Unit Four Drugs Acting on the Respiratory System

Introduction
The respiratory system includes the nasal cavities, pharynx and trachea as well as the bronchi and bronchioles.

The respiratory system is subject to many disorders that interfere with respiration and other lung functions, including Respiratory tract infections Allergic and inflammatory disorders Conditions that obstruct airflow (e.g. asthma and chronic obstructive pulmonary disease, COPD) etc
This chapter will focus on drugs used to treat some of the more common disorders affecting the respiratory system particularly bronchial asthma, cough and nasal congestion

Introduction (Contd)
Drugs to be discussed in this chapter
Bronchodilators Corticosteroids Mast cell stabilizers Leukotriene Pathway inhibitors Cough preparations Nasal decongestants Expectorants and Mucolyitcs

Introduction (Contd)
Drugs acting on the respiratory system, especially for asthma, can be administered by inhalation, the advantages are:
Enhance therapeutic effects Minimize systemic effects Rapid relief of acute attacks

Bronchial Asthma
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyper-responsiveness to a variety of stimuli.
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Drugs used in the treatment of bronchial asthma can

be grouped into four main categories: Bronchodilators -Adrenergic agonists Methyl xanthines Muscarinic receptor antagonists Mast cell stabilizers

Anti-inflammatory drugs
Leukotriene Pathway inhibitors
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Bronchodilators

Bronchodilators (Contd)
- Adrenoceptor agonists
I. Selective beta2 agonists
Stimulate beta2 receptors in smooth muscle of the respiratory tract, promoting bronchodilation, and thereby relieving bronchospasms They are divided into short-acting & long acting types

Bronchodilators (Contd)
Short-acting -2 agonists
Drug Formulation Adult Salbutamol Oral tablet (C.R) 8 mg twice daily Dosage Child 4 mg twice daily

Inhaler, 100mcg/dose

100-200mcg up to three to four times daily

4 mg three to four times daily 5-7.5 mg two times daily 500 mcg up to four times daily

Same as adult

Syrup, 2mg/5ml

1-2 mg three to four times daily (2 yr) -

Terbutaline

Oral tablet (S.R) Inhalation 500mg / dose

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Bronchodilators (Contd)
Long-acting -2 agonists
Drug Formulation Dosage

Adult Formoterol Inhaler 4.5mcg / dose (Turbuhaer) Inhaler 9mcg / dose (Turbuhaer) Salmeterol Inhaler 25mcg / dose (MDI) 50-100 mcg twice daily 4.5-9 mcg once or twice daily

Child Same as adult

Same as adult

50 mcg / dose (Accuhaler) 50 mcg twice

Same as adult

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Bronchodilators (Contd)
Adverse effects
Tachycardia and palpitations Headache Tremor

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Bronchodilators (Contd)
(ii) Other adrenoceptor agonists (none-selective) Less suitable & less safe for use as bronchodilators because they are more likely to cause arrhythmias & other side effects Ephedrine Adrenaline (epinephrine): injection is used in the emergency treatment of acute allergic and anaphylactic reactions
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Bronchodilators (Contd)
N.B
Inform the patient that salmeterol and formoterol, and oral -2 agonists should be taken on a fixed schedule, not on a prn basis Instruct the patient to report chest pain and changes in heart rhythm or rate, because -2 agonists can cause cardiac stimulation Contact physician if symptoms such as nervousness, insomnia, restlessness and tremor become severe

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Bronchodilators (Contd)
Antimuscarinic bronchodilators
Blocks the action of acetylcholine in bronchial smooth muscle, Used for maintenance therapy of bronchoconstriction associated with COPD & emphysema

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Bronchodilators (Contd)
Drug Formulation Adult Dosage Child

Ipratropium

Inhaler 20 mcg / dose (MDI)

20-80 mcg three to four times a day

20-40 mcg three to four times a day (6yrs)

Tiotropium

Inhaler 18 mcg /dose

18 mcg daily

Not recommended in children and adolescents

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Bronchodilators (Contd)
Adverse effects:
Dry mouth Nausea Constipation Headache

