Pharmacology of the Respiratory Tract

What is bronchial asthma? It is chronic inflammatory disorder of airways In susceptible individuals, this inflammation causes recurrent episodes of: 1.Wheezing 2.Breathlessness 3.Chest tightness 4.Cough

 These episodes are associated with wide spread airflow obstruction that is often reversible Airflow obstruction in asthma is due to bronchoconstriction resulting from: 1.contraction of bronchial smooth muscle 2.Inflammation of the bronchial wall 3. mucus secretion

 The inflammatory changes in the airways associated with bronchial hyperresponsiveness (abnormal sensitivity to stimuli).

Comparison of bronchi of normal & asthmatic

individuals

Comparison of bronchi of normal & asthmatic individuals

Stimuli that cause asthmatic attack:

Allergens: e.g. animal dander, pollen Exercise Cold air Respiratory tract infection Environment Tobacco smoke Drug induced: NSAIDs especially Aspirin, -blockers

Classification of asthma
Stage Symptoms Long-term control Quick relief of symptoms Short acting 2 agonists.

Mild intermittent

2 /week

No medication

Mild persistent

>2 /week but not daily

dose of ICS

Short acting 2 agonists.

Classification of asthma
Stage Symptoms Long-term control Quick relief of symptoms

Moderate persistent

Daily to medium Short acting symptoms dose of ICS& 2 agonists.

long acting 2 agonists.
dose of ICS & oral CS& long acting 2 agonists

Severe persistent

Cont. symptoms Throughout the day

Short acting 2 agonists.

THE GOALS OF ASTHMA MANAGEMENT

Achieve and maintain control of symptoms Prevent asthma exacerbations Maintain pulmonary function as close to normal as possible Avoid adverse effects from asthma medications Prevent development of irreversible airflow limitation Prevent asthma mortality

 Approaches to treatment Determine precipitating factors & avoid them if possible Bronchodilator to reverse the bronchospasm Anti-inflammatory agents to inhibit or prevent the inflammatory components & the hyperactivity of the bronchi

A. Bronchodilators:
They are 1st line drug & include: 1.2-receptor agonists (1st choice of bronchodilators) 2.Methylxanthines 3.Muscarinic receptor antagonists

1.Selective 2-agonists:
These drugs are usually given by inhalation (preferable) of aerosol, powder, or nebulized solution or may be given orally or by injection (for emergency) 2 categories of 2 adrenoceptor agonists: Short Acting Agents: Salbutamol, Terbutaline. They are usually used on "as needed" basis to control symptoms of acute attack

Long Acting Agents: Salmeterol, Formeterol They are not used "as needed" but are given regularly twice daily as prophylaxis (prevent bronchospasm at night or with exercise) S/Es: The unwanted effects of 2-adrenoceptor agonists result from systemic absorption 1.Tachycardia 2.Tremor 3.Hyperglycemia

Salbutamol oral side effects :taste changes, teeth discoloration Salmeterol oral side effects: Dental pain, throat dryness

2. Methylxanthines: These are 3 pharmacologically active naturally occurring substances: Theophylline, Caffeine & Theobromine.
The one which employed in clinical medicine is Theophylline & Aminophylline (Theophylline salt) Theophylline is given orally in sustained-release preparation; Aminophylline can be given I.V. infusion (slowly) to treat status asthmaticus.

Has narrow therapeutic index (10-20mg/mL) so: 1. 2. Dont combine oral & I.V. Before giving I.V. Theophylline, always ask if the patient is already taking Theophylline orally Monitor for signs of toxicity: vomiting, headache, tachycardia Obtain Theophylline serum concentration Clinical uses of theophylline: as second line drug, in addition to steroids, in patients whose asthma does not respond to 2 agonists. Intravenously in acute sever asthma.

 S/Es: 1.CNS excitation, tremor, nervousness 2.Tachycardia. 3.Nausea & vomiting.

D/D interaction: possible theophylline toxicity ( metabolism) if used with erythromycin,ciprofloxacin,clarithromycin.

3.Muscarinic Antagonists:
The main compound used specifically as antiasthmatic is Ipratropium It is quaternary derivative given by aerosol, it is not well absorbed thus the possibility of systemic S/E is minimal
S/Es: 1.Cough 2.Dryness of mouth

Clinical uses: 1.As bronchodilator in some patients with bronchospasm precipitated by 2-receptor antagonists 2.As an adjunct to 2-agonists & steroids

B. Anti-inflammatory agents: 1.Glucocorticoids (corticosteroids) Inhaled corticosteroids like: a. Beclomethasone b. Budesonide c. Fluticasone Oral like: Methylprednisolone.

Indication for inhaled glucocorticoids: For asthmatic patients who are inadequate controlled with other regimes Indication for systemic glucocorticoids:
1.For chronic asthma & severe rapidly deteriorating asthma, a short course of oral glucocorticoids is indicated, combined with inhaled steroids to reduce steroids oral dose.

