drugs acting on the respiratory system
TRANSCRIPT
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Unit FourDrugs Acting on the Respiratory System
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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
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Introduction (Cont’d)• Drugs to be discussed in this
chapter– Bronchodilators– Corticosteroids– Mast cell stabilizers– Leukotriene Pathway inhibitors– Cough preparations– Nasal decongestants– Expectorants and Mucolyitcs
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• 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
Introduction (Cont’d)
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• 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.
Bronchial Asthma
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Drugs used in the treatment of bronchial asthma can
be grouped into four main categories:
• Bronchodilators
β-Adrenergic agonists
Methyl xanthines
Muscarinic receptor antagonists
• Mast cell stabilizers
• Anti-inflammatory drugs
• Leukotriene Pathway inhibitors
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Bronchodilators
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Bronchodilators (Cont’d)• β- 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
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Bronchodilators (Cont’d)
Drug Formulation Dosage
Adult Child
Salbutamol Oral tablet (C.R) 8 mg twice daily 4 mg twice daily
Inhaler, 100mcg/dose 100-200mcg up to three to four times daily
Same as adult
Syrup, 2mg/5ml 4 mg three to four times daily
1-2 mg three to four times daily (≥2 yr)
Terbutaline Oral tablet (S.R) 5-7.5 mg two times daily -
Inhalation 500mg / dose 500 mcg up to four times daily
-
Short-acting β-2 agonists
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Bronchodilators (Cont’d)Long-acting β-2 agonists
Drug Formulation Dosage
Adult Child
Formoterol Inhaler 4.5mcg / dose (Turbuhaer)
4.5-9 mcg once or twice daily
Same as adult
Inhaler 9mcg / dose (Turbuhaer)
Salmeterol Inhaler 25mcg / dose (MDI)
50-100 mcg twice daily Same as adult
50 mcg / dose (Accuhaler)
50 mcg twice Same as adult
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Bronchodilators (Cont’d)
• Adverse effects– Tachycardia and
palpitations– Headache– Tremor
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Bronchodilators (Cont’d)• (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 (Cont’d)
– N.B• Inform the patient that salmeterol and formoterol, and oral
β-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 β-2 agonists can cause cardiac stimulation
• Contact physician if symptoms such as nervousness, insomnia, restlessness and tremor become severe
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Bronchodilators (Cont’d)
• 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 (Cont’d)
Drug Formulation Dosage
Adult 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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• Adverse effects:– Dry mouth– Nausea– Constipation– Headache
Bronchodilators (Cont’d)
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Bronchodilators (Cont’d)• 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 (Cont’d)Drug Formulation Dosage
Adult Child
Theophylline Tablet 200 / 300 mg (S.R.)
200 – 300 mg twice daily 10 mg / kg ((≥2yrs) twice daily
Capsule 50 / 100 mg (Slow release)
7-12 mg/ kg / day in two divided doses
10-16 mg / kg / day in two divided doses (9–16yrs)13-20 mg / kg / day in two divided doses (30 months – 8 yrs)
Syrup 80 mg / 15 ml 25 ml q6h 1 ml / kg (Max 25 ml) q6h (≥2yrs)
Aminophylline Injection 25 mg / ml 10 ml
500 mcg / kg / hr IV infusion, adjust when necessary
1 mg / kg /hr (6 months – 9 years)800 mcg / kg /hr (10 – 16 yrs)IV infusion, adjust when necessary
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Bronchodilators (Cont’d)
– Adverse effects:• Toxicity is related to theophyline levels (usually 5-15
µg/ml)• 20-25 µg/ml : Nausea, vomiting, diarrhea, insomnia,
restlessness• >30 µg/ml : Serious adverse effects including
dysrhythmias, convulsions, cardiovascular collapse which may result in death
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Bronchodilators (Cont’d)
– N.B:
• Plasma theophylline levels should be monitored to keep it in the therapeutic range, usually 5-15 µg/ml. Dosage should be adjusted to keep theophylline levels below 20 µg/ml
• If patients miss a dose, the following dose should not be doubled
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N.B:
• Instruct the patient that sustained-release formulations should be swallowed intact
• Caution patients in consuming caffeine containing-beverages and other sources of caffeine. Caffeine can intensify the adverse effects and decrease the metabolism of theophylline
Bronchodilators (Cont’d)
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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 β-receptor agonists, but their most important action is inhibition of the lymphocytic, eosinophilic mucosal inflammation of asthmatic airways.
