Anti Asthmatic.pptx

Pharmacotherapy of Asthma

1. Pharmacotherapeutics of Asthma By : Dr. Sarita S harma Associate Professor Pharmacology MMCP, MMDU

2. INTRODUCTION ASTHMA : The term Asthma is Derived from the Greek word meaning to stay Awake in order to Breathe or Difficulty in Breathing. Defination : Asthma is a chronic inflammatory disease in which the patients suffers with Reversible episodes of Airways, obstruction Inflammation can lead to irreversible Airways obstruction. It is characterised by hyperresponsiveness of tracheobronchial smooth muscle to a variety of stimuli, resulting in narrowing of air tubes.

3. PATHOPHYSIOLOGY : Bronchoconstriction : The airways of asthma patients are " hypersensitive " to certain triggers, also known as  stimuli  . It is usually classified as  type I hypersensitivity . In response to exposure to these triggers, the  bronchi  . Bronchial inflammation: The " hygiene hypothesis " postulates that an imbalance in the regulation of these T H  cell types in early life leads to a long-term domination of the cells involved in allergic responses over those involved in fighting infection.

4. Adrenoceptor mediated bronchospasm 2 Types: alpha & beta Direct Indirect Airway Injury & Inflammation Injury Mediators Immune dysregulation

5. Types of asthma: Mild persistent: Possible chronic cough production. Moderate persistent: Shortness of Breath on excretion possible chronic cough production. Severe persistent: Shortness of Breathe, Reduced excise tolerance.

6. Aetiology : Respiratory infection : Respiratory syncytial virus (RSV), rhinovirus, influenza, parainfluenza , Mycoplasma Pneumonia Allergen: Airborne pollens (grass, trees, weeds), house-dust mites, animal danders , cockroaches, fungal spores Environment: Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke, wood smoke Emotions: Anxiety, stress, laughter Exercise: Particularly in cold, dry climate Drugs/preservatives: Aspirin, nonsteroidal antiinflammatory drugs ( cyclooxygenase inhibitors), sulfites , benzalkonium chloride, nonselective β-blockers Occupational stimuli: Bakers (flour dust); farmers (hay mold ); spice and enzyme workers; printers ( arabic gum); chemical workers ( azo dyes, anthraquinone , ethylenediamine , toluene diisocyanates , polyvinyl chloride); plastics, rubber, and wood workers (formaldehyde, western cedar, dimethylethanolamine , anhydrides)

7. Symptoms: Coughing. Coughing from asthma often is worse at night or early in the morning, making it hard to sleep. Wheezing. Wheezing is a whistling or sound that occurs when you breathe. Chest tightness, pain or pressure Shortness of breath .

8. Basic Approach Issues  -receptor mediated bronchoconstriction Complex inflammatory/allergic response Goals Acute (quick) relief Healing/reverse of inflammatory/allergic response Requires a comprehensive approach from multiple directions

9. Drugs Used In Asthma: Bronchodilators β 2 Sympathomimetics : Salbutamol , Terbutaline , Ephedrine.   Methylxanthines : Theophylline , Aminophylline   Anticholinergics : Ipratropium bromide II. Leukotriene antagonists: Montelukast , Zafirlukast .   III. Mast cell stabilizers : Sodium cromoglycate , Ketotifen .   IV. Corticosteroids Systemic: Hydrocortisone, Prednisolone B. Inhalational: Beclomethasone dipropionate , Fluticasone propionate  V. Anti- IgE antibody: Omalizumab

10. β 2 Sympathomimetics : Salbutamol :  Also known as Albutrol . M.O.A.: They act by directly stimulating the β 2 adrenergic receptor present in the smooth muscle OR bind with respiratory tract smooth muscle. They increase the conversion of cAMP from ATP catalysed by adenelyl cyclase – leads to bronchodilation effect/ muscle relaxation

11. Additional effects: inhibition of inflammatory mediator release inhibition of smooth muscle proliferation stimulation of mucociliary transport cytoprotection of respiratory mucosa attenuation of neutrophil activation

12. Pharmacological action . Respiratory tract: - β 2 adrenoceptor present in the smooth muscles of bronchus -stimulation of β 2 receotors cause bronchodilation 2.Eye: -stimulation of β 2 adrenoceptor will induce the production of aqueous humour 3. GIT: - β 2 adrenoceptor present in the GIT smooth muscle -stimulation of β 2 adrenoceptor will cause relaxation of smooth muscle of GIT which is leading to constipation.

