Antiasthmatic drugs.pptx
- 1. Drugs used in the treatment of Asthma Sapana Jain M. pharm, Quality Assurance
- 2. • The term asthma means “to stay awake in order to breathe” • Its chronic inflammatory disease in which patient suffers from reversible episodes of airway obstruction due to bronchial hyper responsiveness. • The symptoms are breathlessness, wheezing, cough and chest tightness with worsening of these symptoms at night.
- 3. • Its classified as extrinsic or intrinsic. • If its associated with specific allergen like pollen grain, then its called extrinsic asthma. • Unlike this, when there is no identifiable external factor ,then its called as instrinsic asthma • Extrinsic asthma is episodic while intrinsic asthma is perennial
- 4. Pathophysiology of Asthma • Antigens like pollen grains sensitize individuals by promoting production of IgE type of antibodies which remain circulating in the blood or are attracted to the mast cells of nasal/ bronchial tissues and basophils. • On subsequent exposure to same antigen, there is antigen-antibody reaction on the surface of lung mast cells causing release of mediators like histamine, serotonin, PGD2 and leucotrienes like LTC4/LTD4. • Both leucotrienes are powerful broncho- constrictors.
- 5. Pathophysiology of Asthma • In the delayed phase, mast cells release leucotrienes as LTB4 and cytokines like IL-4,IL-5 and IL-13 • Eosinophil ,basophils and alveolar macrophages are rich in these mediators. • There are few other mediators like adenosine, neurokinin—A and platelet activating factor(PAF) which together cause inflammation, increased vascular permeability , chemotaxis of neutrophils, and eosinophil bronchoconstriction and bronchial hypersensitivity
- 6. Classification of anti –Asthamatic drugs • 1)Bronchodilators Selective B2 agonists like salbutamol Non selective sympathomimetics like Ephedrine Anti cholinergic like Ipratropium Methylxanthine like theophylline
- 7. 2)Corticosteroids Orallly active Corticosteroids like prednisolone Parenteral corticosteroids like Hydrocortisone Inhalational Corticosteroids like beclomethasone 3)Mast cells stabilisers Sodium cromoglycate 4) Leucotriene modulators 5-lipooxygense inhibotors like Zileuton Cysteinyl Leucotriene – antagonist like Zafirlucast • 5)Monoclonal antibodies like Omlizumab
- 9. Sympathomimetics • The selective β2 agonist is the primary bronchodilators used in the treatment of asthma/ acute asthmatic attacks. • β2 adrenergic receptor agonists stimulates the beta receptor, increasing the cAMP concentration in smooth muscle and causing bronchodilatation. It also increase the conductance of large Ca2+ sensitive K+ channels in airway smooth muscle, leading to membrane hyperpolarization and relaxation. • The selective β2 agonist relax the bronchial smooth muscle without affecting cardiac function. In higher doses selective β2 agonist increase the heart rate by stimulating the cardiac β1-receptor. Types: – A)Long-acting β2 adrenergic receptor agonists: (Salmeterol; formoterol) B)Short-acting β2 adrenergic receptor agonists: (albuterol, levalbuterol, metaproterenol, terbutaline, and pirbuterol )
- 10. Sympathomimetics • Salbutamol: • Selective β2 agonists with less cardiac side effects • Inhaled salbutamol produce bronchodililation within 5-min and the action lasts for 2-4 h. • Used for acute asthmatic attack. Not suitable for prophylaxis • Side effect: Palpitation, restlessness, nervousness, throat irritation and ankle edema. • Metabolism: metabolized in gut; oral bioavailability is 50%. • Duration of action: oral salbutamol acts 4-6 h. • Dose: 2-4 mg/ oral; 0.25- 0.5 mg/ i.p., or s. c.; 100-200 μg/ inhalation • Terbutaline: – Similar to salbutamol; regular use dose not reduce bronchial hyper-reactivity • Dose: 5 mg/ oral; 0.25 mg/ i,.p., or s.c.,; 250 μg/ inhalation
