Asthma

Pharmacology

1. ASTHMA Dr.Zulcaif Ahmad

2. It is an episodic, reversible bronchoconstriction to tracheo -bronchial tree due to its hyperactivity towards a variety of stimuli which can be extrinsic or intrinsic. Asthma is a reversible condition while bronchoconstriction in COPD is irreversible.

3. Early phase of bronchial asthma starts within 5-30mint upon exposure to allergen APC-CD4 + Helper-T-Cell Cytokinase B-lymphocyte Memory cell Plasma cell IgE

4. Upon Re-entry of antigen : dust particle directly bind to IgE Degranulation Bronchoconstirction Histamine (Mast cell Rupture) Inc.mucous production release White color sputum

5. Histamine is degraded within 60 minute by HISTAMINASE formed by macrophages. Anti histamine has no role in Rx of Bronchial asthma.

6. Activates Histamine Phospholipase A2 Asachideonic acid metabolism (in cell membrane) Lipoxigenase cyclooxygenase Leukotrine A4 PG-G2 Leukorine B4 Leukotrine C4 D4 E4 PG-H2 Chemotactic factor SRSA  Tx-A2 (platelet agregate ) For monocyte  bronchoconstriction  PG-I2 ( inhb agregation ) lymphocyte  inc. Bronchial gland  other PG-D2, E2, secreation F2  vasoconstriction  Pain fever HCL.scr

7. C/F (YOUNG <35 yrs) Episodic symptoms Chest tightness Dyspneae (due to bronchoconstriction of mucus plug) White sputum with cough Wheze 70% of hv Allergic Rhinitis Sneezing Post nasal drip Rhinorrhea

8. Classification:

9. Approach to Treatment:- Prevention of the exposure to antigen Reduction of bronchial inflammation and hyperactivity Dilatation of the narrowed bronchi.

10. Bronchodilators Sympathomimetics ( β 2 receptor agonist), Xanthine derivatives, Anti- cholinergics / muscarinics . Sympathomimetic drugs adrenalin is an agonist for the α 1 , α 2 , β 1 , β 2 receptors. Binding with the β 2 receptor it causes bronchodilatation but binding on the β 1 receptors it causes ↑ HR, ↑ BP, ↑ O 2 demand.

11. Non-selective Epinephrine, Ephedrine, Isoproterenol {ephedrine causes tachyphylaxis / acute tolerance} β receptor selective drugs Isopropanolol , Isoprenalin β 2 receptor selective Salbutamol , Terbutaline , Femoterol β receptors are also present in the peripheral vasculature, so long term use may cause hypotension.

12. Long-acting beta-agonists: Long-acting beta-agonists(LABAs) dilate the airway for up to 12 hours and are to be taken along with your inhaled steroids. Currently, researchers do not think that long-acting bronchodilators can reduce inflammation on their own, but they may help the inhaled steroids to work better. Examples: Formoterol Salmeterol

13. The selective β 2 agonists They can be given orally or inhalation They act selectively on β 2 receptors They have long duration of action Bronchodilatation is maximal in 30 min when given by inhalation and persists for 2-3 hours They produce less cardio-vascular side effects Orally they are given in doses of 4mg 3-4 times

14. Mechanism of Action—it acts in the following ways: 1. Salbutamol → Stimulates β 2 receptors of the bronchial smooth muscle → Stimulation of the Adenylate Cyclase enzyme → Increased intracellular cyclic-AMP (also reduction of the intracellular calcium) → Smooth muscle relaxation → Bronchodilatation occurs. 2. Salbutamol → Acts on the β2 receptor of the mast cell → ↑ c-AMP production → Stabilization of the mast cell membrane → No Histamine release → No bronchoconstriction .

15. 3. Salbutamol increases the muco-ciliary action of the lung. 4. Decreases micro-vascular permeability of the lung. Inihbit release of bronchoconstircting mediators from mast cell.

16. Uses : Used in asthma. Side effects of long-acting bronchodilators include: Increased heart rate Headache Anxiety Tremor

17. Pharmacokinetics Salbutamol is a direct-acting sympathomimetic with β- adrenergic activity and selective action on β2 receptors, producing bronchodilating effects. It also decreases uterine contractility. Onset Inhalation: 5-15 min; oral: 30 min.

