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An acute exacerbation of COPD is a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days. It may be triggered by an infection with bacteria or viruses or by environmental pollutants. Typically, infections cause 75% or more of the exacerbations; bacteria can roughly be found in 25% of cases, viruses in another 25%, and both viruses and bacteria in another 25%
Drugs used in bronchial asthma
Drugs used in Bronchial AsthmaDr. S. Parasuraman, M.Pharm., Ph.D.,Senior Lecturer, Faculty of PharmacyAIMST
Bronchial Asthma• Asthma as an inflammatory illness• Accounting 5000 deaths/ year in USA• Asthma is common disorder and it is characterized by airwayinflammation and hyperresponsiveness to stimuli that producebronchoconstriction. These stimuli include cold air, exercise, a widevariety of allergens and emotional stress.– Extrinsic asthma: It is mostly episodic, less prone to statusasthmaticus.– Intrinsic asthma: It tends to be perennial, status asthmaticus is morecommon.
Chronic obstructive pulmonary diseases (COPD)• Incudes chronic bronchitis and emphysema– chronic bronchitis: cough associated with inflammation of thebronchioles– Emphysema: permanent destruction and enlargement of the airspacesdistal to the bronchioles• COPDs results airway obstruction, dyspnea, ↓ blood O2concentrations and ↑blood CO2 concentrations.• Risk factor of COPD: Smocking and old age• Treatment: Bronchodilators and long time oxygen therapy.Antibiotics can be used to treat acute exacerbations caused bybacterial infections.
Bronchial Asthma: Treatment approaches• Prevention of antigen antibody reaction: Avoidance ofantigen, hyposensitization• Neutralization of IgE: Omalizumab• Suppression of inflammation and bronchial hyper reactivity:Cotricosteroids• Prevention of release of mediators: Mast cell stabilizers• Antagonism of released mediators: Leukotrieneantagonists, antihistamines, platelet aggravating factor (PAF)antagonist• Blacked of constrictor neurotransmitter: Sympathomimetics• Directly acting bronchodilators: Methylxanthines
BronchodilatorsStimulates2-adrenergicreceptors of bronchi2-agonistsAnticholinergicdrugsSmoothmusclerelaxationreduce tonusof vagusMethylxanthinesinhibit phosphodiesterase2-agonists: treatment ofacute asthmatic attacksMuscarinic antagonist: Lessuseful in asthma, used fortreat COPDsMethylxanthines: Long-term/prevent bronchoconstriction
Sympathomimetics• The selective β2 agonist is the primary bronchodilators used in thetreatment of asthma/ acute asthmatic attacks.• β2 adrenergic receptor agonists stimulates the beta receptor, increasingthe cAMP concentration in smooth muscle and causingbronchodilatation. It also increase the conductance of large Ca2+-sensitive K+ channels in airway smooth muscle, leading to membranehyperpolarization and relaxation.• The selective β2 agonist relax the bronchial smooth muscle withoutaffecting cardiac function. In higher doses selective β2 agonist increasingthe heard rate by stimulating the cardiac β1-receptor. The selective β2agonist produce hypertension to patient those receiving digitalis.• Types:– Long-acting β2 adrenergic receptor agonists (Salmeterol; formoterol)– Short-acting β2 adrenergic receptor agonists(albuterol, levalbuterol, metaproterenol, terbutaline, and pirbuterol )
Sympathomimetics• Salbutamol:– Selective β2 agonists with less cardiac side effects– Inhaled salbutamol produce bronchodililation within 5-min and the action lastsfor 2-4 h.– Used for acute asthmatic attack. Not suitable for prophylaxis– Side effect: Palpitation, restlessness, nervousness, throat irritation and ankleedema.– 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/ inhalationCont.,
Sympathomimetics• Bambuterol:– Biocarbamate ester of prodrug of terbutaline– Slowly hydrolyzed in plasma and lung by pseudocholinesterase to release theactive drug over 24 h. It also reversely inhibits pseudocholinesterasein a dosedependent mannor.– Used in chronic bronchial asthma in a singe 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– Concurrent use of inhaled glucocorticoid with salmeterol is advised for patientwith persistent asthma.– COPD: equivalent to inhaled anticholinergics in COPD. Reduce breathlessness byabolishing the reversible component of airway obstruction.• Formoterol:– Long acting selective β2 agonists which acts 12 h when inhaled.– Compare to salmeterol it has a faster onset of action (with in 10 min)Cont.,
Methylxanthines• Theophylline and its derivatives are most commonly used for thetreatment of COPD and asthma.• Caffeine, theophylline and theobromine are naturally occurring xanthinealkaloids which have qualitatively similar actions.• Mechanism of action:– Methylxanthines inhibits cyclic nucleotide phosphodiesterase(PDEs), thereby preventing conversion of cAMP and cGMP to 5’-AMP and5’-GMP, respectively. Inhibition of PDEs will lead to an accumulation ofintracellular cAMP and cGMP. Bronchodilataion, cardiac stimulation andvasodilatation occur when cAMP level rises in the concerned cells.Theophylline and related methylxanthines are relatively nonselective in thePDE subtypes inhibitor.– Theophylline is a competitive antagonist at adenosine receptors.Adenosine can cause bronchoconstriction in asthmatics and potentiateimmunologically induced mediator release from human lung mast cells.Methylxanthines inhibits the adenosine action thereby casingbronchodilataion.
