ESTIMATED MORBIDITY FOR NON COMMUNICABLE DISEASES IN INDIA

(Nongkynrih B et al, JAPI 2004 Feb; 52: 118-123)

WHO, 2002 data

0

10000000

20000000

30000000

40000000

50000000

60000000

70000000

Cancer IHD Stroke Diabetes Chronic respiratory

disease

0.6 million

25 million

1 million

28 million

65 million65 million

Asthma

COPD54 m

80-85% of chronic respiratory diseases in our country are due to

ASTHMA & COPD

Respiratory DiseasesRespiratory Diseases

Allergic RhinitisAllergic RhinitisAsthmaAsthma COPDCOPD

No. of patients with Asthma

• Estimated prevalence of Asthma is increasing 50% every 10 years

30 CRORES 1.5 – 2 CRORES

A S T H M A

Lets understand the respiratory system…….

Asthma is a long term disease that affects the airways.

Tubes that carry air in and out of your lungs.

Parts of the respiratory system

Parts of the respiratory system (Contd…)

AIRWAYS

Parts of the respiratory system (Contd…)

Cross Section of Airway Wall

Classification of the nervous system

Nervous system

Peripheral Central

Somatic Autonomic

Sympathetic Parasympathetic

ALLERGY

A reaction to a specific substance which is foreign to the body.

Allergen is the substance which induces an allergic response.

Normal individual

• Allergen stimulates production of IgE, in equal no. to allergen.

• Allergen destroyed

Allergic individual

• Allergen stimulates excess production of IgE.

• Some Allergens get destroyed.

• Rest cause allergic reaction.

Triggers

Dust mite

Triggers factors are things that when inhaled can start asthma.

They can vary from person to person.

Dust

SmokeCigarette smoke

Smoke from firecrackers

Pollen From plantsAnimal

dander

Exercise

Cold air

Strong smells

Recognition of asthma triggers and Recognition of asthma triggers and

avoiding them avoiding them

is the first step towards controlling asthma…is the first step towards controlling asthma…

On entry of these triggers

The airways get narrower

Less air flows through the lungs

AIRWAY OBSTRUCTION(Blockage in the airways)

This causes symptoms like...........

Asthma Symptoms

Breathlessness or dyspnoea (especially at night or after some exertion)

Wheezing (a whistling sound while breathing out)

Cough (especially at night or after some exertion)

Chest tightness (feeling of congestion)

Definition

Asthma is a

Chronic Inflammatory Disease characterized by

Airway Hyperresponsiveness to a variety of stimuli resulting in

Bronchospasm which reverses, spontaneously

or with treatment.

ABC of AsthmaA

Airway hyper-responsiveness (Airways over-react to triggers)

B Bronchospasm

(Sudden constriction in bronchial tubes)

C Chronic inflammation

(Long term swelling)

Exercise Induced Asthma (EIA)

Asthma attacks which occur after strenuous exercise. EIA symptoms occur after 3-8 min of exertion

Nocturnal Asthma

• Nighttime symptoms of wheezing, cough, breathlessness is known as nocturnal asthma.

• 70% of deaths due to asthma occur at night.

Causes of Nocturnal Asthma

- Exposure to dust mite, animal dander

- Gastro-oesophageal reflux

- Post nasal drip

- Increased parasympathetic activity

- Increased sensitivity to histamine

Diagnosing Asthma

1. History taking

2. Measurements of lung function

3. Bronchodilator reversibility test

1. History taking (Ask questions to Diagnose Asthma)

Does the patient have a troublesome cough, worse particularly at night, or on awakening?

Does the patient cough after physical activity (e.g.. Playing)?

Does the patient have breathing problems during a particular season (or change of season)?

Do the patient’s colds ‘go to the chest’ or take more than 10 days to resolve?

Does the patient use any medication (e.g. bronchodilator) when symptoms occur? Do you get relief?

If the patient answers “YES” to any of the above questions, suspect Asthma.

Also a doctor should ask about: Does anyone else in your family suffer

from Asthma, Allergies, Frequent Colds ?

