THERAPEUTICS I

RESPIRATORY SYSTEM DISORDERS

ASTHMA

Manhal A. Amber B.Sc. Pharmacy, MSc. Clinical Pharmacy

ASTHMA

Asthma is a chronic inflammatory disorder of the airways. Characterized by intermittent or persistent airflow obstruction due to airway wall inflammation and bronchial smooth muscle constriction. The swelling and narrowing of airway wall Leads to wheezing, SOB, chest tightness and coughing. Many cells and celluar elements play a role, in particular, mast cells, esinophils, T lymphocytes, neutrophils and epithelial cells.

EPIDEMIOLOGY

WHO estimates that 235 million people currently suffer from asthma. At least 22 million American have asthma producing annual cost exceeding 12 billion in the United States and leading to more than 4000 deaths per year. Asthma is the most common chronic disease among children. Most asthma-related deaths occur in low- and lowermiddle income countries.

ETIOLOGY

Childhood-onset asthma is usually associated with atopy, which is the genetic predisposition for the development of immunoglobulin E (IgE)-mediated response to common aeroallergens. Atopy is the strongest predisposing factor in the development of asthma. Adult-onset asthma may also be associated with atopy, but many adults with asthma have a negative family history and negative skin tests to common aeroallergens. Asthma can be triggered by inhaling allergens or triggers (Table 1).

Table 1: List of Agents and Events Triggering Asthma

Hygiene Hypothesis

The hygiene hypothesis proposes that genetically susceptible individuals develop allergies and asthma by allowing the allergic immunologic system (T-helper cell type 2 [TH2]-lymphocytes) to develop instead of the immunologic system used to fight infections (T-helper cell type 1 [TH1]-lymphocytes)

Infants who have older siblings, early exposure to day care, and typical childhood infections are more likely to activate TH1 responses (protective immunity), resulting in an appropriate balance of TH1/TH2 cells and the cytokines that they produce. On the other hand, if the immune response is predominately from TH2 cells (which produce cytokines that mediate allergic inflammation), development of diseases such as asthma is more likely. Examples of factors favoring this imbalance include the common use of antimicrobial agents, urban environment, and Western lifestyle.

PATHOPHYSIOLOGY

After exposure to an asthma-precipitating factor (e.g., aeroallergen), inflammatory mediators are released from bronchial mast cells, macrophages, T lymphocytes, and epithelial cells. These mediators direct the migration and activation of other inflammatory cells, most notably Eosinophils, to the airways.

Eosinophils release biochemicals (e.g., major basic protein and eosinophil cationic protein) that cause airway injury, including epithelial damage, mucus hypersecretion, and increased reactivity of smooth muscle.

Symptoms

Asthmatic patients may suffer from a variety of symptoms non of which is specific for asthma.
Shortness of Breath (SOB) Wheezing Cough esp. at night with or without sputum. Recurrent chest tightness Intercostal retraction

The hallmark of asthma is that these symptoms tend to be: Variable Worse at night and early morning Intermittent Provoked by triggers including exercise

Symptoms of Asthmatic attack

Most asthmatic patients have attacks separated by symptom free periods. Asthma attack can last for minutes to days and may includes:
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Bluish color of the lips and face Decrease level of alertness Extreme difficult breathing Rapid pulse Sever anxiety due to SOB Sweating

CLASSIFICATION AND DIGNOSIS

The diagnosis of asthma is based primarily on a detailed history of intermittent symptoms of wheezing, chest tightness, shortness of breath, and coughing. These episodes may be worse seasonally (e.g., springtime or late summer and early fall) or in association with exercise. Classification of asthma severity is of major importance in defining initial long-term treatment. Based on three age groups, asthma is classified into intermittent, mild persistent, moderate persistent, and severe persistent asthma.

Goal of Therapy
Reduce Impairment

Prevent chronic & troublesome symptoms Maintain near normal pulmonary function Maintain normal activity levels Require infrequent use (2 days a week) of inhaled SABA Provide optimal pharmacotherapy with min or no adverse effects Meet patients & families satisfaction with asthma care

Reduce Risk

Prevent recurrent exacerbations of asthma and minimize the need for ED visits or hospitalizations Prevent progressive loss of lung function Provide optimal pharmacotherapy with minimal or no adverse effects.

