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Asthma

Asthma is a chronic inflammatory obstructive lung disease characterized by:

1. Airway obstruction that is reversible either spontaneously orwith treatment

2. Airway inflammation.3. Increased airway responsiveness to a variety of stimuli.

Stimulus could be: physical, chemical, immunological, pharmacological or

pathological (ex: Allergens, viral infection, cold air, dry air, smoke,

pollutants, methacholine).

Asthma has two phases: Early Phase

Late phase

Early phase: immediate and spontaneous bronchoconstriction after inhaling

a specific allergen. This phase improves over an hour is reversed easily by

inhalation of bronchodilators.

Late phase: occurs 4-12 hours later, more severe and prolonged, difficult to

reverse with bronchodilators. Inflammation is a key factor here.

Why are we interested in these phases?

Knowing these phases helps determine what drug we need, for example:

Cromolyn blocks both phases. Bronchodilators (B2-agonists) blocks early phase. Corticosteroids blocks late phase.Symptoms:

Classical:

Expiratory wheezing, dyspnea and coughing.

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Others:

Chest pain (due to the abnormal utilization of accessory muscles of

respiration).

Atelectasis (collapse of pulmonary alveoli or of a segment of the lung).

Classification:

Asthma could be mild, moderate or severe according to the frequency of

symptoms.

Treatment

Goals of therapy:

1. Maintain normal activity levels including exercise.

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2. Maintain near normal pulmonary function rates.3. Prevent chronic and troublesome symptoms (nocturnal symptoms,

exacerbation on exercise).

4. Prevent recurrent exacerbation of asthma.5. Avoid adverse effect from asthma medications.

How can we achieve such goals?

By a complex procedure including patient education, environmental control,

comprehensive pharmacologic therapy, and objective monitoring measures.

Remember: the most common cause of death from asthma is under

treatment.

Non- Pharmacological

Patients education towards their disease (What happens when they getthe attack?) their medication (How to use it properly? Which is used on

exacerbation and which is used on daily bases for chronic management).

How to recognize early signs of deterioration, how to recognize triggers

for asthmatic attacks.

In allergic asthma environmental control is an essential part of therapy,patient should identify the exacerbating factor & try to avoid it. Smoking,

pets, house mist & dust all can exacerbate the case.

New studies reveal the role of diet in asthma: Shellfish & peanuts wereamong the drugs that exacerbate asthma, but further studies are needed to

justify the role they play.

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Antioxidants & magnesium supplements decreased the severity ofasthmatic attacks but why? We are to do further studies!

Pharmacological therapy

2- agonists

Of the four classes of bornchodilators, 2 adrenergic receptor agonists

produce the greatest bronchodilation in patients with bronchial asthma.

Thus, these agents are used for relief of acute symptoms, and for the

prevention of exercise- induced bronchospasm.

They are classified into:

1. Short-acting (3-6 hours) 2 adrenergic receptor agonists2. Long-acting (>12hours) 2-agonists.

Routes of administration:

-Orally inhalation subcutaneously-Intravenous administration.

Inhalation: either as 1. Nebulizers

2. Metered dose inhalers MDI.

This route is preferred in treating acute asthmatic attack, as it is aseffective as parenteral administration with fewer side effects.

Regardless, even when the method is optimalized only 12% of the dose isdelivered from a metered dose inhaler to the lung, while the remainder

deposits in the mouth, pharynx, and larynx.

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When a nebulizer is used, a dose 6-10 times that used for MDI is requiredto produce the same degree of Bronchodilation.

The use of MDI with a spacer device is as effective as nebulizers if doneunder good supervision both in adults and children. [Cost effectiveness].

Psychologically: some doctors like to start with a nebulized 2-agonist asa first dose this relieves the patient as they think.

Mechanism of action:

Direct: by causing bronchodilation due to binding 2-receptors inbronchi.

Indirect: by enhancing mucocilliary clearance and vascular integrity,inhibiting cholinergic neurotransmitters mediators release from mast

cells and basophiles.

Long-term use inhibits the action of alveolar macrophages andeosinophils.

Combination therapy:

Giving nebulized ipratropium [anti-cholinergic] agent does add tothe benefit of 2 agonists.

Theophylline has more risks for serious side effects, so wedont co-administer theophylline and 2-agonists.

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Studies revealed that cardiac arrhythmias myocardialnecrosis, and death increased when the two drugs were

given together. But analysis of data revealed this was only

true with patients having pre-existing arrhythmias, unstable

angina or acute asthma.

Which 2-agonist to use?

For acute asthmatic attacks we prefer the intermediate duration ofaction agents. (albuterol)

Dose:Frequent low doses 0.05mg/kg up to 1.7 every 20minutes are superior

to the standard albuterol dose of 0.15mg/kg to 5mg at 1 hour intervals.

For chronic maintenance therapy salmeterol is preferred for its longduration of action (12hr) it is supplied as a MDI at 25g/puff where 1-

2 puffs are inhaled every 12hr.

o Not used in pregnant or children

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It wasnt long before theophylline lost its role in therapy due to thedevelopment of other bronchodilators that were of a wider therapeutic

index and lower incidence of side effects (ex. 2-adrenergic agonist).

