Drugs used in bronchial asthma

1. Drugs used in Bronchial Asthma Dr. S. Parasuraman , M.Pharm ., Ph.D., Senior Lecturer, Faculty of Pharmacy AIMST

2. Bronchial Asthma Asthma as an inflammatory illness Accounting 5000 deaths/ year in USA Asthma is common disorder and it is characterized by airway inflammation and hyperresponsiveness to stimuli that produce bronchoconstriction. These stimuli include cold air, exercise, a wide variety of allergens and emotional stress. Extrinsic asthma: It is mostly episodic, less prone to status asthmaticus . Intrinsic asthma: It tends to be perennial, status asthmaticus is more common .

3. Pathophysiology of asthma

4. Chronic obstructive pulmonary diseases (COPD) Incudes chronic bronchitis and emphysema chronic bronchitis: cough associated with inflammation of the bronchioles Emphysema: permanent destruction and enlargement of the airspaces distal to the bronchioles COPDs results airway obstruction, dyspnea, ↓ blood O 2 concentrations and ↑blood CO 2 concentrations. Risk factor of COPD: Smocking and old age Treatment: Bronchodilators and long time oxygen therapy. Antibiotics can be used to treat acute exacerbations caused by bacterial infections.

5. Bronchial Asthma: Treatment approaches Prevention of antigen antibody reaction: Avoidance of antigen, hyposensitization Neutralization of IgE : Omalizumab Suppression of inflammation and bronchial hyper reactivity: Cotricosteroids Prevention of release of mediators: Mast cell stabilizers Antagonism of released mediators: Leukotriene antagonists, antihistamines, platelet aggravating factor (PAF) antagonist Blacked of constrictor neurotransmitter: Sympathomimetics Directly acting bronchodilators: Methylxanthines

6. Classification Bronchodilators β Sympathomimetics : Salbutamol, Terbutaline , Bambuterol , Salmeterol , Formoterol , Ephedrine. Methylxanthines : Theophylline (anhydrous), Aminophylline, Choline theophyllinate , Hydroxyethyl theophylline, Theophylline ethanolate of piperazine , Doxophylline . Anticholinergics ( muscarnic receptor antagonist): Ipratropium bromide, Tiotropium bromide. Leukotriene antagonists: Montelukast , Zafirlukast . Mast cell stabilizers: Sodium cromoglycate , Ketotifen . Corticosteroids Systemic: Hydrocortisone, Prednisolone and others. Inhalational: Beclomethasone dipropionate , Budesonide, Fluticasone propionate, Flunisolide , Ciclesonide . Anti- lgE antibody: Omalizumab

7. Bronchodilators Stimulates b 2-adrenergic receptors of bronchi b 2 -agonists Anticholinergic drugs Smooth muscle relaxation reduce tonus of vagus Methylxanthines inhibit phosphodiesterase b 2 -agonists : treatment of acute asthmatic attacks Muscarinic antagonist: Less useful in asthma, used for treat COPDs Methylxanthines : Long-term/ prevent bronchoconstriction

8. Sympathomimetics The selective β 2 agonist is the primary bronchodilators used in the treatment of asthma/ acute asthmatic attacks. β 2 adrenergic receptor agonists stimulates the beta receptor, increasing the cAMP concentration in smooth muscle and causing bronchodilatation . It also increase the conductance of large Ca 2+ -sensitive K + channels in airway smooth muscle, leading to membrane hyperpolarization and relaxation. The selective β 2 agonist relax the bronchial smooth muscle without affecting cardiac function. In higher doses s elective β 2 agonist increasing the heard rate by stimulating the cardiac β 1 -receptor. The selective β 2 agonist produce hypertension to patient those receiving digitalis. Types: Long-acting β 2 adrenergic receptor agonists ( Salmeterol ; formoterol ) Short-acting β 2 adrenergic receptor agonists ( albuterol, levalbuterol , metaproterenol , terbutaline , and pirbuterol )

