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In this essay we will discuss about the drugs used for the treatment of bronchial asthma:- 1. Selective β2 Agonists 2. Methylxanthines 3. Antimuscarinics 4. Anti-Inflammatory Drugs (Controller Medicaments) 5. Sodium Cromoglicate 6. Nedocromil Sodium 7. Leukotriene Receptor Antagonists.
Essay # 1. Selective β2 Agonists:
Salbutamol (albuterol), terbutaline, dibeteol, and metapro- terenol are medium acting (duration of action about 4 hours) β agonist and remain the best bronchodilator treatment for acute asthma when given by aerosol inhalation, as they produce prompt relief of wheezing and dyspnea with minimal side effects.
They do not control the inflammatory component of asthma. If β2 stimulants are required more than once daily or if night time symptoms appear, the treatment should be combined with anti-inflammatory drugs. Orally, they are not very effective and their use has been-replaced by long acting β2 stimulants in controlling asthma symptoms, particularly those at night.
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Salmeterol and formoterol are long acting β2 stimulants with duration of action up to 12 hours and are given by inhalation twice daily. They are superior to salbutamol given four times daily for prevention of nocturnal asthma or exercise induced bronchospasm. They are not useful for the relief of acute attacks and are considered more as a controller rather than a bronchodilator agent.
Parenteral administration is unnecessary if inhaled medications can be administered quickly. In rare settings, three doses of adrenaline (0.3 ml of a 1:1000 solution) subcutaneously can be used at 20 minutes interval. If adrenaline is administered, ECG monitoring is necessary.
Side effects of β2 stimulants are seldom troublesome when given by aerosol inhalation. However, they may cause CNS and CVS symptoms like fine tremors, nervous tension, headache, peripheral vasodilation and arrhythmias. β2stimulants can lead to potentially serious hypokalemia particularly with concomitant treatment with theophylline, corticosteroids and diuretics or by hypoxia and requires monitoring of plasma potassium concentration in severe asthma. Hypersensitivity reactions including paradoxical bronchospasm, urticaria and angioedema have been reported.
Essay # 2. Methylxanthines:
Theophylline, theobromine and caffeine are the naturally occurring methylated xanthine alkaloids. Caffeine is the constituent of coffee and tea and theobromine that of cocoa. Theophylline is only used in therapeutics as a bronchodilator in bronchial asthma, mainly as a controller medication.
Pharmacological actions:
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Theophylline inhibits the enzyme phosphodiesterase and blocks adenosine receptors in CNS, CVS, and smooth muscles that account for its bronchodilator and other (adverse) actions in asthma. Theophylline stimulates the CNS (especially the higher centers), the heart-rate and force of contraction and secretions of acid and pepsin in the stomach. It relaxes the smooth muscles, which is most prominent on bronchi, especially in asthmatics. It has a mild diuretic action.
Pharmacokinetics:
Theophylline has a narrow therapeutic index (small difference between the therapeutic and toxic dose) with substantial variation in metabolism, which makes it a difficult drug to use without monitoring its clinical response and blood concentration. Theophylline is metabolized in the liver, which is dependent on a number of factors.
The metabolism of theophylline is decreased with resultant high blood levels in heart failure, cirrhosis, viral infection, in the elderly, and by drugs such as cimetidine, ciprofloxacin, erythromycin, allopurinol, and oral contraceptives. The metabolism of theophylline is increased with resultant low blood levels in smokers and in chronic alcoholism, and by drugs such as phenytoin, carbamazepine, barbiturates and rifampicin.
Therapeutic uses:
Sustained release theophylline preparations and ultra-sustained release theophylline, uniphyllin may be used as a single dose at night to control nocturnal asthma and early morning wheezing. The use of oral theophylline has declined because of high incidence of side effects associated with rapid absorption and factors influencing its blood concentrations.
Aminophylline, a mixture of theophylline with ethyl-enediamine is given by very slow intravenous injection in acute severe and life threatening asthma if β2 stimulants and corticosteroid fail to produce the desired response. Aminophylline may have a role in the treatment of left ventricular failure in patients who are also suffering from asthma and bronchitis, where opioids are contraindicated.
Adverse effects:
Side effects are dose related and include nausea, anxiety, palpitation, arrhythmias, and convulsions. Presence of ethyl-enediamine may give rise to allergic reactions.
Essay # 3. Antimuscarinics:
Ipratropium is related to atropine and acts as a bronchodilator by virtue of its anticholinergic action. It is given via an inhaler or nebulizer by inhalation. It has a powerful local action on the bronchi, without any significant systemic side effects of atropine. Ipratropium by inhalation is indicated in the management of chronic asthma in patients with coexistent heart disease, in whom the use of methylxanthines and β2 agonists may be dangerous.
