The chief functions of respiration are to supply oxygen (O 2 ) and remove carbon dioxide (CO 2 ) from the body. The main disorders of the respiratory system are asthma and chronic obstructive pulmonary disease (COPD), but respiratory depression can be caused by overdosage of many drugs that have a depressive effect on the central nervous system (CNS).
Control of airway muscle and glands
Airway smooth muscle
The upper airways are under the control of the parasympathetic nervous system with acetylcholine (ACh) acting on muscarinic M 3 receptors on airway smooth muscle leading to contraction. The lower airways can be constricted by excitatory non-adrenergic, non-cholinergic (NANC) transmitters (e.g. inflammatory peptides released from sensory neurons) and are relaxed by inhibitory NANC transmitters (e.g. nitric oxide). Airway smooth muscle contraction can also be inhibited by circulating adrenaline acting on β 2 -adrenoceptors, although there is no sympathetic nerve supply to airway smooth muscle. However, sympathetic nerve fibres can indirectly influence airway smooth muscle tone by inhibiting parasympathetic ganglia.
Mucus secretion is inhibited by the sympathetic system and is stimulated by the parasympathetic system, by inflammatory mediators and by chemical (e.g. air pollutants) and physical (e.g. cold air) stimuli.
Asthma is a syndrome in which there are recurrent attacks of reversible airway obstruction – caused by bronchoconstriction and mucus secretion – occurring in response to stimuli that are not in themselves noxious due to underlying bronchial hyperresponsiveness. Asthma is recognized as a chronic inflammatory condition ( Fig. 19.1 ) with an asthma attack being characterized by difficulty breathing out, wheezing and cough. Many asthmatics have associated allergic diseases, whilst others have so-called intrinsic asthma where allergy is not thought to play a major role. Certain subjects can also have asthma attacks precipitated by exposure to aspirin or tartrazine.
Drugs used in the treatment of asthma
Two main types of drug are used:
β 2 -adrenoceptor agonists
Examples: salbutamol and terbutaline (both short acting, peak action in 30 min, duration 4–6 h) are used for symptomatic relief by relaxing airway smooth muscle. Longer acting β 2 agonists such as salmeterol (longer acting, duration 12 h) or indacaterol (duration 24 h) are used for maintenance treatment to prevent symptoms, usually administered in combination with an inhaled corticosteroid (see below).
Mechanism of action
All act as physiological antagonists to counter the airway smooth muscle contraction induced by various spasmogenic mediators released during an asthma attack, e.g. histamine and cysteinyl-leukotrienes ( Fig. 19.1 ). They have no effect on bronchial hyperresponsiveness or the inflammatory components of asthma.
Usually given by inhalation but can be given orally or by injection. Salbutamol can be given intravenously (IV) for the treatment of acute severe asthma.
The main unwanted effect during asthma treatment is tremor. Other effects that can occur if the drugs are absorbed are given in Chapter 11 , with hypokalemia and tachycardia being the most serious.
Examples: the methylxanthines theophylline, doxophylline and aminophylline (theophylline ethylene diamine).
Xanthines are now recognized as having both bronchodilator and anti-inflammatory actions.
Mechanism of action
Xanthines have traditionally been considered to work as non-selective phosphodiesterase (PDE) inhibitors that result in an increase in cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). In airway smooth muscle it is the inhibition of PDE 3 that leads to relaxation, with inhibition of PDE 4 contributing to the anti-inflammatory effects of xanthines. Theophylline, but not doxophylline, is also known to act as an adenosine receptor antagonist, although this action is more likely the cause of the side effect profile of this drug.
