Dose-response curves in bronchial hyperresponsiveness

The responsiveness of the bronchial tree can be studied from the relationship between the dose of the agonist and the response of the airway to the agonist.

There are various ways in which the airways can be challenged and the response of the airways assessed. Agonists may be administered by inhalation, using nebulizers which produce aerosols with particles small enough to reach the intrathoracic airways. Hypotonic or hypertonic solutions may be administered in a similar way. The airways may also be challenged by breathing cold air during normal ventilation and voluntary hyperventilation.

Histamine, in addition to smooth muscle contraction, also induces vasodilatation, interstitial edema and hypersecretion of bronchial glands. Histamine and methacholine are metabolised within minutes, so that it is generally assumed that subsequent doses do not lead to a cumulative response. In addition, the response to these nonspecific stimuli occurs immediately, allowing the effect upon airway calibre to be measured shortly after administration.

The dose-response curves of asthmatics and non-asthmatics differ as follows:

• Airway sensitivity is increased (airway narrowing occurs at low concentrations of agonist) for the asthmatic;
• The reactivity is increased (there is more airway narrowing per unit of agonist, i.e. the slope of the dose-response curve is steeper) for the asthmatic;
• The maximal response is increased in the asthmatic. In non-asthmatic subjects, asthmatic subjects with mild increase in airway responsiveness, and some patients with COPD a plateau in airway narrowing is achieved at high dosages of agonist. Increasing the dose does not produce further airway narrowing.

The asthmatic with mild disease and the patient with COPD exhibit plateaus, but these are associated with greater airway narrowing than in the non-asthmatic. In patients with moderate or severe asthma, a plateau is not obtained. The bronchial challenge has to be stopped at relatively low doses of agonist secondary to symptoms from severe airways obstruction.

Exercise challenge often produces an initial bronchodilation in asthmatics (see peak expiratory flow: PEF, on the right) secondary to the release of catecholamines. Following the early bronchodilation continued exercise results in sustained bronchoconstriction. One cannot therefore construct cumulative dose-response curves using exercise as the agonist. The response to physical exercise is therefore commonly studied as a function of time.

One can also assess the dose-response relationship to a bronchodilator. In patients with (suspected) lung disease the response to a bronchodilator drug is often assessed from a single dose, usually delivered as an aerosol. Bronchodilator drugs are designed to be effective for many hours, and therefore, subsequent doses of such agonists can produce a cumulative effect on airway diameter.

The advantage to using aerosols for drug delivery is the high local concentration of drug delivered to the airway and the low system delivery of the drug. This combination produces maximal local effects in the airway and minimal systemic side effects.

Airway challenges can also be performed by inhaling an aerosol of a hypertonic solution of salt (NaCl, sodium chloride).