But still, theophylline is recommended as primary therapy in caseswhere the use of an inhaled corticosteroid is difficult (toddlers &

preschool children).

Primary therapy when patient adheres to oral therapy much better thanto inhaled one, additive therapy in patients whose asthma is not well

controlled with conventional doses of inhaled corticosteroids.

Initiating theophylline:

Bronchodilation occurs in a linear fashion with logarithmicincreases in serum concentration.

The safest therapeutic range for theophylline is 5-15 mcg/ml, asit is associated with little side effect and toxicity and with the

same efficacy as the 10-20 mcg/ml range.

Close monitoring of theophylline serum levels is important dueto the interpersonal variation in pharmacokinetics. Clinical

signs and symptoms of toxicity should also be monitored

carefully. (Headache, tacchycardia, and vomiting).

Loading dose:

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This could be given I.V over 20-30 minutes to avoid severe cardiac

arrhythmias or orally as a rapid release formula.

LD= (Cp _ Cpo) (Vd) (weight).

Vd= 0.5 L/kg.

Cp= desired conc. (5-15 g/ml).

Cpo= measured serum concentration.

Weight = of patient in (Kg) if patient is obese use ideal body weight.

Maintenance dose:

Theophylline is cleared primarily by the hepatic metabolism. Metabolized by cytochrome P450 3A3, 1A2. This clearance is affected by age (lower in elderly), concurrent disease

(hepatic cirrhosis, fever, congestive heart disease); concurrent drug

therapy (erythromycin), smoking, diet.

Smoking increases clearance and decreases half-life.

MD= (Cpss)(C1) if IV theophylline is to be given.

aminophylline = 80% of theophylline, and is the preferred injectableproduct owing to increase solubility.

Total dose per day = Infusion rate (mg/hr) * (24hr) * (0.8)

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The total daily dose is to be divided into several doses. As long as thepatient can swallow, there is no need for I.V. theophylline as oral doses

are more convenient and less costly.

To improve compliance use sustained release formulas twice daily.

When switching from infusion to oral doses start the first SR dose assoon as you stop the infusion.

Monitoring Therapy:

Serum theophylline concentration should be checked at least onceeach year.

While in children checking should occur each 6 months specially asthey grow since clearance changes constantly.

More frequent monitoring is required if the patient is initiated on adrug that alters theophyllines clearance or if a disease that influences

clearance occurs or if theophylline toxicity symptoms are observed.

Drugs that can decrease theophylline clearance for example:o Cimetidine, macrolides, allopurinol, ciprofloxacin, interferones,

ticlopidine.

Drugs that can increase theophylline clearance for example:o Rifampin, carbamezapine, phenytion, smoking.

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Mechanism of action:Inhibit phosphodiesterase and induce epinephrine release form adrenal

medulla.

Dosing: For adults

1. Initiate dose at 10mg/kg/day or 300mg/day maximum.2. Increase at 3-day intervals if tolerated to 400mg/day maximum.3. Check serum levels:

a. 4-6 hours after morning dose of 12hour sustained releaseformulation

b. 8 hours after 24hour sustained release formulation.4. Further dosage adjustment based on patient symptoms and serum

concentration

Adverse Effects:

Nausea and vomiting are the most common adverse effects observed,usually when blood levels exceed 20mcg/ml.

Seizures occur when levels exceed 40mcg/ml, with restlessness,agitation, and cardiac symptoms (arrhythmia, hypotension, cardiac

arrest).

Corticosteroids

As inflammation is present even in patients with mild asthma, inhaledcorticosteroids should be added to therapy in an early stage.

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Long-term daily-inhaled corticosteroid therapy is recommended in themanagement of chronic asthma.

Inhaled corticosteroids are preferred over oral ones, as they dont causesystemic side effects, for their either poorly absorbed or when absorbed

they are rapidly inactivated.

Doses:

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Adverse Effects:

Local: Dysphonia (this may be disabling in singers).Candidiasis: use large volume spacers. To avoid oropharyngial candidiasis.

Systemic: Reduces bone mass directly by inhibiting bone formation andindirectly by inhibiting the secretion of androgen, and by decreasing

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calcium absorption and reabsorption. Cataracts upon long-term use.

Increase susceptibility to infections.

Cromolyn Sodium

Though cromolyn sodium had been the drug of choice for maintenancetherapy of asthma, especially in children. It is no more recommended in

therapy as corticosteroids are gaining popularity.

Mechanism of action:Stabilizes mast cells and prevent mediator release. But one should bear in

mind that cromolyn sodium doesnt cause bronchodilation nor does it inhibit

action of the already released chemical mediators, so it only prevent the late-

phase reactions from happening but doesnt relief the acute attacks.

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Dosing:20mg capsules that are used for inhalation by utilizing spinhaler

device.

0.8 mg/ inhalation using MDI.

1% solution for nebulization.

Dont use spinhalers in children since they require highinspiratory flow rate.

Neblization solution is compatible with all existing 2-agonists. Since cromolyn sodium is used for prophylaxis compliance on

continuous therapy should be emphasized to patients and their

parents.

