LC1 FALL 23.pdf

Respiratory system Dr. Ghada Ragab Introduction Respiratory disorders: 1.Asthma 2.Chronic obstructive pulmonary disease (COPD) 3.Allergic rhinitis 4.Cough ASTHMA Asthma: is a chronic inflammatory disease of the airways characterized by episodes of acute bronchoconstriction causing shortnes...

Respiratory system Dr. Ghada Ragab Introduction Respiratory disorders: 1.Asthma 2.Chronic obstructive pulmonary disease (COPD) 3.Allergic rhinitis 4.Cough ASTHMA Asthma: is a chronic inflammatory disease of the airways characterized by episodes of acute bronchoconstriction causing shortness of breath, cough, chest tightness, wheezing, and rapid respiration at night and early morning. Pathophysiology of Asthma Airflow obstruction in asthma is due to bronchoconstriction that results from: 1. Contraction of bronchial smooth muscle 2. Inflammation of the bronchial wall 3. Increased secretion of mucus 4. The underlying inflammation of the airways contributes to airway hyperresponsiveness  airflow limitation, respiratory symptoms, and disease chronicity. Asthma attacks may be triggered by exposure to allergens, exercise, stress, and respiratory infections (exogenous or endogenous stimuli). Goals of therapy The goals of asthma therapy are to decrease the intensity and frequency of asthma symptoms and the degree to which the patient is limited by these symptoms. All patients need to have a “quick-relief” medication to treat acute asthma symptoms. Drug therapy for long-term control of asthma is designed to reverse and prevent airway inflammation. First-line treatment agents based on disease classification  Drugs used to treat respiratory conditions can be delivered topically to the nasal mucosa, inhaled into the lungs, or given orally or parenterally for systemic absorption. Local delivery methods, such as nasal sprays or inhalers, are preferred to target affected tissues while minimizing systemic side effects. 1. β2 -Adrenergic Agonists Inhaled β2 -adrenergic agonists directly relax airway smooth muscle. They are used for the quick relief of asthma symptoms, as well as adjunctive therapy for long-term control of the disease. This drugs are not selective so effect also on β1 receptors in heart and induce contractions and tachycardia Inhibition of mast cell degranulation A-Quick relief used for acute asthma Short-acting β2 agonists (SABAs) have a rapid onset of action (5 to 30 minutes) and provide relief for 4 to 6 hours. They are used for symptomatic treatment of bronchospasm, providing quick relief of acute bronchoconstriction. All patients with asthma should be prescribed a SABA inhaler. β2 agonists have no anti inflammatory effects, and they should never be used as the sole therapeutic agents for patients with persistent asthma. However, monotherapy with SABAs may be appropriate for patients with intermittent asthma or exercise-induced bronchospasm.  Direct acting β2 -selective agonists include albuterol or salbutamol [al-BYOO-ter-all] and levalbuterol [leh-val-BYOO- ter-all]. These agents provide significant bronchodilation with little of the undesired effect of α or β1 stimulation Adverse effects: such as tachycardia, hyperglycemia, hypokalemia, and hypomagnesemia, are minimized with inhaled delivery versus systemic administration. These agents can cause β2 -mediated skeletal muscle tremors. Salbutamol or albuterol is the most commonly used bronchodilators that is available in many forms; nebulizers , inhaler or orally B- Long-term control: Salmeterol [sal-MEE-ter-all] and formoterol [for-MOE-ter-all] are long-acting β2 agonists (LABAs) and chemical analogs of albuterol. Salmeterol and formoterol have a long duration of action, providing bronchodilation for at least 12 hours. Twice daily Neither salmeterol nor formoterol should be used for quick relief of an acute asthma attack. Use of LABA monotherapy in chronic asthma is contraindicated, and LABAs should be used only in combination with an asthma controller medication. + ICS to prevent asthma- related death so, Some LABAs are available as a combination product  Inhaled corticosteroids (ICS) remain the long-term controllers of choice in asthma, and LABAs are considered to be useful adjunctive therapy for attaining asthma control. Adverse effects of LABAs are similar to quick-relief β2 agonists. LABAs may be used alone to prevent symptoms B4 exercises or in COPD 2-Corticosteroids ICS are the drugs of choice for long-term control in patients with any degree of persistent asthma No other medications are as effective as ICS in the long- term control of asthma in children and adults. To be effective in controlling inflammation, glucocorticoids must be used regularly. Severe persistent asthma may require the addition of a short course of oral glucocorticoid treatment. Actions on lung: ICS do not directly affect the airway smooth muscle. Instead, ICS therapy directly targets underlying airway inflammation by: 1. Decreasing the inflammatory cascade (eosinophils, macrophages, and T lymphocytes) 2. Reversing mucosal edema 3. Decreasing the permeability of capillaries 4. Inhibiting the release of leukotrienes.  