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Asthma by Zeshan Haider R# 16-2nd Semester

Asthma by Zeshan Haider R# 16-2nd Semester

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Published by: Zeshan Haider Kazmi on Mar 08, 2009
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epidemiology / pathology

 

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%)

Asthma definition

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

 

GINA Guidelines 1998

Comparisons of asthma
Pathophysiology: chronic inflammation Clinical history: symptoms Asthma
  

CD 4+ lymphocytes Eosinophils Mast cells

Vary over time and in severity
   

cough wheeze chest tightness breathlessness

Modern view of asthma
Macrophage/ dendritic cell Th2 cell

Allergen Mast cell Neutrophil Eosinophil

Mucus plug

Nerve activation

Epithelial shedding

Plasma leak Oedema

Subepithelial fibrosis Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy / hyperplasia

Mucus hypersecretion Hyperplasia

Vasodilatation New vessels

Barnes PJ

Inflammatory processes

Barnes PJ

Epidemiology / pathology

Asthma - an inflammatory disease Normal


Risk factors that lead to asthma development
Predisposing Factors
 atopy

Contributing Factors
 respiratory

Causal Factors
 indoor
– – – –


infections  small size at birth  diet  air pollution
– –

dust mites animal dander cockroach fungi

outdoor indoor passive active

 smoking
– –

 outdoor
– –

allergens sensitisers

pollens fungi

 occupational
GINA Guidelines 1998

Common occupational agents

flour / grain dust (bakery) paint, glue or plastic fumes soldering flux natural rubber latex wood dust

Asthma diagnosis
  

history and pattern of symptoms physical examination measurements of lung function - reversibility test - diurnal variability

evaluation of allergic status

Is it asthma?

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

Ask about triggers
Symptoms can occur or worsen in the presence of: Others Allergens  exercise  animal dander  viral infection  dust mites  smoke  pollen  changes in temperature


  

strong emotional expression aerosol chemicals drugs (NSAIDs, ß-blockers)

‘Clinical’ classification of severity
Clinical features before treatment
Night-time symptoms PEF

Severe persistent

Continuous Limited physical activity Daily Use β2-agonist daily Attacks affect activity >1 time a week but <1 time a day <1 time a week Asymptomatic and normal PEF between attacks


<60% predicted Variability >30% >60% - <80% predicted Variability >30%

Moderate persistent

>1 time a week

Mild persistent

>2 times a month

>80% predicted Variability 20-30%


<2 times a month

>80% predicted Variability <20%

Asthma severity is graded, in the GINA guidelines, according to the frequency of symptoms, occurrence of symptoms at night, and PEF measurement before treatment.

Treatment goal: take control of asthma
      

no chronic symptoms no asthma attacks no emergency visits no need for quick relief (as needed) ß2-agonist normal physical activity including exercise lung function as close to normal as possible no adverse effects from medicine

GINA Guidelines 1998

Treatment strategy

identify and avoid triggers that make asthma worse achieve control by selecting appropriate medication treat asthma attacks promptly and effectively educate patients to manage their condition monitor and modify asthma care to maintain effective long-term control

 

GINA Guidelines 1998

Pharmacological therapy
 inhaled  inhaled

inhaled corticosteroids  inhaled long-acting ß 2 agonists  inhaled cromones  oral anti-leukotrienes  oral theophyllines  oral corticosteroids

fast-acting ß2-agonists anticholinergics

 Quick

relief medicine or rescue medicine. acting bronchodilators that act to relieve bronchoconstriction.

 Rapid


    

Pressurized metered dose inhalers ( MDI) MDI-plus-spacer Breath actuated MDI Dry powder inhalers Nebulised


Classes of ß2-agonists
Speed of onset

fast onset, long duration


inhaled terbutaline inhaled salbutamol

inhaled formoterol


oral terbutaline oral salbutamol oral formoterol

inhaled salmeterol oral bambuterol

Duration of action



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

Short-acting inhaled B-agonist

Use intermittently to control episodes of bronchoconstriction Avoid regular scheduled use if possible An increase use is an indication of deteriorating control


Mechanism of action:  Bronchodilator (They stimulate intracellular adenyl

cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells)
Enhance mucociliary clearance Modulate mediators release from mast cells and basophils

 

Example : Inhaled : Salmeterol (Seretide), formeterol Oral : Bambuterol Salbutamol (Ventolin) Terbutaline (Bricanyl) Clenbuterol


Inhaled β2 Agonists have fewer side effects than oral formulations. Side-effects : tachycardia, palpitations, tremors, anxiety, headache and hypokalaemia.

Differences between ß2-agonists
chemical structure pharmacological properties:
   

 

mode of action in the ß2-receptor region potency efficacy (ie full / partial agonism) selectivity


 

Are medications taken daily on a long term basis that are useful in getting and keeping persistent asthma under control. Prophylactic, preventive or maintenance medications Include
     

Inhaled glucocorticosteroids Systemic glucocorticosteroids Theophylline Long acting inhaled β2 agonist Long acting oral β2 agonist Leukotriene modifiers


Mechanisms of action :  Reduced airway inflammation (They are anti-

inflammatory agents which inhibit the production of cytokines, an effect which reduces eosinophil infiltration, inhibits macrophage and eosinophil function, decreases mediator cells in the epithelium, reduces vascular

permeability, and reduces the production of leukotrienes)

Efficacy in improving lung function, decreasing airways hyperresponsiveness, reducing symptoms, reducing frequency and severity of exacerbations and improving quality of life.


Inhaled : Beclomethasone (Becotide, Clenil A) Budesonide Fluticasone Oral : Prednisolone Dexamethasone

Parenteral : Hydrocortisone Methylprednisolone

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 the gut, first past effect of liver.  Systemic adverse effects include : skin thinning, easy bruising, cataract, obesity, adrenal suppression, hypertension, diabetes and myopathy.

