Causes of changes in bronchial calibre
Leukotrienes are involved in the development of bronchospasm. They are so named because of their presence in white blood cells (the leuko component) and their chemical bonds (a triene system of double bonds). They are a group of eicosanoids (bioactive lipid derivatives of arachidonic acid). Leukotrienes are produced by the action of the enzyme 5-lipoxygenase, which is found in white blood cells (particularly eosinophils) and mast cells, among other tissues. When activated, 5-lipoxygenase binds to the cell membrane and associates with five-lipoxygenase-activating protein (FLAP), the resulting complex causing change in arachidonic acid to produce leukotriene A4 (LTA4). This is a precursor of a whole family of leukotrienes, LTA4 to LTF4. LTC4, D4 and E4 are spasmogenic, and comprise the substance formerly termed ‘sRS-A’.
Control of bronchial calibre
Adrenoceptor agonists
β2-agonists
Examples – bambuterol, formoterol, salbutamol, salmeterol, terbutaline
Selective β2-adrenoceptor agonists are used in the treatment of bronchospasm and for prophylaxis. This selectivity is not absolute, and high doses of these drugs will cause β1 effects (tachycardia, tremor, hyperglycaemia, increased insulin secretion and hypokalaemia).
β2-agonists reverse bronchospasm caused by histamine release, platelet-activating factor and members of the leukotriene family, particularly C4, D4 and E4.
The β2-agonist salbutamol is the most widely used agent in the treatment of asthma. It is conjugated in the liver and excreted in both conjugated and unchanged forms in urine and faeces. Terbutaline is a similar drug that may have advantages in some patients because it has fewer sympathomimetic side effects. Terbutaline may be used antenatally to stimulate fetal lung surfactant production. Bambuterol is a prodrug of terbutaline.
β2-agonists (in particular ritodrine, salbutamol and terbutaline) may be used as uterine relaxants for the management of premature labour or excessive contractions, or during Caesarean section to facilitate delivery. Administration for this purpose may be inhalational.
Other adrenoceptor agonists
Examples – adrenaline, ephedrine, isoprenaline, orciprenaline
Ephedrine, isoprenaline, orciprenaline and adrenaline are non-selective sympathetic agonists with bronchodilator (β2) actions, which are infrequently used. Adrenaline has re-emerged as an effective inhaled agent for the treatment of acute tracheolaryngobronchitis (croup) and laryngeal oedema. A dose of 0.5 mL kg−1 1:1000 adrenaline up to a maximum of 5 mL may be nebulised, and given according to effect.
Anticholinergic agents
Examples – ipratropium bromide, tiotropium bromide
Anticholinergic agents are given inhalationally and, as with other inhaled bronchodilators, only 10% of the dose reaches the lungs. These drugs act at muscarinic acetylcholine receptors and so inhibit bronchoconstriction. Systemically administered anticholinergic drugs also affect these receptors. Anticholinergic agents have the following respiratory effects:
Bronchodilatation
Reduced airways resistance
Increased anatomical dead space
Increased physiological dead space
Ipratropium bromide (N-isopropylatropine) is a non-selective muscarinic antagonist at M1, M2 and M3. It has a rapid onset of action, but takes 2 hours to peak, lasting for 4–6 hours. Of the orally deposited drug, 70% passes unprocessed into the faeces. A small amount of drug is absorbed systemically from the oral mucosa, and this is metabolised by the liver. Antagonism at the (negative feedback) M2 receptor increases acetylcholine release, which may limit the effectiveness of its M1-mediated bronchodilatation. Ipratropium also blocks the M1-muscarinic acetylcholine receptors on mast cells, limiting degranulation. It is primarily used for prophylaxis of bronchospasm, frequently in combination with other inhaled agents.
Tiotropium has a longer half-life, allowing once-daily administration, and remains preferentially bound to M1 and M3 compared with M2, so improving efficacy.
Methylxanthines
Examples – caffeine, theophylline
The methylxanthines are stimulant bronchodilators derived from plant alkaloids which have both a local effect on the bronchial tree and a general central stimulating effect which increases respiratory drive. They have a multimodal mechanism of action that includes:
Phosphodiesterase inhibition
Facilitation of β2 action
Enhanced Ca2+ release from sarcoplasmic reticulum in striated muscle
Adenosine receptor antagonism
Inhibition of phosphodiesterase directly and via β2 effects causes bronchodilatation similar to that of β2-agonists. The enhanced release of calcium within the sarcoplasmic reticulum improves the function of the respiratory muscles. Methylxanthines are potent inhibitors of adenosine receptors and inhibit smooth muscle contraction by increasing cAMP and by direct interference with calcium entry.
Clinical effects
Respiratory system
Methylxanthines cause bronchodilatation, with increased anatomical dead space. They are effective against bronchospasm owing to the release of histamine, platelet-activating factor and leukotrienes. The force of respiratory skeletal muscle contraction is increased, as is respiratory rate. Respiratory work is increased with relatively less fatigue. Methylxanthines are effective prophylactically, and are also indicated for the treatment of acute attacks of bronchospasm.
Cardiovascular system
Heart rate and cardiac contractility are increased and peripheral vascular resistance is markedly reduced due to smooth muscle relaxation. This combination of effects may be helpful in the treatment of left ventricular failure.
Central nervous system
There is general stimulation, which increases respiratory rate. Although CNS excitation is relatively non-specific, both vasomotor and respiratory centres are markedly affected. Convulsions are a potential hazard.
Other effects
These include the stimulation of gastric acid and pepsin secretion, diuresis (by dilatation of afferent glomerular arterioles) and inhibition of uterine contraction.
The methylxanthines can be considered as a family of agents with theophylline as the parent compound. Although theophylline is well absorbed orally, its rapid elimination in the liver by cytochrome P450, and variable protein binding of about 40%, leads to unpredictable clinical effects. Theophylline levels are measured in the plasma during chronic administration to ensure adequate therapeutic concentrations. Aminophylline, the ethylene diamine salt of theophylline, is more water-soluble (but highly alkaline in solution). This improved water solubility is required for intravenous administration.
Steroids
Examples – beclomethasone, budesonide, fluticasone
Inhaled and systemic steroids may be used in the treatment and prevention of bronchospasm secondary to obstructive airways disease. Steroids act directly on intracellular receptor sites, have an anti-inflammatory action that reduces mucosal oedema and swelling, and also interfere with many mediators of airways resistance. Chemical mediators suppressed by steroid treatment include prostaglandins, thromboxanes, prostacyclin, leukotrienes, platelet-activating factor and histamine. There are multiple other effects of steroids, including reductions in inflammation, smooth muscle tone, vascular permeability and pulmonary vascular resistance, all of which are useful in the treatment of bronchospasm.
The effects of inhaled steroids can be summarised as follows:
Inhibition of arachidonic acid metabolites
Inhibition of inflammatory response
Stabilisation of mast cells
Catecholamine synergism
Although inhaled steroids are used for prophylaxis, acute attacks require systemic steroids – but their action by this route is slow in onset.
Beclomethasone is an inhaled steroid given in typical doses of 100–400 μg, 2–4 times a day. Budesonide may have advantages in reaching the bronchioles in a more reliable manner, with less systemic effects.
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