2.In status asthmaticus, hydrocortisone is given I.V.

followed by oral steroids.

Pharmacokinetics of Inhaled Corticosteroids

23

S/Es:
Inhaled corticosteroids S/Es are minimal: 1. Oral candidiasis 2.Dysphonia These are less likely to occur if spacing devices are used

Effect of Spacer on The delivery Of an inhaled aerosol

 Oral & systemic corticosteroids S/Es are: 1.hypertension. 2.hyperglycemia..etc 3.Osteoporosis 4.Cushinglike syndrome: moon face, acne, increased body hair growth, edema, redistribution of fats

2.Cromoglycate & Nedocromil

MOA: Stop the release of mediators from mast cells in the bronchi

They are given by inhalation prophylactically

They are effective in antigen-induced, exercise-induced & irritant induced asthma S/Es: bitter taste ,irritation of the pharynx & larynx

These agents should never replace inhaled corticosteroids or quick relief 2 agonists as the mainstay of asthma therapy.

3.Leukotriene Modifiers
Leukotrienes are substances, produced by inflammatory cells which cause spasm of bronchial muscle Leukotrienes receptor antagonists include: Montelukast, Zafirlukast

Zileuton is a selective inhibitor for 5lipoxygenase enzyme so it production of Leukotrienes

 Clinical uses: These agents are use prophylactically Used mainly as add on therapy for mild to moderate asthma. Inhibit exercise-induced bronchospasm & aspirin induced asthma

 Sites of action of leukotriene modifying drugs

4. Omalizumab Is a recombinant DNA- derived monoclonal antibody that is selectively binds to human IgE
prevents binding of IgE to mast cells & basophils decreases release of mediators following allergen exposure

Use:
allergic asthma not well controlled by corticosteroids severe persistent asthma

Management of Status Asthmaticus Severe acute asthma is a medical emergency requiring hospitalization Treatment 1.Ensure adequate hydration of the patient if necessary by infusion as this will prevent the sputum become sticky 2.Oxygen, inhalation of Salbutamol in oxygen given by nebulizer 3.In severe attack Salbutamol 250mcg or Aminophylline 250mg can be given I.V.

4.Hydrocortisone 200mg I.V. every 6 hours followed by Prednisolone 60mg orally for 2 weeks 5.Antibiotics if definite evidence of infection.

NO sedatives of any kind e.g. Diazepam

Exposure to antigen (Dust, pollen, etc)

avoidance
Antigen & IgE on mast cell cromolyn corticosteroids ziluton

Mediators (Leukotrienes, Cytokines) 2agonists Theophylline Muscarinic antagonists Corticosteroids Cromolyn Leukotriene antagonists

Early response (Bronchoconstriction)

Late response: (inflammation)

Clinical implications:
Acute bronchoconstriction can occur during dental treatment, have bronchodilator available. Ensure that bronchodilator inhaler is present at each dental appointment.

Be aware that sulfites in local anesthetic with vasoconstrictor can precipitate acute asthma attack in susceptible individuals.
Inhalants can dry oral mucosa, anticipate candidiasis, increased plaque levels & increased caries.

Oral health educations:

If chronic dry mouth occurs, recommend home fluoride therapy & use nonalcoholic oral health care products. Rinse mouth with water after bronchodilator to prevent dryness. Teach the patient to rinse mouth & gargle vigorously with water after inhaled corticosteroids to minimize the potential candidiasis. Encourage daily plaque control procedures for effective self-care.

Treatment of Cough
Cough is a normal physiological reflexes that free the respiratory tract of accumulated secretions & removes particulate matter & environmental irritants Types of cough: 1.Productive cough Effectively expels secretions & foreign substances Generally should not be suppressed

2.Unproductive cough

It is also called irritant cough

No materials come out from respiratory tract when coughing, but we feel of pain & dryness & something irritating

Interferes with sleep or exhausts the patient It should be suppressed

 Treatment:
Antitussives: Drugs that suppress cough 1.Peripherally Acting a. Demulcents Used as: lozenges, syrups Soothing coat the pharynx They protect underlying mucosa from irritation b. Water aerosol inhalation They sooth the lower part of pharynx

2. Centrally Acting
These are used to suppress cough when peripherally acting methods were not effective a. Morphine Related Drugs (such as: Codeine) b. Dextromethorphan c. Antihistamines Oral health education: Inform the patients that syrup contain sugar & to use fluoride products to prevent dental caries.

Drugs that facilitate productive cough

1.Expectorants They encourage & facilitate productive cough by increasing the volume & decreases viscosity of bronchial secretion E.g.: Bromohexine

2.Mucolytics They facilitate the productive cough by reducing the sputum viscosity E.g.: Acetylcysteine