Drugs Acting On The Respiratory System PDF

DRUGS ACTING ON THE RESPIRATORY SYSTEM 1 DRUGS USED IN THE TREATMENT OF BRONCHIAL ASTHMA Dr Sindwa Kanyimba Lecturer, Pharmacology 2 INTRODUCTION Bronchial asthma is a syndrome characterized by recurrent reve...

DRUGS ACTING ON THE RESPIRATORY SYSTEM 1 DRUGS USED IN THE TREATMENT OF BRONCHIAL ASTHMA Dr Sindwa Kanyimba Lecturer, Pharmacology 2 INTRODUCTION Bronchial asthma is a syndrome characterized by recurrent reversible airway obstruction It is primarily an inflammatory disorder that has bronchial hyper-reactivity and bronchospasm as a result Asthma is a chronic inflammatory condition of the lung airways resulting in episodic airflow obstruction 3 INTRODUCTION …. CONT’D Chronic inflammation increases airway hyper-responsiveness to provocative exposures Asthma may chronic or acute Chronic asthma is characterised by intermittent attacks of dyspnoea (there is difficult in breathing out), wheezing and cough 4 LEARNING OBJECTIVES List the chemical mediators involved in the pathogenesis of bronchial asthma and state their roles in asthma Describe the drugs used in the management of bronchial asthma with regard to their mechanisms of actions, routes of administration, role in the management of asthma and unwanted effects 5 MEDIATORS INVOLVED IN THE PATHOGENESIS OF BRONCHIAL ASTHMA Cysteinyl leukotrienes [LTC4 and LTD4] (bronchospasm, bronchial inflammation and hyper-reactivity) Prostaglandin D2 (bronchospasm) Histamine (bronchospasm) Neuropeptides – substance P, neurokinin A (bronchial inflammation and hyper-reactivity) Nitric oxide (bronchial inflammation and hyper-reactivity) Adenosine acting on A1 receptors (bronchospasm, bronchial inflammation and hyper-reactivity 6 MEDIATORS INVOLVED IN THE PATHOGENESIS OF BRONCHIAL ASTHMA …. CONT’D Platelet activating factor (bronchospasm, bronchial inflammation and hyper-reactivity) Eosinophil major basic protein (epithelial damage) Eosinophil cationic protein (epithelial damage) Interleukins: IL-3, IL-4, IL-5, IL-8 and IL-13 (chemokines and chemotaxins – attract eosinophils and mononuclear cells setting the stage for the late phase) Macrophage inflammatory protein-1 (bronchial inflammation and hyper-reactivity) Tumour necrosis factor- [TNF-] (bronchial inflammation and hyper-reactivity) 7 DRUGS USED IN THE MANAGEMENT OF BRONCHIAL ASTHMA Selective beta-2 adrenergic agonists Methyl-xanthines Muscarinic receptor antagonists Leukotriene receptor antagonists Zileuton Glucocorticoids Chromones: Sodium cromoglicate and nedocromil sodium Biologic agents (anti-IgE and anti-interleukin-5 monoclonal antibodies) Magnesium sulphate 8 SELECTIVE BETA2 ADRENOCEPTOR AGONISTS (Β2-AGONISTS) Mechanism of action The primary effect of 2-agonists in asthma is to dilate the bronchi by a direct action on the 2-adrenoceptors on the smooth muscle Are physiological antagonists to the mediators of asthma, and therefore relax bronchial muscle whatever spasmogens are involved Also inhibit mediator release from mast cells and release of TNF- Also increase mucus clearance by an action on cilia 9 SELECTIVE Β2-AGONISTS …. CONT’D Categories of 2-agonists used in asthma Short acting: salbutamol, fenoterol and terbutaline. Duration of action is 4 – 6 hours. Usually used on ‘as needed’ basis for quick relief of symptoms Long acting: salmeterol, pirbuterol, formoterol and reproterol. Duration of action is 12 hours. They are not used ‘as needed’ but are given regularly twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by glucocorticoids. 10 SELECTIVE Β2-AGONISTS …. CONT’D Route of administration The 2-agonists are given by inhalation (aerosol, powder, nebulised solution) and by injection (IV and SC) Unwanted effects Skeletal muscle tremor, tachycardia, anxiety and hypokalaemia at high doses 11 METHYL-XANTHINES The three pharmacologically active naturally occurring methyl-xanthines are theophylline, theobromine and caffeine The methyl-xanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle and smooth muscle Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects. The methyl-xanthine used clinically is theophylline 12 THEOPHYLLINE: MECHANISM OF ACTION Inhibition of phosphodiesterase (PDE) isoenzymes with resultant increase in cAMP and cGMP – Phosphodiesterases are the enzymes that degrade cAMP and cGMP – Cyclic AMP relax bronchial smooth muscle, and reduces immune and