18. Duration Inhalation: 3-6 hr; oral: 8 hr; modified-release preparation: 12 hr. Absorption Readily absorbed from the GI tract. Metabolism Hepatic and in the gut wall. Excretion Via the urine as metabolites and unchanged drug. Some excretion in the faeces .

19. Xanthine derivatives: Chemically they are purine having similar chemical structure with adenine and uric acid. Wide spreads pharmacological action so, not used. These drugs have low therapeutic index. Increases intra-cellular cyclic-AMP concentration within the bronchial smooth muscle cell. Theophylline is the prototype, it is water insoluble but it’s salts are water soluble

20. Mechanism of Action of Theophylline 1. Combines with the adenosine receptor (PI) and acts as antagonist of adenosine thus prevents it to cause contraction of the bronchial smooth muscle. 2. Combines and inactivates phospho-diesterase enzyme and degradation of the cyclic-AMP stops. C-AMP accumulates in the bronchial smooth muscle and causes bronchodilatation . C-AMP has negative effect on the release of the calcium from the endoplasmic reticulum.

21. Pharmacological effects: Lung: bronchodilatation CNS: Cortical stimulation, excitement, ↓ mental exhaustion and fatigue. Loss of sleep. Stimulate medullary respiratory and vomiting center. CVS : Positive ionotropic and chronotropic effects. ↑ CO, ↑ HR, ↑ force of contraction. At large doses it causes cerebral vaso -constriction. In high level — toxicity—cardiac arrhythmia, tachycardia

22. Kidney: Diabetic action. ↑ renal blood supply and GFR. ↓ Na + and other electrolyte absorption. Skeletal muscle : Diaphragmatic contraction is stimulated. ↓ fatigue of the skeletal muscle. Causes tremor. GIT : ↑ gastric acid secretion.

23. Adverse effects of Theophylline Therapeutic index is very low Nausea, vomiting Therapeutic blood level is 0.2-2mg/100ml Nausea, vomiting may appear in <2mg/100ml Convulsion in >4mg/100ml Cardiac arrhythmia may occur (total dose should be given at least in 20min)

24. Points Salbutamol Aminophylline Mechanism of Action Selective stimulation of the β 2 adrenoceptor of bronchial smooth muscle and causes bronchodilatation Competitive inhibition of the bronchial adenosine receptors and causes bronchodilatation Onset of action Slower Rapid Duration of action Longer Shorter Therapeutic index Larger Narrow In acute asthma Suitable in inhaler form Suitable in IV form Drug of choice Mildest asthmatic with intermittent attack Severe acute asthma and chronic asthma Side effects Tremor, headache, cardiac arrhythmia Headache, vomiting

25. Anticholinergic drugs Atropine is the prototype, cheap, causes bronchodilatation . Mechanism of Action: Vagal nerve innervation → acetyle choline → muscarinic receptor→ bronchoconstriction Anticholinergics act here by inhibiting the muscarinic receptors ↑ Uses: Used in asthma

26. Adverse effects of Atropine Can cross the BBB and go to the CNS. Mouth dryness. Destroy the cilia of the respiratory tract—prone to infection. an allergic reaction (swelling of your lips, tongue, or face, difficulty breathing, closing of your throat, or hives); an irregular or fast heart rate; rash or flushing; or eye pain.

27. Corticosteroids (MOA) They: inhibit chemical mediators, whether these are performed, like histamine, or newly formed, like arachidonic acid metabolites (prostaglandins and leukotrienes ) or the platelet-activating factor (PAF); restore the sensitivity of beta-adrenergic receptors to sympathomimetic drugs; exert a powerful anti-inflammatory effect, notably reducing bronchial mucus secretion; reduce bronchial hyperreactivity and modify the bronchial response to bronchoconstrictors ; act on respiratory function and gas exchanges.

28. Many effects of corticosteroids in asthma involve the synthesis of proteins, such as lipomodulin (or macrocortin ) which inhibits phospholipase A2, a key-enzyme in the synthesis of numerous chemical mediators derived from membrane phospholipids. The multiple effects of corticosteroids account for their broad spectrum of activity and their effectiveness against both acute and chronic manifestations of asthma.

