO) is plotted against flow (L/s). A representative averaged curve shows that the inspiratory limb is closed. The data represent the average pressure-flow relationship of at least ten breaths. Pulmonary resistance was calculated at inspiratory flows of 1.5 and 1.0 L/s.