9. Sympathomimetics Salbutamol: Selective β 2 agonists with less cardiac side effects Inhaled salbutamol produce bronchodililation within 5-min and the action lasts for 2-4 h. Used for acute asthmatic attack. Not suitable for prophylaxis Side effect: Palpitation, restlessness, nervousness, throat irritation and ankle edema. Metabolism: metabolized in gut; oral bioavailability is 50%. Duration of action: oral salbutamol acts 4-6 h. Dose: 2-4 mg/ oral; 0.25- 0.5 mg/ i ,.p., or s.c. ,; 100-200 μ g/ inhalation Terbutaline : Similar to salbutamol; regular use dose not reduce bronchial hyper-reactivity Dose: 5 mg/ oral; 0.25 mg/ i ,.p., or s.c. ,; 250 μ g/ inhalation Cont.,

10. Sympathomimetics Bambuterol : Biocarbamate ester of prodrug of terbutaline Slowly hydrolyzed in plasma and lung by pseudocholinesterase to release the active drug over 24 h. It also reversely inhibits pseudocholinesterasein a dose dependent mannor . Used in chronic bronchial asthma in a singe evening dose of 10-20 mg/ oral. Salmeterol : First long acting selective β 2 agonists with slow onset of action Twice daily for maintain the therapy/ nocturnal asthma, but not for acute asthma Concurrent use of inhaled glucocorticoid with salmeterol is advised for patient with persistent asthma. COPD: equivalent to inhaled anticholinergics in COPD. Reduce breathlessness by abolishing the reversible component of airway obstruction. Formoterol : Long acting selective β 2 agonists which acts 12 h when inhaled. Compare to salmeterol it has a faster onset of action (with in 10 min) Cont.,

11. Methylxanthines Theophylline and its derivatives are most commonly used for the treatment of COPD and asthma. Caffeine, theophylline and theobromine are naturally occurring xanthine alkaloids which have qualitatively similar actions. Mechanism of action: Methylxanthines inhibits cyclic nucleotide phosphodiesterase (PDEs), thereby preventing conversion of cAMP and cGMP to 5’-AMP and 5’-GMP, respectively. Inhibition of PDEs will lead to an accumulation of intracellular cAMP and cGMP . Bronchodilataion , cardiac stimulation and vasodilatation occur when cAMP level rises in the concerned cells . Theophylline and related methylxanthines are relatively nonselective in the PDE subtypes inhibitor . Theophylline is a competitive antagonist at adenosine receptors . Adenosine can cause bronchoconstriction in asthmatics and potentiate immunologically induced mediator release from human lung mast cells. Methylxanthines inhibits the adenosine action thereby casing bronchodilataion .

12. Methylxanthines Mechanism of action: Bronchodilation Bronchial tone Muscarinic antagonist Acetylcholine Adenosine Theophylline cAMP ATP AMP Adenylyl cyclase Phosphodiesterase (PDE) Theophylline Beta agonist

13. Methylxanthines Pharmacological action: CNS: Stimulant; affects higher center. Caffeine 150-200 mg produce a sense of wellbeing, alertness, beats boredom, allays fatigue and improve performance and increase the motor activity. Caffeine is more active than theophylline in producing these effects. Higher dose cause nervousness, restlessness, panic, insomnia and excitements. Still higher dose cause tremors, delirium and convulsions. Theophylline is more toxic than caffeine. Stimulates medullary vagal, respiratory and vasomotor centers. High dose: Vomiting and gastric irritation and CTZ stimulation. Cont.,

