Pharmacotherapy of bronchial asthma

Pharmacotherapy of Bronchial Asthma

Dr.Vinay BajajJR1

Dept of Pharmacology

Pharmacotherapy of bronchial asthma


OverviewIntroductionEtiopathogenesisPharmacotherapyPhenotypes of AsthmaRecent guidelines for treatmentVarious devices used now-a-daysRecent advancesSummary


• Chronic inflammatory airway disease associated with increased airway responsiveness and reversible airway obstruction.

• It can present at any age; majority of cases diagnosed in childhood

• Most of them become asymptomatic by adolescence

• Disease severity rarely progresses; patients with severe asthma have it at the onset.

What is bronchial asthma?


Asthma is one of the most common disease encountered in clinical practice

300 million people suffer from asthma worldwide out of which 30 million asthmatics are in India

According to WHO, India has the largest number of asthma deaths in the world, contributing to 22.3% of all global asthma deaths

Burden of disease


Recurrent episodes characterized by:• Breathlessness• Wheezing• Coughing- especially at night or early

morning• Tightness in the chest• Hyperinflation• Increased mucus production

Clinical features


Endogenous

• Atopy• Genetic

predisposition• Obesity • Early

infections

Environmental

• Indoor allergens

• Outdoor allergens

• Passive smoking

Risk Factors


Etiopathogenesis


Pharmacotherapy


Relievers

• Beta 2 agonists• Anticholinergics• Methylxanthines

Controller

• Corticosteroids• Mast cell stabilizers• Anti Leukotriens• Biological Agents


Classified as: SABAs(short acting)- Salbutamol, Terbutaline,

Levalbuterol, Fenoterol, Pirbuterol, Metaproterenol

LABAs(Long acting) - Salmeterol, Formoterol

Ultra LABA: Indicaterol ( yet not approved for asthma)

Beta-2 Agonists


Mechanism:cause bronchial smooth muscle relaxation by decreasing calcium, opening potassium channels, inhibiting myosin light chain kinase (MLCK) and stimulating myosin light chain phosphorylase(MLCP)

Short acting drugs :Onset of action is 5 minutes,duration of action (4-6 hrs) & hence are drug of choice for acute attack

Long acting drugs:Duration of action (12 hrs)& hence at BD doses used for prophylaxis

Beta-2 Agonists


Ultra long acting drugs : duration of action is 24 hrs & hence used at OD doses for prophylaxis of asthma

Side effects :Tremors are most common due to β2 receptor stimulation in skeletal muscles

Other-palpitations, QT prolongation

Beta-2 Agonists Contd…


Name Oral Parentral Inhaled

Salbutamol(albuterol)

2- 4 mg 0.25-0.5mg,IM/SC

100-200g

Levalbuterol - - 0.63-1.25 mg

Terbutaline 5mg 0.25mg,SC 250 g

Metaproteronol - - 650 g

Pirbuterol - - 200 g

Doses


Doses

Name Oral Inhalation

Salmeterol - 50-100 g.

Formoterol - 12-24g.

Bambuterol 10-20mg. -


• Trials comparing salmeterol with placebo found increased mortality and exacerbations in salmeterol group

• Discontiuation of ICS after LABA results in increased markers of inflammation

• Black box warning issued by FDA on all LABA• Postulated mechanisms are: A direct deleterious effect on bronchial smooth muscle Maintenance of lung function despite worsening

inflammation; so that patients tend to delay seeking treatment for an exacerbation

Safety issues of LABA


• These drugs mainly cause dilation of large airways

• Less effective than beta-2 agonists as they inhibit only the cholinergic reflex component of bronchoconstriction

• These drugs are not approved by FDA but used off label in patients not responding to or intolerant to β2 agonists

• Combined with β2-agonists in treating acute severe asthma

Anticholinergics


Anticholinergics

M3 > M1

Ipratropium

Tiotropium

Oxitropium


• Ipratropium : short acting (6 hrs) & hence can be used for an acute attack of bronchial asthma

• Oxitropium: Intermediate acting & can be used in nocturnal asthma

• Tiotropium : longest acting(24 hrs) & used in long term prophylaxis in combination with corticosteroids

Anticholinergics Contd…


Drugs include :Theophylline, Aminophylline, Theobromine

Mechanism : Act by inhibiting Phosphodiesterase which is

involved in breakdown of cAMP & by blockade of adenosine receptors

Inhibition of phosphodiesterase in lymphocytes gives additional anti-inflammatory effect