Theophylline is given orally as a sustained-release preparation and acts for up to 24 h depending on the preparation. It is useful for nocturnal asthma. Aminophylline, which is more soluble, is given by a slow IV injection (at least 20 min) for the treatment of acute severe asthma. The xanthines are metabolized in the liver with a half-life of approximately 8 h, although this varies widely among individuals. Xanthines have a narrow therapeutic window with 5–10 ug/mL in plasma being recommended for maintenance treatment, although higher plasma levels are often required for acute bronchodilation. Above 20 ug/mL plasma levels serious side effects can occur (see below) and so measurement of plasma levels of theophylline is recommended. A number of drug-drug interactions occur with xanthines which can become clinically important in view of the narrow range of safe plasma concentrations. Some drugs increase the plasma xanthine concentration (e.g. oral contraceptives, erythromycin, ciprofloxacin, cimetidine, some calcium channel blockers), whilst some decrease it (e.g. rifampicin, carbamazepine).
Unwanted effects of the xanthines
Xanthines have stimulant effects on the heart and the CNS and cause gastrointestinal (GI) tract disturbances. Xanthines are also mild diuretics and can cause sleep disturbance.
Muscarinic receptor antagonists
Muscarinic receptor antagonists are also used in the treatment of asthma. They antagonize the effects of ACh released from the parasympathetic nerves carried in vagus nerve X that innervate the lung and thus reduce airway smooth muscle contraction and mucous secretion. Short-acting muscarinic receptor antagonists are exemplified by ipratropium bromide are used for the acute treatment of asthma exacerbations, often in combination with salbutamol. Longer acting muscarinic receptor antagonists such as tiotropium bromide that have been widely used in the treatment of COPD are now being more frequently used in the treatment of asthma, often in combination with a long-acting β 2 agonist. This class of drug has no anti-inflammatory actions.
Cysteinyl leukotriene receptor antagonists and 5-lipoxygenase inhibitors
Montelukast blocks the CysLT 1 receptor and reduces the effects of leukotrienes released during an asthma attack. Zileuton is a 5-lipoxygenase inhibitor that inhibits the production of leukotrienes. These drugs are used in prevention of exercise induced bronchospasm and are often used by paediatricians in patients who do not take their glucocorticoids (steroid phobia), although they have at best very modest anti-inflammatory actions. Montelukast is administered orally once daily and may provide additional improvement in lung function when used along with other drug classes. Unwanted effects include headache and GI tract disturbances.
Examples used in the treatment of asthma include beclomethasone diproprionate, budesonide , fluticasone propionate and mometasone (all given by inhalation), prednisolone (given orally) and hydrocortisone (given IV for the treatment of acute severe asthma). These drugs are ineffective for relieving acute symptoms as they have no bronchodilator activity, but they are highly effective at reducing airway inflammation, particularly eosinophil infiltration. The mechanism of action is described in Chapter 16 . Glucocorticoids also reduce the activation of inflammatory cells as well as the release of proinflammatory cytokines ( Fig. 16.3 ) and other inflammatory mediators.
Inhaled glucocorticoids may cause thrush (oropharyngeal candidiasis) and voice problems; spacing devices that reduce deposition of the drug in the pharynx and promote deposition in the smaller airways can ameliorate these effects. Systemic adverse effects (see Chapter 16 ) are rare with inhaled agents but can occur with regular large doses of oral agents.
Cromoglycate and nedocromil sodium
Mechanism of action
Cromoglycate and nedocromil sodium are administered by inhalation of an aerosol or powder, prophylactically to prevent allergic responses in the airways. It has been suggested that they work to reduce the release of inflammatory mediators from mast cells to reduce bronchoconstriction and airway inflammation, although they are not able to induce bronchodilation and so should not be used to treat acute attacks of asthma. These drugs are also able to inhibit the activation of sensory nerve fibres in the lung and can therefore reduce airway irritability and cough.
These drugs have a very good safety profile but rarely cause irritation of the upper respiratory tract.
Anti-immunoglobulin E (anti-IgE) and anti-interleukin-5 (anti-IL-5) antibodies may be administered by injection for patients with severe atopic asthma or certain eosinophilic asthma phenotypes and are described in Chapter 16 .
Regimen for the treatment of asthma
Mild asthma is usually treated with inhaled β 2 -agonists taken as required for symptomatic relief. With progressively more severe asthma, inhaled corticosteroids, long-acting β 2 -agonists and xanthines are introduced on a prophylactic basis. Because of their more serious side effects, oral steroids are used only in severe asthma.