14. Methylxanthines Pharmacological action: CVS Stimulates the heart and increase force of contraction. Increase the heart rate (direct action) but decrease it by vagal stimulation- net effect is variable. Tachycardia; increased cardiac output; increased cardiac work High dose: cardiac arrhythmias Effect on blood pressure is variable and unpredictable. Usually a rise in systolic and fall in diastolic BP is observed. Vasomotor center and direct cardiac stimulation- tends to raise BP Vagal stimulation and direct vasodilatation- tends to lower BP Smooth muscles: Relaxation Theophylline is more potent and slow, sustained dose related bronchodilatation Increase vital capacity Direct action due to adrenergic stimulation Biliary spasm is relived, but the effects on intestines and urinary tract is negligible. Theophylline is more potent; caffeine has minimal actions. Cont.,

15. Methylxanthines Pharmacological action: Kidney Mild diuretics Inhibiting tubular reabsorption of Na + and water Increasing vascular blood flow and g.f.r . Theophylline is more potent; caffeine has minimal actions. Skeletal muscles: Caffeine enhance contractile power. In high dose it increases release of Ca + from sarcoplasmic reticulum by direct action. Twitch response at low doses. Caffeine facilitates neuromuscular transmission by increasing Ach release. Stomach: Enhance secretion of acid and pepsin Gastric irritation (more with theophylline) Cont.,

16. Methylxanthines Pharmacological action: Metabolism Increase BMR. Plasma free fatty acid levels are increased. Mast cells and inflammatory cells: Theophylline inhibits the release of histamine and other mediators form mast cells and active inflammatory cells. Cont.,

17. Pharmacological actions of Methyl xanthines CNS Stimulation Increase motor activity Improve the performance CVS Stimulate the heart Increase the force of contraction High dose: cardiac arrhythmias BP: effect is variable Stimulation of Vegas stimulation: ↓ BP Vasomotor center : ↑ BP Smooth muscle Relaxation Lungs vital capacity- increased Biliary spasm: relieved Kidney Mild diuretics (Inhibiting reabsorption of Na + & H 2 O) Increase the renal blood flow Increase the g.f.r . Mast cell Inhibit the release of histamine Stomach Enhance the secretion of acid, Pepsin Metabolism Increase BMR It has variable physiological actions

18. Methylxanthines - Theophylline Pharmacokinetics: Absorption: Absorbed orally; rectal absorption form suppositories is erratic. Distribution: All tissues; cross BBM; crosses placenta and is secreted in milk; 50% plasma protein bound Metabolism: Metabolized in liver (CYPP1A2 ) by demethylation and oxidation. Excretion: Excreted in urine; 10 % of total administration excreted unchanged form. Elimination rat various considerably with age (age dependent excretion). Adult t 1/2 is around 7-12 h. Children elimination is much faster ( t 1/2 3-5 h ); In premature infants has prolonged t 1/2 (24-36 h). In higher dose pharmacokinetics changes form first order to zero order.

19. Methylxanthines - Theophylline Cont., Adverse effects: Narrow margin safety CVS and CNS stimulant; ADRs not dependent to dose; GIT distress Children are more liable to developed CNS toxicity Rapid i.v injection cause- precordial pain, syncope and sudden death Bronchodilatation

20. Methylxanthines - Theophylline Interactions: Theophylline metabolism decreased by smoking, phenytoin, rifampicin, phenobarbitone and charcoal broiled meat meal., which increases the parenthesis. Erythromycin, ciprofloxacin, cimetidine, oral contraceptives and allopurinol inhibits CYP1A2 and increasing the theophylline plasma concentraction ; dose should be reduced to 2/3. Theophylline reduce the effects of phenytoin, lithium. Theophylline enhance the effects of furosemide, sympathomimetics , digitalis, oral anticoagulants and hypoglycemics . Indications: Primarily used to treat chronic obstructive lung disorders and asthma. Also used to treat apnea Cont.,

21. Anticholinergics Ipratropium/ tiotropium (derivative of atropine) Parasympathetic activation/ release of ACh cause bronchoconstriction and increase mucus secretion. Blocking the action of ACh by anticholinergic drugs produce bronchodilation and also reduce the volume of respiratory secretion. Less effective than sympathomimetic. Inhaled ipratropium/ tiotropium are choice of bronchodilator choice in COPD. Tritropium produce longer duration of action than ipratropium ADR: Dry mouth, respiratory tract discomfort

