Asthma and Cough, PHARMACOLOGY OF DISEASE AFFECTING THE RESPIRATORY SYSTEM

LECTURE NOTES ON COUGH AND ASTHMA FOR MEDICINE, PHARMACY AND ALLIED HEALTH SCIENCES

1. PCL-302 SYSTEMIC PHARMACOLOGY ASTHMA AND COUGH BY Dr. Kabiru Abubakar

2. ASTHMA Asthma: One of the main disorders of the respiratory system, others include cough, chronic bronchitis and emphysema. Bronchial asthma : - Is a recurrent reversible airway obstruction characterized by hyper responsiveness of tracheobronchial smooth muscle to a variety of stimuli, resulting in narrowing of the air tubes, often accompanied by increased secretion, mucosal edema and mucus plugging. Two characteristic features are: inflammatory changes in the airways and bronchial hyper responsiveness (abnormal sensitivity to stimuli)

3. Symptoms of asthmatic attack comprises: Dyspnoea , Wheezing, Cough, shortness of breadth and tightness in the chest. Etiology:- The bronchi of asthmatics respond to a variety of specific and non-specific stimuli. Therefore asthma may be classified according to the precipitating factors as follows Extrinsic (allergic, immunologic and atopic) asthma occurs to some individuals who are exposed to environmental allergins . This type starts early in childhood and may be genetic in origin as the family history may reveal previous atopic disorders such as asthma and hay-fever. Asthmatic attacks are frequently seasonal and their incidence may increase during the high pollen counts. The immunoglobulin which mediates this type-1, or immediate hypersensitivity reaction is gamma E ( IgE ). Intrinsic (Non-immunologic, non-allergic, non-atopic) asthma has no genetic or familial explanation. In this group of patients non specific irritants including smoke, cold air and dust may precipitate an attack. This type of asthma may depend on the level of irritability at which the bronchi react to various irritants. Psychological factors: - Psychological stimuli and emotional upsets have been implicated in asthmatic attacks. Such patients must have hyper responsive bronchi. The attack may be precipitated by the central nervous system.

4. Pulmonary infections: - Either of viral or bacterial origin has been associated with asthma attacks. The particles of the infective organism may precipitate allergic or hypersensitivity reactions. Pulmonary infections may cause deterioration in the physiological state of the sensitive bronchi resulting in asthma. Physical exertion has been shown to precipitate asthma in predisposed individuals, and many patients suffer attacks of wheezing and dyspnea during or immediately after exercise Drugs: -Few drugs are known to precipitate asthma in hypersensitive patients. Aspirin, indomethacin, ibuprofen, mefenamic acid and yellow tartrazine which is added to various foodstuffs and cosmetics which inhibit synthesis of prostaglandins is most frequently implicated in asthma. Drugs such as propranolol, histamine and prostaglandin F, have been associated with asthma attacks. Such reactions occur in predisposed individuals and are associated with the pharmacological properties of the drugs.

5. Anti-asthmatic agents: - While asthma cannot be cured, it can be controlled: 1. Medications Long term: Inhaled corticosteroid,Leukotriene modifiers, Long-acting beta agonists,Combination inhalers Quick relief: (rescue) medications Short-acting beta agonists Ipratropium Oral and intravenous corticosteroids 2. Bronchial thermoplasty 3. Learning to recognize one’s own triggers and taking steps to avoid them.

6. Goals of Therapy Minimal or no chronic symptoms day or night Minimal or no exacerbations No limitations on activities; no school/work missed Maintain (near) normal pulmonary function Minimal use of short-acting inhaled beta 2 agonist Minimal or no adverse effects from medications

7. General classification Β 2 -adrenoceptor agonist ( Sympathomimetic): Adrenoceptor drugs cause bronchodilation through β 2 receptor stimulation resulting to increase in cyclic AMP formation in bronchial muscle cell thereby causing relaxation. In addition, increased cyclic AMP in mast cells and other inflammatory cells decreases mediator release. Adrenergic drugs is the mainstay of treatment of reversible airway obstruction but should be cautiously used in hypertensive, ischemic heart disease patients and in those receiving digitalis. They are the fastest acting bronchodilators when inhaled. Though adrenaline and isoprenaline are effective bronchodilators, it is the selective β 2 agonists that are now used in asthma to minimize cardiac side effects