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Bronchodilators (Contd)
Xanthine Derivatives
Main xanthine used clinically is theophylline Theophylline is a bronchodilator which relaxes smooth muscle of the bronchi, it is used for reversible airway obstruction One proposed mechanism of action is that it acts by inhibiting phosphodiesterase, thereby increasing cAMP, leading to bronchodialtion

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Bronchodilators (Contd)
Drug Formulation Dosage Adult Theophylline Tablet 200 / 300 mg (S.R.) Capsule 50 / 100 mg (Slow release) 200 300 mg twice daily 7-12 mg/ kg / day in two divided doses Child 10 mg / kg ((2yrs) twice daily 10-16 mg / kg / day in two divided doses (916yrs) 13-20 mg / kg / day in two divided doses (30 months 8 yrs) 1 ml / kg (Max 25 ml) q6h (2yrs) 1 mg / kg /hr (6 months 9 years) 800 mcg / kg /hr (10 16 yrs) IV infusion, adjust when necessary
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Syrup 80 mg / 15 ml

25 ml q6h

Aminophylline

Injection 25 mg / ml 10 ml

500 mcg / kg / hr IV infusion, adjust when necessary

Bronchodilators (Contd)
Adverse effects:
Toxicity is related to theophyline levels (usually 5-15 g/ml) 20-25 g/ml : Nausea, vomiting, diarrhea, insomnia, restlessness >30 g/ml : Serious adverse effects including dysrhythmias, convulsions, cardiovascular collapse which may result in death

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Bronchodilators (Contd)
N.B:
Plasma theophylline levels should be monitored to keep it in the therapeutic range, usually 5-15 g/ml. Dosage should be adjusted to keep theophylline levels below 20 g/ml If patients miss a dose, the following dose should not be doubled

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Bronchodilators (Contd)
N.B:
Instruct the patient that sustained-release formulations should be swallowed intact Caution patients in consuming caffeine containingbeverages and other sources of caffeine. Caffeine can intensify the adverse effects and decrease the metabolism of theophylline

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Corticosteroids
Corticosteroids have been used to treat asthma since 1950 and are presumed to act by their broad anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines. They do not relax airway smooth muscle directly but reduce bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly. Their effect on airway obstruction may be due in part to their contraction of engorged vessels in the bronchial mucosa and their potentiation of the effects of -receptor agonists, but their most important action is inhibition of the lymphocytic, eosinophilic mucosal inflammation of asthmatic airways.
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Corticosteroids (Contd)
MOA Decrease synthesis & release of inflammatory mediators Decrease infiltration & activity of inflammatory cells Decrease edema of the airway mucosa Effects on air way increase air way caliber decrease bronchial reactivity decrease frequency of asthma exacerbations and severity of symptoms.

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Corticosteroids (Contd)
Systemic Corticosteroids Systemic corticosteroids are used for severe acute asthma exacerbations and chronic severe asthma. Urgent treatment is often begun with an oral dose of 3060 mg prednisone per day or an intravenous dose of 1 mg/kg methylprednisolone every 6 hours; the daily dose is decreased after airway obstruction has improved. In most patients, systemic corticosteroid therapy can be discontinued in a week or 10 days. More protracted bouts of severe asthma may require longer treatment and slower tapering of the dose to avoid exacerbating asthma symptoms and suppressing pituitary/adrenal function. Now most patients with asthma are better treated with inhaled corticosteroids.
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Corticosteroids (Contd)
Inhaled corticosteroids. Although corticosteroids are very effective in controlling asthma, treatment with systemic corticosteroids comes at the cost of considerable adverse effects. A major advance in asthma therapy was the development of inhaled corticosteroids that targeted the drug directly to the relevant site of inflammation. These formulations greatly enhance the therapeutic index of the drugs, substantially diminishing the number and degree of side effects without sacrificing clinical utility.

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Corticosteroids (Contd)
There are currently five corticosteroids available for inhalation therapy:
beclomethasone dipropionate, triamcinolone acetonide,

flunisolide,
budesonide, and fluticasone propionate. While they differ markedly in their affinities for the glucocorticoid receptor, with fluticasone and budesonide having much higher affinities than beclomethasone, they are all effective in controlling asthma at the appropriate doses.