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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.
Corticosteroids (Cont’d)
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Systemic CorticosteroidsSystemic corticosteroids are used for severe acute asthma exacerbations and chronic severe asthma. Urgent treatment is often begun with an oral dose of 30–60 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.
Corticosteroids (Cont’d)
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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.
Corticosteroids (Cont’d)
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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.
Corticosteroids (Cont’d)
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Corticosteroids (Cont’d)• 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 (Cont’d)
• 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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Cont’d 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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Cont’d
Adverse effects measures
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.
A selective β2 agonist such as salbutamol or terbutaline may be inhaled a few minutes before hand
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• 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
Cont’d
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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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• In US, the following drugs are approved for use in an oral dosage forms. – zileuton, 400–800 mg for administration 2–4 times
daily– zafirlukast, 20 mg twice daily; and– montelukast, 10 mg (for adults) or 4 mg (for
children) once daily.
Leukotriene Pathway inhibitors (Cont’d)
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• Adverse effects:– GI disturbances– Hypersensitivity reactions– Restlessness & headache– Manufacturer advises to avoid these drugs in
pregnancy & breast-feeding unless essential
Leukotriene Pathway inhibitors (Cont’d)
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Cough preparations
• There are three classes of cough preparations:– Antitussives– Expectorants– Mucolytics
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• Antitussives– Drugs that suppress cough– Some act within the CNS, some act peripherally– Indicated in dry, hacking, nonproductive cough
that interfere with rest & sleep
Cough preparations (Cont’d)
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Cough preparations (Cont’d)
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
10-30 mg q4-8h
Diphenhydramine 10 mg/ 5ml 25 mg q4h, Max:150 mg daily
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• 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
Cough preparations (Cont’d)
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• 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
Cough preparations (Cont’d)
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• 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
Cough preparations (Cont’d)
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• Dosage– Guaifenesin
• 100-400 mg q4h po
– Ammonia & Ipecacuaha Mixture• 10-20 ml three to four times daily po
Cough preparations (Cont’d)
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• Mucolytics– Reacts directly with mucus to make it more
watery. This should help make the cough more productive
• Drugs– Acetylcysteine– Bromhexine – Carbocisteine
Cough preparations (Cont’d)
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• Sympathomimetics are used to reduce nasal congestion
• Stimulate alpha1-adrenergic receptors on nasal blood vessels, which causes vasoconstriction & hence shrinkage of swollen membranes
Nasal Decongestants
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• Topical administration:– Response is rapid & intense
• Oral administration:– Response are delayed, moderate & prolonged
Nasal Decongestants (Cont’d)
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Nasal Decongestants (Cont’d)Drug Formulation Dosage
Adult Child
Oxymetazoline Nasal Drops 0.025% 20 ml - 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 (Cont’d)• 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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• Adverse effects (Cont’d):– Sympathomimetics can cause vasoconstriction by
stimulating α-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
Nasal Decongestants (Cont’d)
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Nasal Decongestants (Cont’d)• 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 patient’s 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 (Cont’d)Drug Formulation Dosage
Adult Child
Beclomethasone Dipropionate
Nasal Spray 50 mcg / dose
1 spray in each nostril four times daily Max. 10 sprays / day
4-6 sprays / day
Nasal Spray 50 mcg dose (Aqueous)
2 applications into each nostril twice to four times dailyMax. 400 mcg daily
Same as adult (>6 yrs)Not recommended in children <6yrs
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Intranasal Corticosteroids (Cont’d)
Drug (Cont’d) Formulation Dosage
Adult Child
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
Not recommended for age 12 yrs or below
Turbuhaler 100mcg / dose
400 mcg in the morning given as 2 applications into each nostril; then reduce to the smallest amount necessary
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Intranasal Corticosteroids (Cont’d)
Drug (Cont’d) Formulation Dosage
Adult Child
Fluticasone Nasal Spray 50 mcg / dose (Aqueous)
2 sprays into each nostril in the morning Max: 8 sprays/day
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 maintenanceMax: 8 sprays/day
1 spray in each nostril once daily(3-11yrs)
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• Adverse effects:– Mild– Most common effects are drying of nasal
mucosa & sensations of burning or itching
Intranasal Corticosteroids (Cont’d)