How Inhalation works
How inhalation works. Mechanisms influencing aerosol deposition.
Mechanisms influencing deposition of particles dependent on their size Deposition of particles in different regions of the respiratory tract depends on particle size and inspiration profile. Large particles (>8 µm) are predominately deposited in the extrathoracic area (oropharyngeal). Smaller particles with a size between 4 to 10 µm reach the tracheobronchial system, while very small particles (1-5 µm) may even arrive at peripheral alveoli.
Impaction is the physical phenomenon, which mainly influences the deposition of larger particles. With growing size, particles become more inert, setting rate increases and their ability to follow the respiratory flow is reduced proportional to velocity of flow. Thus, larger particles precipitate in flexions and narrow parts of the respiratory tract, i.e. nose, larynx and bifurcation of the larger airways.
The second important mechanism leading to particle deposition is sedimentation, i.e. gravitational attraction. This process is proportional to aerodynamic particle size and to the period during which the particles stay in the lungs. Therefore, a short arrest at the end of inhalation increases the likelihood of lung deposition. Both impaction and sedimentation result in deposition of particles larger than 3-5 µm before reaching the alveoli. For particles smaller than 0.5 µm, deposition is mainly influenced by diffusion. This mechanism increases in inverse proportion to particle size and direct proportion to the length of stay in the lungs.
Reliever medications are used to rapidly reduce bronchoconstriction and associated symptoms in acute exacerbations.
Rapid-acting β2-agonists are the treatment of choice in acute exacerbations of asthma and are useful for the pre-treatment of exercise-induced asthma. However frequent or regular administration of these substances do not control asthma adequately. Increased use of short-acting β2-agonists may indicate deterioration of asthma and the need to intensify anti-inflammatory therapy.
Compared with oral administration, which is only indicated in patients unable to use inhaled medication, inhaled β2-agonists cause fewer adverse effects like cardiovascular stimulation, skeletal muscle tremor or hypokalemia.
Anticholinergics produce bronchodilation by reducing intrinsic vagal cholinergic tone and blocking reflex bronchoconstriction. Compared to inhaled short-acting β2-agonists they are less potent bronchodilators and have a slower onset of action. Mostly they are applied in combination with β2-agonists. Additionally anticholinergics provide an alternative for patients experiencing adverse effects from β2-agonists like tachycardia or tremor.
After inhalation of anticholinergics dryness of the mouth or a bitter taste may occur. No adverse effect on mucus secretion has been observed.
Other orally applied medications like glucocorticosteroids or methylxanthines may also be indicated in the treatment of acute asthma exacerbations.
MODE OF ACTION OF INHALED DRUGS IN ACUTE ASTHMA THERAPY
Controller medications are applied daily on a long-term basis to achieve and maintain control of persistent asthma.
Glucocorticosteroids inhaled daily for at least one month significantly reduce the pathological signs of airway inflammation in asthma. Compared with other substances they are most effective in improving lung function, decreasing airway hyperresponsiveness, reducing clinical symptoms as well as frequency and severity of exacerbations and improving quality of life.
Efficacy doses of corticosteroids depend on their potency and bioavailability as well as on the inhalation device used. Although a clear relationship between dose and prevention of acute exacerbations exists, add-on therapy is preferred over increasing the dose of an inhaled corticosteroid. Due to their flat dose-response curve higher dosing provides only little benefit regarding asthma control but increases the risk of adverse effects.
Oropharyngeal candidiasis, dysphonia and coughing are locally observed side effects. Systemic adverse effects include skin thinning, adrenal suppression and decreased bone mineral density. For adults doses equivalent to 500 µg or less beclomethasone seem to be no problem concerning systemic side effects. In comparative studies budesonide and fluticasone were shown to have less systemic effects compared to beclomethasone and triamcinolone. In children no significant adverse effect on growth have been observed in daily doses of 100 to 200 µg. Generally children less than 10 years of age seem to be more susceptible than adolescents. However uncontrolled or severe asthma itself may adversely influence growth and final adult height.
Cromones reduce the IgE-dependant mediator release from mast cells and have a suppressive effect on other inflammatory cells. In mild persistent asthma cromones may be used to inhibit allergen-induced symptoms and acute airflow limitation after exposure to exercise, cold air and sulfur dioxide. Only minimal side effects like occasional coughing are observed following treatment with cromones.
Long-acting β2-agonists relax airway smooth muscle, increase mucociliary clearance, reduce vascular permeability and modulate mediator release. They also provide protection against bronchoconstrictor stimuli although this effect decreases when treatment is applied regularly. However even when used on a long-term basis the overall efficacy of long-acting β2-agonists remains unchanged over time.
Since long-acting β2-agonists do not influence chronic inflammatory changes they should always be combined with inhaled glucocorticosteroids. If steroids fail to control symptoms sufficiently β2-agonists are administered additionally before increasing the steroid dose. Add-on therapy with long-acting β2-agonists reduces clinical symptoms, improves lung function and decreases acute exacerbations as well as use of rapid-acting β2-agonists. With inhaled therapy fewer adverse effects, like cardiovascular stimulation, skeletal muscle tremor or hypokalemia, occur compared to oral medication.
MODE OF ACTION OF INHALED DRUGS IN CHRONIC ASTHMA THERAPY