Pathophysiology and drug treatment of bronchial asthma

Dr. Bushra Hasan KhanDeptt of PharmacologyJNMC, AMUManagement of Bronchial Asthma1Introduction Asthma is a chronic inflammatory disorder of the airways that is characterized:clinically by recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night / early morning. physiologically by reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness.

2300 million people around the globe suffer from Asthma.World-wide, deaths from this condition have reached over 180,000 annually.In Western Europe as a whole, asthma has doubled in ten years.India has an estimated 15-20 million Asthmatics.In India, rough estimates indicate a prevalence of between 10% and 15% in 5-11 year old children. The human and economic burden associated with this condition is severe. WHO

Classification A heterogenous disorder, no universally accepted classificationAtopic /extrinsic /allergic (70%) IgE mediated immune responses to environmental antigens.Non-atopic/ intrinsic /non-allergic(30%) triggered by non immune stimuli. Patients have negative skin test to common inhalant allergens and normal serum concentrations of IgE. 4The ultimate humoral and cellular mediators of airway obstruction are common to both atopic and non-atopic variants of asthma, and hence they are treated in a similar way. 5Pathophysiology Chronic inflammation

Airway Hyper-responsiveness

6 Inflammation Chronic inflammatory stateSuperimposed acute inflammatory episodesInvolves respiratory mucosa from trachea to terminal bronchioles, predominantly in the bronchi.Eosinophilic bronchitis, mast cell infiltration.T-helper type 2 response - IL-4, IL-5, and IL-13.

7InflammationIL-4 stimulates IgE production IL-5 activates eosinophilsIL-13 stimulates mucus productionInflammatory mediators8Inflammation

9Asthma TriggersAllergensVirus InfectionsDrugsExerciseFoodAir pollutantsStress Occupational factors10Cellular mechanisms of asthma

Cellular mechanisms of asthma. Myriad inflammatory cells are recruited and activated in the airways, where they release multiple inflammatory mediators, which can also arise from structural cells. These mediators lead to bronchoconstriction, plasma exudation and edema, vasodilation, mucus hypersecretion, and activation of sensory nerves. Chronic inflammation leads to structural changes, including subepithelial fibrosis (basement membrane thickening), airway smooth muscle hypertrophy and hyperplasia, angiogenesis, and hyperplasia of mucus-secreting cells.

11InflammationExact cause of airway inflammation is unknown.Thought to be an interplay between endogenous and environmental factors.Endogenous factors Atopy Genetic predisposition to IgE mediated type I hypersensitivityAn excessive TH2 reaction against environmental antigensThe major risk factor for asthmaAsthma is commonly associated with other atopic diseases allergic rhinitis(80%), atopic dermatitis, urticaria, etc.Genetics : Polymorphism of gene on chr. 5q , ADAM-33, DPP-10 , GPRA gene .

ADAM-33 ::: a disintegrin and metalloprotease domain. Containinng protein 33. is an enzyme that in humans is encoded by the ADAM-33 gene. 12InflammationEnvironmental factorsViral infections RSV, Mycoplasma, ChlamydiaAir pollutionAllergens house dust miteHygeine hypothesis

13Airway Hyper-responsivenessBronchial hyper-responsiveness is a state characterised by easily triggeredbronchospasm.Bronchial hyper-responsiveness can be assessed with abronchial challenge test.Concentration of a bronchial spasmogen (methacholine/histamine), needed to produce a 20% increase in airway resistance in asthmatics is often only 1% to 2% of the equally effective concentration in healthy control subjects.

14Effects of inflammationAirway epithelium damage and shedding may lead to AHR.Mucus hypersecretionNerves sensitization of nerve terminals and reflex activation of cholinergic nerves.Vessels increased in number, blood flow is increased.Smooth muscle hyperplasia and hypertrophyFibrosis subepithelial. 15

16Clinical presentationWheezing, dyspnea and cough.Tenaceous mucus production.Symptoms worse at night.Limitation of activity.Signs respiratory rate, use of accessory musclesHyper-resonant percussion noteExpiratory wheeze May be SILENT CHESTNo findings when asthma is under control or b/w attacks

17Investigations Pulmonary function testsSpirometry estimate degree of obstructionFEV1, FEV1/FVC, PEF. >12% increase in FEV1, 15 minutes after 2 agonist inhalation.AHR histamine / methacholine provocation test> 20% fall in FEV1 CXR hyperinflatedArterial blood-gas analysishypoxia & hypocarbia (severe acute asthmahypercarbia)Skin hypersensitivity testSputum & Blood eosinophiliaElevated serum IgE levels

18Aims of anti asthmatic drugs:

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 ).