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Corticosteroids (Contd)
Adverse effects
Inhaled corticosteroids:
Candidiasis of the mouth or throat Hoarseness

Systemic corticosteroids
Can slow growth in children Adrenal suppression may occur in long-term, high dose therapy Increases the risk of cataracts osteoporesis fluid electrolyte imbalance hyperglycemia

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Corticosteroids (Contd)
N.B
Rinse mouth with water without swallowing after administration to reduce the risk of candidiasis If taking bronchodilators by inhalation, use bronchodilators several minutes before the corticosteroid to enhance application of the corticosteroid into the bronchial tract

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Mast cell stabilizers

Stabilise mast cells & prevent the release of bronchoconstrictive & inflammatory substances when mast cells are confronted with allergens & other stimuli Only for prophylaxis of acute asthma attacks

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Contd
Cromolyn sodium (disodium cromoglycate) and nedocromil sodium are stable but extremely insoluble salts. When used as aerosols (by nebulizer or metered-dose inhaler), they effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times

daily) slightly reduces the overall level of bronchial reactivity.

However, these drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm; they are

only of value when taken prophylactically.

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Contd
Adverse effects
Adverse effects of cromolyn and nedocromil are minor and are localized to the sites of deposition. These include such minor symptoms as throat irritation, cough, and mouth dryness, and, rarely, chest tightness, and wheezing. Serious adverse effects are rare.

measures A selective 2 agonist such as salbutamol or terbutaline may be inhaled a few minutes before hand

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Contd
N.B
Cromolyn are for long-term prophylaxis, patients should administer on a regular schedule & the full therapeutic effects may take several weeks, up to 4 weeks, to develop They are contraindicated in patients who are hypersensitive to the drugs

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Leukotrien Pathway inhibitors

Act by suppressing the effects of leukotrienes, compounds that promote bronchoconstriction as well as eosinophil infiltration, mucus productions, & airway edema Help to prevent acute asthma attacks induced by allergens & other stimuli Indicated for long-term treatment of asthma

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Leukotriene Pathway inhibitors (Contd)

In US, the following drugs are approved for use in an oral dosage forms.
zileuton, 400800 mg for administration 24 times daily zafirlukast, 20 mg twice daily; and montelukast, 10 mg (for adults) or 4 mg (for children) once daily.

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Leukotriene Pathway inhibitors (Contd)

Adverse effects:
GI disturbances Hypersensitivity reactions Restlessness & headache Manufacturer advises to avoid these drugs in pregnancy & breast-feeding unless essential

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Cough preparations
There are three classes of cough preparations:
Antitussives Expectorants Mucolytics

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Cough preparations (Contd)

Antitussives
Drugs that suppress cough Some act within the CNS, some act peripherally Indicated in dry, hacking, nonproductive cough that interfere with rest & sleep

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Cough preparations (Contd)

Drug Dosage

Codeine phosphate 25mg/5ml syrup

15-30 mg three to four times daily

Pholcodine 5mg/5ml Elixir

5-10 mg three to four times daily

Dextromethorphan 10mg/5ml in Promethazine Compound Linctus Diphenhydramine 10 mg/ 5ml

10-30 mg q4-8h

25 mg q4h, Max:150 mg daily

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Cough preparations (Contd)

Adverse effects:
Drowsiness Respiratory depression (for opioid antitussives) Constipation (for opioid antitussives) Preparations containing codeine or similar analgesics are not generally recommended in children & should be avoided altogether in those under 1 year of age
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Cough preparations (Contd)

Alerts:
Observe for excessive suppression of the cough reflex (inability to cough effectively when secretions are present). This is a potentially serious adverse effect because retained secretions may lead to lungs collapse, pneumonia, hypoxia, and respiratory failure

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Cough preparations (Contd)

Expectorants
Render the cough more productive by stimulating the flow of respiratory tract secretions Guaifenesin is most commonly used Available alone & as an ingredient in many combination cough & cold remedies