Adverse Effects:

The least toxic of all present therapies. Adverse effect include cough, wheezing, dryness of throat, laryngeal

edema, swollen parotid gland, joint swelling and pair, angioedma,

urticaria, nasal congestion, nausea, headache.

Leukotriene modifiers:

Leukotrienes are produced during asthmatic reactions by cellsinvolved in the pathogenesis of asthma. They usually stimulate airway

obstruction by a non-histaminergic mechanism.

So leukotrienes modifiers are the 1st new drugs for the treatment ofasthma to be introduced in more than 20 years.

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It was found that in patients with mild to moderate asthma, thoseagent improved lung functions, decreased the need for -adrenergic

agonists, and result in fewer symptoms of asthma especially at night.

Since they are given orally they would be associated with bettercompliance than the inhaled glucocoticoids, so they might gain higher

popularity as 1st

choice therapy in mild to moderate cases.

In patients with severe asthma leukotriene modifiers are not preferredas monotherapy, but can be combined with inhaled glucocorticoids.

Examples on leukotriene modifiers:o Montelukasto Pranlukasto Zafilukasto Zileuton

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Anti-IgE (Omalizumab):

Recombinant anti-IgE antibody approved for the treatment of allergicasthma not well controlled by oral corticosteroids

Omalizumab is administered subcutaneously Rate of anaphylaxis is 0.1%, should be administered under medical

supervision with drugs for treating anaphylaxis available and patients

should remain in physicins office for adequate time because70% of

reactions occur within 2 hours.

Counsel patients about signs and symptoms of anaphylaxis becausesome reactions have occurred up to 24 hours following an injection.

Regimens:

Acute Asthma:

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Chronic Asthma:

According to severity:

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Seasonal Asthma

o In this case antihistamines are added to the 2-agonists, as seasonalasthma is almost always allergic and so antihistamines improve nasal

symptoms.

o Patients should be notified about the sedative effect of those agentsespecially if he is to operate machinary or drive.

o Desensitization could be useful allergen is known.

Exercise Induced Asthma EIA:

o During sustained exercise asthmatic patients will experience an initialimprovement in pulmonary functions followed by a significant

decline.

o As breathing heated, humidified air completely blocks EIA, the causeof this type of asthma is thought to be respiratory heat loss or water

loss or both. So masks are indicated for patients with EIA in winter, as

well as advising patients on engaging in mild sports that will not

promote EIA.

o Pretreatment with a 2-agonist few minutes before exercise is useful inpreventing EIA, and if those agents can not be used then cromolyn

can be used and is preferred over theophylline, due to its rapid onset,

convenience and low side effects.

Nocturnal Asthma:

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o The use of inhaled corticosteroids is effective in eliminating nocturnalasthma.

o A long-acting inhaled 2-agonist such as salmeterol or formoterol isindicated if nocturnal symptoms persist.

o Good control of rhinitis should also be considered.

o Oral 2-agonist should not be used, as they are accompanied withmore side effects especially interference with sleep, and they are less

efficacious

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Patients Education

o Asthmatic patients require special efforts in education. It is important toknow that the first step in educating asthmatics is to be good listeners,

caring, and establish a partnership with the patient by:

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1. First asking the following question: What is bothering you the mostabout your asthma?

2. Many patients under use long-term preventive therapy because nohealth professional took the time to adequately instruct them that

asthma is preventable. While under-using the most important

medicines for long-term control, many patient overuse quick

relievers (e.g. Short-acting inhaled agonists).

3. Difficulty using dose inhaler, teaching patients the correct use ofMDIs and MDIs plus spacers is absolutely essential. In one study,

89% of patient could not perform all steps correctly. Competent

teaching requires observation of the patient using the devices

initially and again on repeat visits to the clinic, hospital, or

community pharmacy.

Spacers:

o Spacers should be used in virtually all patients receiving inhaledcorticosteroids,

o Even those with perfect technique because spacers enhance efficacy andgreatly reduce the risk of oropharyngeal candidiasis.

o On the other hand, spacers do not add efficacy to correct use of a betaagonist MDI.

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o Some asthma experts prefer large volume over small volume spacers,especially with inhaled corticosteroids. The clinical significance of

differences in spacer volume is yet to be clearly demonstrated.

o The clinician should practice with a placebo inhaler and gain competencebefore teaching a patient. Among clinicians who educate asthmatics,

pharmacists have been shown to be very helpful in teaching correct use

of MDIs.

o Clinicians can help patients via education regarding correct use of breathactivity dry powder inhalers, (eg. Rotahaler) breath-activated MDIs

(eg.Autohaer), and nebulizing machines.

o When using the rotahaler, patients must clearly understand the need for aquick, rapid inhalation (not slow as with an MDI).

o First approach is that using a rapid onset bronchodilator like a betaagonist first.

o Then an anti-inflammatory second has some appeal quick relief, betaagonists generally are preferred for as needed use (and before

exercise), and are not usually preferred as scheduled agents.

o When two inhaled bronchodilators are used (a beta agonist andipratropium) the technically correct answer related to sequencing is to

inhale the ipratropium first and the beta agoinst one hour later, which

will give a greater improvement.