2. Measurements of lung function

The Peak Flow Meter

The thermometer for Asthma

1. Measure peak flow reading

2. Give bronchodilator

4. Measure peak flow reading again

3. Wait for 10 to 15 minutes

5. If: 15 – 20 % increase in this reading from previous

6. Indication of a significant degree of reversible airflow

obstruction

ASTHMAASTHMA

3. Bronchodilator reversibility test

Peak Flow Master

• Diagnose asthma >15 % improvement in PEFR

( Reversibility )

• Monitoring > 20 % variability in AM-PM PEFR

indicates poor control

• To determine effectiveness of therapy

• Identify factors which worsen asthma

• Warn of an impending attack

• Incentive for the patients

Inflammatory Cells

Granulocytes Agranulocytes

RBCs WBCs Platelets

Eosinophils

Neutrophils

Basophils

Mast cells

Lymphocytes

(T cells & B cells)

Monocytes

Macrophages

INFLAMMATION

Treatment of Asthma

Routes of administration of anti-asthma drugs

Oral Inhaled Parenteral

Tablets

Syrup

Metered dose inhaler (MDI)

Dry powder inhaler (DPI)

Injections

Which is the best route for anti-asthmatic drugs???

Nebulizers

EyesEyes

SkinSkinNasal blockageNasal blockage

LungsLungs

Eye Drops Ear Drops

Lotions / ointments Nasal inhaler

INHALERS

NOT ORALS

EarsEars

ORAL OR INHALED

For Example…..

• Tab ASTHALIN 4mg = 4000 mcg

• 100mcg/Puff ASTHALIN x 2 puff = 200 mcg

20 times less drug is required for

desired effect from INHALATION route!

4000/200 = 20

ORAL OR INHALED

Oral

• Large dosage used

• Greater side effects

• Slow onset of action

• Not useful in acute symptoms

Inhaled

• Small amount of dosage used

• Lesser side effects

• Fast onset of action (e.g. bronchodilators)

• Useful in acute symptoms

ORAL OR INHALED

Advantages of inhalation therapy over oral route

Direct action in lungsSmall doses requiredQuick onset of ActionMinimum side effects

Asthma DiseaseBronchospasm & Inflammation (Swelling)

• Bronchospasm needs a Reliever Bronchodilator

• Inflammation (Swelling) needs a Controller

Anti-inflammatory

Drug treatment

Bronchodilators Anti-inflammatory

Relievers Controllers

Duration of action: shortshort Duration of action: longlong

Onset of action: faster Onset of action: slower

Quickly relieve symptoms Prevent asthma attacks

Rescue medicine Regular medicine

AVAILABLE DRUGS

RELIEVERSShort acting

bronchodilators

CONTROLLERSLong acting

bronchodilators Inhaled CorticosteroidsCombination Therapy Anti Leukotrienes

CiplaAVAILABLE RELIEVERS

Short acting bronchodilators

Salbutamol - ASTHALIN Levosalbutamol - LEVOLIN

To be taken as and when required

Cipla AVAILABLE CONTROLLERS

Inhaled corticosteroids

Beclomethasone BECLATE

Budesonide BUDECORT

Fluticasone FLOHALE

Ciclesonide CICLOHALE

Long acting bronchodilators

Salmeterol SEROBID

Formoterol FORATEC

Anti-leukotrienesMontelukast MONTAIR

To be taken regularly ,whether patient has symptoms or not

ICS + bronchodilators

SEROFLO – Salmeterol / Fluticasone FORACORT – Budesonide / FormoterolSIMPLYONE – Ciclesonide / Formoterol

FULLFORM – Beclomethasone / Formoterol BEKFORM - Beclomethasone / Formoterol AEROCORT - Beclomethasone / Salbutamol

To be taken regularly ,whether patient has symptoms or not

Cipla AVAILABLE CONTROLLERS (Contd…)

THE STORY OF ASTHMA TREATMENT

Traditional treatmentOccasional RelieversIdeal treatment

Regular ControllersSteroid

Mechanism of Action

Inhalation Therapy in Asthma

MOA of Bronchodilators

• Beta2-Agonists

• Short acting beta2-agonists

- Salbutamol

- Levosalbutamol

• Long acting beta2-agonists

- Salmeterol

-Formoterol

Mode of action of ß2 agonists

Smooth

muscle cell

Smooth musclecell relaxation

- agonist

Activates Proteinkinase

Decreasesintracellular Ca

2+

cAMP

ATP

2

2 -receptor

Mode of action of inhaled corticosteroids

Mode of action of inhaled corticosteroidsMode of action of inhaled corticosteroids