Stepwise Approach for Managing Asthma

Asthma Type Intermittent Up to 4 years age SABA PRN 5-11 years SABA PRN 12years and above SABA PRN Steps 1

Low dose ICS Or Montelukast Or Crmolyn

Medium dose ICS
Medium dose ICS + Either Montlukast Or LABA

Low dose ICS or Cromolyn or Nedocromil Or LTRA orTheophylline

Medium dose ICS
Medium dose ICS + LABA OR + LTRA OR + Theophyline

Low dose ICS or Cromolyn or Nedocromil Or LTRA orTheophylline

Medium dose ICS
Medium dose ICS + LABA OR + LTRA OR + Theophyline Or + Zileuton

High dose ICS and Either Montelukast Or LABA

High dose ICS + LABA Or + LTRA Or + Theophylline

High dose ICS + LABA And consider Omalizumab For patient with allergies

High dose ICS + Oral CS And either LABA Or Montelukast

(High dose ICS + Oral CS ) + either LABA, LTRA or Theophylline

High dose ICS + LABA + oral CS And consider Omalizumab For patient with allergies

Long Term Control Medication

Inhaled CS LABA Combination inhalers Leukotriene modifiers Cromolyn Sodium and Nedocromil Sodium Methylxanthines Anti-IgE (Omalizumab) Miscellaneous Therapies Future therapy

ICS

High topical potency to reduce inflammation in the lung and low systemic activity, lower risk of SE. Local adverse effects from ICSs include oropharyngeal candidiasis and dysphonia that are dose-dependent. The response to ICSs is somewhat delayed. Most patients symptoms will improve in the first 1 to 2 weeks of therapy and will reach maximum improvement in 4 to 8 weeks Most patients with moderate disease can be controlled with twice daily dosing of most ICSs. In milder asthma, oncedaily dosing is often sufficient to maintain control. Beclomethasone dipropionate,budesonide, flunisolide, fluticasone propionate, mometasone furoate

Long-Acting Inhaled 2-Agonists

The two LABAs, formoterol and salmeterol, provide long-lasting bronchodilation (12 or more hours) when administered as aerosols. The principal differences between formoterol and salmeterol are that formoterol has a more rapid onset of action (similar to that of albuterol) and formoterol is a full agonist. Both cant be used for quick relief, patients need to continue using their short-acting inhaled 2-agonist for acute exacerbations while receiving the LABAs. Responsiveness to short-acting 2-agonists is reported to be slightly decreased but easily overcome by increasing the dose (by approximately 1 puff) following chronic therapy with LABAs

LABAs are the preferred adjunctive therapy to ICSs. Because they are devoidof antiinflammatory activity, LABAs should not be used as monotherapy for asthma

Combinations

Importantly, the addition of a LABA allows reduction in ICS dosage by 50% in most patients with persistent asthma Combination therapy is more effective than higherdose ICS alone in reducing asthma exacerbations Single inhaler combination products containing fluticasone propionate and salmeterol or budesonide and formoterol The inhalers, both DPIs and MDIs, contain varied doses of the ICSs and a fixed dose of the respective LABAs.

Methylxanthine Drugs

Methylxanthines have been used for asthma therapy for more than 50 years but their use in recent years has declined markedly owing to the high risk of severe life-threatening toxicity and numerous drug interactions, as well as decreased efficacy when compared with ICSs and LABAs.

Theophylline, the primary methylxanthine of interest, is a moderately potent bronchodilator with mild antiinflammatory properties through nonselective phosphodiesterase inhibition.
Clinical usefulness is limited by their low therapeutic index, have potential adverse effects: insomnia, gastric upset and dose related acute toxicities; tachycardia, nausea, vomiting and tachyarrhythmias.

Cromolyn Sodium and Nedocromil Sodium

They are classified as mast cell stabilizers, and the principal difference appears to be potency, with 4 mg nedocromil by MDI equivalent to 10 mg cromolyn. However, there is no apparent difference in the clinical efficacy They inhibit the early and late asthmatic response to allergen challenge, as well inhibit EIB. Cromolyn and nedocromil are only effective by inhalation and are available as MDIs, whereas cromolyn also is available as a nebulizer solution Cough and wheeze have been reported following inhalation of each, and bad taste and headache following nedocromil are reported

Leukotriene Modifiers

Leukotrienes: potent biochemical mediators released from mast cells, eosinophils & basophils activate inflammation. Two clinically distinct cysteinyl leukotriene receptor antagonists (zafirlukast and montelukast) and one 5lipoxygenase inhibitor (zileuton) are available. they reduce allergen-, exercise-, cold air hyperventilation, irritant, and aspirin-induced asthma in children and adult. Clinical use of zileuton is limited because of the potential for elevated liver enzymes zafirlukast and montelukast administered once or twice a day, and contribute to patient adherence and satisfaction. Montelukast has been prescribed widely worldwide owin to its approval for use in young children

Anti-IgE (Omalizumab)

Omalizumab is a recombinant anti-IgE antibody approved for patients older than 12 years of age who have allergic asthma not well controlled by oral corticosteroids or ICSs Omalizumab is administered subcutaneously every 2-4 weeks and has a slow absorption rate Because of its significant cost, it is only indicated in the last steps of asthma management.

