Respiratory System Part 1.pdf

Respiratory System Drugs Respiratory System C o Components n NASAL CAVITY d u LARYNX c t TRACHEA i o n BRONCHUS z o Respiratory LUNGS n zone e Upper respiratory tract Lower respiratory tract 25 cm T5 Pneumocyte Type 1 Endothelial cell Pneumocyte Type 2 Pneumocyte type 1 = gas exchange Pneumocyte typ...

Respiratory System Drugs Respiratory System C o Components n NASAL CAVITY d u LARYNX c t TRACHEA i o n BRONCHUS z o Respiratory LUNGS n zone e Upper respiratory tract Lower respiratory tract 25 cm T5 Pneumocyte Type 1 Endothelial cell Pneumocyte Type 2 Pneumocyte type 1 = gas exchange Pneumocyte type 2 = surfactant production Alveolar macrophage = phagocytosis Respiratory System Functions Deliver oxygen to the cells Eliminate CO2 Regulate blood pH Respiratory Function Components of Lungs VENTILATION Movement of air through the airways DISTRIBUTION Air entering lungs are distributed to all parts including the alveoli DIFFUSION Oxygen from the inspired air diffuses through the walls of the alveoli to the blood capillaries surrounding the alveoli-similarly carbon dioxide diffuses in opposite direction PERFUSION Blood with high concentrations of carbon dioxide and low in oxygen is pumped to the pulmonary arteries by the right ventricle and after diffusion, the arterial blood is returned to the left atrium by the pulmonary veins atmosphere c Carbon dioxide o oxygen Right heartarteries Left heart-arteries Systemic circulation Carbon dioxide oxygen Common Disorders of Respiratory Functions Bronchial asthma Cough Allergic rhinitis Chronic obstructive pulmonary disease (COPD) Bronchial Asthma (BA) Chronic inflammatory disorder of bronchial airways that results in airway obstruction in response to external stimuli (as pollen grains, cold air and tobacco smoke) Tends to be progressive in many cases Clinical course characterized by remissions and exacerbations Manifestations Bronchoconstriction (wheezing) shortness of breath tachypnea Acute phase (immediate phase) Chronic phase (late phase) Characteristics of Airways in BA Inflammation Swelling Thick mucus production Bronchospasm - Constriction of the bronchial muscles Symptoms of BA Recurrent episodes Acute bronchoconstriction Shortness of breath Chest tightness Wheezing Rapid respiration Cough Causes of BA Infection Exercise Pets Seasonal changes Some drugs as aspirin, β blockers Could be precipitated by stress or emotional conditions Airways Innervations Afferent nerves (sensory) C-fiber receptors irritant receptors sensitized by endogenous inflammatory mediators after exogenous irritation A-fibers C-fibers upstream Efferent nerves (motor) Parasympathetic supply M3 receptors in smooth muscles and glands No sympathetic supply in the reaction ß2-Adrenergic receptors are are uncoupled, leading to functional hyporesponsiveness Probably due to the effects of inflammatory mediators These effect seems unlikely to be of primary importance in the pathogenesis Spirometry FEV 1 tends to be low during asthma exacerbation Classification Type Bronchoconstrictive episodes Peak flow spirometry Long term control Quick relief of symptoms Mild intermittent Less than 2 / week Near normal No daily medication Short acting B2 agonist Mild persistent More than 2 / week Near normal Low dose inhaled corticosteroid Short acting B2 agonist Moderate persistent Daily 60 – 80% of normal Low to medium dose of inhaled corticosteroid and long acting B2 agonist Short acting B2 agonist Severe persistent Constant Less than 60% of normal High dose of inhaled corticosteroid and long acting B2 agonist Short acting B2 agonist Status asthmaticus Prolonged asthma attack that does not respond to typical drug therapy May last several minutes to hours Medical emergency Goals of BA Tx To relieve acute episodic attacks of asthma (bronchodilators, quick relief medications) To reduce the frequency of attacks, and nocturnal awakenings (anti-inflammatory drugs, prophylactic or control therapy ) Anti Asthmatic Drugs Acute Attacks Quick relief medications Bronchodilators - Short acting 2agonists - Antimuscarinics - Xanthine preparations Maintenance Therapy Reduce the frequency of exacerbations Anti-inflammatory agents - Corticosteroids - Mast cell stabilizers - Leukotrienes