Efferent nerves (motor)

Parasympathetic supplyM3 receptors in bronchial smooth muscles and glands.

No sympathetic supply but 2 receptors in bronchial smooth muscles and glands

Classification of drugsRELIEVERS (RESCUE MEDICATIONS)2 Agonists Anticholinergic AgentsMethylxanthines CONTROLLERS GlucocorticoidsLeukotrienes pathway inhibitorsCromonesAnti-IgE therapy

RES21DrugsAdenyl cyclase

cAMP

Short acting main choice in acute attack of Asthma InhalationB2 agonists Salbutamol, Terbutaline Long acting, Prophylaxis Nocturnal AsthmaSalmeterol, FormoterolBlocks M3 receptorsMain drugs For COPDInhalationInhalationAntimuscarinicsIpratropium (Short)Tiotropium (long)Inhibits phosphodiesterase cAMP(orally)(parenterally)

Xanthine derivativesTheophyllineAminophyllineBronchodilators (relievers for bronchospasm)InhalationCorticosteroids (Inhibits phospholipase A2)Beclomethasone, Fluticasone, Budesonide OrallyprednisoloneparenterallyHydrocortisoneInhalation, prophylaxis in childrenMast cell stabilizersCromoglycate (Cromolyn), NedocromilorallyCysteinyl Leukotriene antagonistsZafirlukastInjection, SCOmalizumab (Anti IgE antibody)

Anti-inflammatory drugs (prophylactic)2 Agonists in asthma Bronchodilators, Usually given by inhalation route. MOA:Relaxation of airway smooth muscleNon-bronchodilator effectsInhibition of mast cell mediator releaseReduction in plasma exudationIncreased mucociliary transportInhibition of sensory nerve activation Inflammatory cells express 2 receptors but these are rapidly downregulated.No effect on airway inflammation and AHR.

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252 Agonists in asthmaShort-Acting 2 Agonists Salbutamol Terbutaline Bambuterol PirbuterolMetaproterenol Long-Acting 2AgonistsSalmeterol Formoterol

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Short-Acting 2 Agonists

Duration of action : 3-6 hrs.Convenient, rapid onset, without significant systemic side effectBronchodilator of choice in acute severe asthmaUsed for symptomatic relief on as required basis.Only treatment required for mild, intermittent asthma.Use >2 times a week indicates need of a regular controller therapy.

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Long-Acting 2Agonists

Duration of action >12 hrs.Used in combination with inhaled corticosteroid (ICS) therapy.Improve asthma control and reduce frequency of exacerbations.Allow asthma to be controlled at lower dose of ICS.Fixed dose combination of corticosteroid with long acting 2 agonist : e.g. Salmeterol + Fluticasone, Formoterol + Budesonide.

28Long-Acting 2AgonistsShould not be used as monotherapy (increased mortality).Combination shows synergistic action.Not effective for acute bronchospasm.Salmeterol : slow onset, 2 puffs of 25 g twice a dayFormoterol : rapid onset, 2 puffs of 6 g twice a day

29Risks with LABA monotherapyMeta-analyses have shown that LABAs are associated with increased risk of overall death when used as monotherapy. The use of LABAs concomitantly with inhaled corticosteroids significantly reduces asthma hospitalizations and is not associated with life-threatening events and asthma-related deaths.The evidence appears to support the use of LABAs plus inhaled steroids in a single inhaler device for patients with moderate to severe asthma.

Thorax 2012;67:342-349 ADRs 2 agonistsMuscle tremorsTachycardiaHypokalemiaHypoxemiaRestlessnessCautious use HypertensionIschemic heart disease

31Anticholinergic agentsIpratropium bromide, Tiotropium.Prevent cholinergic nerve induced bronchoconstriction.Block M3 receptor on bronchial smooth muscles. Less effective than 2 agonists.Response varies with existing vagal tone.

32Anticholinergic agentsUse in asthmaIntolerance to inhaled 2 agonist.Status asthmaticus additive effect with 2 agonist.Ipratropium -- bitter taste, precipitate glaucomaTiotropium longer acting, approved for treatment of COPD.