Methylxanthines• Mechanism of action:BronchodilationBronchial toneMuscarinic antagonistAcetylcholineAdenosineTheophyllinecAMPATPAMPAdenylyl cyclasePhosphodiesterase (PDE)TheophyllineBeta agonist
Methylxanthines• Pharmacological action:• CNS:– Stimulant; affects higher center.– Caffeine 150-200 mg produce a sense of wellbeing, alertness, beatsboredom, allays fatigue and improve performance and increase the motoractivity. 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 moretoxic than caffeine.– Stimulates medullary vagal, respiratory and vasomotor centers.– High dose: Vomiting and gastric irritation and CTZ stimulation.Cont.,
Methylxanthines• 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.– Tachycardia; increased cardiac output; increased cardiac work– High dose: cardiac arrhythmias– Effect on blood pressure is variable and unpredictable. Usually a rise in systolicand 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– Direct action due to adrenergic stimulation– Biliary spasm is relived, but the effects on intestines and urinary tract isnegligible.– Theophylline is more potent; caffeine has minimal actions.Cont.,
Methylxanthines• 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+ fromsarcoplasmic 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)Cont.,
Methylxanthines• Pharmacological action:• Metabolism– Increase BMR.– Plasma free fatty acid levels are increased.• Mast cells and inflammatory cells:– Theophylline inhibits the release of histamine and other mediators form mastcells and active inflammatory cells.Cont.,
Pharmacological actionsof Methyl xanthinesCNSStimulationIncrease motor activityImprove the performanceCVSStimulate the heartIncrease the force of contractionHigh dose: cardiac arrhythmiasBP: effect is variableStimulation ofVegas stimulation: ↓ BPVasomotor center : ↑ BPSmooth muscleRelaxationLungs vital capacity- increasedBiliary spasm: relievedKidneyMild diuretics (Inhibiting reabsorption of Na+ & H2O)Increase the renal blood flowIncrease the g.f.r.Mast cellInhibit the release of histamineStomachEnhance the secretion of acid, PepsinMetabolismIncrease BMRIt has variable physiological actions
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 unchangedform. Elimination rat various considerably with age (age dependent excretion).– Adult t1/2 is around 7-12 h. Children elimination is much faster (t1/2 3-5 h); Inpremature infants has prolonged t1/2 (24-36 h).– In higher dose pharmacokinetics changes form first order to zero order.
