Asthma - Recent advances in treatment

1

Recent advances in Asthma treatment

Dr. Divya Krishnan Calicut medical college

2

CONTENTSCONTENTS

Introduction Etiology Pathogenesis Diagnosis

Current managementRecent advances in treatmentConclusion

3

Common disease with enormous socioeconomic impact.Prevalent in 10% of the world population. Can occur at any age with peak incidence in childhood.Males affected more(childhood), Females affected more in adults.

Asthma……………Asthma……………

4

Clinical syndrome characterised by airway inflammation and increased airway hyperresponsiveness that leads to recurrent episodes of wheezing, shortness of breath, chest tightness and cough.

Symptoms are associated with widespread but variable bronchoconstriction that is at least partly reversible, either spontaneously or with treatment.

Asthma……………….Asthma……………….

5

Asthma-EtiologyAsthma-Etiology

A Atopy Family history Prematurity, abnormal lung function at birth Aeroallergen exposures Viral respiratory tract infections Tobacco smoke Air pollutants Exercise Cold air Food additives Drugs ( Beta blockers, Aspirin, Bisphosphonates)

TRIGGERS

Etiological classification of Etiological classification of asthmaasthma

Extrinsic( atopic) asthma Intrinsic (non atopic)asthma- History of atopy - No allergen identified- Serum IgE raised - Serum IgE not raised- Onset in childhood - Onset in adulthood- Episodic type - Chronic type

Classification not popular now as it fails to define treatment strategies

6

Pathogenesis of asthmaPathogenesis of asthma

Immunological model of asthma pathogenesis 2 phases----early (bronchoconstriction) phase late (inflammation and hyper-reactivity) phase reactions 7

Pathogenesis………Pathogenesis………

How it starts….?

8

PathogenesisPathogenesis

Early phase reaction

Bronchoconstriction

start of late phase

9

Pathogenesis……Pathogenesis……

PathogenesisPathogenesis

Role of neuronal pathways in asthma Bronchial tone results due to a balance between - Parasympathetic-bronchoconstriction - Sympathetic - bronchodilatation - NANC – releases neuropeptides (substance P, neurokinin A

causing bronchoconstriction and nitric oxide causing bronchodilatation)(NO also produced by iNOS besides being a neuropeptide) Other mediatorsAdenosine causes bronchoconstriction (A1 receptors on smooth muscle)Endothelins, Bradykinins and many more………. 11

Pathogenesis………Pathogenesis………

AIRWAY REMODELING

DiagnosingDiagnosing AsthmaAsthma

13

Medical History-Wheezing, dyspnoea, chest tightness, coughing-Symptoms worse at night/early morning-Symptoms exacerbated by known triggers-Positive h/o atopy; family h/o asthma

Physical examination-Rhonchi-Hyperexpansion of thorax-Associated atopic dermatitis/eczema

Diagnosing AsthmaDiagnosing Asthma

14

Spirometry - Decreased FEV1 , FEV1/FVC ratio, PEF-Reversibility after inhalation of beta 2 agonist->20% diurnal variation in PEF

Other tests- Methacholine/histamine challenge test- Total serum IgE levels/ blood eosinophils- Skin tests for common allergens- Exhaled NO test

Clinical classification of AsthmaClinical classification of AsthmaMild intermittent

Mild Persistent

Moderate persistent

Severe Persistent

Symptoms ≤ 2 times a weekAsymptomatic between exacerbationsBrief exacerbations

>2 times a week but <1 time a dayExacerbations affect activity

Daily symptomsExacerbations≥2 times a week & may last for days

Daily symptomsLimited physical activityFrequent severe exacerbations

Night time symptoms

≤ 2 times a month

> 2 times a month

> 1 per week Almost every night

Lung functionFEV1

PEF variability

≥80% predicted < 20%

≥80% predicted20-30%

>60-<80% predicted>30%

≤ 60% predicted>30%

15

AsthmaAsthma exacerbationsexacerbations

Mild Moderate Severe Respiratory failure (Status asthmaticus) imminent - breathless at rest if - talks in words drowsy - respiratory rate >30/min - loud wheeze no wheeze - pulse >120/min bradycardia - PEF < 60% - Arterial O2 saturation<90% - PaO2 < 6O ; PaCO2 > 45 mm of hg

16

Management of Management of asthma asthma

17

Asthma Management GoalsAsthma Management Goals

Achieve & maintain symptom controlMaintain normal activity including exerciseMaintain pulmonary function as close to normal as possiblePrevent asthma exacerbationsAvoid adverse effects from asthma medicationsPrevent asthma mortality

18

Asthma managementAsthma management

Pharmacological measures Non pharmacological measures

- Patient education - Avoidance of triggers - Avoid smoking - Graded exercise training - Psychological treatment - Yoga, acupuncture, hypnosis

19

Targets of drug actionTargets of drug action

20

Suppression of inflammation and hyper-reactivity-steroidsPrevention of release of mediators from mast cells-mast cell

stabilizersAntagonism of released mediators- LTRABlockade of constrictor neurotransmitter- anticholinergicsMimicking dilator neurotransmitter- beta 2 agonistsDirectly acting bronchodilator- methyl xanthines

+ new targets

Drugs for asthmaDrugs for asthma

Short term relievers Long term controllers

Immediate reversal of bronchospasm but no effect on underlying inflammation.