8. continuation Salbutamol (Albuterol) is a highly selective β 2 -agonist, cardiac side effects are less prominent. Inhaled salbutamol produces bronchodilation within 5 min and the action lasts for 2-4 hours. It is therefore used to abort or terminate asthma attacks. Oral bioavailability is 50%. Oral salbutamol acts for 4-6 hours, is longer acting and safer than isoprenaline , but similar in efficacy Dose: 2-4 mg oral, 0.25-0.5 mg i.m / s.c , 100-200 µg by inhalation Side effects include: -Muscle tremor, Palpitation, Restlessness, Nervousness, Throat irritation, -Ankle edema

9. Terbuterline is similar to salbutamol in properties and use. Inhaled terbutaline are currently the most popular drugs for quick reversal of bronchospasm, but should not be used on any regular schedule. This is because diminished responsiveness has been observed after long term use of these drugs. Regular use also down regulates bronchial β2- agonist Dose: 5 mg oral, 0.25 mg s.c , 250 µg by inhalation Salmeterol is the first long-acting selective β2-agonist with a slow onset of action; used by inhalation on a twice daily schedule for maintenance therapy and nocturnal asthma, but not for acute symptoms. It is also more β2 selective than salbutamol, more lipophilic which probably accounts for its longer action.

10. Formoterol is another long-acting selective β2-agonist which acts for 12 hours when inhaled. In comparison to salmeterol , it has a faster onset of action. It is used on a regular morning-evening schedule for round-the-clock bronchodilation Dose: 12-24 µg by inhalation twice daily.

11. Phosphodiesterase inhibitors ( Methylxanthines ) Theophylline is one of the most frequent used xanthine derivatives in the treatment of asthma. It is effective orally, hence widely used and available in various salts. Mechanism of action: The mechanism of action of xanthines is still not well understood. However, it is believed that it inhibit phosphodiesterase which is responsible for cleavage of cyclic AMP. This leads to the accumulation of the cyclic AMP resulting in relaxation of the bronchial smooth muscle. It is also believed to inhibit mediators release from the mast cells Pharmacokinetics: administered both orally and IV, IV administration is far more effective. The average half-life of the drug is approximately 3-6 hours in adult and 3-4 hours in children. About 10% is excreted unchanged Dose: Aminophylline – Tablets; by oral administration 100-300mg 3-4 times after food, by IV injection (over 20 minutes 250-500mg, 5mg/Kg) when necessary.

12. Chromones (sodium cromoglycate ):- This is a mast cell stabilizer, which is a synthetic derivative of a naturally occurring substance called Khellin , which was observed to relax smooth muscle. Mechanism of action: Sodium cromoglycate does not have a direct bronchodilation effect, but inhibits antigen-induced bronchospasm and stabilizes the mast cell membrane. It is also claimed to inhibit phosphodiesterase activity, resulting in a higher concentration of plasma cyclic AMP. By stabilizing the mast cells, it inhibits the release of the chemical mediators involved in allergic and non-allergic asthma.

13. Cromolyn sodium It has no effect once the mediators have been release and does not affect the fixation of reaginic antibodies to mast cells. Consequently, cromolyn sodium is not beneficial in acute attacks of asthma. It is useful as a prophylactic agent, especially in children with allergic asthma. Depending on the asthma, patients show wide variations in their response to cromolyn , some may achieve an adequate response. Administration before known precipitating factors, such as exercise, benefits some patients. Cromolyn can also be effectively used to reduced or withdraw steroids in some patients . USES Bronchial asthma: Is used as a long-term prophylactic in mild-to-moderate asthma . Therapeutic benefit develops slowly over 2-4 weeks and lasts 1-2 weeks after discontinuing. However , the prophylactic effect of cromoglygate is less marked and less consistent than that of corticosteroids. Allergic rhinitis: Cromoglycate is not a nasal decongestant, but regular 4 times daily prophylactic use as a nasal spray produces symptomatic improvement in many patients Regular use as eye drops is beneficial in some chronic cases for allergic conjuctivitis