22. Leukotriene antagonists Montelukast , Zafirlukast Both are having similar action and clincial utility Block the cys-leukotrienes C 4 , D 4 and E 4 (LTC 4 , LTD 4 , LTE 4 ) Alternative for inhaled glucocorticoids Prophylactic therapy for mild, moderate asthma; not used for terminating asthma. Both are very safe drugs and ADRs are few (headache, rashes); eosinophilia and neuropathy are infrequent. Few cases Churg -Strauss syndrome ( vasculitis with eosinophilia) have been reported. Dose : Montelukast 10 mg OD, Zafirlukast 20 mg BD

23. Leukotriene antagonists Mechanism of action of leukotriene antagonist, antiinflammatory drugs Cont., Bronchoconstriction, Inflammation, increased mucus Bronchoconstriction, Inflammation, Pain Block by steroidal antiinflammatory drugs Block by nonsteroidal antiinflammatory drugs Block by Leukotriene antagonists

24. Corticosteroids Corticosteroids are not bronchodilator; benefit by reducing bronchial hyperreactivity , mucosal edema and by suppressing inflammatory. Inhaled glucocorticoids are partially absorbed and because of their systemic AEs oral glucocorticoids are usually reserved for patients with severe persistent asthma. Systemic steroid therapy Sever chronic asthma: Not contorted by bronchodilator and inhaled steroids. Status asthmaticus / acute asthma exacerbation: ‘’’

25. Corticosteroids Inhaled steroids High topical and low systemic activity (due to poor absorption/ fast pass metabolism). Inhaled steroids are not recommended for patient with mild or episodic asthma. High dose inhaled steroids are beneficial for advanced COPD with frequent exacerbations. Systemic steroid therapy Sever chronic asthma: Not contorted by bronchodilator and inhaled steroids. Status asthmaticus / acute asthma exacerbation: ‘’’

26. Mast cell stabilizers Sodium cromoglycate , Ketotifen Inhibits degranulation of mast cell by trigger stimuli and prevent the release of histamine, LTs, PAF, interleukins etc. from mast cells. Inhibition of mediator release by cromolyn is through blockade of calcium influx in mast cells. Long time therapy reduce cellular inflammatory response. It is not histamine antagonist/ bronchodilator- ineffective in asthmatic attack. Pharmacokinetic: Not absorbed orally. It is administered as an aerosol through metered dose inhaler delivering 1 mg per dose; 2 puffs 4 times a day Not popular- production of cough and bronchospasm because of particulate nature of the inhalation. Small fraction of the inhaled drug is absorbed systemically and excreted unchanged form in urine and bile.

27. Mast cell stabilizers Use: Bronchial asthma: Sodium. Cromoglycate is used as a long term prophylactic in patients not adequately controlled by inhaled bronchodilators. Alternative for inhaled steroids in mild to moderate asthma but not severe cases. Allergic rhinitis: Cromoglycate is not nasal decongestant, regular prophylactic use as a nasal spray produces symptomatic improvement in many patients. Allergic conjunctivitis: Regular use as eye drops is benificial in some chronic cases Cont., Adverse effect ( cromoglycate ): Bronchospasm Throat irritation Cough, headache Arthralgia, rashes and dysuria Rarely nasal congestion Adverse effect ( Ketotifen ): Generally well tolerated Sedation and dry m outh Dizziness, nausea and weight gain

28. Anti- lgE antibody: Omalizumab recombinant DNA-derived monoclonal antibody Selectively binds to human immunoglobulin E ( IgE ) and decrease binding affinity of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils, reduce allergic response. Omalizumab may be particularly useful for treatment of moderate to severe allergic asthma in patients who are poorly controlled with conventional therapy. Due to the high cost of the drug, limitations on dosage, and limited clinical trial data, it is not currently used as firstline therapy .

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