13. 4. Genito -urinary system: - β 2 adrenoceptor present in the genito -urinary tract - β 2 effect will cause relaxation in pregnant uterus (contraction in non pregnant) -Urinary bladder-relaxation of detrussor muscle leading to micturation 5. CNS: -does not produce any marked CNS effect because of the poor penetration in brain -other minor effects: restlessness, tremor, apprehension 6. CVS: -Less cardiac effect due to its selective β 2 stimulation

14. Uses: -Asthma -COPD -Cystic fibrosis ( salbutamol + ipratropium bromide or acetyl cysteine ) -Congenital myasthenic syndrome - Tocolytic hyperkalemia -Spinal muscle atropy : under trial -To reduce uterine contraction in pre mature labor Dose Oral- 2 to 4 mg x TDS or QID for adult Parenteral : 0.25 to 0.5 mg i.m or s.c Inhalation: 100 to 200 μ g

15. Adverse effects: 1.CNS: -anxiety, tremor, headache, nervousness, restlessness, palpitation 2.GIT: -dry mouth, constipation 3. Allergic reaction: - urtricaria , angioedema , hypotension, paradoxial bronchospasm 4. High dose: - Hypokalemia , Renal failure 5. Others: -Tachycardia, Arrythmia , Flushing, Myocardial ischaemia (rare)

16. Contraindication: -Chronic diabetic -Renal disease - Crohn’s disease Precaution : Used in patient with caution suffering from CVS disease because they can still stimulate ( though minimally) β 1 of heart.

17. Methylxanthines : Theophylline : have been extensively used in asthma, but are not considered first line drugs any more. They are used more often in COPD. Theophylline is methyl xanthine derivative Alkaloid obtained from Thea sinensis ( Tea ) Mechanism of action: (a) They inhibit the phosphodiesterase enzymes i.e. responsible for the degradation of cAMP . Thus due to the inhibition of phosphodiesterase enzyme, the intra cellular conc of cAMP is increased thus reduced the bronchial tone producing bronchodilator. (b) Blockade of adenosine receptors: inhibition of such receptor, bronchoconstriction is prevented.

18. Phamacological actions: On bronchial smooth muscles Theophylline causes direct relaxation of bronchial smooth muscles. - It also inhibit the release of inflammatory mediators from mast cells in bronchi. 2) On CNS They are CNS stimulant and causes euphoria, enhance motor activity, performance enhancement. Also stimulates vasomotor and respiratory centre in medulla. In higher dose, they cause nervousness, insomnia, tremors, convulsion, delirium, restlessness, excitement. Vomiting at high dose is due to gastric irritration and CTZ stimulation.

19. 3) Diuretic effect (kidney) They have mild diuretic effect due to decrease tubular reabsorption of sodium ion and water. 4) On mast cells and inflammatory cells They decrease release of histamine from mast cells and activated inflammatory cells This may contribute its therapeutic effect in bronchial asthma. 5) On skeletal muscle They cause contraction of skeletal muscle. this contraction is useful in patient with COPD as it decreases diaphragmatic fatigue and reduce dyspnoea .

20. On CVS a) Heart Methyl xanthine directly stimulate the heart and produce positive inotropic effect( increase force of myocardial contraction), tachycardia, increase cardiac output, arrhythmia( in high dose) b) Blood vessels Produce vasodilation . c) Blood pressure - Vasomotor centre and direct cardiac stimulation can produce increased BP. - Vagal stimulation and direct vasodilation can produce decreased BP

21. Pharmacokinetic Absorption : well absorbed from GIT Distribution: all parts of body and cross placenta Metabolism : in liver Excretion : excreted unchanged in urine Half life : children ( 3-5 hrs) ; adults (7-12 hrs) USES Asthma COPD Anti inflammatory effect Treatment of recurrent apnea in premature infants DOSE: Poorly water soluble, cannot be injected. 100–300 mg TDS (15 mg/kg/day)

22. Adverse effects: They have narrow therapeutic index so TDM is required. Its toxicity can be treated with beta blockers. Gastric irritation, nausea, vomiting, headache, dizzyness , increased heart rate, diarrhoea , arrhythmia, CNS excitement, insomnia, seizures, irritability. Contraindications: Peptic ulcer, heart disease Precautions rapid IV administration of theophylline ( in therapeutic doses) may cause cardiac arrhythmia so it should be administered slowly to avoid toxic effect.

23. Drug interaction: Rifampicin , phenytoin , phenobarbitone increase the metabolism of theophylline ( i.e. decreased plasma level of theophylline ). Ciprofloxacin, cimetidine , allopurinol , erythromycin decrease the metabolism of theophylline ( i.e. increase the plasma level of theophylline ). Theophylline enhance the efficacy of hypoglycemic, oral anticoagulant and diuretic.

24. Anticholinergics : Ipratropium bromide : It is the semi synthetic derivative of atropine. It is a anticholinergic drugs. MOA They bind with muscarinic recceptors on bronchial smooth muscles and competitively inhibit the bronchoconstrictive action of acetylcholine released from parasympathetic nerves. Thus they cause relaxation of bronchial smooth muscle. less efficacious than sympathomimetics Combination of inhaled ipratropium with β2 agonist produces more marked and longer lasting bronchodilatation .

25. Pharmacokinetics Absorption- poorly or not absorbed from GIT on oral administration. Given by aerosol inhalation or nebulized form. Metabolism: in liver Excretion: - Urine Half life : - 2 hrs Dose: Salbutamol + Ipratropium DUOLIN INHALER: 100 μg + 20 μg per metered dose Uses COPD ( inhalation) Combine with salbutamol ( in asthma) 0.03% ( Rhinorrhoea )

26. Adverse effect - Dry mouth, sedation, skin flushing, headache, urinary retention, tachycardia, acute angle closure glaucoma, nausea, palpitation, bad taste. Contraindication Hypersensitivity to it. Glaucoma Urinary retention Obstruction in GIT Drug interaction - Theophylline + ipratropium bromide+ beta adrenergic agonist can increase the dilating efffect on bronchi.

