PHARMACOLOGICAL BASIS OF

TREATMENT OF BRONCHIAL

ASTHMA

Asthma - Greek word meaning “to stay awake in order to breath” or “difficulty in breathing”

Asthma is a chronic inflammatory disorder of the airways.

Chronically inflamed airways are hyper responsive; they become obstructed and airflow is limited by :

1. Broncho-constriction 2. Mucus plugs 3. Increased inflammation when airways are exposed to various risk factors.

Asthma is a chronic inflammatory disease in

which the patient suffers with reversible

episodes of airways obstruction due to

bronchial hyper-responsiveness.

Predisposing factors:

Heredity Age: Pediatric group most affected Sex: within 10 years of age male:

female ratio(2:1) and equal in adults.

Allergens – Food, Inhalants, Bacteria.

Respiratory infections, pharmacologic stimulants occupational factors, exercise, climatic factors, low socio-economic status.

Passive smoking. Air pollution. Obesity.

Triggering Factors

Domestic dust mites

Air pollution

Tobacco smoke

Occupational irritants

Cockroach

Animal with fur

Pollen

Asthma affects 8% in adults and 10% in

children.

Asthma is common in industrialized nations

such as Canada, England, Australia, Germany,

and New Zealand, where much of the data have

been collected.

The prevalence rate of severe asthma in

industrialized countries ranges from 2-10%

Bronchial ToneBronchial Tone

BronchoconstrictionBronchoconstriction

BronchodilitationBronchodilitation

Bronchial Smooth Bronchial Smooth MuscleMuscle

IgE-Antigen ComplexIgE-Antigen Complex

BasophilBasophil

ActivatioActivationn

EosinophEosinophilil

ActivatioActivationn

Chemical mediatorsChemical mediators

Histamine, LTCHistamine, LTC44, LTD, LTD44, LTB, LTB44,,

Cytokines, Adenosine, PGDCytokines, Adenosine, PGD22, PAF,, PAF,ECP and NeuropeptidesECP and Neuropeptides

Cause inflammation, oedema, Cause inflammation, oedema, bronchospasm, muscus bronchospasm, muscus secretion, epithelial damagesecretion, epithelial damage

ββ22 AGONISTS AGONISTS Inhibit Inhibit releaserelease

ββ22

SALBUTAMOSALBUTAMOLLββ22 AGONISTS AGONISTS

ATATPP

ACAC

cAMPcAMP

CORTICOSTEROIDCORTICOSTEROIDSS

PDPDEE

AMPAMP

THEOPHYLLINETHEOPHYLLINE

MM33

GTGTPP

GCGC

cGMPcGMP

IPRATR

OPI

UM

IPRATR

OPI

UM

MM33

ANTA

GONIS

T

ANTA

GONIS

T

SS

AdenosineAdenosine

Mast CellMast CellDegranulatioDegranulationn

Pathophysiology

Bronchial Tone

Bronchoconstriction

Bronchodilitation

Bronchial Smooth Muscle

IgE-Antigen Complex

Basophil

Activation

Eosinophil

Activation

Chemical mediators

Histamine, LTC4, LTD4, LTB4,

Cytokines, Adenosine, PGD2, PAF,ECP and Neuropeptides

Cause inflammation, oedema, bronchospasm, muscus secretion, epithelial damage

CORTICOSTEROIDS

LT-ANTAGONIST

Leukotrienes

SOD. CROMOGLYCATE

Stabilises Mast Cells

Mast CellDegranulation

INFECTION

NITRIC OXIDE

DONORS

NEURAL CONTROLPARASYMPATHETICPARASYMPATHETIC

AcetylcholineAcetylcholine

Bronchial Bronchial Smooth MuscleSmooth Muscle

++

MM33

22

Circulating CatecholaminesCirculating Catecholamines

AdenosineAdenosine

AA22Mast CellMast Cell

AA33

NONO

++++

Neurokinin A Neurokinin A Substance PSubstance P++

NNAANNCC

MediatorsMediators

Unmyelinated Unmyelinated Sensory C fiberSensory C fiber

SOSO22, ,

Cigarette SmokeCigarette Smoke

SYMPATHETICSYMPATHETIC

Neuro-Neuro-peptidespeptides

ASTHMA MANIFESTS AS

1. Breathlessness and

2. Cough

3. Recurrent episodes of wheezing

4. Chest tightness

Goals of asthma therapy

› To prevent chronic and troublesome symptoms

› To maintain near normal pulmonary function

› To maintain normal activity levels (including

exercise and other physical activity)

› To prevent recurrent exacerbations of asthma

and minimise the need for emergency

department visits to hospitalizations

› To provide optimal pharmacotherapy with

minimal or no adverse effects

› To meet pts & families expectations and

satisfaction with asthma care.