Methylxanthines- Theophylline Cont.,• 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 deathBronchodilatation
Methylxanthines- Theophylline• Interactions:– Theophylline metabolism decreased bysmoking, phenytoin, rifampicin, phenobarbitone and charcoal broiled meatmeal., which increases the parenthesis.– Erythromycin, ciprofloxacin, cimetidine, oral contraceptives and allopurinolinhibits CYP1A2 and increasing the theophylline plasma concentraction; doseshould be reduced to 2/3.– Theophylline reduce the effects of phenytoin, lithium.– Theophylline enhance the effects offurosemide, sympathomimetics, digitalis, oral anticoagulants and hypoglycemics.• Indications:– Primarily used to treat chronic obstructive lung disorders and asthma.– Also used to treat apneaCont.,
AnticholinergicsIpratropium/ tiotropium (derivative of atropine)• Parasympathetic activation/ release of ACh cause bronchoconstriction andincrease mucus secretion.• Blocking the action of ACh by anticholinergic drugs produce bronchodilationand also reduce the volume of respiratory secretion.• Less effective than sympathomimetic.• Inhaled ipratropium/ tiotropium are choice of bronchodilator choice inCOPD.• Tritropium produce longer duration of action than ipratropium• ADR: Dry mouth, respiratory tract discomfort
Leukotriene antagonistsMontelukast, Zafirlukast• Both are having similar action and clincial utility• Block the cys-leukotrienes C4, D4 and E4 (LTC4, LTD4, LTE4)• Alternative for inhaled glucocorticoids• Prophylactic therapy for mild, moderate asthma; not used forterminating asthma.• Both are very safe drugs and ADRs are few (headache, rashes);eosinophilia and neuropathy are infrequent. Few cases Churg-Strausssyndrome (vasculitis with eosinophilia) have been reported.• Dose: Montelukast 10 mg OD, Zafirlukast 20 mg BD
Leukotriene antagonists• Mechanism of action of leukotriene antagonist, antiinflammatory drugsCont.,Bronchoconstriction, Inflammation, increased mucusBronchoconstriction, Inflammation, PainBlock by steroidalantiinflammatorydrugsBlock by nonsteroidalantiinflammatorydrugsBlock byLeukotrieneantagonists
Corticosteroids• Corticosteroids are not bronchodilator; benefit by reducing bronchialhyperreactivity, mucosal edema and by suppressing inflammatory.• Inhaled glucocorticoids are partially absorbed and because of theirsystemic AEs oral glucocorticoids are usually reserved for patientswith severe persistent asthma.• Systemic steroid therapy– Sever chronic asthma: Not contorted by bronchodilator and inhaled steroids.– Status asthmaticus/ acute asthma exacerbation: ‘’’
CorticosteroidsInhaled steroids• High topical and low systemic activity (due to poor absorption/ fastpass metabolism).• Inhaled steroids are not recommended for patient with mild orepisodic asthma. High dose inhaled steroids are beneficial foradvanced COPD with frequent exacerbations.• Systemic steroid therapy– Sever chronic asthma: Not contorted by bronchodilator and inhaled steroids.– Status asthmaticus/ acute asthma exacerbation: ‘’’
Mast cell stabilizersSodium cromoglycate, Ketotifen• Inhibits degranulation of mast cell by trigger stimuli and prevent therelease of histamine, LTs, PAF, interleukins etc. from mast cells.Inhibition of mediator release by cromolyn is through blockade ofcalcium influx in mast cells.• Long time therapy reduce cellular inflammatory response.• It is not histamine antagonist/ bronchodilator- ineffective in asthmaticattack.• Pharmacokinetic:– Not absorbed orally. It is administered as an aerosol through metered doseinhaler delivering 1 mg per dose; 2 puffs 4 times a day– Not popular- production of cough and bronchospasm because of particulatenature of the inhalation.– Small fraction of the inhaled drug is absorbed systemically and excretedunchanged form in urine and bile.
Mast cell stabilizers• Use:– Bronchial asthma: Sodium. Cromoglycate is used as a long term prophylactic inpatients not adequately controlled by inhaled bronchodilators. Alternative forinhaled steroids in mild to moderate asthma but not severe cases.– Allergic rhinitis: Cromoglycate is not nasal decongestant, regular prophylactic useas a nasal spray produces symptomatic improvement in many patients.– Allergic conjunctivitis: Regular use as eye drops is benificial in some chronic casesCont.,Adverse effect (cromoglycate):BronchospasmThroat irritationCough, headacheArthralgia, rashes and dysuriaRarely nasal congestionAdverse effect (Ketotifen):Generally well toleratedSedation and dry mouthDizziness, nausea and weight gain
Anti-lgE antibody: Omalizumab• recombinant DNA-derived monoclonal antibody• Selectively binds to human immunoglobulin E (IgE) and decrease bindingaffinity of IgE to the high-affinity IgE receptor on the surface of mast cellsand basophils, reduce allergic response.• Omalizumab may be particularly useful for treatment of moderate to severeallergic asthma in patients who are poorly controlled with conventionaltherapy.• Due to the high cost of the drug, limitations on dosage, and limited clinicaltrial data, it is not currently used as firstline therapy.