14. Corticosteroids Corticosteroids are the most potent of all anti-asthmatic drugs. They are often effective in asthmatic patients who appear to be resistant to bronchodilators. The major draw back in the use of steroids is their numerous side effects . MOA: The mechanism of action of steroids in asthma therapy is not clear as patients show varied responses.. It is claimed that steroids relax bronchial smooth muscles and suppress the activity of inflammatory cells. Another aspect of their action is the enhancement of the effect of beta-adrenergic drugs on cyclic AMP production Steroid therapy is of benefit in severe forms of asthma such as status asthmaticus . Prednisolone and methyl prednisolone are the most commonly employed steroids in oral therapy whereas other steroids such as hydrocortisone show no advantages. For continuous therapy the smallest possible doses should be used, that is about 30 to 60 mg per day of prednisone or its equivalent. For maximum effects steroids and bronchodilators should be given simultaneously . Inhaled steroids eg Beclomethasone for prophylaxis

15. Leukotriene antagonist It was realized that cystenyl leukotienes (LT-C4/D4) are important mediators of bronchial asthma, two cysLT1, receptor antagonists’ montelukast and zafirlukast were developed. Montelukast and Zafirlukast act by competitively antagonizing cysLT1 receptor mediated bronchoconstriction, increased vascular permiability and recruitment of eosinophils . This leads to Bronchodilatation , reduced sputum eosinophil count, suppression of bronchial inflammation. Montelukast and zafirlukast are indicated for prophylactic therapy of mild-to-moderate asthma as alternative to glucocorticoid. They are well absorbed orally, highly plasma protein bound and metabolized by CYP2C9 ( Montelukast also by CYP3A4). The plasma half-life of montelukast is 3-6 hours, while that of zafirlukast is 8-12 hours

16. Anticholinergics Atropinic drugs cause bronchodilation by blocking cholinergic constrictor tone; act primarily in the larger airways. Inhaled Ipratropium bromide is less efficacious than sympathomimetic. Patients of asthmatic bronchitis, COPD and psychogenic asthma respond better to anticholinergics . Inhaled ipratropium/ tiotropium is the bronchodilators of choice in COPD . They produce slower response than inhaled sympathomimetic and are better suited for regular prophylactic use (ipratropium2-4 puffs 6 hourly or tiotropium 1 rotacap OD than for control of an acute attack. Combination of inhaled ipratropium with β2 agonist produces more marked and longer lasting bronchodilation ; can be utilized in severe asthma. Nebulized ipratropium mixed with salbutamol like DUOLIN INHALER (salbutamol 100 µg + ipratropium 20 µg is employed in refractory asthma

17. Miscellaneous Anti IgE therapy: Recombinant humanized antibody omalizumab ( Xolair ) binds IgE with high affinity Developed for the treatment of allergic diseases Considered as an add-on therapy to reduce or discontinue treatment with oral corticosteroids May also be indicated in patients who have severe allergic symptoms of asthma and rhinitis and who have very high circulating levels of IgE SQ injection every 2 to 4 weeks Dose determined by levels of serum IgE Exhaled nitric oxide:

18. Pregnancy and Asthma Beta 2 agonist, methyxanthines and anticholinergics are indicated for use during pregnancy Corticosteroids should be used with caution Extensive animal studies with chromones and Leukotriene modifiers did not show any teratogenic effects

19. Conclusion

20. Cough This is a protective reflex, its main purpose being expulsion of respiratory secretions or foreign particles from air passages. It occurs due to stimulation of mechano - or chemoreceptors in the throat, respiratory passages or stretch receptors in the lungs. Cough is categorized as: Productive (useful) – serves to drain the airway, its suppression is not desirable, may even be harmful except if the amount of expectoration achieved is small compared to the effort of continuous coughing Nonproductive (useless) – This should be suppressed  