S Steroid

CELL

Steroidreceptor

NUCLEUSDNA

S

New Protein Synthesis

lipocortin

phospholipase A

(inhibits)

phospholipid arachidonic acid

leukotrienes prostaglandins

complexS

Classification of Severity-GINA

CLASSIFY SEVERITYClinical Features Before Treatment

SymptomsSymptoms NocturnalNocturnalSymptomsSymptoms FEVFEV1 1 or PEFor PEF

STEP 4STEP 4

Severe Severe PersistentPersistent

STEP 3STEP 3

Moderate Moderate PersistentPersistent

STEP 2STEP 2

Mild Mild PersistentPersistent

STEP 1STEP 1

IntermittentIntermittent

ContinuousContinuous

Limited physical Limited physical activityactivity

DailyDailyAttacks affect activityAttacks affect activity

> 1 time a week > 1 time a week but < 1 time a day but < 1 time a day

< 1 time a week< 1 time a week

Asymptomatic and Asymptomatic and normal PEF normal PEF between attacksbetween attacks

FrequentFrequent

> 1 time week> 1 time week

> 2 times a month> 2 times a month

2 times a month2 times a month2 times a month2 times a month

60% predicted60% predicted

Variability > 30%Variability > 30%

60 - 80% predicted 60 - 80% predicted

Variability > 30%Variability > 30%

80% predicted80% predicted

Variability 20 - 30%Variability 20 - 30%

80% predicted80% predicted

Variability < 20%Variability < 20%

The presence of one feature of severity is sufficient to place patient in that category.The presence of one feature of severity is sufficient to place patient in that category.

Stepwise Approach to Asthma Therapy - AdultsStepwise Approach to Asthma Therapy - Adults

Reliever: Rapid-acting inhaled β2-agonist prn

Controller: Daily inhaledcorticosteroid

Controller: Daily inhaled

corticosteroid Daily long-acting

inhaled β2-agonist

Controller: Daily inhaled

corticosteroid Daily long –acting

inhaled β2-agonist plus (if needed)

When asthma is controlled, reduce therapy

Monitor

STEP 1:STEP 1:IntermittentIntermittent

STEP 2:STEP 2:Mild PersistentMild Persistent

STEP 3:STEP 3: Moderate Moderate PersistentPersistent

STEP 3:STEP 3: Moderate Moderate PersistentPersistent

STEP 4:STEP 4:Severe Severe

PersistentPersistentSTEP DownSTEP DownSTEP DownSTEP Down

Outcome: Asthma Control Outcome: Best Possible Results

Controller:None

-Theophylline-SR -Anti-Leukotriene -Long-acting inhaled β2- agonist -Oral corticosteroid

New GINA guidelines:Focus on Asthma Control rather than severity

Global Initiative for Asthma (GINA) 2006

Characteristic Controlled(All of the following)

Partly Controlled(Any measure present in any

week)

Uncontrolled

Daytime symptoms None (twice or less/week)

More than twice/week

Three or more features of partly

controlled asthma present

in any week

Limitations of activities

None Any

Nocturnal symptoms/awakening

None Any

Need for reliever/rescue treatment

None (twice or less/week)

More than twice/week

Lung function (PEF or FEV1)

Normal < 80% predicted or personal best (if

known)

Exacerbations None One or more/year One in any week

MANAGEMENT APPROACH BASED ON CONTROL

Level of control Treatment Action

Reduce

Controlled Maintain and find lowest controlling step

Partly controlled Consider stepping up to gain control

Uncontrolled Increases Step up until controlled

Exacerbation Treat as exacerbation

Treatment Steps

The New Dimension

In

ASTHMA

CONTROLLERS

Combination TherapyCombination Therapy

THE CHANGE IN VIEW OVER YEARS

Time Period Goal of Management Preferred Medication

1960’s Relieve Bronchospasm

Epinephrine, Salbutamol, Levosalbutamol

1990’s Prevent and resolve inflammation

Inhaled glucucorticosteroids

Leukotriene modifiers

2000’s Resolve symptoms and disease process

Combination of ICS and LABAs

• It is now well accepted that asthma is an inflammatory diseases of the airways

• The bronchoconstriction that gives rise to dyspnoea is effect of the inflammatory process.