33Methylxanthines Theophylline, Theobromine, CaffeineRecently interest has declined in this class of drugs:Side effectsNeed for plasma drug levels monitoringPharmacokineticsAvailability of other effective drugs

Still widely used in developing countries due to their lower cost.Availability of slow release tablets stable plasma levels

34Methylxanthines: MOAInhibition of several members of the phosphodiesterase (PDE) enzyme family

Inhibition of cell-surface receptors for adenosine

Enhancement of histone deacetylation.

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36Methylxanthines Theophylline base is poorly soluble in water.Soluble salts of theophylline:Aminophylline -85%Etophylline 80%Oxtriphylline -64%

37ADRs of TheophyllineAt conc >20 mg/L : Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety start (PDE4 inhibition)At conc.>40 mg/L : Seizures or arrhythmias (A1 receptor antagonism)

DoxoyphyllineLong acting, oralInhibit PDEAdenosine A1 & A2 reduced affinitysafeDose - 400mg OD

Corticosteroids asthmaEffective drugs for treatment of asthma.Development of inhaled corticosteroids is a major advance in asthma therapy.Used prophylactically as a controller therapy.Reduce the need for rescue 2 agonist.Benefit starts in 1week but continues upto several months.If asthma not controlled at low dose of ICS :- addition of long acting 2 agonist is more effective than doubling steroid dose.

40GlucocorticoidsMechanism 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 2 receptors (have additive effect to 2 agonists).

ICSBeclomethasone dipropionateBudesonide Fluticasone hemihydrateFluticasone propionate Ciclesonide TriamcinoloneFlunisolide Mometasone furoate Budesonide, fluticasone, mometasone, and ciclesonide : lower oral bioavailability than beclomethasone dipropionateThis results in reduced systemic absorption from the fraction of the inhaled drug that is swallowed and thus reduced adverse effects. Ciclesonide is a prodrug - converted to the active metabolite by esterases in the lung : low oral bioavailability and a high therapeutic index.When doses of inhaled steroid exceed 800 g beclomethasone dipropionate daily, a large volume spacer is recommended to reduce oropharyngeal deposition and systemic absorption.

They do not relax airway smooth muscle directly but reduce bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly.

43ADRs of inhaled corticosteroidsOropharyngeal candidiasis, dysphonia, cough frequent at high doses. Reduced by using spacer device.Decreased bone mineral density.Hypothalamic-pituitary-adrenal axis suppression- >1500g/d of budesonide.Metabolic abnormalitiesSkin thinning, purpura- dose related effect.Growth retardation in children controversial. ICS may have local side effects due to the deposition of inhaled steroid in the oropharynx. The most common problem is hoarseness and weakness of the voice (dysphonia) due to atrophy of the vocal cords following laryngeal deposition of steroid; it may occur in up to 40% of patients and is noticed particularly by patients who need to use their voices during their work (lecturers, teachers, and singers). Throat irritation and coughing after inhalation are common with MDI and appear to be due to additives because these problems are not usually seen if the patient switches to a DPI. There is no evidence for atrophy of the lining of the airway. Oropharyngeal candidiasis occurs in 5% of patients. Most studies have been reassuring that doses 400 g/day have not been associated with impaired growth; on the contrary, there may even be a growth spurt as asthma is better controlled.

44Systemic steroids in asthmaIndicationAcute exacerbationChronic severe asthmaA 5-10 day course of Prednisolone 30-40 mg/d is used.1% of patients may require regular maintenance therapy.Side effects of long-term oral corticosteroid therapy :Fluid retention, increased appetite, weight gain, osteoporosis, capillary fragility, hypertension, peptic ulceration, diabetes, cataracts, and psychosis.Corticosteroid resistance is a major barrier to effective therapy in patients with severe asthma, in asthmatic patients who smoke, and in patients with COPD and cystic fibrosis (Barnes and Adcock, 2009). "Steroid-resistant" asthma is thought to be due to reduced anti-inflammatory actions of corticosteroids. 45

Leukotrienes pathway inhibitors

Two approaches to interrupt the leukotriene pathway :Inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis - Zileuton.Inhibition of the binding of LTD4 to its receptor on target tissues, thereby preventing its action - Zafirlukast, Montelukast, Pranlukast. Oral route.Side effects :- Hepatic dysfunction Churg Strauss synd.(vasculitis with eosinophilia)

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Leukotrienes pathway inhibitorsThey are less effective than ICSs in controlling asthma

Use in asthmaPatients unable to manipulate inhaler devices.Aspirin induced asthma.Mild asthma alternative to ICS.Moderate to severe asthma may allow reduction of ICS dose.