antagonists - Anti-IgE monoclonal antibody Bronchodilators - Long acting ß2agonists Quick Relief Medications - adrenoceptor Agonists Mechanism of Action Direct 2 stimulation ⎯→ stimulate adenyl cyclase ⎯→ Increase cAMP ⎯→ bronchodilation Inhibit mediators release from mast cells Increase mucus clearance by (increasing ciliary activity Quick Relief Medications - adrenoceptor Agonists Classification Non-selective  agonists: - Epinephrine - isoprenaline - Potent bronchodilator rapid action (max. effect within 15 min). - S.C. or by inhalation (aerosol or nebulizer) - Short duration of action (60-90 min) - Drug of choice for acute anaphylaxis - Disadvantages Not effective orally. Hyperglycemia CVS side effects: tachycardia, arrhythmia, hypertension Skeletal muscle tremor Not suitable for asthmatic patients with hypertension or heart failure - Contraindication: CVA patients, diabetic patients Quick Relief Medications - adrenoceptor Agonists Classification Selective 2 – agonists - Albuterol, Terbutaline, Salmeterol, Formoterol - Drugs of choice for acute attack of asthma - Mainly given by inhalation (metered dose inhaler or nebulizer) - Short acting ß2 agonists Albuterol - inhalation, orally, I.V. Terbutaline, inhalation, orally, S.C. Have rapid onset of action (15-30 min) Short duration of action (4-6 hr) Used for symptomatic treatment of acute episodic attack of asthma or maintenance in severe asthma Quick Relief Medications - adrenoceptor Agonists Classification Selective 2 – agonists - Long acting selective ß2 agonists - Salmeterol & formoterol: Long-acting bronchodilators (12 hours) High lipid solubility (creates depot effect) Given by inhalation (inhaler) Not used to relieve acute episodes of asthma Used for nocturnal asthma (long acting relievers). Combined with inhaled corticosteroids to control asthma (decreases the number and severity of asthma attacks). Nebulizer Inhaler Quick Relief Medications - adrenoceptor Agonists Advantages of ß2 agonists Minimal CVS side effects Suitable for asthmatic patients with hypertension or heart failure Disadvantages of ß2 agonists Skeletal muscle tremors Nervousness Tolerance (B-receptors down regulation) Tachycardia overdose (B1-stimulation) Quick Relief Medications Muscarinic antagonists Ipratropium – Tiotropium Act by blocking muscarinic receptors Given by aerosol inhalation Quaternary derivatives of atropine Does not diffuse into the blood Do not enter CNS, minimal systemic side effects. Delayed onset of action Ipratropium has short duration of action (3-5 hrs) Tiotropium has longer duration of action (24 hrs) Quick Relief Medications Muscarinic antagonists Pharmacodynamics are short-acting bronchodilator Inhibit bronchoconstriction and mucus secretion Less effective than β2-agonists No anti-inflammatory action Uses Main choice in chronic obstructive pulmonary diseases (COPD) In acute severe asthma combined with β2-agonists & steroids Methylxanthines Purine-derived group of pharmacologic agents Theophylline - Aminophylline Mechanism of Action Phosphodiesterase inhibitors  cAMP → bronchodilation Adenosine receptors antagonists (A1) Respiratory effects Bronchial muscle relaxation contraction of diaphragm→ improve ventilation ATP Bronchodilation Adenyl cyclase B-agonists cAMP Bronchial tree Adenosine Bronchoconstriction Phosphodiesterase Theophylline 3,5,AMP Methylxanthines Pharmacokinetics Metabolized by Cyt P450 enzymes in liver T ½= 8 hours Drug interactions Enzyme inducers: as phenobarbitone-rifampicin → ↑metabolism of theophylline → ↓ T ½ Enzyme inhibitors: as erythromycin→ ↓ metabolism of theophylline → ↑T ½ Uses Second line drug in asthma (theophylline) For status asthmatics (aminophylline, is given as slow infusion) Side Effects Low therapeutic index, narrow safety margin monitoring of theophylline blood level is necessary. Hypotension, arrhythmia, nausea & vomiting CNS side effects: tremors, nervousness, insomnia, convulsion Maintenance Therapy Drugs Anti - inflammatory agents Control medications / prophylactic therapy for BA Reduce the number of inflammatory cells in the airways and prevent blood vessels from leaking fluid into the airway tissues By reducing inflammation, they reduce the spasm of airways & bronchial hyper-reactivity Types