Drugs Used in Cough and Asthma 233 to isoprenaline It is given by oral as well as inhalation route by nebulizer Palpitation, restlessness, nervousness are the common side effects with salbutamol TERBUTALINE It is highly selective β2 agonist similar to salbutamol, useful by oral as well as inhalational route SALMETEROL It is newer long acting selective β2 adrenergic agonist with slow onset of action, used for maintenance therapy in asthma, nocturnal asthma and asthma induced by exercise The β2 selective adrenergic agonists are most widely used drugs for the treatment of asthma They are effective after oral and inhaled administration and have a longer duration of action Albuterol (salbutamol), salmeterol, bitolterol, pirbuterol are available as aerosol pack in metered dose BAMBUTEROL It is a latest selective adrenergic β2 agonist with long plasma half life and given once daily in a dose of 10-20 mg orally METHYLXANTHINES (THEOPHYLLINE DERIVATIVES) AND ITS Among the methylxanthines, aminophylline is most commonly used drug in the treatment of bronchial asthma It is a stable mixture of theophylline and ethylenediamine These drugs inhibit the enzyme phosphodiesterase, this inhibition results in higher concentration of intracellular cyclic AMP Increased cAMP leads to bronchodilatation, cardiac stimulation and vasodilatation Pharmacological Actions CNS: The caffeine and theophylline are pharmacologically CNS stimulants and produce alertness and cortical arousal, but in higher doses causes restlessness, nervousness and insomnia CVS: Methylxanthines stimulate the heart and increase the force of myocardial contraction Tachycardia is more common with theophylline Cardiac output is increased in CHF patients Smooth muscles: Methylxanthines relax smooth muscles especially bronchi in asthmatic patients Theophylline produces sustained bronchodilator action Kidney: Methylxanthines exert mild diuretic action by inhibiting tubular reabsorption of sodium and water, In addition, it increases renal blood flow and glomerular filtration rate Skeletal muscles: Methylxanthines facilitate neuromuscular transmission by increasing acetylcholine release Mast cells: Methylxanthines inhibit the release of histamine and other mediators from mast cells which indirectly help in the management of bronchial asthma THEOPHYLLINE Theophylline has two distinct action: smooth muscle relaxation (i.e bronchodilatation) and suppression of the response of the airways to stimuli (i.e non-bronchodilator prophylactic effects) Bronchodilatation is mediated by inhibition of Section 5/ Autacoids 234 two isozymes of phosphodiesterase (PDE III and to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are mediated through one or more different molecular mechanisms, that not involve inhibition of PDE III or antagonism of adenosine receptors Theophylline increases the force of contraction of diaphragmatic muscles It is well absorbed orally It is distributed to all tissues and is 50% plasma protein bound It is extensively metabolized in liver by demethylation and oxidation Only 10% is excreted unchanged in urine Adverse Effects Side effects are usually associated with the increasing serum concentration of theophylline and includes nausea, vomiting, headache, insomnia, tachypnea, epigastric pain, palpitation, hypotension, irritability Higher doses can cause persistent vomiting, cardiac arrhythmias, intractable seizures, tachycardia Other side effects include alopecia, hyperglycemia, inappropriate ADH syndrome, rash ANTICHOLINERGICS Anticholinergics, like atropine and its derivative ipratropium bromide block cholinergic pathways that cause airway constriction They may provide added bronchodilator effect in patients who are receiving beta2-adrenergic agents for asthma The detailed pharmacology is discussed in chapter ‘Cholinergic blocking agents.’ MAST CELL STABILIZERS SODIUM CROMOGLYCATE It is a synthetic chromone derivative, highly effective in preventing asthma attacks It inhibits degranulation of mast cells by trigger stimuli It also inhibits the release of various asthma provoking mediators e.g histamine, leukotrienes, platelet activating factor (PAF) and interleukins (IL’s) from mast cells It prevents the late response and subsequent bronchial hyperresponsiveness by acting on inflammatory cells such as macrophages or eosinophils It does not produce bronchodilatation and also does not antagonize the constrictor effect of histamine etc therefore not found beneficial in acute attack of asthma and used for prophylaxis only Sodium cromoglycate is not absorbed orally and is to be administered by aerosol Only a small fraction of inhaled drug is absorbed systemically and it is rapidly excreted unchanged in urine and bile Adverse reactions reported are bronchospasm, throat irritation and rarely headache, dizziness, rashes and nasal congestion Therapeutic Uses Bronchial asthma: It is used for prophylactic treatment of bronchial asthma Allergic rhinitis: Two percent aqueous nasal spray (FINTAL nasal spray) is used for nasal decongestion although it is not a nasal decongestant Allergic conjunctivitis: Two percent aqueous eye solution (FINTAL eye Drugs Used in Cough and Asthma drop) is used in allergic conjunctivitis in chronic cases KETOTIFEN It is a cromolyn analogue It is an antihistaminic (H1 antagonist) and probably inhibits airway inflammation induced by platelet activating factor (PAF) in primate It is not a bronchodilator It is used in asthma and symptomatic relief in atopic dermatitis, rhinitis, conjunctivitis and urticaria It is absorbed orally and well tolerated Bioavailability is 50% due to first pass metabolism and is primarily metabolized The common side effects include dry mouth, sedation, dizziness and nausea CORTICOSTEROIDS Like mast cell stabilizer, corticosteroids not relax airway smooth muscle directly but reduce bronchial reactivity, increase airway caliber, suppress inflammatory response to antigen antibody reaction or trigger stimuli and reduce the frequency of asthma exacerbations They produce more sustained symptomatic relief than any bronchodilator and mast cell stabilizer Systemic steroids are used in both severe chronic asthma and in acute emergency of asthma (status asthmaticus) Among the inhaled steroids, beclomethasone is a halogenated corticosteroid ester used in aerosol form It suppresses asthma by a topical antiinflammatory action without causing any systemic side effects They reduce the bronchial hyperreactivity 235 and increase the peak expiratory flow rate in asthmatic patients They are not effective during an acute attack or in status asthmaticus Side effects are sore throat, hoarseness of voice, dysphonia, oropharyngeal candidiasis LEUKOTRIENE PATHWAY INHIBITORS Apart from histamine, leukotrienes liberated during inflammation are more powerful bronchoconstrictor and longer acting Leukotrienes also increase bronchial mucus secretion and increase vascular permeability All the leukotrienes are derived from 5lipoxygenase pathway of arachidonic acid and are synthesized by a variety of inflammatory cells in the airways e.g eosinophils, mast cells, basophils and macrophages The LTB4, C4 & D4 exert many effects known to occur in bronchial asthma, including bronchoconstriction and increased bronchial reactivity The drug, montelukast (LTB4 antagonist) and zafirlukast (LTD4 antagonist) have the advantage of being used when taken orally in asthmatic patients MONTELUKAST It is a cysteinyl leukotriene receptor antagonist indicated for the management of persistent asthma It has been shown to have substantial blockade of airway leukotriene receptors 24 hours after oral dosing Montelukast appears to be a useful alternative or adjunct to inhaled corticosteroid therapy in adults and an alternative to sodium cromoglycate in children This page intentionally left blank Section Drugs Acting On Blood ... adenosine receptors Theophylline increases the force of contraction of diaphragmatic muscles It is well absorbed orally It is distributed to all tissues and is 50% plasma protein bound It is extensively... provide added bronchodilator effect in patients who are receiving beta2-adrenergic agents for asthma The detailed pharmacology is discussed in chapter ‘Cholinergic blocking agents.’ MAST CELL STABILIZERS... does not antagonize the constrictor effect of histamine etc therefore not found beneficial in acute attack of asthma and used for prophylaxis only Sodium cromoglycate is not absorbed orally and