Respiratory Function Assays in Safety Pharmacology
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Respiratory Function Assays – General Approach . . . . . . . . . . . . . . Respiratory Function in Conscious Rats . . . . . . . . . . . . . . Respiratory Function in Monkeys and Dogs . . . . . . . . . . . Distinguishing Central from Peripheral Nervous System Effects of Drugs . . . . . . . . . . . . . . . . Continuous Measurement of Expired CO2 . . . . . . . . . . . . . . . .
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and minute volume since normal ventilation requires that the pumping apparatus provide both adequate total pulmonary ventilation (minute volume) and the appropriate depth (tidal volume) and frequency (rate) of breathing. If a change in these parameters occurs, inspiratory flow (mean or peak), expiratory flow (mean or peak), fractional inspiratory time (inspiratory time/total breath time) and time between breaths (expiratory pause or apnea) should be evaluated to help define the mechanism (see Figure 1).
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I.F.1 Respiratory Function Assays – General Approach The objectives of a safety pharmacology study of the respiratory system are to determine whether a drug has the potential to produce a change in respiratory function and to establish whether this change is a liability. Such changes can result from either the primary or secondary pharmacological properties of a drug or from organ dysfunction resulting from the toxicological properties of a drug. The respiratory system consists of two functional units, the pumping apparatus and the gas exchange unit. As such, a complete assessment of respiratory function in safety pharmacology must include an evaluation of both of these components. The pumping apparatus includes those components of the nervous and muscular systems that are responsible for generating and regulating breathing patterns, whereas the gas exchange unit consists of the lung with its associated airways, alveoli, and interstitial area that contains blood and lymph vessels and an elastic fibrous network. The function of the pumping apparatus is ensure the appropriate movement of gases between the environment and the central airways and is evaluated by measuring ventilatory patterns. Ventilatory parameters must include measures of respiratory rate, tidal volume
Fig. 1. Tracings of lung airflow and lung volume changes during spontaneous breathing in a conscious rat. Airflow was measured directly using a “head-out” plethysmograph chamber. The functional endpoints can be automatically calculated for each breath using a data acquisition and analysis software system.
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Chapter I.F · Respiratory Function Assays in Safety Pharmacology
The function of the gas exchange unit is to ensure that gas which enters the airways from the environment reaches the alveoli during inspiration and is removed from the alveoli during expiration. This is accomplished by maintaining patent (open) airways and elastic recoil in the parenchyma of the lung. The function of the gas exchange unit is evaluated by measuring the mechanical properties of the lung. This is most effectively accomplished in conscious
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