Used at the time of acute attacks

Short acting beta 2 agonists Anticholinergics Methyl xanthines

Control degree of inflammation and bring about an improvement of overall asthma control

Taken regularly on a long term basis.

CorticosteroidsMast cell stabilizersLong acting beta 2 agonistsLeukotriene modifiersMethyl Xanthines

21

Short term relieversShort term relievers

Short acting beta 2 agonists(SABA) Salbutamol (albuterol), Terbutaline, Fenoterol, Remiterol, Pirbuterol, Levalbuterol

- Beta 2 receptor agonism-bronchodilatation- Given by inhalation/oral/parenteral-S/E : Tachycardia, tremors, hypokalemia, decreased response on long term use ( at higher inhaled dose or with oral and parenteral dose)-Levalbuterol considered to be more potent with less side effects than racemic mixture – evidence from trials lacking

22

Short term relieversShort term relievers

Anticholinergics

Ipratropium, Tiotropium

-Less effective than beta agonists-Used as additional to beta 2 agonists in severe asthma-S/E : Dry mouth, urinary retension-Tiotropium has longer duration of action and doesn’t inhibit M2 receptors

23

Long term controllersLong term controllers

CorticosteroidsInhaled Corticosteroids: Beclomethasone, Budesonide, Fluticasone, Flunisolide, Ciclesonide

- Have high topical to systemic activity-Reduce inflammation and hyperresponsiveness and improve all indices of asthma control-Peak effect seen after 5-7days. No role in acute episodes.-S/E : sore throat, hoarseness of voice, oropharyngeal candidiasis (local)

Mood changes, osteoporosis, growth retardation, hyperglycemia, pituitary adrenal suppression(systemic effects a high doses)

24

Corticosteroids contd……

Fluticasone -higher potency - longer duration of action - negligible systemic bioavailabilityCiclesonide – prodrug cleaved by esterases in bronchial epithelium - oral bioavailability < 1% - In circulation highly plasma bound thus decreasing

exposure of tissue cells to free active drug Systemic steroids in asthma-In severe persistent asthma not controlled by other drugs(oral prednisolone)-Status asthmaticus (iv hydrocortisone)

25


Long acting beta 2 agonists (LABA) salmeterol, formoterol-Highly lipid soluble drugs with longer duration of action (>12hrs) than SABA.-Salmeterol has slow onset of action but formoterol’s onset of action is comparable to SABA.-They do not have anti-inflammatory actions. Their best use is as an add on to ICS in patients not controlled by ICS alone. The combination is better than increasing the dose of steroids in terms of symptom control and improvement of lung function

26


Leukotriene modifiers

- lipoxygenase inhibitor- Zileuton (hepatotoxicity)

- LTRA – Montelukast, Zafirlukast

. Oral administration

27

Stepwise management of Stepwise management of asthmaasthma

Step 1Mild intermittent asthma

Step 2Mild persistent asthma

Step 3Moderate persistent asthma

Step 4Severe persistent asthma

Step 5Continuous use of oral steroids

Inhaled short acting beta 2 agonist as and when needed

As needed short acting beta 2 agonist with regular controller therapy

Low dose inhaled steroid or LTRA

Medium dose steroid Or Low dose steroid + LABA/LTRA/Sustained release theophylline

Medium or high dose steroid + one or more of the following options:-LABALTRASustained release theophylline

To step 3, add oral steroids

28

Management of acute severe Management of acute severe exacerbationsexacerbations

Parenteral steroid(hydrocortisone)Nebulized salbutamol+ ipratropiumHigh flow humidified oxygenSalbutamol/ terbutaline im or subcutaneouslyIntubation & mechanical ventilation if needed.Correct dehydration & acidosis with saline+ sodium bicarbonate infusionAntibiotics to treat chest infection

29

Recent Advances in theRecent Advances in thetreatment of asthmatreatment of asthma

30

Why the search for new drugs??Why the search for new drugs??

Asthma has a complex pathogenesis—many putative targets still remain to be exploredPatients not controlled even by oral steroids need an alternativeA drug which can reduce the dose of steroids/replace it without producing side effects of its own.Asthma still remains an incurable disease though it can be managed effectively.

31

Newer approaches to treatmentNewer approaches to treatment

Novel class of bronchodilatorsImmunomodulatory therapiesNewer anti-inflammatory therapiesMediator antagonistsMiscellaneous approaches

32

Novel class of bronchodilatorsNovel class of bronchodilators

1. Magnesium Sulphate

-Reduces cytosolic calcium in airway smooth muscle-bronchodilatation-Can be given by IV/nebulisation-Useful as an additional drug to SABA in A/c severe asthma.

