Bronchodilators and Anti-Intlammatories

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Bronchodilators b2-Agonists: Relax airway smooth muscle through stimulation of b2-adrenoceptors which activate adenylate cyclase leading to an increase in intracellular cAMP and a decrease in intracellular calcium concentration. There are two classes of b2-agonists:

(1) Short-Acting : fenoterol, salbutamol, terbutaline have a rapid onset of action and relieve symptoms for 3 to 6 hours. They block the early phase response and may also inhibit the release of bronchospastic mediators from mast cells, sensory nerves and other inflammatory cells. Short-acting b2-agonists should be used as short term reliever therapy in all patients with symptomatic asthma. They should be administered by inhalation as required rather than on a regular basis. Reduction in the duration of effect, or an increase in use, indicates poor control and treatment should be reviewed. In children, inhaled b2-agonists are more effective and have fewer side effects than bronchodilator syrups, although occasional symptoms can be managed with oral therapy.

(2) Long-Acting : bambuterol, formoterol, salmeterol can be used to improve symptom control, particularly at night or with exercise-induced symptoms, and are indicated for use on a long term basis. They should not be used for symptomatic relief, or as a replacement for alternative prophylactic therapy. Long-acting b2-agonists should be used with caution in those given slow release b2-agonist tablets.

Salmeterol is administered by inhalation. It has a slow onset of action but bronchoconstrictlon is relieved for, up to 12 hours and both early and late phase responses are inhibited. It can be used in children over 4 years, but the long term effects have not been fully documented. Long acting b2-agonists should be reserved to supplement children already receiving anti-inflammatory therapy. Formoterol is administered by inhalation. It has a rapid onset of action, that is comparable to the short-acting b2-agonists, and a duration of action of approximately 12 hours. Bambuterol is a pro-drug of the short acting b2-agonist terbutaline. It is taken orally and has a sustained bronchodilator effect, lasting up to 24 hours. It is not recommended in children. All b2-agonists are contraindicated for use with b2-blockers, including eye drops. Over usage may result in dose-related increases in pulse rate, physiological tremor, blood glucose concentration and potentially serious hypokalaemia.

Xanthines : Aminophylline, theophylline. The mechanism of action is unclear, although xanthines probably relax airway smooth muscle by increasing intracellular cAMP via phosphodiesterase inhibition and through mediator and receptor antagonism. They inhibit the early and late phase response. Xanthines are indicated as adjuncts to maximal anti-inflammatory treatment and short-acting b2-agonists PRN. Patients with severe asthma receiving high doses of these drugs should have serum potassium levels measured as hypokalaemia may be potentiated. Sustained-release preparations are of particular benefit in preventing nocturnal asthma. In children, however, up to one third will experience GI disturbance, sleep disruption and/or psychological changes. The high incidence of side effects requires close monitoring to maintain serum levels at 10 to 20 micrograms per ml. Clearance of xanthines is increased by smoking and alcohol, but reduced in acute viral infection, cardiac failure and hepatic disease. Clearance can also be affected by a wide range of drugs:

Bioavailability

Sustained-release preparations containing the same quantity of xanthine are unlikely to have the same pharmacokinetic profile. It is essential that they are prescribed by brand name and patients are not transferred from one preparation to another without full clinical assessment and retitration.

Antimuscarinics (antichollnergics) relax airway smooth muscle by blocking vagal reflex bronchoconstriction, and inhibit the early phase response of an asthma attack. Regular inhalation of antimuscarinics such as ipratropium is indicated where control is inadequate with maximal anti-inflammatory treatment and short-acting [5C]f23 b[OD]}2-agonist PRN. Under specialist guidance, ipratropium can be of use for symptom relief during the first year of life when short-acting b2-agonists may be ineffective.

Antimuscarinics are of great value in the treatment of chronic obstructive pulmonary disease (COPD) since vagal cholinergic tone appears to be the only reversible component of airway narrowing. They have a slow onset but prolonged duration of action, ipratropium lasting up to 8 hours. Tiotropium owes its long duration of action, up to 24 hours, and hence its once daily dose to its slow dissociation from the M3 receptor site. It is indicated for the maintenance treatment of COPD. Side effects are very uncommon, but caution should be exercised in patients with glaucoma and prostatic hypertrophy and in children where sputum viscosity may be increased.

Prophylaxis

Anti-Lnflammatories Corticosteroids : Prevent attacks by reducing airway hyper-responsiveness and bronchial mucosal inflammatory reactions such as oedema and mucous secretion. Corticosteroids block the late phase response.