Inhaled steroids are first line maintenance therapy

Laitinen LA et al, J Allergy Clin Immunol 1992

Mechanism of action: Anti-inflammatory effects & bronchodilator (The proposed mechanism of action was inhibition of phosphodiesterase, which results in an increase in cAMP. However, this effect is negligible at therapeutic concentrations) Side effects :
  

GIT Symptoms – nausea, vomiting CVS Symptoms – tachycardia, arrhythmias Drug interaction : Erythromycin, cimetidine and rifampicin


Inhaled Ipratropium bromide (ATEM, spiriva) Mechanism of action : Bronchodilator. Efficacy : Bronchodilator actions are less potent than those of inhaled ß2-agonists, slower onset of action which peaks 30 – 60 min. Side-effect : Dry mouth.



Block the synthesis of all leukotrienes (The leukotriene receptor antagonists are selective and competitive antagonists of the cysteinyl leukotriene (Cys LT1) receptor. Cysteinyl leukotriene (LTC4, LTD4 and LTE4) production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process. Zafirlukast is the first Cys LT1 receptor antagonist to be released)

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

Adverse Effects
  

Headache Gastritis Rhinitis

Considerations: *Zafirlukast should be taken one hour before meals or two hours after meals because food can decrease the bioavail-ability. *Montelukast should be taken in the evening and may be taken without regard to food.

Cromolyn Sodium And Nedocromil

Mechanism of Action: Cromolyn and nedocromil are mast-cell stabilizers. They prevent the release of the mediators of type I allergic reactions, including histamine and slow-reacting substance of anaphylaxis, from sensitized mast cells. They also inhibit type III reactions to a lesser extent. It has been suggested that the drugs may block calcium channels in mast cell membranes. The specific mechanism(s) of action of the drug on mast cells remains to be established

Cromolyn Sodium And Nedocromil

Use: Cromolyn or nedocromil is recommended for prophylaxis of exercise induced bronchospasm or exposure to a known allergen. They are also recommended as anti-inflammatory long-term control medications in patients with mild persistent asthma.

 2. 3. 4. 5.

Adverse Effects: Dryness of throat Bad Taste wheezing 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.

R-DNA derived Monoclonal Antibodies

Mechanism: These bind to human IgE selectively, this leads to decrease binding of IgE to the high affinity IgE receptor on the surface of mast cells and basophiles release of mediators of the allergic response

Reduction in surface binding of IgE limits the degree of

Omalizumab useful for treatment of moderate to severe allergic asthma

CONTROLLER: daily multiple medications • Inhaled steroid • Long-acting bronchodilator • Oral steroid

RELIEVER • Inhaled ß2agonist p.r.n.

Step down when controlle d

Avoid or control triggers STEP 3: MODERATE PERSISTENT
CONTROLLER: daily medications • Inhaled steroid and long-acting bronchodilator • Consider anti-leukotriene

RELIEVER • Inhaled ß2agonist p.r.n.

Avoid or control triggers STEP 2: MILD PERSISTENT
CONTROLLER: daily medications • Inhaled steroid • Or possibly cromone, oral theophylline or anti-leukotriene

RELIEVER • Inhaled ß2agonist p.r.n.

• Patient education essential at every step • Reduce therapy if controlled for at least 3 months • Continue monitoring

Avoid or control triggers STEP 1: INTERMITTENT CONTROLLER: none RELIEVER • Inhaled ß2agonist p.r.n. Step up if not controlled (after check on inhaler technique and compliance)

Avoid or control triggers TREATMENT GINA Guidelines 1998

Step 1
Step 1: Intermittent asthma

Inhaled β 2-agonist prn (not more than 3x a week) Inhaled β 2-agonist or cromone prior to exercise or allergen exposure

None required

Avoid or control triggers

ICS should be prescribed to asthmatic patients requiring daily B-agonist use

If asthma symptoms are intermittent, then reliever therapy alone is sufficient.

Step 2
Step 2: Mild persistent asthma
Daily inhaled corticosteroid (200-500 µg), cromone, sustained release theophylline, or anti-leukotriene
 


Inhaled β2-agonist prn (but less than 3-4 times per day)

If still not controlled, particularly nocturnal symptoms, increase inhaled steroid (500-800 µg) or add long-acting bronchodilator

Avoid or control triggers
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 3
Step 3: Moderate persistent asthma
Daily inhaled corticosteroid > 500 µg  Daily long-acting bronchodilator  Consider anti-leukotriene


Inhaled β2-agonist prn (but less than 3-4 times per day)

Avoid or control triggers

A long-acting inhaled β2-agonist is the first choice add on therapy to inhaled steroids

Step 4
Step 4: Severe persistent asthma
Daily inhaled corticosteroid 800-2000 µg  Daily long-acting bronchodilator  Daily / alternate day oral corticosteroid


Inhaled β2-agonist prn (but less than 3-4 times per day)

Avoid or control triggers

Patients with severe persistent asthma are often poorly controlled despite using combinations of all available controller medications.

Summary of GINA guidelines 1998
  

gain control step up if control is not achieved and sustained step down if control is sustained for at least 3 months review treatment every 3-6 months

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


There is a synergistic effect on treatment 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 constituents separately.

Management of Asthma in Pregnancy.

Management of asthma during pregnancy should be aggressive. Cooperation between the resp. physician and obstetrcian throughout pregnancy for women with severe asthma.

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 in pregnant women.

Theophyllines.  May aggravate the nausea and gastroesophageal reflux.  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 in pregnant women.

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 during pregnancy and lactation and the benefits outweigh any potential risks to the foetus and baby.

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