Methylxanthines


Theophylline can be used by oral route at a dose of 8 mg/kg BD for persistent asthma along with inhalational corticosteroids

Aminophylline can be used by I.V route with a loading dose of 6mg/kg followed by 0.5 mg/kg/hr for treatment of Acute attack of asthma

Methylxanthines Contd…

Theophylline has a low therapeutic index and hence therapeutic monitoring is done to maintain plasma concentration within range i.e 5-15 mg/L


These are potent anti-inflammatory drugs & also decrease bronchial hyperactivity & mucosal edema.

Mechanism: Arachidonic acid (AA) is releasedfrom the membrane phospholipids with the help of enzyme phospholipase A2 that isinhibited by corticosteroids. AA is converted to PG and TX by cyclooxygenase and to LTwith the help of enzyme 5-lipooxygenase (5 LOX). Thus, these mediators are not generatedwhen corticosteroid therapy is initiated

Corticosteroids


• Steroids are used if patient has to use SABA more than 2 times a week for symptomatic relief

• Systemic steroids have a lot of adverse effects,therefore are reserved for resistant severe chronic asthma and in status asthmaticus

• Hydrocortisone( 100 mg bolus) is I.V. Steroid of choice as it is fastest acting systemic steroid

• Oral prednisolone can be used for persistent asthma

Corticosteroids


• Inhalational corticosteroids are drug of choice for persistent asthma

Corticosteroids Contd..

Beclomethasone dipropionate 200-400 g BD Flunisolide 25 g BD Budesonide 200-400 g BD Fluticasone propionate 100-250 g BD Ciclosenide 40 – 160 g OD

Synergism between steroids and β2 agonists

• They interact with each other to potentiate their actions

• Steroids: a) Increase transcription of β2 receptor gene in airway

mucosab) Prevent downregulation of β2 receptors

• β2 agonists:a) Enhance binding of Glucocorticoid Receptors to DNAb) Increase in translocation of Glucorticoid Receptors

to the nucleus


• Lipooxygenase inhibitors:Zileuton inhibits synthesis of LTB4 (chemotactic) , LTC4 and LTD4 (bronchoconstrictor).Limitions- short duration of action and hepatotoxicity.

• Leukotrine receptor antagonists:Montelukast and zafirlukast inhibit the bronchoconstrictor action of LeukotrinesProphylactic agents for bronchial asthma, few cases of Churg Strauss syndrome (vasculitis with eosinophilia) have been associated with their use.


• Sodium cromoglycate and nedocromil prevent the degranulation of mast cells by triggerstimuli indicated only for prophylaxis of bronchial asthma given by inhalational route.

• Ketotifen has antihistaminic action apart from mast cell stabilizing property and is specially indicated for patients with multiple disorders (atopic dermatitis,perennial rhinitis, conjunctivitis etc.).

Mast cell stabilizers


Omalizumab is a monoclonal antibody against IgE and is indicated to prevent the attack ofbronchial asthma in patients not responding to combination of long acting β2 agonist and ahigh dose of inhalational steroid. It is administered by Subcutaneous route

Drug inhibiting IgE Action


Allergic asthma :

Most easily recognized asthma phenotype Often commences in childhood

Associated with a past and/or family history of

allergic disease such as eczema, allergic rhinitis, or food or drug allergy.

Examination of sputum reveals eosinophilic airwayinflammation

Respond well to inhaled corticosteroid (ICS) treatment.

Phenotypes


Non-allergic asthma : The sputum of these patients may be

neutrophilic, eosinophilic or contain only a few inflammatory cells(paucigranulocytic).

Patients with non-allergic asthma often respond less well to Inhaled corticosteroids


Late-onset asthma : Women, present with asthma for the first time in

adult life, non-allergic and often require higher doses of ICS or are relatively refractory to corticosteroid

Asthma with obesity : Some obese patients with asthma have prominent respiratory symptoms and little eosinophilic airway inflammation


Acute severe asthma : Uncontrolled asthma progress to an acute state

in which inflammation, airway edema, mucus accumulation and severe bronchospasm - profound airway narrowing, poorly responsive to bronchodilator therapy.

Chronic Asthma : Asthma can vary from chronic daily symptoms to

only intermittent symptoms.Intervals between symptoms may be days, weeks, months or years.


