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Pharmacology of Respiratory system both upper and lower
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- 2. I. Drug Therapyof Bronchial Asthma The term asthma is derived from the Greek word meaning difficulty in breathing. Asthma is a chronic inflammatory allergic disease: the patients suffer with reversible episodes of airways obstruction due to bronchial hyper-responsiveness. In the early (acute) phase there are smooth muscle spasm and excessive bronchial secretion of mucus. In the late (chronic or delayed) phase, inflammation continues, accompanied by fibrosis, oedema and necrosis of bronchial epithelial cells.
- 3. FACTORS THAT EXACERBATEASTHMA
- 4. The symptoms ofasthma are breathlessness wheezing, cough and chest tightness with worsening of these symptoms at night. In the acute attack there are ra- pid respiratory rate and tachycardia. The majority of patients suffer with atopic extrinsic asthma, which is associated with exposure to specific allergen (pollen or house-dust mite) . In non-atopic extrinsic asthma the attack may be stimulated with some non-specific stimulus, e.g. chemical irritants. In such cases, IgG antibodies circulate in the blood but are not attached to the mast cells or basophils. Neutrophils destroy these antigen-antibody complexes. As a result, the liberated lysosomal enzymes
- 5. can digest theremaining mucoproteins. Drugs which stabilize the lysosomal membrane, e.g. GCS provide relief to these patients. In contrast, the many patients who acquire asthma after the age of 40 years have no identifiable external precipitating factor or immunological basis for asthmatic attack. This can be described as intrinsic asthma. Many patients suffer from both extrinsic and intrinsic forms of asthma. In comparison with intrinsic asthma, extrinsic asthma is episodic and less prone to develop into status asthmaticus. Status asthmaticus is a severe acute asthma, which is a life-threatening condition involving exhaustion, cyanosis, bradycardia, hypotension, dehydration and metabolic acidosis.
- 7. Classification of AntiasthmaticDrugs 1. Bronchodilators • Selective β2-agonists: Clenbuterol, Salbutamol, Fenoterol, Levosalbutamol, Salmeterol, Terbutaline • Nonselective β-agonists: Epinephrine, Isoprenaline, Orciprenaline; Ephedrine • M-cholinolytics: Ipratropium, Tiotropium, Oxitropium • Methyl Xanthines: Theophylline, Aminophylline, Theotard 2. Mast Cell Stabilizers: Sodium Cromoglycate, Ketotifen, Nedocromil
- 8. 3. Glucocorticosteroids (GCS) •Oral: Prednisone, Methylprednisolone • Parenteral: Methylprednisolone, Betamethasone • Inhalational: Beclomethasone, Budenoside, Fluticasone, Triamcinolone 4. Inhalational β2-agonists/Glucocorticosteroids Seretide® (fluticasone/salmeterol) Symbicort® (budenoside/formoterol) 5. Leukotriene Modulators • 5-Lipoxygenase Inhibitor: Zileuton • LTD4-antgonists: Zafirlukast, Montelukast 6. Monoclonal Anti-IgE Antibody: Omalizumab 7. Miscellaneous: NO-donors, Calcium antagonists
- 9. Bronchodilators – relievers(β-agonists, M-cholinolytics, Methyl Xanthins) provide a rapid sympto- matic relief but they do not control the disease process. Selective β2-agonists activate β2-receptors present on airway smooth muscle and mast cells too. These agents elax airway smooth muscle, inhibit the release of bronchoconstricting mediators from the adipocytes and increase the mucociliary transport by increasing the mucociliary activity. ADRs: tremor, tachycardia.
- 10. Adrenaline (b1&b2) Gs AC ATP cAMP PKAEffects Ex In (+)
- 12. Short acting beta-2 agonists:the onset of effect (per inhalation) begins after 3 to 5 min and continues 4–6 h: • Salbutamol (albuterol) • Fenoterol, Terbutaline Highly lipid, soluble long-acting agents (t1/2 12 h) Effect: after 15–20 min, duration 12 h: • Salmeterol, Formoterol Beta-2-agonists are available as metered-dose aerosol.