Bronchial Thermoplasty

It is reserved for patients whose asthma is severe and refractory, as it involves three sessions of bronchoscopy, each lasting up to 1 hour, during which the smooth muscle layer is methodically ablated from the airway using radiofrequency energy. FDA has approved bronchial thermoplasty, and although it does not cure asthma or completely eliminate its symptoms, it provide long-lasting asthma control and improving asthma-related quality of life. It is not widely available and valid for adults patients only.

Future Therapies

Mooclonal antibodies against cytokines IL-4, 1L-5 and IL-3. Protease inhibitors Cell adhesion antagonists Immunomodulators aiming to shift TH2 to TH1.

Managing Sever Acute Asthma (SA)

Status Asthmaticus is an acute severe attack of asthma that doesnt respond to the usually used inhaled bronchodilators and is associated with signs of respiratory failure (increased heart rate, decreased breath sounds, agitation from worsening hypoxia, or lethargy from increased CO2 retention). SA is life threatening and require immediate medical attention.
The principal goals of treatment include: Correction of significant hypoxemia (Oxygen therapy) Rapid reversal of airflow obstruction (Inhaled B2 Agonist) Reduction of the likelihood of relapse of the exacerbation or future recurrence of severe airflow obstruction (Systemic CS) Development of a written asthma action plan in case of a further exacerbation.

Management of SA

Providing adequate oxygen supplementation to maintain oxygen (O2) saturations above 90%. Inhaled selective short-acting B2-agonist every 60 min (albuterol) by MDI or Nebulizer. Systemic corticosteroid (prednison or methyl prednisolone 1-2 mg/kg/day. Add inhaled anti-cholinergic to ASBA, Ipratropium bromide 0.5 mg through nebulizer. Systemic B agonist (injection of epinephrine or terbutaline). Nebulized isotonic magnesium sulfate IV aminophylline (Bolus aminophylline should not be given to patients already taking oral theophylline).

Mechanical ventilation if needed.

Quick relief Medications (Rescue)

Used as needed for rapid short-term symptom relief during an asthma attach, on need or before exercise. The medications include: Short acting beta agonists (SABA) Anticholinergics Systemic Corticosteroids (oral and intravenous) Magnesium sulphate (Clinical controversy) why? Methylxanthine drugs (Clinical controversy) why?

Short-Acting 2-Agonists

The most effective bronchodilators available Equal to greater efficacy and greater safety of aerosolized 2-agonists over systemic administration Systemic adverse effects, hypokalemia, hyperglycemia, tachycardia, and cardiac dysrhythmias are more pronounced via systemic route. Follow log-linear dose response curve. Act within minutes and the effects last for several hours, ex: albuterol, levalbuterol and pirbuterol. Salmeterol and formoterol have long duration of action due to high lipid solubility.

Systemic Corticosteroids

The most effective anti-inflammatories available to treat asthma through increasing the number of 2-adrenergic receptors, reducing mucus production and hypersecretion, reducing BHR, and reducing airway edema and exudation Recommended for all patients with acute severe asthma not responding completely to initial inhaled 2-agonist. Intravenous therapy offers no therapeutic advantage over oral administration Long term use can produce serious toxicities, preferred to use on short term basis and using shorter-acting corticosteroids, such as prednisone, produces less adrenal suppression than the longer-acting dexamethasone Example: prednison, prednisolone and methylprednisolone.

Anti-cholinergics

Have a long history of use for asthma, but they do not have an FDA-approved indication for asthma It block the contraction of airway smooth muscle and mucous secretion in response to vagal activity. Only the quaternary ammonium derivatives such as ipratropium bromide should be used because they have the advantage of poor absorption across mucosae and the bloodbrain barrier, produces minimal or no systemic effects. Ipratropium bromide has a duration of action of 4 to 8 hours. Both intensity and duratio of action are dosedependent. Inhaled ipratropium bromide produces a further improvement in lung function of 10% to 15% over inhaled 2-agonists alone