asthma by zeshan haider r# 16-2nd semester

8/14/2019 Asthma by Zeshan Haider R# 16-2nd Semester

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OVERVIEW OF ASTHMA

MANAGEMENT

ZESHAN HAIDER KAZMI

M.PHIL (PHARMACOLOGY)


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Asthma:epidemiology / pathology


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Epidemiology

Common disease

Prevalence of asthma :

Primary school children : 13.8%

Children aged 13-14 : 9.6%

Adults : 4.1%

Higher prevalence in rural (4.5%),compared to urban areas (4.0%)


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chronic inflammatory disorder of the airways

infiltration of mast cells, eosinophils and lymphocytes

wheeze, cough, chest tightness and shortness of breath symptoms vary over time and in severity

widespread, variable and reversible airflow limitation

airway hyper responsiveness

Asthma definition

GINA Guidelines 1998


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Patho-physiology:chronicinflammation

Comparisons of asthma

Asthma CD 4+ lymphocytes

Eosinophils

Mast cells

Vary over time and inseverity

cough

wheeze chest tightness

breathlessness

Clinical

history:

symptoms


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Mucus

hypersecretion

Hyperplasia

Eosinophil

Mast cell

Allergen

Th2 cell

Vasodilatation

New vessels

Plasma leakOedema

Neutrophil

Mucus plug

Macrophage/dendritic cell

Bronchoconstriction

Hypertrophy / hyperplasia

Cholinergicreflex

Epithelial shedding

Subepithelial

fibrosis

Sensory nerveactivation

Nerve activ

ation

Modern view ofasthma

Barnes PJ


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Inflammatory processes

Barnes PJ Epidemiology / pathology


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AsthmaNormal

Asthma - an inflammatorydisease


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Risk factors that lead toasthma development

Predisposing Factorsatopy

Causal Factors indoor allergens

dust mites animal dander cockroach fungi

outdoor allergens pollens fungi

occupational sensitisers

Contributing Factors respiratory infectionssmall size at birthdiet

air pollution outdoor indoor

smoking passive

active



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flour / grain dust (bakery)

paint, glue or plastic fumes

soldering flux

natural rubber latex

wood dust

Common occupationalagents


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Asthma diagnosis

history and pattern of symptoms

physical examination

measurements of lung function

- reversibility test

- diurnal variability

evaluation of allergic status


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symptoms - vary over time and in

severity:

cough wheeze

breathlessness

chest tightness

symptoms occur or worsen at night or

after exposure to trigger

colds go to the chest or take >10

days to clear

Is it asthma?


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Allergens

animal dander dust mites

pollen

fungi

Symptoms can occur or worsen in the presence of:

Others

exercise

viral infection

smoke

changes in temperature

strong emotional expression aerosol chemicals

drugs (NSAIDs, -blockers)

Ask about triggers


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Clinical classification of severity

Clinical features before treatment

Symptoms Night-timesymptoms

PEF

STEP 4

Severepersistent

STEP 3

Moderatepersistent

STEP 2

Mild persistent

STEP 1

Intermittent

Continuous

Limited physical

activityDaily

Use 2-agonist daily

Attacks affect activity

>1 time a week

but 2 times a month

60% - 30%

>80% predicted

Variability 20-30%

>80% predicted

Variability


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no chronic symptoms

no asthma attacks

no emergency visits

no need for quick relief (as needed) 2-agonist

normal physical activity including exercise

lung function as close to normal as possible no adverse effects from medicine


Treatment goal: takecontrol of asthma


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Pharmacological therapy

Controllers inhaled corticosteroids

inhaled long-acting 2-

agonists

inhaled cromones

oral anti-leukotrienes

oral theophyllines oral corticosteroids

Relievers inhaled fast-acting

2-agonists

inhaled anticholinergics


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RELIEVERS MEDICATION

Quick relief medicine or rescuemedicine.

Rapid acting bronchodilators that act to

relieve bronchoconstriction.


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ROUTE OF ADMINISTRATION

INHALATION Pressurized metered dose inhalers ( MDI) MDI-plus-spacer

Breath actuated MDI Dry powder inhalers Nebulised

ORAL

PARENTERAL

Cl f i


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Classes of 2-agonists

fast onset, long duration

inhaled terbutaline

inhaled salbutamol inhaled formoterol

oral terbutaline

oral salbutamol

oral formoterol

inhaled salmeterol

oral bambuterol

MAI

NTENAN

CE

RESCUE MEDICATIONSpeed of

onset

Duration

of action

fast

slow

longshort

Inhaled formoterol belongs to a new class of bronchodilator, in thatit has both a long duration and fast onset of effect.


