Respiratory system

3 Respiratory system



Objectives


After reading this chapter, you will:


• Be able to describe the characteristics of the main diseases of the respiratory system and their pharmacological management

• Know the main drug categories, their mechanism of action, when they are and are not used, and their adverse effects.


Basic concepts


Respiration is the process of exchange of oxygen and carbon dioxide between an organism and its external environment. This principally involves the lungs, which possess the largest surface area in the body in contact with the external environment. The respiratory system (Fig. 3.1) has defence mechanisms which can be divided into physical (such as coughing or the mucociliary escalator, to remove foreign agents) and immunological (such as enzymes, pulmonary macrophages and lymphoid tissue, to ‘disarm’ foreign agents). These defence mechanisms can be launched inappropriately or may be insufficient to deal with the triggering agent, and thus disease may occur.


image

Fig. 3.1 A schematic diagram of the respiratory tract.


(From McGowan et al. Respiratory System, 2nd edition. Mosby, London, 2003.)



Obstructive airways diseases



Asthma


Asthma is a chronic inflammatory disease of the bronchiolar airways. It is characterized by recurrent reversible obstruction to airflow causing airflow limitation, airway hyperresponsiveness and inflammation of the bronchi. Asthma may be allergic (extrinsic) or non-allergic (intrinsic).


In asthma, smooth muscle that surrounds the bronchi is hyperresponsive to stimuli, and underlying inflammatory changes are present in the airways. Asthmatic stimuli include inhaled allergens (e.g. pollen, animal dander), occupational allergens, and drugs or non-specific stimuli such as cold air, exercise, stress and pollution.


The stimuli cause asthmatic changes through several complex pathways (Fig. 3.2). The possible mechanisms of these pathways include the following:


• Immune reactions (type 1 hypersensitivity) and release of inflammatory mediators: the cross-linking of IgE by allergens causes mast cell degranulation which releases histamine, eosinophilic and neutrophilic chemotactic factors. The eosinophils, neutrophils and other inflammatory cells release inflammatory mediators that cause a bronchial inflammatory reaction, tissue damage and an increase in bronchial hyperresponsiveness. Bronchial inflammatory mediators include leukotrienes, prostaglandins, thromboxane, platelet-activating factor and eosinophilic major basic protein.

• An imbalance in airway smooth muscle tone involving the parasympathetic nerves (vagus), non-adrenergic non-cholinergic (NANC) nerves and circulating noradrenaline that act under normal circumstances to control airway diameter.

• Abnormal calcium flux across cell membranes, increasing smooth muscle contraction and mast cell degranulation.

• Leaky tight junctions between bronchial epithelial cells allowing allergen access.

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Fig. 3.2 Pathogenesis and drug action in asthma. Allergens interact with respiratory mucosa (1), and trigger IgE-mediated mast cell response (2). Activation of mast cells causes them to degranulate (3) and release various proinflammatory mediators (4) which attract and recruit further inflammatory response cells (5). These cells also secrete mediators which amplifies the inflammatory response (6). The overall effect is narrowing of small airways (7) by bronchospasm, oedema and increased secretions. (PDE, phosphodiesterase; LT-Rc, leukotriene receptor.)


The above result in symptoms of wheezing, breathlessness and sometimes cough. In many people the asthmatic attack consists of two phases: an immediate-phase response and a late-phase response.



Immediate-phase response


An immediate-phase response occurs on exposure to the eliciting stimulus. The response consists mainly of bronchospasm. Bronchodilators are effective in this early phase.



Late-phase response


Several hours later, the late-phase response occurs. This consists of bronchospasm, vasodilatation, oedema and mucus secretion caused by inflammatory mediators released from eosinophils, platelets and other cells, and neuropeptides released by axon reflexes. Anti-inflammatory drug action is necessary for the prevention and/or treatment of this phase (Fig. 3.2).