27. Leukotriene antagonists Montelukast & zafirlukast : Both have similar actions and clinical utility MOA: They competitively antagonize cys LT1 receptor mediated bronchoconstriction , increased vascular permeability and recruitment of eosinophils . Both are indicated for prophylactic therapy of mild-to-moderate asthma as alternatives to inhaled glucocorticoids .

28. Side effects: safe drugs; few side effects like headache and rashes. Eosinophilia and neuropathy are infrequent . Pharmacokinetics: They are well absorbed orally, highly plasma protein bound and metabolized by CYP2C9 The plasma t½ of montelukast is 3–6 hours, while that of zafirlukast is 8–12 hours. Dose: Montelukast : 10 mg OD; children 2–5 yr mg OD, 6–14 yr 5 mg OD; Zafirlukast : 20 mg BD; children 5–11 yr 10 mg BD;

29. MAST CELL STABILIZERS: Sodium cromoglycate It is a synthetic chromone derivative. MOA: inhibits degranulation of mast cells (as well as other inflammatory cells) by trigger stimuli. Release of mediators of asthma like histamine, LTs, PAF, interleukins, etc. is restricted. The basis of this effect is not well understood. Pharmacokinetics: Not absorbed orally. It is administered as an aerosol through metered dose inhaler delivering 1 mg per dose: 2 puffs 4 times a day. rapidly excreted unchanged in urine and bile.

30. Uses: 1.Bronchial asthma: 2. Allergic rhinitis 3. Allergic conjunctivitis Dose: Inhaler: 1 mg metered dose aerosol; 2 puffs 4 times daily. Adverse effects: Bronchospasm , throat irritation cough Rarely nasal congestion headache, dizziness, rashes.

31. CORTICOSTEROIDS: They are not bronchodilators. They benefit by reducing bronchial hyperreactivity , mucosal edema and by suppressing inflammatory response to AG:AB reaction or other trigger stimuli. These drugs are given in conbination of other anti asthmatic drugs. They can be given by inhalation & systemic route.

32. ANTI- IgE ANTIBODY: Omalizumab : It is a humanized monoclonal antibody against IgE . Administered i.v . or s.c ., it neutralizes free IgE in circulation without activating mast cells and other inflammatory cells. On antigen challenge, little IgE is available bound to the mast cell surface receptors (FcεR1) to trigger mediator release and cause bronchoconstriction .

33. Medication to treat asthma: Medications come in several forms Two major categories of medications are: Long-term control Quick relief 1) Long term control: Taken daily over a long period of time Used to reduce inflammation, relax airway muscles, and improve symptoms and lung function Inhaled corticosteroids Long-acting beta 2 -agonists Leukotriene modifiers

34. Quick relief: Used in acute episodes. Generally short-acting beta 2 agonists.

35. Others: Inhalers and Spacers : Spacers can help patients who have difficulty with inhaler use and can reduce potential for adverse effects from medication. Nebulizer: Machine produces a mist of the medication. Used for small children or for severe asthma episodes. No evidence that it is more effective than an inhaler used with a spacer.

36. Prevention: Reducing Exposure to House Dust Mites Reducing Exposure to Environmental Tobacco Smoke Reducing Exposure to Cockroaches Reducing Exposure to Pets Reducing Exposure to Mold Other Asthma Triggers: Air pollution Trees, grass, and weed pollen

37. Diagnosing Asthma Troublesome cough, particularly at night Awakened by coughing Coughing or wheezing after physical activity Breathing problems during particular seasons Coughing, wheezing, or chest tightness after allergen exposure Colds that last more than 10 days Relief when medication is used Wheezing sounds during normal breathing Hyperexpansion of the thorax Increased nasal secretions or nasal polyps Atopic dermatitis, eczema, or other allergic skin conditions

38. Diagnostic test: Chest x-ray : Lab tests on your blood and sputum (phlegm, mucus) By forced expiratory volume : in 1 second (FEV1) TREATMENT OF STATUS ASTHMATICUS: Life-threatening Acute attack of Severe Asthma needing Immediate treatment. A High Concentration (40-60%) of O2 is Administered with high flow rate along with high doses of inhaled Short acting Beta2-Agonost.

39. PATIENT COUNSELLING Advice and support on stop smoking Nutritional assessment Aerobic exercise training Breathing training with closed lips to improve ventilatory pattern and gas exchange. Relaxation techniques Education about medicines, nutrition, self-management of disease and lifestyle issues Psychological support

40. References: Clinical Pharmacy and Therapeutics: Edited by Roger Walker ESSENTIAL OF MEDICAL PHARMACOLOGY (K.D. Tripathi .) Pharmacotherapy:A Pathophysiologic Approach Seventh Edition by Joseph T. DiPiro

41. Thank you