inflammatory activity of specific cells Competitive antagonism of adenosine at adenosine receptors (activation of adenosine A1 receptors causes bronchoconstriction and A3 receptor activation causes release of mediators from mast cells) Enhancement of histone deacetylation thereby reducing activation of inflammatory gene transcription 13 THEOPHYLLINE: PHARMACOLOGICAL ACTIONS RS: Bronchodilatation CNS: CNS stimulation causing alertness, tremor, nervousness, interference with sleep, stimulates respiration [stimulate the respiratory centre] CVS: Positive chronotropic and inotropic effects on the heart, vasodilatation in most blood vessels, and vasoconstriction in coronary and cerebral blood vessels GIT: Stimulate secretion of gastric acid and digestive enzymes Renal system: Weak diuretic effect (increase GFR, and reduce sodium and water reabsorption in the tubules) 14 THEOPHYLLINE: PHARMACOKINETICS Theophylline is well absorbed orally Elimination of theophylline is affected by various factors and there is wide individual variation in drug response:  Elimination is reduced by drugs that inhibit P450 enzymes (e.g. erythromycin, ciprofloxacin, fluconazole, calcium channel blockers), in liver disease, cardiac failure and viral infections (due to decreased hepatic metabolism): results in increased drug response  Elimination is increased by drugs that increase P450 enzymes (e.g. rifampicin, phenobarbital, phenytoin and carbamazepine, in heavy tobacco use and chronic ethanol intake (due to increased hepatic metabolism): results in reduced drug response 15 THEOPHYLLINE …. CONT’D ROUTES OF ADMINISTRATION AND USES IN ASTHMA Given orally in sustained release preparations for prophylaxis Theophylline is complexed with ethylene-diamine (aminophylline) to make it more water soluble to allow for IV administration Aminophylline is given by slow IV injection (bolus) of a loading dose followed by IV infusion for treatment of severe acute asthma 16 THEOPHYLLINE: ADVERSE EFFECTS Common unwanted effects include nausea, vomiting, dyspepsia. tremors, tachycardia, nervousness, headache and insomnia Toxic effects: Tachy-arrythmias (supraventricular and ventricular) and seizures Theophylline has a narrow therapeutic window (55 – 110 mol/L). Toxic effects are likely to occur when plasma concentration exceeds 110 mol/L. Measurements of the plasma concentration are needed to optimize therapy 17 MUSCARINIC RECEPTOR ANTAGONISTS Examples: ipratropium bromide, oxitropium They relax bronchial constriction caused by parasympathetic stimulation They are regarded to be more effective in relieving bronchoconstriction associated with chronic obstructive pulmonary disease Given by aerosol inhalation or nebulised solution Can be used with 2-adrenoceptor agonists Inhaled muscarinic antagonists are well tolerated. Dry mouth and blurred vision may occur. 18 LEUKOTRIENE RECEPTOR ANTAGONISTS Examples: montelukast, zafirlukast MOA: they block the effects of cysteinyl leukotrienes (LTC4 and LTD4) in the airways Their bronchodilator activity is one-third that of salbutamol Have moderate anti-inflammatory activity Their action is additive with 2-adrenoceptor agonists 19 LEUKOTRIENE RECEPTOR ANTAGONISTS …. CONT’D Use in asthma As add-on therapy for mild-to-moderate asthma that is not controlled by short acting 2-agonist taken together with an inhaled steroid Used to prevent aspirin-induced asthma and exercise- induced asthma Given orally Unwanted effects Dry mouth, headache and GIT disturbances 20 ZILEUTON MOA: Inhibits 5-lipoxygenase, the rate limiting enzyme in leukotriene synthesis Effective in relief of exercise-induced bronchoconstriction Given orally Adverse effects include hepatotoxicity, chills, fatigue and fever 21 GLUCOCORTICOIDS Glucocorticoids reduce the inflammatory component in chronic asthma Mode of action in asthma Decrease formation of cytokines Stabilise cell membranes and therefore inhibit release of inflammatory mediators Inhibit production of prostaglandins and leukotrienes (through induction of lipocortin which inhibits phospholipase A2) Up-regulate 2-adrenoceptors (i.e. restore the sensivity to 2-agonists) 22 GLUCOCORTICOIDS USED IN ASTHMA Beclomethasone dipropionate, budenoside and fluticasone propionate – given by inhalation Prednisolone – given orally in chronic asthma and severe or rapidly deteriorating asthma Hydrocortisone – given intravenously