- 11. Sympathomimetics • Bambuterol: • Bicarbamate ester prodrug of terbutaline • It also reversely inhibits pseudo cholinesterase in a dose dependent manner. • Used in chronic bronchial asthma in a single evening dose of 10-20 mg/ oral. • Salmeterol: • First long acting selective β2 agonists with slow onset of action • Twice daily for maintain the therapy/ nocturnal asthma, but not for acute asthma COPD: equivalent to inhaled anticholinergics in COPD. Reduce breathlessness by abolishing the reversible component of airway obstruction. • Formoterol: – Long acting selective β2 agonists which acts 12 h when inhaled. – Compared to salmeterol it has a faster onset of action (with in 10 min)
- 12. Methylxanthines • Theophylline and its derivatives are most commonly used for the treatment of COPD and asthma. • Caffeine, theophylline and theobromine are naturally occurring xanthine alkaloids which have qualitatively similar actions. • Mechanism of action: Methylxanthines inhibits cyclic nucleotide phosphodiesterase (PDEs), thereby preventing conversion of cAMP and cGMP to 5’- AMP and 5’-GMP, respectively. Inhibition of PDEs will lead to an accumulation of intracellular cAMP and cGMP. Bronchodilataion, cardiac stimulation and vasodilatation occur when cAMP level rises in the concerned cells. Theophylline and related methylxanthines are relatively nonselective in the PDE subtypes inhibitor. Theophylline is a competitive antagonist at adenosine receptors. Adenosine can cause bronchoconstriction in asthmatics and potentiate immunologically induced mediator release from human lung mast cells. Methylxanthines inhibits the adenosine action thereby casing bronchodilataion.
- 14. Methylxanthines • Pharmacological action: CNS: • Stimulant; affects higher center. • Caffeine 150-200 mg produce a sense of wellbeing, alertness, beats boredom, allays fatigue and improve performance and increase the motor activity. Caffeine is more active than theophylline in producing these effects. • Higher dose cause nervousness, restlessness, panic, insomnia and excitements. • Still higher dose cause tremors, delirium and convulsions. Theophylline is more toxic than caffeine. • Stimulates medullary vagal, respiratory and vasomotor centers. • High dose: Vomiting and gastric irritation and CTZ stimulation.
- 15. Pharmacological action • CVS • Stimulates the heart and increase force of contraction. Increase the heart rate (direct action) but decrease it by vagal stimulation- net effect is variable. • High dose: cardiac arrhythmias • Effect on blood pressure is variable and unpredictable. Usually a rise in systolic and fall in diastolic BP is observed. • Vasomotor center and direct cardiac stimulation- tends to raise BP • Vagal stimulation and direct vasodilatation- tends to lower BP • Smooth muscles: • Relaxation • Theophylline is more potent and slow, sustained dose related bronchodilatation – Increase vital capacity • Theophylline is more potent; caffeine has minimal actions.
- 16. Pharmacological action • Kidney • Mild diuretics • Inhibiting tubular reabsorption of Na+ and water – Increasing vascular blood flow and g.f.r. • Theophylline is more potent; caffeine has minimal actions. • Skeletal muscles: – Caffeine enhance contractile power. In high dose it increases release of Ca+ from sarcoplasmic reticulum by direct action. – Twitch response at low doses. – Caffeine facilitates neuromuscular transmission by increasing Ach release. • Stomach: – Enhance secretion of acid and pepsin – Gastric irritation (more with theophylline)
- 17. Methylxanthines- • Theophylline • Pharmacokinetics: • Absorption: Absorbed orally; rectal absorption form suppositories is erratic. • Distribution: All tissues; cross BBM; crosses placenta and is secreted in milk; 50% plasma protein bound • Metabolism: Metabolized in liver (CYPP1A2) by demethylation and oxidation. • Excretion: Excreted in urine; 10 % of total administration excreted unchanged form. Elimination rate varies considerably with age (age dependent excretion).