The major disadvantages of ipratropium are slow onset of action (60 to 90 minutes may be required before peak bronchodilation is achieved) and modest potency. Side effects are infrequent and include dry mouth and rarely urinary retention and constipation.
Essay # 4. Anti-Inflammatory Drugs(Controller Medicaments):
Corticosteroids:
Glucocorticoids are the most potent and most effective anti-inflammatory medications available. Inhaled corticosteroids are used in the long-term control of asthma as they restore the integrity of the airway epithelium and markedly suppress the inflammatory and allergic aspects of asthma. Beclometasone, budesonide, flunisolide, fluticasone and triamcinolone are the steroids available for use by inhalation.
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Low doses of topical corticosteroids do not cause any significant systemic side effects because of low oral bioavailability of any swallowed dose of topical steroid. Fluticasone has been reported to be most active with extensive first pass hepatic metabolism and low systemic oral bioavailability.
Side effects of inhaled steroids are considerably fewer than oral steroids and include risk of glaucoma, cataract, osteoporosis, and growth retardation in children. Occasionally Candida infection of the mouth and hoarseness of voice may occur; the risk and severity of this complication can be reduced by means of aerosol spacers and good oral hygiene (i.e. rinsing out the mouth by gargling after dosing).
Glucosteroids possibly act by inducing the synthesis of a new protein, lipocortin, which inhibits phospholipase A2 and thus the generation by inflammatory cells of prostaglandin, leukotriene’s, and platelet activating factor does not take place.
Systemic or oral steroids are indicated in acute illness (uncontrolled asthma or acute severe asthma) when severe airway obstruction is not resolving or is worsening despite intense optimal bronchodilator therapy, and in chronic disease where there has been failure of a previously optimal regimen with frequent recurrences of symptoms of increasing severity. Methyl- prednisolone is the drug of choice for IV therapy for life threatening asthma.
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Since the intravenous and oral administration produce the same effects, oral prednisone can be substituted. It should be emphasized that the effects of steroids in acute asthma are not immediate and may not be seen for 6 hours or more after the initial administration. Consequently, it is mandatory to continue vigorous bronchodilator therapy during this interval.
The tapering of steroid therapy depends on clinical situations. Normally, the dose of steroids is reduced by one-half every third to fifth day after an acute episode, but in situations in which it appears that continued steroid therapy will be needed, an alternate-day schedule should be initiated to minimize side effects. This is particularly important in children, since continuous steroid administration interrupts growth.
Essay # 5. Sodium Cromoglicate:
Cromoglicate prevents the release of mediators (such as histamine, leukotriene) from mast cells in the bronchi which are responsible for bronchospasm. It can reduce the incidence of asthmatic attacks and allow dose reduction of β2 stimulants and oral steroids. Sodium cromoglicate is of no value in the treatment of acute attacks of asthma and even for prophylaxis, it is much less effective than steroid inhalations.
Therapeutic uses:
Sodium cromoglicate inhalations are used for prevention of exercise induced asthma. It is also used topically as 2% solution in allergic conjunctivitis and allergic rhinitis. Adverse effects include cough, bronchospasm and throat irritation.
Essay # 6. Nedocromil Sodium:
Nedocromil is chemically different from cromoglicate. It has a more potent anti-inflammatory effect. It is also a mast cell stabiliser. Nedocormil inhalations have greater prophylactic value than cromoglicate but less than that of inhaled steroid treatment in asthma. No serious side effect has been reported but some patients complain of unpleasant taste and nausea.
Essay # 7. Leukotriene Receptor Antagonists:
Leukotrienes are substances produced by inflammatory white cells, which cause spasm of bronchial muscles. The leukotriene receptor antagonists, montelukast and zafirlucast, block the effects of leukotriene’s on the airways. These drugs are indicated for the prophylaxis of asthma for add-on therapy in patients who are not adequately controlled with an inhaled steroid and a short acting β2stimulant. Adverse effects include GIT disturbances, hypersensitivity reactions, upper respiratory infections, cardiac complications and peripheral neuropathy.
Miscellaneous agents:
The use of immunosuppressant agents such as gold, methotrexate or cyclosporine has been suggested as adjunctive treatment for patients with severe chronic asthma, who cannot otherwise discontinue high-dose steroid treatment. The effects of these agents on steroid dosage and disease activity are minor, and side effects can be considerable. Consequently, this form of treatment can be viewed only as experimental, and their routine use is unwarranted.
Opiates, sedatives, and tranquillizers should be absolutely avoided in the acutely ill patient with asthma because the risk of depressing alveolar ventilation is great, and respiratory arrest has been reported to occur shortly after their use. Expectorants and mucolytic drugs are of no significant value in the treatment of the acute or chronic phase of this disease. Mucolytic drugs such as acetyl-cysteine may actually produce bronchospasm when administered to susceptible patients with asthma.