Communication


Children with asthma who are very young can have difficulty using inhalers or nebulizers, and it is therefore more effective to give them theophylline, as this can be given in tablet form. Zara is a 4-year-old girl who is on theophylline for this reason. Zara presents to accident and emergency (with her mother) in pain, distress and with pyrexia (a high temperature). She is found to have an infection. Should she be given erythromycin as normal? No! Theophylline plasma concentrations would increase because enzymes involved in its breakdown would be occupied with erythromycin as well. Theophylline has a very narrow therapeutic range and so small increases above the therapeutic dose can be toxic and even fatal.



Chronic obstructive pulmonary disease


Chronic obstructive pulmonary disease (COPD) is a chronic and progressive disease with fixed or poorly reversible airflow obstruction. It encompasses several disease components, namely chronic bronchitis and bronchiolitis, consisting of inflammation and mucus hypersecretion and emphysema, involving destruction of alveolar walls. Long-term smoking is the leading factor in the development of COPD. Cigarette smoke activates inflammatory cells (mainly macrophages and neutrophils), which can cause connective tissue damage in the lung parenchyma, resulting in emphysema and hypersecretion of mucus. α1-Antitrypsin is a protease inhibitor, deficiency of which can result in decreased inhibition of proteases released by neutrophils, thus predisposing to destruction of lung tissue leading to emphysema. Other factors, such as atmospheric pollution, can also have causal links.


Patients with COPD experience cough with the production of sputum, wheeze and breathlessness. Infective exacerbations can occur, giving purulent sputum.



Communication


Mrs Connors is a 62-year-old woman who has been smoking approximately 15 cigarettes a day for the past 40 years. She presents with breathlessness and a 3-month history of cough, which is productive of sputum. After examination a diagnosis of COPD is made, concurrent with her presenting history. She is given Combivent® – a mixture of salbutamol (a β-agonist) and ipratropium bromide (an anticholinergic) – to relax the airways and increase the flow of air. In her case, she was not given a corticosteroid (such as fluticasone propionate) because her condition is currently mild, and it stabilized with the Combivent® treatment. In the future, as the disease progresses, a corticosteroid may be added and she may also be put on long-term oxygen therapy. She is advised to have regular flu and pneumonia vaccinations to prevent exacerbation of her COPD.



Management of obstructive airways disease


Anti-asthmatic drugs include symptomatic bronchodilators (these are most effective in the immediate-phase response), and prophylactic or anti-inflammatory agents, which prevent and/or resolve the late-phase response. The step-wise management of asthma is summarized in Figure 3.3; the stage-dependent treatment of COPD is shown in Figure 3.4. Most patients with COPD get some symptom relief from bronchodilators and anti-inflammatory agents in a fashion similar to people with asthma, yet the response of their airways to these drugs is much less marked, and there are no proved benefits for life expectancy. Long-term oxygen therapy does prolong survival in patients with COPD; however, this must be undertaken with care in patients with carbon dioxide retention because it will reduce their hypoxic drive to breathe.


image

Fig. 3.3 Management of asthma in adults and children over the age of 5 years. Therapy should be started at step 1 and worked upwards until control of symptoms is achieved. Once symptoms have been controlled it may be possible to step down


Adapted from the British National Formulary, 41, March 2001.


image

Fig. 3.4 Stage-dependent COPD treatment


Adapted from the GOLD Executive Summary (2005 update).



Bronchodilators



β2-Adrenoceptor agonists


Examples of β2-adrenoceptor agonists include salbutamol (short acting) and salmeterol (long acting).




Mechanism of action

Airway smooth muscle does not have a sympathetic nervous supply, but it does contain β2-adrenoceptors that respond to circulating adrenaline. The stimulation of β2-adrenoceptors leads to a rise in intracellular cAMP levels and subsequent smooth muscle relaxation and bronchodilation.


• β2-Adrenoceptor agonists may also help prevent the activation of mast cells, as a minor effect.

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Apr 8, 2017 | Posted by in PHARMACY | Comments Off on Respiratory system

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