After several months of regular use, ICS reduce the hyperresponsiveness of the airway smooth muscle to a variety of bronchoconstrictor stimuli, such as allergens, irritants, cold air, and exercise. Routes of administration 3-ALTERNATIVE DRUGS USED TO TREAT ASTHMA These drugs are useful for treatment of asthma in patients who are poorly controlled by conventional therapy or experience adverse effects secondary to corticosteroid treatment. These drugs should be used in conjunction with ICS therapy for most patients, not as monotherapy. A-Leukotriene modifiers Leukotrienes (LT) B4 and the cysteinyl leukotrienes, LTC4, LTD4, and LTE4, are products of the 5-lipoxygenase pathway of arachidonic acid metabolism and part of the inflammatory cascade. 5-Lipoxygenase is found in cells of myeloid origin, such as mast cells, basophils, eosinophils, and neutrophils. LTB4 is a potent chemoattractant for neutrophils and eosinophils, whereas the cysteinyl leukotrienes constrict bronchiolar smooth muscle, increase endothelial permeability, and promote mucus secretion.  Zileuton [zye-LOO-ton] is a selective and specific inhibitor of 5- lipoxygenase, preventing the formation of both LTB4 and the cysteinyl leukotrienes. Because zafirlukast [za-FIR-loo-kast] and montelukast [mon-te-LOO- kast] are selective antagonists of the cysteinyl leukotriene-1 receptor, they block the effects of cysteinyl leukotrienes All three drugs are approved for the prevention of asthma symptoms. They should not be used in situations where immediate bronchodilation is required. Leukotriene receptor antagonists have also shown efficacy for the prevention of exercise induced bronchospasm NOT USED IN ACUTE B. Cromolyn Cromolyn [KRO-moe-lin] is a prophylactic anti-inflammatory agent that inhibits mast cell degranulation and release of histamine. It is an alternative therapy for mild persistent asthma. However, it is not useful in managing an acute asthma attack, because it is not a bronchodilator. Cromolyn is available as a nebulized solution for use in asthma. Due to its short duration of action, this agent requires dosing three or four times daily, which affects adherence and limits its use. Adverse effects are minor and include cough, irritation, and unpleasant taste. C-Cholinergic antagonists The anticholinergic agents block vagally mediated contraction of airway smooth muscle and mucus secretion Inhaled ipratropium [IP-ra-TROE-pee-um], a quaternary derivative of atropine, is not recommended for the routine treatment of acute bronchospasm in asthma, as its onset is much slower than inhaled SABAs. However, it may be useful in patients who are unable to tolerate a SABA or patients with concomitant COPD. 30-60 min Ipratropium also offers additional benefit when used with a SABA for the treatment of acute asthma exacerbations in the emergency department. Adverse effects such as atropine like side effects D. Theophylline Theophylline [thee-OFF-i-lin] is a bronchodilator that relieves airflow obstruction in chronic asthma and decreases its symptoms. It may also possess anti-inflammatory activity, although the mechanism of action is unclear. Previously, the mainstay of asthma therapy, theophylline has been largely replaced with β2 agonists and corticosteroids due to its narrow therapeutic window, Adverse effect profile, and potential for drug interactions.  Overdose may cause seizures or potentially fatal arrhythmias. Theophylline is metabolized in the liver and is a CYP1A2 and 3A4 substrate. It is subject to numerous drug interactions. Serum concentration monitoring should be performed when theophylline is used chronically. E. Monoclonal antibody (Omalizumab) Omalizumab [OH-ma-LIZ-oo-mab] is a recombinant DNA-derived monoclonal antibody that selectively binds to human immunoglobulin E (IgE) so anti immunoglobulin E. This leads to decreased binding of IgE to its receptor on the surface of mast cells and basophils. Reduction in surface-bound IgE limits the release of mediators of the allergic response. Omalizumab is indicated for the treatment of moderate to severe persistent asthma in patients who are poorly controlled with conventional therapy. Its use is limited by the high cost, route of administration (subcutaneous) every 2 weeks, and adverse effect profile. Adverse effects include serious anaphylactic reaction (rare), arthralgias, fever, and rash. Secondary malignancies have been reported. Study Questions 12-year-old girl with a childhood history of asthma complained of cough, dyspnea, and wheezing after visiting a riding stable. Her symptoms became so severe that her parents brought her to the emergency room. Which of the following is the most appropriate drug to rapidly reverse her bronchoconstriction? A. Inhaled fluticasone. B. Inhaled beclomethasone. C. Inhaled albuterol. D. Intravenous propranolol. E. Oral theophylline. Study Questions A 9-year-old girl has severe asthma, which required three hospitalizations in the last year. She is now receiving therapy that has greatly reduced the frequency of these severe attacks. Which of the following therapies is most likely responsible for this benefit? A. Inhaled albuterol. B. Inhaled ipratropium. C. Inhaled fluticasone. D. Oral theophylline. E. Oral zafirlukast.