in status asthmaticus (acute severe asthma) 23 GLUCOCORTICOIDS …. CONT’D Adverse effects Inhaled glucocorticoids: dysphonia, oro-pharyngeal candidiasis (can be prevented or minimized by using a spacer and/or gargling with water after inhalation) Systemic glucocorticoids: many adverse effects with prolonged use (including adrenal-pituitary axis suppression, osteoporosis, cataracts, skin atrophy, growth retardation in children, susceptibility to infections) 24 USE OF GLUCOCORTICOIDS IN ASTHMA Glucocorticoids are not bronchodilators and are not effective in the treatment of acute asthma attacks Inhaled corticosteroids are the most effective and safe and are used as the first line drugs for prophylactic asthma treatment Systemic glucocorticoids are used for short term treatment mainly in case of severe persistent asthma (prednisolone) or asthmatic status (hydrocortisone or prednisolone) 25 CHROMONES Include Sodium cromoglicate and the related drug nedocromil sodium They are not bronchodilators and are of no value in the treatment of acute attacks of asthma If given prophylactically they reduce both the immediate and the late-phase asthmatic responses and reduce bronchial hyper-reactivity They are effective in antigen-induced, exercise-induced and irritant-induced asthma Used mainly in pediatric practice (children respond better than adults) in intermittent or mild persistent asthma Given by inhalation 26 CHROMONES …. CONT’D Mechanism of action Inhibit tachykinin receptors: this suppresses neurogenic inflammation that results from activity of tachykinins (substance P and neurokinin A) Stabilize antigen-sensitized mast cells by reducing calcium influx and subsequent release of inflammatory mediators Inhibit the interaction between platelet activating factor and eosinophils The above actions result in reduced bronchial smooth muscle hyper- reactivity, and the early and late responses to allergens are blocked Adverse effects Cough, throat irritation and transient bronchospasm 27 ANTI-IGE MONOCLONAL ANTIBODIES (ANTI-IGE MAB) Example: Omalizumab Anti-IgE monoclonal antibody that inactivates immunoglobulin E (IgE). IgE plays a key role in allergic reactions. Repeated administration of anti-IgE Mab lessens asthma severity and reduces the need for corticosteroids They work best in patients with a clear environmental antigen precipitating factor They also improve nasal and conjunctival symptoms in patients with perennial or seasonal allergic rhinitis 28 OMALIZUMAB Mechanism of action Inhibits the binding of IgE to mast cells and IgE synthesis by B lymphocytes Clinical uses Reduces the frequency and severity of asthma exacerbations, and corticosteroid requirements Used as additional therapy in patients with severe allergic asthma inadequately controlled by high dose inhaled corticosteroid plus long acting β2-agonist Given subcutaneously Adverse effects include hypersensitivity reactions, headache, muscle aches, joint pains and fatigue 29 ANTI-INTERLEUKIN-5 THERAPY Another target for bronchial asthma therapy is IL-5 T2 cells secrete IL-5 as a pro-eosinophilic cytokine that results in eosinophilic airway inflammation. Some patients with severe asthma have airway and peripheral eosinophilia driven by up-regulation of IL-5-secreting T2 lymphocytes Monoclonal antibodies targeting IL-5 have been developed for the treatment of asthma: – Mepolizumab and reslizumab: Bind IL-5 and inhibit its interactions with its receptors – Benralizumab: Blocks the IL-5 receptor 30 ANTI-INTERLEUKIN-5 THERAPY …. CONT’D Anti-IL-5 drugs are effective in preventing exacerbations in asthmatic patients with peripheral eosinophilia Indication: Add-on, maintenance therapy of severe asthma in patients with an eosinophilic asthma They are given by IV infusion Adverse effects include hypersensitivity reactions 31 MAGNESIUM SULPHATE MOA in asthma: relaxes bronchial smooth muscle by reducing calcium concentrations in bronchial smooth muscle cells Magnesium sulphate is useful as an additional bronchodilator in children and adults with acute severe asthma Intravenous or nebulized MgSO4 benefits adults and children with severe exacerbations, giving improvement in lung function when added to nebulized β2 agonists Adverse effects of parenteral magnesium sulphate include hypotension, muscle weakness, drowsiness and respiratory depression 32  END Thanks for listening 33