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Cough preparations (Contd)

Dosage
Guaifenesin
100-400 mg q4h po

Ammonia & Ipecacuaha Mixture

10-20 ml three to four times daily po

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Cough preparations (Contd)

Mucolytics
Reacts directly with mucus to make it more watery. This should help make the cough more productive

Drugs
Acetylcysteine Bromhexine Carbocisteine

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Nasal Decongestants
Sympathomimetics are used to reduce nasal congestion Stimulate alpha1-adrenergic receptors on nasal blood vessels, which causes vasoconstriction & hence shrinkage of swollen membranes

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Nasal Decongestants (Contd)

Topical administration:
Response is rapid & intense

Oral administration:
Response are delayed, moderate & prolonged

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Nasal Decongestants (Contd)

Drug Formulation Dosage Adult Oxymetazoline Nasal Drops 0.025% 20 ml Child 2-3 drops q12h (2-5 yrs)

Nasal Spray 0.05% 15 ml

2-3 sprays q12h

Same as adults for children >6 yrs -

Phenylephrine

Nasal Drops 0.5% 10 ml

Several drops q2-4h

Xylometazoline

Nasal Drops 0.05% / 0.1%

2-3 drops q8-10h (0.1%)

2-3 drops q8-10h (2-12 yrs) (0.05%)

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Nasal Decongestants (Contd)

Adverse effects:
Rebound congestion develops with topical agents when used for more than a few days CNS stimulation (such as restlessness, irritability, anxiety and insomnia) occurs with oral sympathomimetics

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Nasal Decongestants (Contd)

Adverse effects (Contd):
Sympathomimetics can cause vasoconstriction by stimulating -1 adrenergic receptors. More common with oral agents Sympathomimetics cause CNS stimulation, and can produce effects similar to amphetamine. Hence, these drugs are subject to abuse

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Nasal Decongestants (Contd)

Alerts:
Overuse of topical nasal decongestants can cause rebound congestion, meaning that the congestion can be worse with the use of drug. To minimise this, drug therapy should be discontinued gradually. The use of topical agents is limited to no more than 3 to 5 days The patients blood pressure and pulse should be assessed before a decongestant is administered Inform the patient that nasal burning and stinging may occur with topical decongestants
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Intranasal Corticosteroids
Intranasal Corticosteroids
Most effective for treatment of seasonal and perennial rhinitis Have inflammatory actions and can prevent or suppress all major symptoms of allergic rhinitis including congestion, rhinorrhea, sneezing, nasal itching and erythema

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Intranasal Corticosteroids (Contd)

Drug Formulation Adult Beclomethasone Dipropionate Nasal Spray 50 mcg / dose 1 spray in each nostril four times daily Max. 10 sprays / day 2 applications into each nostril twice to four times daily Max. 400 mcg daily Dosage Child 4-6 sprays / day

Nasal Spray 50 mcg dose (Aqueous)

Same as adult (>6 yrs) Not recommended in children <6yrs

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Intranasal Corticosteroids (Contd)

Drug (Contd) Formulation Dosage

Adult Budesonide Nasal Spray 50 mcg / dose (Aqueous) 1-2 sprays into each nostril twice daily; after 2-3days: 1 spray into each nostril twice daily 400 mcg in the morning given as 2 applications into each nostril; then reduce to the smallest amount necessary

Child Not recommended for age 12 yrs or below

Turbuhaler 100mcg / dose

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Intranasal Corticosteroids (Contd)

Drug (Contd) Formulation Dosage Adult Fluticasone Nasal Spray 50 mcg / dose (Aqueous) 2 sprays into each nostril in the morning Max: 8 sprays/day Child 1 spray into each nostril in the morning (4-11yrs) Max: 4 sprays/day

Mometasone

Nasal Spray 50 mcg / dose

2 sprays in each nostril once daily; 1spray in each nostril as maintenance Max: 8 sprays/day

1 spray in each nostril once daily (3-11yrs)

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Intranasal Corticosteroids (Contd)

Adverse effects:
Mild Most common effects are drying of nasal mucosa & sensations of burning or itching

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