ASTHMA MANAGEMENT -GINA GUIDELINES


The long-term goals of asthma management are:• To achieve good control of symptoms and maintain normal activity levels• To minimize future risk of exacerbations, fixed airflow limitation and side-effects.

It is also important to elicit the patient’s own goals regarding their asthma, as these may differ from conventional medical goals.

Goals of manangement

Identify and reduce exposure to risk factors

• Clinician should evaluate potential role of allergens, particularly indoor inhalant allergens

• Reduce, if possible, exposure to allergens to which the patient is sensitized

• Avoid exposure to environmental tobacco smoke and other respiratory irritants

• Avoid exertion outdoors when levels of air pollution are high


Pharmacological and non-pharmacological treatment is adjusted in a continuous cycle that involves assessment, treatment and review

Asthma outcomes have been shown to improve afterthe introduction of control-based guidelines

CONTROL-BASED ASTHMA MANAGEMENT


Medication is adjusted up or down in a Stepwise approach to achieve good symptom control and minimize future risk of exacerbations, fixed airflow limitation and medication side-effects. Once good asthma control has been maintained for 2–3 months, treatment may be stepped down in order to find the patient’s minimum effective treatment .

STEPWISE approach for asthma Rx


For Step 4 treatment, add-on tiotropium is now extended to patients aged ≥12 years with a history of exacerbations

For Step 5 treatment, add-on treatment options

for patients with severe asthma uncontrolled on Step 4 which includes mepolizumab (anti-IL5) for patients aged ≥12 years with severe eosinophilic asthma

What’s new in GINA 2016 guidelines


If a patient has persisting symptoms and/or exacerbations despite 2–3 months of controller treatment, assess and correct the following common problems before considering any step up in treatment:• Incorrect inhaler technique• Poor adherence• Persistent exposure to agents such as allergens, tobacco smoke, indoor or outdoor air pollution, or to medications such as beta-blockers or NSAIDs• Comorbidities that may contribute to respiratory symptoms and poor quality of life• Incorrect diagnosis


o For adults and adolescents, the preferred step-up treatment is combination ICS/long-acting beta2-agonist(LABA).o For children 6–11 years, increasing the ICS dose is preferred over combination ICS/LABA.

• Consider step down once good asthma control has been achieved and maintained for about 3 months, to find the patient’s lowest treatment that controls both symptoms and exacerbations

Status Asthmaticus

• Acute asthmatic attack not responding to routine treatment & β2 agonist, life threatening condition

• Precipitated by: – Acute respiratory infection – Abrupt cessation of steroid therapy – Pharmacological stimuli/allergens – Acute emotional stress

Status Asthmaticus (Cont’d• Hydrocortisone Hemisuccinate 100mg iv stat 4-8

hourly infusion (take 6 hours to act)• Nebulized salbutamol (2.5-5mg) + Ipratropium

Bromide (0.5mg) • High flow humidified O2 • Salbutamol/Terbutaline 0.4mg S.C/I.M • Intubation and mechanical ventilation • Antibiotics• Saline + Sod. Bicarbonate


SPECIAL CONSIDERATIONS

Exercise-induced bronchospasm• Pretreatment before exercise- Inhaled beta2-agonists- prevent EIB in more

than 80 percent SABA use may be helpful for 2–3 hours LABAs can be protective up to 12 hours

Leukotrine receptor antagonist can attenuate EIB in up to 50 percent of patients

Cromolyn or nedocromil taken shortly before exercise is an alternative

Surgery and Asthma• Attempts made to improve lung function

preoperatively

• Short course of oral systemic corticosteroids may be required

• For patients who have received oral systemic corticosteroids during the past 6 months and for pts on a long-term high dose of ICS

• 100 mg hydrocortisone every 8 hours i.v during the surgical period & reduce dose rapidly within 24 hours after surgery

Pregnancy and Asthma• Asthma increases risk of preterm birth, IUGR and

perinatal mortality.• NEVER WITHHOLD TREATMENT• Monitoring of asthma status during prenatal visits • Albuterol is the preferred SABA because it has an

excellent safety profile • ICS are the preferred treatment for long-term

control medication• Budesonide is the preferred ICS because more

data are available


DEVICES

Inhalational delivery systems

Dry Powder Inhalers

Metered Dose Inhaler Spacer

Nebuliser

METERED DOSE INHALER

1. Take off the cap. Shake the inhaler well.

2. Breathe out though your mouth.

3. Place the inhaler between your lips. As you start to breathe in, press the top end of the inhaler and keep breathing in steadily and deeply.