(more studies needed to document this)

- Not suitable to be employed alone as clinical benefit is small.-Cheap, well tolerated with minor S/E like nausea & flushing

33


2. Potassium channel openersPotassium channel openers that open calcium activated large conductanceK+ channels in smooth muscles(maxi K+ channels) better tolerated. ( Potassium channel openers that open ATP dependent K+ channels donot produce bronchodilatation as expected and also produce CVS side effects)

3. Calcium channel blockers – Nifedipine, verapamil-Prevent calcium entry into smooth muscle-Inhibit stimuli induced bronchoconstriction but no effect on basal airway calibre.-Bronchodilator effect less than SABA.

34

35


5. ANP & related peptide Urodilatin-Activates membrane guanylyl cyclasecGMPbronchodilatation-Bronchodilator effects comparable to SABA.-Useful for additional bronchodilatation in A/c severe asthma

6. VIP analogs-VIP binds to VPAC1(smooth muscles of blood vessels) & VPAC2(airway smooth muscle)-couple to Gs --adenylyl cyclase stimulated-smooth muscle relaxation-VIP potent bronchodilator in vitro studies but in patients it is rapidly metabolised and also has vasodilator S/E.

-More stable analog of VIP (RO 25-1533) selectively stimulate VPAC2-produces rapid bronchodilatation but effect is not prolonged

Immunomodulatory therapiesImmunomodulatory therapies

1. Immunosuppressive therapy - Considered when other treatments are unsuccessful or to reduce

the dose of oral steroids (in step 5)-Methotrexate, Cyclosporine, Gold salts, IV immunoglobulin-Not routinely employed due to greater side effects and lesser efficacy

2.Anti IgE therapy

3. Specific immunotherapy

36


Anti IgE therapy - Omalizumab

37

- Humanized monoclonal antibody- MOA: Neutralises IgE in circulation Inhibits activation of IgE bound to

mast cells Down regulates IgE receptors on mast

cells-Route : S/c or IV every 2- 4 weeks-Use : severe persistent extrinsic asthma who are resistant to other forms of treatment. Reduces exacerbations and requirement of oral and inhaled steroids in them-Drawback : high cost-S/E : local reaction at inj. site- rarely anaphylactic reaction


Specific immunotherapy-Injection of low doses of allergen to cause desensitization-Benefit in asthma not well documented-Mechanism : induces secretion of anti-inflammatory cytokine(IL 10) from regulatory helper T cells. This blocks co-stimulatory transduction in T cells so that they are unable to react to allergens.-Drawback : risk of anaphylaxis and local reactions : time consuming therapy-Better specific immunotherapy developed with:- cloned allergen epitopes, T cell peptide fragments of allergens, DNA vaccines composed of allergen complement DNA.

38

Newer anti-inflammatory drugsNewer anti-inflammatory drugs

NF-kB inhibitors-NF is a transcription factor regulating inflammatory genes in asthma.-NF degraded by inhibitory protein IkB. IkB is degraded by IB Kinase.-Inhibitors of IB kinase in clinical trials.-Drawback: susceptibility to infections when NF is inhibited.

Mitogen activated protein kinase inhibitors-MAP kinase pathways involved in C/C inflammation-SB203580, RW567657 block p 38 MAP kinase pathways-These inhibit synthesis of inflammatory mediators but severe toxicity reported.

39

Newer mediator antagonistNewer mediator antagonist

Several mediators involved.Inhibitors of bradykinin, PAF found to be disappointing in asthmaNo new mediator antagonists deserves mention

40

Miscellaneous approachesMiscellaneous approaches

Cytokine modifiers-IL5 plays pivotal role in eosinophilic inflammation-Anti IL5 antibodies shown to decrease exacerbations in severe asthma with eosinophilia.-Antibodies against IL 4, 13 showed disappointing results

Chemokine receptor antagonist-CCR3 antagonists tried in asthma expecting to block eosinophil recruitment in the airways-Results disappointing due to high degree of toxicity.

41

Miscellaneous approachesMiscellaneous approaches

CRTH2 antagonists in development show promising results in asthmaEndothelin antagonists may improve structural changes in asthma. However not tested.Antioxidants more potent than Vit C&E, N-Acetyl cysteine in development as oxidative stress important in asthma.Macrolide antibiotics like Clarithromycin reported to be effective in many cases of c/c asthma. Causation of c/c asthma linked to Chlamydia pneumonia or mycoplasma pneumonia

42

ConclusionsConclusions

Newer drugs in the already available classes of drugs may be better in certain respects when compared to their predecessors.Among newer classes of drugs, none holds promise.

- Among bronchodilators-MgSO4, ANP, VIP analogs may be used as additional drugs to SABA but seem to be less efficient than SABA.

- Anti IgE therapy with Omalizumab holds promise but it is too costly for the majority of patients to afford.

As of now, the drugs in current use are the possibly the best

that can be offered to a asthma patient.

43

44

Thank you………………

Health & Medicine

Asthma - Recent advances in treatment