(1) Inhaled Steroids : beclometasone, budesonide, fluticasone are the mainstay of prophylactic therapy. They are the recommended preventer drugs for adults and children for achieving overall treatment goals. They should be prescribed for those with recent exacerbations, nocturnal asthma, impaired lung function or those using inhaled b2-agonists more than once daily. Relatively small doses of inhaled steroids may be effective although an increase in dosage may be used temporarily to achieve stability. Therapy should be reviewed regularly and titrated down to the lowest effective dose to control symptoms. Persisting symptoms, despite good inhaler technique, suggest the need for higher or more frequent doses. If a child's asthma is not controlled on the maximum licensed dose, refer child to a specialist in paediatric asthma.

Using a medium or large volume spacer in conjunction with an MIDI will enhance lung deposition and reduce oropharyngeal deposition. Absorption can also be minimised by rinsing the mouth after inhalation of high dose steroids. Side effects with inhaled steroids are uncommon, minor local effects become evident at higher doses. However, children's growth should be regularly monitored and the possibility of adrenal insufficiency should be considered, particularly if presenting with reduced level of consciousness. NB: Not all inhaled steroid doses are clinically equivalent and care should be taken when transferring therapies.

(2) Oral Steroids : betamethasone, dexamethasone, methylprednisolone, prednisolnne, prednisone, triamcinolone. Short course rescue therapy in the control of asthma exacerbations is associated with few side effects. Where control of symptoms cannot be achieved with maximal doses of inhaled steroids and bronchodilators the addition of steroid tablets may also be used to prevent severe attacks. In young severe asthmatics low, alternate I day dosing under specialist guidance may be of use. Suppression of the hypothalamic pituitary-adrenal axis is possible although systemic side effects are more frequent with prolonged use and at high doses, therefore regular assessment of response is essential to facilitate dose reduction. Oral and injectable corticosteroids for use in asthma can be found in section 6B.

Leukotriene Receptor

Antagonists: Montelukast and zafirlukast are selective CysLTt receptor antagonists that bind with high affinity to the receptor site preventing the inflammatory mediators, the leukotrienes, from exerting their effect. As a result both the early and the late phase of the asthma response are reduced. Montelukast is used as add-on therapy in mild to moderate asthma inadequately controlled by inhaled corticosteroids and short acting b2-agonists. Zafirlukast is simply indicated for the treatment of asthma.

Anti-Inflammatories, Now Steroid : Sodium cromoglicate, nedocromil sodium are for prophylactic use. They prevent the release of bronchospastic mediators from mast cells and other inflammatory cells, although nedocromil has an effect on a wider range of inflammatory cells. They block the early and late phase response and prevent exercise-induced attacks. Administration is on a regular basis by inhalation. Cromoglycate and nedocromil are indicated in adults who require bronchodilatation more than once daily or who have nocturnal symptoms and where steroid therapy is inappropriate.

In children nedocromil should not be given but cromoglycate by MIDI is a first line drug in preventative therapy. Sodium cromoglycate may also be administered if necessary by nebuliser in children under 5 years. Children who fail to respond to an initial 4 to 6 week trial of cromoglycate may be given an inhaled steroid. Side effects are extremely rare.

Anti-Allergics : Ketotifen is an orally administered anti-allergic that has undefined anti-asthmatic properties. It pre-empts the action of cytokines on mast cells and eosinophils thus reducing their influx at sites of inflammation. It also exerts a sustained inhibitory effect on histamine reactions. Ketotifen may be of greater benefit in infancy than in older children, particulary in those intolerant of other therapies. Drowsiness is a potential side effect.

Additional Management for Children

In children suitable inhaler devices and co-ordination for effective dosage are often lacking. Nebulisers may be necessary, but in infants nebuliser therapy may produce paradoxical bronchoconstriction, therefore, treatment should be attempted using an MDI with a medium or large volume spacer and face mask or polystyrene cup (for relief therapy only). Bronchodilator response in the first year of life is variable and ipratropium bromide has been suggested to be more effective than salbutamol.

Nebulised budesonide, inhaled via a face mask may be used in children under 18 months old.

Relief therapy in children of any age can be repeated 2 to 4 hourly but failure to respond or deterioration in condition require urgent medical assessment. Children of any age should be referred to a respiratory specialist if receiving more than 800 micrograms per day of inhaled steroid or in excess of 4 short courses per year of steroid tablets.

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