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Short-acting inhaled B-agonist

Use intermittently to controlepisodes of bronchoconstriction

Avoid regular scheduled use ifpossible

An increase use is an indication ofdeteriorating control


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LONG ACTING 2 AGONIST

Mechanism of action: Bronchodilator (They stimulate intracellular adenyl

cyclase, the enzyme that catalyzes the conversion ofadenosine triphosphate to cyclic-3',5'-adenosinemonophosphate (cAMP). Increased cAMP levels causerelaxation of bronchial smooth muscle and inhibition ofrelease of mediators of immediate hypersensitivity fromcells, especially from mast cells)

Enhance mucociliary clearance Modulate mediators release from mast cells and basophils

Example : Inhaled : Salmeterol (Seretide), formeterol

Oral : BambuterolSalbutamol (Ventolin)Terbutaline (Bricanyl)Clenbuterol


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LONG ACTING 2 AGONIST

Inhaled 2 Agonists have fewer side effects thanoral formulations.

Side-effects : tachycardia, palpitations, tremors,anxiety, headache and hypokalaemia.


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Differences between 2-agonists

chemical structure

pharmacological properties:

mode of action in the 2-receptor region

potency

efficacy (ie full / partial agonism)

selectivity


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CONTROLLER MEDICATIONS

Are medications taken daily on a long termbasis that are useful in getting and keepingpersistent asthma under control.

Prophylactic, preventive or maintenance

medications Include

Inhaled glucocorticosteroids Systemic glucocorticosteroids Theophylline Long acting inhaled 2 agonist Long acting oral 2 agonist Leukotriene modifiers


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GLUCOCORTICOSTEROIDS

Mechanisms of action :

Reduced airway inflammation (They are anti-inflammatory agents which inhibit the production ofcytokines, an effect which reduces eosinophil infiltration,

inhibits macrophage and eosinophil function, decreasesmediator cells in the epithelium, reduces vascular

permeability, and reduces the production of leukotrienes)

Efficacy in improving lung function, decreasing

airways hyperresponsiveness, reducingsymptoms, reducing frequency and severity ofexacerbations and improving quality of life.


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GLUCOCORTICOSTEROID

Inhaled : Beclomethasone (Becotide, Clenil A)

Budesonide

Fluticasone

Oral : Prednisolone

Dexamethasone

Parenteral : Hydrocortisone

Methylprednisolone


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Side effects

Local effects

oropharyngeal candidiasis, dysphonia, upper airway

irritation How to prevent ? Mouth washing after inhalation &

use of spacer

Systemic adverse effects depends on the dose and potency of

glucocrticosteroids , absorption in thegut, first pasteffect of liver.

Systemic adverse effects include : skin thinning,easy bruising, cataract, obesity, adrenalsuppression, hypertension, diabetes and myopathy.


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Laitinen LA et al, J Allergy Clin Immunol 1992J Allergy Clin Immunol 1992

maintenance therapy


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METHYLXANTHINES

Mechanism of action: Anti-inflammatoryeffects & bronchodilator (The proposedmechanism of action was inhibition ofphosphodiesterase, which results in anincrease in cAMP. However, this effect isnegligible at therapeutic concentrations)

Side effects : GIT Symptoms nausea, vomiting

CVS Symptoms tachycardia, arrhythmias Drug interaction : Erythromycin, cimetidine

and rifampicin


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Anti-cholinergics

Inhaled Ipratropium bromide (ATEM,spiriva)

Mechanism of action : Bronchodilator.

Efficacy : Bronchodilator actions are less

potent than those of inhaled 2-agonists,slower onset of action which peaks 30 60 min.

Side-effect : Dry mouth.


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LEUKOTRIENE MODULATORS

MECHANISM OF ACTION : Block the synthesis of all leukotrienes (The

leukotriene receptor antagonists are selective andcompetitive antagonists of the cysteinyl leukotriene(Cys LT1) receptor. Cysteinyl leukotriene (LTC4,LTD4 and LTE4) production and receptor occupationhave been correlated with the pathophysiology ofasthma, including airway edema, smooth muscleconstriction, and altered cellular activity associatedwith the inflammatory process. Zafirlukast is thefirst Cys LT1 receptor antagonist to be released)

Example : montelukast ( Singulair, Montiget,Montair ), Zafirlukast (Accolate)


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Adverse Effects

Headache

Gastritis

Rhinitis

Considerations:*Zafirlukast should be taken one hour before meals or two hours after mealsbecause food can decrease the bioavail-ability.