Drugs used in Bronchial Drugs used in Bronchial Asthma Asthma

1. Selective β2- Agonists Short acting Salbutamol Terbutaline Remiterol Fenoterol

Long-acting Salmeterol, Formoterol, Bambuterol.

2. Non-selective Sympathomimetics

Adrenaline Ephedrine, Isoprenaline, Orciprenaline,

(Metaproterenol). Isoetharine.

BronchodilatorsBronchodilators

3. Anticholinergics - Ipratropium, Tiotropium,

Oxitropium,

4. Methyl Xanthines- Theophylline, Aminophylline,

Diprophylline, choline theophyllinate.

Anti inflammatory drugs.Corticosteroids

1. Oral: Prednisolone, Methylprednisolone,

2. Parenteral: Mehtyl Prednisolone, Hydrocorticsone

3. Inhalational: Beclomethasone, fluticasone,

Triamcinolone, Budesonide, Flunisolide

Mast Cell Stabilisers

Sodium Cromoglvcate, Nedocromil, Ketotifen,

Leukotriene Modulators:

1. 5-Lipoxygenase inhibitor: Zileuton

2. LT-rceptor Antagonists: Zafirlukast,

Montelukast, Iralukast, Pranlukast,

Monoclonal Anti-lgE Antibody

omalizumab

1. β2-Selective adrenoceptor agonist

most widely used sympathomimetics for the

treatment of asthma at the present time.

1. Short acting:- albuterol-Terbutaline

used only for acute attack of

bronchospasm

1. Long acting:- salmeterol –formeterol

used for only prophlaxis and not for acute

attack of bronchospasm.

Selective β2 receptor agonist

mechanism of action

Bronchial smooth

muscle relaxation

Stimulation of Stimulation of β2-receptors

Intracellular Intracellular cAMPcAMP

Selectively β2 receptor agonist

1. Route of administration: Usually delivered via a metered dose inhaler

with immediate effect Orally used in children. i.v used for acute attack. S.C. (terbutaline)2. Adverse effect: Cardiac arrhythmias (at high dose has β1

effects) Tolerance to β agonist (tachyphylaxis) Skeletal muscle tremors.

Non-selective

Sympathomimetics Adrenaline/epinephrineAdrenaline/epinephrine:

Agonist of α and β receptor

Adverse effect of cardiovascular system usually

occurs thereby less usable

S.C. injection

Ephedrine:Ephedrine:

Orally administered

Similar action to Adrenaline

Less usable for central excitation

Mechanism of Action: It stimulates the β2 receptors and cause bronchodilation.

Rout of administration:

As aerosol

Adverse effects:

Tachycardia,

Hypertension

Worsening of angina and even arrhythmias

They are divided into two types:

1. Salt complex: increased water solubility

without augmentation of pharmacological

action, such as: aminophylline.

2. Slow-release form: small fluctuation of

blood concentration after oral administration

thus used for nocturnal attack of asthma.

Theophylline

Mechanism of action

Inhibit activity of PDE cAMP

bronchial relaxation

cAMP AMP

3. Inhibition of the cell surface receptor of

adenosine

PDEPDE

Theophylline

1. Route of administration: Orally Metabolised by P450 enzyme system

2. Pharmacodynamics Direct positive chronotropic and inotropic

effects on the heart. In large dose, these agents also relax

vascular smooth muscle.

Theophylline:

Adverse effect

It has a narrow therapeutic index

Its therapeutic and toxic effects are related to

its plasma concentration.

<20mg/L: nausea, vomiting, headache,

anxiety, abdominal discomfort.

20-40mg/L: arrhythmia

Muscarinic antagonist

1. Mechanism: Act by competitive blocking of muscarinic

receptors (M3 subtype)

2. Route of administration: Metered dose inhaler e.g Ipratropium

bromide

3. indication: Used as adjuncts to β2-adrenoceptor agonist

in treatment of asthma.