- 13. Primarily, the siteof bronchodilation action of inhaled β2-adrenergic agonists is mainly the bronchiolar smooth muscle. Atropinic drugs cause bronchodilation by blocking cholinergic constrictor tone, act primarily in large airways. Anticholinergics in asthma • Ipratropium • Tiotropium
- 14. Methyl Xanthines (Theophylline, Aminophylline,Theotard): a) inhibit phosphodiesterase III (present in airway muscle) and IV (present in eosinophil and mast cells), the two specific isoenzymes responsible for the degradation of cAMP;
- 15. Glucocorticosteroids provide long-term stabilizationof the symptoms due to their anti-inflammatory effects. Inhaled GCS, along with beta-2-agonists are the first choice drugs for chronic asthma. GCS inhibit the release of PGs and LTs and thus prevent smooth muscle contraction, vascular permeability and airway mucus secretion. GCS produce eosinopenia which prevents cytotoxic effects of the mediators released from eosinophils. GCS enhance beta-2-adrenergic response by up-regulating the beta-2-receptors in lung cells and leucocytes.
- 16. The anti-inflammatory actionsof GCS are mediated by stimulation of synthesis of lipocortin, which inhibits pathways for production of PGs, LTs. These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration, fibrin deposition.
- 18. • Cushing’s syndrome •Osteoporosis • Tendency to hyperglycaemia • Increased appetite • Increased susceptibility to infections • Obesity etc. Adverse effects of GCS Cushing’s syndrome
- 19. Leukotriene Modulators Metabolism ofarachidonic acid via 5-lipoxigenase pathway yields the cysteinyl LTs – C4, D4 and E4, which activate cysteinyl leukotriene receptors to cause bronchoconstriction, stimulate mucus secretion and increase capillary permeability, leading to pulmonary oedema. Zileuton (p.o.) inhibits the 5-lipoxigenase and blocks synthesis of LTs. Zafirlukast, Montelukast and Pranlukast (new agent) block cysteinyl LT-receptors and used with inhaled GCS in poorly respond asthmatic patients.
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- 21. Cromoglycate – perinh. Ketotifen (p.o.) Nedocromil – per inh. Mast cell stabilizers prevent transmembrane influx of calcium ions, provoked by antigen-IgE antibody reaction on the mast cell membrane. They prevent degranulation and release of histamine and other autacoids from mast cells. They also inhibit leukocyte activation and chemotaxis. Indications: prophylactic treatment of asthma.
- 22. Monoclonal Anti-IgE Antibody Omalizumabis a recombinant humanized monoclonal antibody. (1) It inhibits the binding of IgE to mast cells and basophils; (3) it inhibits the activation of IgE already bound to mast cells and prevents their degranulations; (3) it down-regulates Fc epsilon receptor-1, present on mast cells and basophils. Omalizumab is indicated for asthmatic patients who are not adequately controlled by inhaled GCS and who demonstrate sensitivity to aero-allergens.
- 23. Treatment of StatusAsthmaticus It is a potentially life-threatening acute attack of severe asthma needing immediate treatment. Most often hospitalization is necessary. (1) A high concentration (40–60%) of O2 is administered. (2) High doses of inhaled short acting beta-2-agonist. (3) High doses of systemic GCS (p.o./i.v.) (4) Ipratropium through inhalation.
- 24. II. Drug Therapyof Cough The cough is a physiological useful protective reflex that clears the respiratory pathway of the accumulated mucus and foreign substances. Many times it occurs as a symptom of an underlying disorder and needs treatment. The cough may be non-productive (dry) and productive. The productive cough is characterized by the presence of excessive sputum and may be associated with chronic bronchitis and bronchiectasis.
- 25. . Antitussive Agentsare used for the treatment f non-productive cough which increases discomfort to e patients. entrally Acting Antitussives upress the cough center that mediates the cough reflex) Codeine (methylmorphine) Dihydrocodeine Dextrometorphan Glaucin (Glauvent® ) erpheral Acting Antitussives Prenoxidiazine (Libexin® – tabl. 100 mg) Poppy
- 26. 2. Expectorants These drugsincrease the volume or/and decrease the viscosity of the respiratory secretions and facilitate their removal by ciliary action and coughing. Mucokinetic Expectorants stimulate the flow of respiratory tract secretions by stimulating the bronchial secretory cells (to increase the volume) and the ciliary movement (to facilitate their removal). • Essential oils (oil anise, oil eucalyptus) • Syrup of Ipecacauanha (in sub-emetic doses) • Infusum of Radix Primulae • Ammonium chloride, Sodium citrate • Guaiacol and Guaifenasin (obtained from creosote wood)
- 27. Mucolytic Expectorants decreasethe viscosity of mucus by splitting the disulfide (–S–S–) bonds of mucoproteins. This action is further facilitated by alkaline pH (7–9). • Ambroxol • Acetylcystene (used also for the treatment of paracetamol intoxication) • Bromhexine • Dornase-alfa • Mesna (used also for protection of cancerogenic activity of cyclophosphamide and ifosphamide too)