Glucocorticoids Leukotrienes antagonists Mast cell stabilizers Anti-IgE monoclonal antibody (omalizumab) Glucocorticoids in Asthma No bronchodilation Reduce bronchial inflammation Reduce bronchial hyper-reactivity to stimuli Have delayed onset of action (effect usually attained after 2-4 weeks). Maximum action at 9-12 months. Given as prophylactic medications, used alone or combined with beta-agonists Effective in allergic, exercise, antigen and irritant-induced asthma Glucocorticoids Mechanism of action Inhibition of phospholipase A2 ↓ prostaglandin and leukotrienes ↓ Number of inflammatory cells in airways Mast cell stabilization →↓ histamine release ↓ capillary permeability and mucosal edema Inhibition of antigen-antibody reaction Upregulate β2 receptors (have additive effect to B2 agonists) Glucocorticoids Metabolic effects – Hyperglycemia – ↑ protein catabolism, ↓ protein anabolism Mineralocorticoid effects – sodium/fluid retention –Increase potassium excretion (hypokalemia) –Increase blood volume (hypertension) Behavioral changes: depression Bone loss (osteoporosis) due to Inhibit bone formation ↓ calcium absorption Glucocorticoids Routes of administration Inhalation: - Budesonide, Fluticasone, beclomethasone - Given by inhalation, given by metered-dose inhaler - Best choice in asthma, less side effects Orally: Prednisone, methyl prednisolone, orals can be used to treat persistent cough associated to bronchial inflammation IV Systemic steroids – Hydrocortisone, dexamethasone, reserve for Status asthmaticus (IV) and severe asthma exacerbation Glucocorticoids Side effects due to systemic administration Adrenal suppression Osteoporosis Fluid retention, weight gain, hypertension Hyperglycemia Susceptibility to infections Glaucoma/Cataract Fat distribution, wasting of the muscles Glucocorticoids Inhalation has very less side effects: - Oropharyngeal candidiasis (thrush) - Dysphonia (voice hoarseness) Withdrawal - Abrupt stop of corticosteroids should be avoided - Dose should be tapered (adrenal insufficiency syndrome/adrenal crisis) - Adrenal crisis is a life-threatening condition in which your adrenal glands don't make enough cortisol Symptoms - lightheadedness or dizziness, weakness, sweating, abdominal pain, nausea and vomiting, or even loss of consciousness Mast Cell Stabilizers Cromolyn (cromoglycate) – Nedocromil Act by stabilization of mast cell membrane. Given by inhalation (aerosol, microfine powder, nebulizer Have poor oral absorption (10%) Pharmacodynamics Not bronchodilators Not effective in acute attack of asthma. Prophylactic anti-inflammatory drug Reduce bronchial hyper-reactivity Effective in exercise, antigen and irritant-induced asthma Children respond better than adults Mast Cell Stabilizers Uses Prophylactic therapy in asthma especially in children. Allergic rhinitis. Conjunctivitis. Side effects Bitter taste minor upper respiratory tract irritation (burning sensation, nasal congestion) Leukotrienes Antagonists Leukotrienes Produced by the action of 5lipoxygenase on arachidonic acid Synthesized by inflammatory cells found in the airways (eosinophils, macrophages, mast cells) Leukotriene B4: chemotaxis of neutrophils Cysteinyl leukotrienes: - Bronchoconstriction - Increase bronchial hyperreactivity - Mucosal edema, mucus hyper-secretion Leukotriene Receptor Antagonists Zafirlukast, montelukast, pranlukast Are selective, reversible antagonists of cysteinyl leukotriene receptors (CysLT1receptors) Taken orally Are bronchodilators Have anti-inflammatory action Less effective than inhaled corticosteroids Have glucocorticoids sparing effect (potentiate corticosteroid actions) Leukotriene Receptor Antagonists Uses of leukotriene receptor antagonists Are not effective to relieve acute attack of asthma. Prophylaxis of mild to moderate asthma. Aspirin-induced asthma Antigen and exercise-induced asthma Can be combined with glucocorticoids (additive effects, low dose of glucocorticoids can be used). Side effects: Elevation of liver enzymes, headache, dyspepsia Omalizumab A monoclonal antibody directed against human IgE prevents IgE binding with its receptors on mast cells & basophiles ↓ release of allergic mediators used for treatment of allergic asthma Expensive-not first line therapy Summary