Anti-inflammatory drug Glucocorticoids

Mechanism:

1. Depress the inflammatory response in bronchial

mucosa thus diminish bronchial

hyperresponsiveness.

2. Anti-inflammatory effect (inhibit

phospholypaseA2)

3. Immunosuppressive effect.

Glucocorticoids

Route of administration

1. Metered dose inhaler: (deeply & slowly

inhale) Beclomethasone, dexamethasone

2. Intravenous used for: severe asthma status

asthmaticus (prednisolone or

hydrocortisone)

3. oral

Monoclonal anti IgE antibody Omalizumab

Mechanism of action:

It prevents the binding of IgE to mast cell &

thus prevents mast cell degranulation

Rout of administration:

i.v or s.c

Side effects:

Redness, stinging, itching, induration.

1. NSAIDS like aspirin,ibuprofen,diclofenac etc.

(paracetamol can be used)

2. Beta-adrenergic blockers

3. Cholinergic agents.

1. Mild episodic asthmaInhaled short-acting beta2

agonist at onset of each episode (step-1)

2. Seasonal asthmastart regular inhaled cromoglycate/low dose

inhaled steroid(200-400micro g/day) 3-4 wks before

anticipated seasonal attacks continue till 3-4 wks

after the season is over treat individual episodes

with inhaled short acting β2 agonist.

3. Mild chronic asthma with

occasional exacerbations: regular inhaled cromoglycate, episodic-short

acting β2 agonist(step-2)

4. Moderate asthma with frequent

exacerbations: increases doses of steroid (up to 800μg/day)

+inhaled long acting β2 agonist(step-3)

5. Severe asthma:

Regular high dose inhaled (steroids 800-2000μg/day)

though a large volume spacer device + inhaled long-

acting β2 agonist (salmeterol) twice daily .

6. Status asthmaticus

Any pt of asthma has the potential to develop

acute severe asthma which may be life

Threatening.

upper respiratory tract infection is the most

common precipitant.

Hydrocortisone hemisuccinate 100mg I.V stat

followed by 100-200mg 4-8 hourly infusion

Nebulized salbutamol (2.5-5mg)+ipratropium

bromide (0.5mg) intermittent inhalations driven

by 02.

Management of status asthmaticus

High flow humidified oxygen inhalation.

Salbutamol/terbutaline 0.4mg i.m/s.c may be

added, since inhaled drug may not reach smaller

bronchi due to severe narrowing/plugging.

Intubation & mechanical ventilation, if needed.

Treat chest infection with intensive antibiotic

therapy.

Correct dehydration and acidosis with

saline+sod. bicarbonate/lactate infusion.

Aerosol Delivery of Drugs

High local concentration in bronchioles

Low systemic side effect.

Increased bioavailability.

Optimal particle size for deposition in small

airways – 1to 5μm

Four classes of antiasthma drugs, i.e β2 agonists,

anti-cholinergics, cromoglycate and

Glucocorticoids are available for inhalational use.

They are aimed at delivering the drug to the site

of action so that lower dose is needed and

systemic side effects are minimized.

Most asthma patients are now maintained on

inhaled medication only.

Aerosol Delivery Devices:

Liquid aerosols Metered dose inhaler (MDI)

Nebulizer

Powdered drugs Dry powder inhaler (DPI), Spinhaler, Rotahaler

Pressurized Metered Dose Inhaler (pMDI)

In pMDI drug is dissolved or suspended in propellant under pressure and when actuated releases a predetermined dose.

Pressurized MDI can be used with spacer or without spacer.

User of spacer improves drug deposition in lungs and reduces oropharyngeal drug deposition.

Use of spacer reduces oropharyngeal drug deposition by 10-15 folds when compared to pMDI alone.

Spacer acts as reservoir for drug from which

patients can breathe easily.

Depending on patient’s technique, drug

delivery varies from 7 to 20%.

An oropharyngeal drug deposition is about

80% with pMDI.

The particle size distribution through HFA was

1.07 micrometer and that of with CFC is 3.36

micrometer.

Lung deposition of drug with HFA is 50% while

with CFC it is 10-20%.

With HFA the oropharyngeal deposition is 30%

whereas with CFC it is 90-94%.