4. Remove the inhaler from your mouth. Hold your breath for 10 seconds or as long as you find comfortable. Breathe out.

The Spacer is a holding chamber which can be attached to the Metered Dose Inhaler.

1. Assemble the Spacer by pushing the notch of one half into the slot of the other half.

2. After shaking the inhaler well, fit it into the Spacer.

3. Breathe out through your mouth. Then close your lips around the Spacer.

4. Press the top end of the inhaler. Then, breathe in deeply though your mouth.

SPACER

Dry Powder Inhalers

1. Insert the transparent end of the Rotacap into the raised square hole of the rotahaler.

2. Hold the top of the Rotahaler firmly with one hand. Rotate the base until the capsule breaks.

3. Breathe out through your mouth. Then, placing the Rotahaler between your lips (as shown), breathe in though your mouth as deeply as possible.

4. Remove the Rotahaler from your from your mouth. Hold your breathe for 10 seconds or as long as you find comfortable. Breathe out.

Attach the hose and mouthpiece to the medicine cup

Place the mouthpiece in your mouth. Breathe through your mouth until all the medicine is used, about 10-15 minutes.

Wash the medicine cup and mouthpiece with water, and air-dry until your next treatment

NEBULISERS

2 types: Jet nebulisers Ultrasonic nebulisers


RECENT ADVANCES


INDICATEROL: Inhaled once-daily β2 agonist Onset of action faster than salmeterol Duration of action ~ 24 hrs Has been approved only for COPD Clinical trials in asthma underway to test safety

and efficacy of once-daily combination of indacaterol with mometasone

Mapracorat: Selective glucocorticoid receptor agonist that targets receptors for inflammation only & is devoid of systemic side effects

Abediterol: Ultra LABA under trial for bronchial asthma prophylaxis

Recently MgSo4 by I.V. and inhalational route has been tried for acute severe asthma.

Recent advances Contd…


Allergen-specific immunotherapy may be an option if allergy plays a prominent role, e.g. asthma with allergic rhinoconjunctivitis.

There are currently two approaches: Subcutaneous immunotherapy (SCIT) and Sublingual immunotherapy (SLIT).

Allergen Immunotherapy

Bronchial Thermoplasty• Catheter introduced through a

bronchoscope

• It delivers thermal energy to the airway wall to reduce excess smooth muscle

• Increases symptom-free days, improves PEFR and reduces the use of reliever medicines.

• FDA approval obtained in 2010 for treatment of severe asthma.

Cho JY. Recent Advances in Mechanisms and Treatments of Airway Remodeling in Asthma: A Message from the Bench Side to the Clinic. Korean J Intern Med 2011; 26:367-383


Influenza causes significant morbidity and mortality in the general population, and the risk can be reduced by annual vaccination. Influenza contributes to some acute asthma exacerbations, and patients with moderate-severe asthma are advised to receive an influenza vaccination every year

Vaccination


Asthma is a serious global health problem affecting all age groups

Despite of better understanding of Pathophysiology Presence of reliable diagnostic tools,availability

of a wide range of effective & affordable drugs Simplified national and international asthma

management guidelines Asthma remains poorly managed across the

globe

SUMMARY


Global Initiative for Asthma. Global Strategy for Asthma Management andPrevention, 2016. Available from: www.ginasthma.org

Asthma insights & management in India; JAPI(SEP. 2015 vol.63)

Medicine Update 2016:volume 2 (GurpreetS Wander,kk Pareek)

Crofton & dougla’s respiratory diseases:5th edition

Goodman and Gilman's -12th The Pharmacological basis of therapeutics

REFERENCES

http://www.ginasthma.org/


Principles of pharmacology-HL Sharma & kk sharma

Harrison’s principles of internal medicine:19th edition

Tiotropium respimat:a review of its use in asthma poorly controlled with ICS & LABA { DRUGS vol.75}


Next topic- Pharmacotherapy of Epilepsy Date: 14/09/16

Pharmacotherapy of bronchial asthma

Health & Medicine

Transcript of Pharmacotherapy of bronchial asthma