49Montelukast is effective as a once-daily oral preparation (10 mg in adults, 5 mg in children). In addition, oral administration may treat Concomitant allergic rhinitis.

Cromones

Cromolyn sodium & Nedocromil sodiumOn chronic use (four times daily) reduce the bronchial reactivity. These drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm; they are only of value when taken prophylactically.Inhalation route51

Cromones

Exact mechanism of action unknown

Alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation.Mast cells - inhibition of mediator releaseEosinophils - inhibition of the inflammatory response to inhalation of allergens.

52Cromones : Uses

Asthma - Prevention of asthmatic attacks in mild to moderate asthma

Adverse effectsWell tolerated drugsMinor side effects- Throat irritation, Nausea, Headache.53

Anti-IgE therapy

Omalizumab - recombinant humanized monoclonal antibody targeted against IgE.MOA - IgE bound to Omalizumab cannot bind to IgE receptors on mast cells and basophils :- preventing the allergic reaction at a very early step in the process.Pharmacokinetics Single subcutaneous injection every 2 to 4 weeks.Peak serum levels after 7 to 8 days.

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Immunoglobulin (Ig)E plays a central role in allergic diseases. Blocking IgE using an antibody, such as omalizumab, is a rational therapeutic approach. IgE may activate high-affinity receptors (FcRI) on mast cells as well as low-affinity receptors (FcRII, CD23) on other inflammatory cells. Omalizumab prevents these interactions and the resulting inflammation. Omalizumab also reduces levels of circulating IgE.55Omalizumab Use in asthmaPersons >12 years of age with moderate-to-severe persistent asthma. Omalizumab is not an acute bronchodilator and should not be used as a rescue medication or as a treatment of status asthmaticus.Expensive drugHas to be given under direct medical supervision due to the risk of anaphylaxis.

56Classification of Asthma severity (GINA)GradeSymptomsNight-time Symptoms

IntermittentSymptoms 2 times/week

2 times/monthMild persistentSymptoms 2 times/week but 1/day

2 times/monthModerate persistentDaily Symptoms

1/weekSevere persistentDaily symptomsLimited physical activity

Frequent

Stepwise approach to asthma

58Aerosol delivery of drugsTopical application of drugs to lungs.Least systemic deliveryPoor absorbtion from GITHigh first pass metaobolismTherpeutic index of drugs is Increased.Drug particles of 1-5 are produced.Devices - Metered dose inhalers, nebulisers, dry powder inhaler.59Disposition of inhaled drugs

60Status asthmaticusSevere airway obstruction Symptoms persist despite initial standard acute asthma therapy.Severe dyspnoea & coughPatient adopts upright position fixing shoulder girdle to assist accessory muscles of respirationSweating, central cyanosis, tachycardia URTI mc precipitant

Treatment of Status asthmaticusHigh flow humidified Oxygen through facemaskHydrocortisone hemisuccinate 100 mg i.v. stat, followed by 100-200mg, 4-8 hrly infusion.Nebulised Salbutamol (5mg) in Oxygen given immediatelyIpratopium bromide (0.5mg) + Salbutamol (5mg) nebulised in oxygen,who dont respond within 15-30 minTerbutaline (0.25-0.5mg) s.c. or (0.1g/kg/min) i.v. excessive coughing or too weak to inspire adequately.ET intubation & mechanical ventilation if above Treatment fails

Asthma medicines and pregnancyA review of the animal and human studies on the effects of asthma medicines taken during pregnancy found few risks to the woman or her fetus. It is safer for a pregnant woman who has asthma to be treated with asthma medicines than for her to have asthma symptoms and asthma attacks.Poor control of asthma is a greater risk to the fetus than asthma medicines are.Budesonide is labeled by the U.S. Food and Drug Administration (FDA) as the safest inhaled corticosteroid to use during pregnancy. One study found that low-dose inhaled budesonide in pregnant women seemed to be safe for the mother and the fetus.

Thank you 64