• It is no longer considered sufficient to treat the episodes of respiratory distress as and when they occur except in very mild cases.

• Shift in the focus of treatment

Bronchodilator Anti-inflammatory

Indian Pediatr 1998; 35: 871-881

Inhaled steroids and risk of death (NEJM, 2000)

Factor for Poor response to inhaled corticosteroids

• No immediate symptomatic relief• Resulting in low rates of compliance• No benefit in increasing the dose of ICS

beyond a particular dose

• Flat dose – response curve

• Local side effects (hoarseness, URTIs)

• Systemic side effects (cataracts / growth

retardation/ osteoporosis)

Favorable Benefiit-Risk Ratio

Wanted Effects

Dose

Unw

ante

d E

ffect

s

Flat Dose Response of ICS

1600mcgbudesonide

Response

Combination Therapy

Use of ICS and LABA is accepted as the most effective treatment regime to control moderate and severe asthma

Rationale for Combination Therapy

A fixed dose combination of a

long-acting beta2-agonist and

an inhaled corticosteroid

Complementary Action

• Corticosteroids and LABA act on two different

components of asthma.

• Inflammation can be taken care of by steroids

and

• Abnormalities in the bronchial smooth muscle

by LABA.

Synergistic Activity

• Beta2-agonists are potent activators of

the GC receptor.

• In addition, regular use of inhaled corticosteroids helps in increasing the activity of Beta 2-agonists

1) ICS enters the cell membrane, targets the intracellular inactive steroid receptor and binds to it

2) This leads to formation of an active receptor complex

…..which then binds to a target gene and the result is anti-inflammatory activity.

4) Synthesis of beta-2 receptor protein which is then inserted in the cell membrane.

5) LABA interacts with this membraneassociated beta-2 receptor

6) The subsequent beta-2 submit then interacts with the inactive corticosteroid receptor leading to a priming of

the receptor. This primed receptor is more susceptible to activation with steroids and importantly it requires less steroid then to convert the primed receptor to the active

receptor

Co deposition

Co-deposition of LABA and steroid

when administered in a single inhaler.

Flat Dose Response

• Inhaled steroids have a flat dose

response curve. Thus, addition of LABA

to a low dose of inhaled steroid is an

attractive therapeutic option to increasing

the dose of steroid.

Guidelines

• Prevents tolerance development

• Use of such a combination is in accordance with current guidelines for the management of asthma

Patient Compliance

• Simplifies therapy

• Improves compliance since only one inhaler is used

Reduced Cost

• Reduces cost of therapy due to better control of asthma and a better quality of life

Rationale of Combination Therapy-RECAP

• Complementary Action

• Synergistic Action

• Co- Deposition

• Taking care of Flat Dose Response

• Guidelines Recommendation

• Patient Compliance

• Reduced Cost

Combination therapy

• Formoterol ( fast relief and sustained relief )

+

• Budesonide ( twice or even once daily use )

Dose: 1- 4 inhalations ( OD/BD )

Combination therapy• salmeterol (sustained relief )

+

• fluticasone ( 3 times more potent than

budesonide )

Dose: 1- 2 inhalations (BD )

Combination therapy

• Formoterol ( fast relief and sustained relief )

+

• Ciclesonide ( the ideal ICS )

Dose: 1- 4 inhalations ( OD/BD )

Airway Remodeling

• Permanent structural changes in the airway wall which are irreversible.

• Increased mucus production• Fibrosis• Neovascularization

Goals of Asthma Therapy

• Minimal (ideally no) chronic symptoms

• Minimal (ideally no) need for “as needed” use of relievers

• No emergency visits

• (Near) normal PEF

• Minimal (infrequent) exacerbations

• PEF circadian variation of less than 20 percent

• No limitations on activities, including exercise

• Minimal (or no) adverse effects from medicine

MUST KNOW

• Routes of administration of anti-asthma drugs

• Advantages of inhalation therapy over oral route

• Drug therapy for asthma

• Differences between relievers and controllers

• Cipla’s available relievers & controllers