21. Cough preparations Demulcents – Lozenges, cough drops, linctuses containing syrups, glycerine , and liquorice - These sooth the throat and reduce afferent impulses from the inflamed /irritated pharyngeal mucosa, thus, provide symptomatic relief in dry cough arising from throat. Expectorants ( Mucokinetics ): Bronchial secretion enhancers - Sodium or potassium citrate, potassium iodide, Guaiphenesin ( Glyceryl guaiacolate ), balsam of Tolu , Vasaka , and Ammonium chloride , They are drugs use to increase bronchial secretion or reduce its viscosity, thereby facilitating its removal by coughing.

22. Cough preparations Mucolytics – Bromhexine ; is a potent mucolytic and mucokinetic capable of inducing thin copious bronchial secretion. It depolymerises mucopolysaccharides directly. It is particularly useful if mucus plugs are present Side effects: are rhinorrhea and lacrimation, gastric irritation, hypersensitivity Dose: Adult 8 mg TDS, children 1-5 years 4 mg BD, 5-10 years 4 mg TDS

23. Cough preparations Antitussives These are drugs that act in the CNS to raise the threshold of cough center or act peripherally in the respiratory tract to reduce tussal impulses or both these actions. Because they aim to control rather than to eliminate cough, antitussives should be used only for dry unproductive cough or if cough is unduly tiring, disturbs sleep or is hazardous (hernia, piles, cardiac diseases, ocular surgery)

24. Cough preparations OPIOIDS Codeine: - This is an opium alkaloid, qualitatively similar to but less potent than morphine. It is more selective for cough centre and is treated as the standard antitussive; suppresses cough for about 6 hours. The antitussive action is blocked by naloxone indicating that it exerted it’s action through opioid receptors in the brain. Abuse liability is low, but present; constipation is the chief drawback. At higher doses respiratory depression and drowsiness can occur. Like morphine, it is contraindicated in asthmatics and in patients with diminished respiratory reserve Dose 10-30 mg; children 2-5 years 2.5-5 mg, 6-12 years 5-10 mg , frequently used as syrup codeine phosphate 4-8 ml CODINE 15 mg tab, 15 mg/5 ml linctus

25. Cough preparations NON-OPIOIDS Noscapine ( Narcotine ): - An opium alkaloid of the benzoisoquinoline series. It depresses cough but has no narcotic, analgesic or dependence inducing properties. It is nearly equipotent antitussive as codeine, especially useful in spasmodic cough. Headache and nausea occur occasionally as side effect. It can release histamine and produce bronchoconstriction in asthmatics. Dose 15-30 mg, children 2-6 years 7.5 mg, 6-12 years 15 mg.

26. Cough preparations Dextromethorphan: - Is a synthetic compound with a selective antitussive action (raises threshold of cough centre ). It is as effective as codeine, does not depress mucociliary function of the airway mucosa and is practically devoid of constipating and addicting actions. The antitussive action lasts for 6 hours and is not blocked by naloxone: therefore not exerting it’s action through opioid receptors Side effect: Dizziness, nausea, drowsiness, ataxia Dose 10-20 mg, children 2-6 years 2-5-5 mg, 6-12 years 5-10 mg

27. Cough preparations Antihistamine it was implicated as a mediator of hypersensitivity phenomena and tissue injury reactions. It is located mostly within storage granules of mast cells. Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs, liver and placenta. These are added to antitussive/expectorant to afford relief in cough due to their sedative and anticholinergic activity, but lack selectivity for cough centre . They have no expectorant property, may even reduces secretions by anticholinergic actions. They have been especially promoted for cough in respiratory allergic states, though their lack of efficacy in asthma is legendary Chlorpheniramine (2-5 mg), Diphenhydramine (15-25 mg) and Promethazine (15-25 mg) are commonly used. Second generation antihistamines like fexofenadine, loratadine are ineffective.