29. Uses: Inhaled glucocorticoids are the second-line treatment for asthma . Glucocorticoids may be used in low doses in adrenal insufficiency . In much higher doses, oral or inhaled glucocorticoids are used to suppress various allergic , inflammatory , and autoimmune disorders

30. Side effects Growth failure, delayed puberty Increased plasma amino acids , increased urea formation, negative nitrogen balance Excitatory effect on central nervous system (euphoria, psychosis) Glaucoma due to increased cranial pressure Cataracts

31. Possible side effects of long-term oral corticosteroid use include: Water retention Bruising Puffy face Increased appetite Weight gain Stomach irritation Mood changes Fractures

32. Leukotriene : The leukotriene receptor antagonists are among the most prescribed drugs for the management of asthma, used both for treatment and prevention of acute asthmatic attacks.  This class of drugs acts by binding to cysteinyl leukotriene receptors (CysLT1 and CysLT2) and blocking their activation and the subsequent inflammatory cascade which cause the symptoms commonly associated with asthma and allergic rhinitis.

33. Mchanism of Action: Leukotrienes are synthesized in response to many triggers, including receptor activation, antigen-antibody interaction, physical stimuli such as cold, and any stimulation that increases intercellular calcium.These potent inflammatory mediators promote neutrophil -endothelial interactions, inducing bronchoconstriction and enhancing airway hyperresponsiveness . They also stimulate smooth muscle hypertrophy, mucus hypersecretion , and the influx of eosinophils into airway tissues therefore, inhibition of leukotrienes potentially plays an important role in the treatment of asthma and other allergic conditions such as allergic rhinitis, atopic dermatitis, and chronic urticaria

34. Leukotriene receptor antagonists, called LTRAs for short, are a class of oral medication that is non-steroidal. They may also be referred to as anti-inflammatory bronchoconstriction preventors . LTRAs work by blocking a chemical reaction that can lead to inflammation in the airways. Although not preferred first choice therapy, LTRAs can be tried when an inhaled steroid can not, or will not, be used, or if the dose cannot be increased

35. Uses: It is used in Asthama . Side Effects: Elevation in serum hepatic enzyme Nausea Headache Inhibitors of cytochrome P450.

36. Mechanism of action: Alter the function of delayed chloride channels in cell membrane. Inhibiting cell activation This action thought to mediate inhibition of cough. Inhibit the function of cells other then mast cell degranulation and release of histamine.

37. Clinical uses: Used for non seasonal asthma Particularly used in children and pragnant woman. Side effects: Throat irritation Cough Mouth dryness Chest tightness Wheezing

38. Anti Immunoglobulin E (Anti-IgE) Therapy Anti- IgE treatment might be recommended if you have allergic asthma and you keep experiencing persistent symptoms despite taking your controller medications. If you have allergic asthma (about 60% of asthma is caused by allergy), your symptoms are triggered when you inhale certain allergens in the air.

39. MOA: These allergens cause a chain reaction that leads to inflammation in the lungs. While inhaled steroids work by treating and reducing the inflammation, anti- IgE therapy works by keeping inflammation from developing in the first place. It does so by blocking immunoglobulin E, a substance in the body that is one of the underlying causes of inflammation in allergic asthma.

40. Anti- IgE therapy is only available by prescription. Unlike other asthma medications, it is not administered by pill or by inhaler. It needs to be injected once every two or four weeks by a doctor or other trained healthcare professional. The only anti- IgE therapy available in Canada is omalizumab .

41. Side Effects: Skin irritation Reaction at the site of the injection Respiratory tract infections (e.g., common cold).

42. Combination Medications Some pharmaceutical manufacturers have combined two controller medications into one inhaler. These inhalers are referred to as "Combination Medications". Combination medications contain both an inhaled long-acting bronchodilator (LABA) and an inhaled corticosteroid.

43. Combination Medications Corticosteroids Long-Acting Bronchodilators Symbicort ® Budesonide ( Pumicort ®) Formoterol ( Oxeze ®) Advair ® Fluticasone ( Flovent ®) Salmeterol ( Severent ®)

44. This means that two areas of asthma can be effectively treated at the same time the bronchodilator works by widening your airways, making it easier for you to breathe, and the inhaled steroid reduces and prevents inflammation of your airways. Recent studies show that many people with asthma find that combination medications give them better control and are convenient to use.

45. Possible side effects of combination medications include: Rapid heart beat Tremor or nervousness Cough, throat irritation or hoarseness