- 18. Methylxanthines- • Theophylline • Adverse effects: • Narrow margin safety • CVS and CNS stimulant; ADRs not dependent to dose; GIT distress • Children are more liable to developed CNS toxicity • Rapid i.v injection cause- precordial pain, syncope and sudden death Bronchodilatation
- 19. Methylxanthines- Theophylline-Interactions: – • Theophylline metabolism decreased by smoking, phenytoin, rifampicin, phenobarbitone and charcoal broiled meat meal., which increases the parenthesis. • Erythromycin, ciprofloxacin, cimetidine, oral contraceptives and allopurinol inhibits CYP1A2 and increasing the theophylline plasma concentrations; dose should be reduced to 2/3. • Theophylline reduce the effects of phenytoin, lithium. – Theophylline enhance the effects of furosemide, sympathomimetic, digitalis, oral anticoagulants and hypoglycemic. • Indications: Primarily used to treat chronic obstructive lung disorders and asthma. Also used to treat apnea
- 20. Anticholinergics Ipratropium/ tiotropium (derivative of atropine) • Parasympathetic activation/ release of ACh cause bronchoconstriction and increase mucus secretion. • Blocking the action of ACh by anticholinergic drugs produce bronchodilation and reduce the volume of respiratory secretion. • Less effective than sympathomimetic. • Inhaled ipratropium/ tiotropium are choice of bronchodilator choice in COPD. • Triotropium produce longer duration of action than ipratropium • ADR: Dry mouth, respiratory tract discomfort
- 21. Leukotriene antagonists Leukotriene antagonists :Montelukast, Zafirlukast • Both are having similar action and clinical utility • Block the cys-leukotrienes C4, D4 and E4 (LTC4, LTD4, LTE4) • Alternative for inhaled glucocorticoids • Prophylactic therapy for mild, moderate asthma; not used for terminating asthma. • Both are very safe drugs and ADRs are few (headache, rashes); eosinophilia and neuropathy are infrequent. Dose: Montelukast 10 mg OD, Zafirlukast 20 mg BD
- 22. Corticosteroids • Corticosteroids are not bronchodilator; benefit by reducing bronchial hyper reactivity, mucosal edema and by suppressing inflammatory response. • Inhaled glucocorticoids are partially absorbed and because of their systemic AEs oral glucocorticoids are usually reserved for patients with severe persistent asthma. • Systemic steroid therapy – Severe chronic asthma: Not controlled by bronchodilator and inhaled steroids. – Status asthmaticus/ acute asthma exacerbation:
- 23. Corticosteroids • Inhaled steroids • High topical and low systemic activity (due to poor absorption/ fast pass metabolism). • Inhaled steroids are not recommended for patient with mild or episodic asthma. High dose inhaled steroids are beneficial for advanced COPD with frequent exacerbations.
- 24. Mast cell stabilizers • Sodium cromoglycate, Ketotifen • Inhibits degranulation of mast cell by trigger stimuli and prevent the release of histamine, LTs, PAF, interleukins etc. from mast cells. • Inhibition of mediator release by cromolyn is through blockade of calcium influx in mast cells. • Long time therapy reduce cellular inflammatory response. • It is not histamine antagonist/ bronchodilator- ineffective in asthmatic attack. • Pharmacokinetic: – Not absorbed orally. It is administered as an aerosol through metered dose inhaler delivering 1 mg per dose; 2 puffs 4 times a day – Not popular- production of cough and bronchospasm because of particulate nature of the inhalation. – Small fraction of the inhaled drug is absorbed systemically and excreted unchanged form in urine and bile.
- 25. Mast cell stabilizers • Uses: • Bronchial asthma: Sodium Cromoglycate is used as a long term prophylactic in patients not adequately controlled by inhaled bronchodilators. Alternative for inhaled steroids in mild to moderate asthma but not severe cases. • Allergic rhinitis: Cromoglycate is not nasal decongestant, regular prophylactic use as a nasal spray produces symptomatic improvement in many patient s. • Allergic conjunctivitis: Regular use as eye drops is beneficial in some chronic cases • Adverse effect (cromoglycate): Bronchospasm Throat irritation Cough, headache Arthralgia, rashes and dysuria Rarely nasal congestion • Adverse effect (Ketotifen): Generally well tolerated Sedation and dry mouth Dizziness, nausea and weight gain
- 26. Anti-lgE antibody: Omalizumab • Recombinant DNA-derived monoclonal antibody • Selectively binds to human immunoglobulin E (IgE) and decrease binding affinity of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils, reduce allergic response. • Omalizumab may be particularly useful for treatment of moderate to severe allergic asthma in patients who are poorly controlled with conventional therapy. • Due to the high cost of the drug, limitations on dosage, and limited clinical trial data, it is not currently used as first line therapy.
- 27. References • K.D, Tripathi, Essentials of Medical Pharmacology, Seventh edition