*Montelukast should be taken in the eveningand may be taken without regard to food.


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Cromolyn Sodium And Nedocromil

Mechanism of Action: Cromolyn andnedocromil are mast-cell stabilizers. Theyprevent the release of the mediators oftype I allergic reactions, including

histamine and slow-reacting substance ofanaphylaxis, from sensitized mast cells.They also inhibit type III reactions to alesser extent. It has been suggested thatthe drugs may block calcium channels in

mast cell membranes. The specificmechanism(s) of action of the drug onmast cells remains to be established


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Cromolyn Sodium And Nedocromil

Use: Cromolyn ornedocromil isrecommended forprophylaxis ofexercise induced

bronchospasm orexposure to a knownallergen. They arealso recommended asanti-inflammatorylong-term control

medications inpatients with mildpersistent asthma.

Adverse Effects:2. Dryness of throat3. Bad Taste4. wheezing

5. nausea

*The therapeutic response may occur within the first two weeks of therapy,but may take up to six weeks to determine the maximum benefit.The primary advantage of these agents is safety.


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R-DNA derived Monoclonal Antibodies

Mechanism: These bind to human IgE selectively,this leads to decrease binding of IgE to the highaffinity IgE receptor on the surface of mast cells andbasophiles

Reduction in surface binding of IgE limits the degree of

release of mediators of the allergic response

Omalizumab useful for treatment of

moderate to severe allergic asthma


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Step 1

Step 1: Intermittent asthma

Controller

None required

Reliever

Inhaled 2-agonist prn(not more than 3x a week)

Inhaled 2-agonist orcromone prior to exerciseor allergen exposure

Avoid or control triggers

If asthma symptoms are intermittent, then reliever therapy

alone is sufficient.

ICS should be prescribedto asthmatic patients

requiring daily B-agonist use


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Step 2

It is often best to initiate an inhaled steroid early and at a high dose to

establish rapid control and then reduce the dose.

Step 2: Mild persistent asthma


Controller

Daily inhaled corticosteroid

(200-500 g), cromone,sustained release theophylline,or anti-leukotriene

Reliever

Inhaled 2-agonist prn

(but less than 3-4 timesper day)

If still not controlled, particularlynocturnal symptoms, increase

inhaled steroid (500-800g) oradd long-acting bronchodilator


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Step 3

A long-acting inhaled 2-agonist is the first choice add on therapy to

inhaled steroids

Step 3: Moderate persistent asthma


Reliever

Inhaled 2-agonist prn

(but less than 3-4 timesper day)

Controller

Daily inhaled corticosteroid

> 500 g Daily long-acting

bronchodilator

Consider anti-leukotriene


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Summary of GINAguidelines 1998

gain control

step up if control is not achieved and sustained

step down if control is sustained for at least 3months

review treatment every 3-6 months

Future?stepping up and down should involve both LAA and ICS


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Conclusion

There is a synergistic effect ontreatment when these agents are combined.

The combination of these agents also

makes the treatment simpler for the patient,

which may improve compliance.

Co-formulated products are generally less

expensive than giving the two constituentsseparately.


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Management of Asthma in Pregnancy.

Management of asthma duringpregnancy should be aggressive.

Cooperation between the resp.physician and obstetrcianthroughout pregnancy for women

with severe asthma.


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Beta2 agonists.

There is no evidence of a teratogenic risk.

Ipratopium bromide / Sodium cromoglycate. Safe for use during pregnancy.

Salmeterol/formoterol.

Have not been tested extensively inpregnant women.


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Theophyllines.

May aggravate the nausea and gastroesophagealreflux.

May cause transient neonatal tachycardia and

irritability.

Inhaled corticosteroids.

Has good safety profile in pregnancy.

Experience with fluticasone in pregnancy is limited.

Anti-leukotrienes.

No data is available on the use of this agent inpregnant women.


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Oral corticosteroids. Sometimes necessary for severe asthma but usually

only for short periods. An increased risk of cleft palate has been reported in

animals given huge doses.

Breastfeeding. Should be continued in women with asthma.

In general, asthma medications are safe duringpregnancy and lactation and the benefits outweighany potential risks to the foetus and baby.


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asthma by zeshan haider r# 16-2nd semester

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