Spacer/holding chamber

Slow (3-5 secs) inhalation or tidal breathing

immediately following actuation

Easier to use than MDI alone

Recommended for anyone using MDI

Spacer

Nebulizers Nebulizer convert a liquid solution or

suspension into an aerosol using either a jet or ultrasonic energy.

Aerosol is then delivered to the patient through either a face mask or a mouthpiece.

Nebulzer requires least patient cooperation and coordination.

Nebulzers are preferred in patients who are unable to use other devices or in acute attacks when inspiratory flow is

limited.

Only about 13% of the dose used is

deposited in the lungs.

The doses used in nebulizers are higher than

those used in other aerosol devices.

Therefore patients will receive 10-20 times

the dose received from a MDI.

Dry Powder Inhaler (DPI) In PDI drug is provided as micronized particles in

large aggregates with or without carrier substances.

Drug delivery in DPI depends on patient’s inspiratory effort to disperse the drug and deliver it to the lungs.

Drugs deposition in lungs with DPI is 15-40% with considerable inter device variability and drug deposition in oropharynx is <60%.

DPI dose not require propellants and hand breath

coordination

› Rapid (1-2 secs), deep inhalation; dose lost if

client exhales through device

› Population: > 4-5 years

Rotahaler

Spinhaler

1. Hold spinhaler upright with mouthpiece downwards, and unscrew body

2. Put coloured end of spincap into cup of propeller, making sure it spins freely3. Screw the two parts together and hold horizontal. Move grey sleeve up and down

once or twice, this will pierce capsule

4. Breathe out gently, tilt head back, put

spinhaler into mouth so lips touch flange and breathe in quickly and deeply

5. Remove spinhaler from mouth and hold

breath for about 10 seconds, then breathe out

slowly

6. If any powder is left in spincap, repeat steps

4 and 5 until it is empty

Always Demonstrate To The Patient How To Use The Spinhaler

Route of Administration & Dose

Drug Route & Dose

1. Selective β2 Agonists Salbutamol

Inhalant: 90 μg/puff aerosol; 0.83, 0.5% solution for nebulized Oral: 2,4 mg tab; 2mg/5ml syrup.

Formoterol Inhalant: 12 μg/puff aerosol. 12mg/unit inhalant powder.

Salmeterol Inhalant aerosol: 25 μg salmeterol base/puff in 60 & 120 dose containers inhalant powder50 μg/ unit

Terbutaline Inhalant: 0.2mg/puff aerosol.Oral: 2.5, 5 mg tab.

Cont….2. Selective Sympathomimetics Ephedrine

Oral: 25mg capsules Parenteral: 25,50mg/ml/ injection

Epinephrine Inhalant: 0.1,1, 2.25% for nebulization Parenteral: 1:10000 (0.1mg/ml)

3. Anti-cholinergics Ipratropium.

Aerosol: 18mg/μg/puff in 200 metered-dose inhaler.

4. Methyl xanthenes Aminophylline

Oral: 105mg/5ml liquid, 100, 200mg tablet

5. Leukotriene Inhibitors Montelukast Zafirlukast Zileuton

Oral: 10 mg tablets, chewable tabletsOral: 20 mg tabletsOral: 600 mg tablets

Cont…

6. Corticosteroids Beclomethasone Budesonide Dexamethasone

Aerosol Powder: 42 μg/puff in 200 dose container Aerosol Powder: 160 μg/activation

Aerosol powder: 84 μg/puff in 170 dose container

7. Mast cell stabilisers Cromolyn sodium Nedocromil sodium

Pulmonary aerosol: 800 μg/puff in 200 dose container; 20mg/2ml for nebulization. Pulmonary aerosol: 1.75 mg/puff in 113 metered-dose container.

Asthma cannot be cured but can be controlled

with regular use of medications.

Asthma is treated with two types of medicines:

Long term control

Quick-relief medicines

Long term control medicines help to reduce

airway inflammation and prevent asthma

symptoms.

Quick-relief,or “rescue", medicines relieve

asthma symptoms that may flare up.

Initial asthma treatment will depend on

severity of the disease.

Patient counseling on drug therapy should

concentrate on drugs used to relieve

symptoms, drugs used to prevent asthma

attacks and those drugs which are given only

as reverse treatment for severe attacks.