Respiratory Pharmacology

Lecture Outline:
Learning Objectives | Recommended Reading | Limitations and Objectives of Drug Use in Respiratory Disease Bronchodilators | Mast Cell Stabilizers for Asthma Prophylaxis | Corticosteroids Inhibitors of Leukotriene Effects | Mucolytic Agents | Antitussives | Decongestants Antihistamines | Synthetic Pulmonary Surfactant Preparations Agent to Treat Cystic Fibrosis | Learning Resources

Learning Objectives
Upon completion of the respiratory pharmacology unit each student will be able to: 1. Identify the limitations and objectives of drug therapy in respiratory disease. 2. Explain the chemical cascade of early and late inflammatory mediators of asthma, including major sites of pharmacologic intervention. 3. Define the following terms: bronchodilator mucolytic antitussive cough suppressant expectorant pulmonary surfactant 4. Explain the basic concepts of aerosol delivery of drugs and list the various kinds of delivery devices. 5. List the drugs of choice for each of the following classes and know their mechanism of action, major adverse effects of other distinguishing properties: bronchodilators mast cell stabilizers corticosteroids leukotriene inhibitors mucolytics antitussives (cough suppressants and expectorants) decongestants antihistamines synthetic pulmonary surfactant preparations 6. Identify the agent to treat cystic fibrosis. 7. Recognize the common drugs used to treat respiratory disease.

Recommended Reading
Katzung, B.G. Basic and Clinical Pharmacology. 7th ed., 1998. Hardman et al. The Pharmacological Basis of Therapeutics. 1996, chapter 28, p. 659.

I.

Limitations and Objectives of Drug Use in Respiratory Disease

A. Three limitations and objectives 1. Diseases are often chronic in nature or caused by viruses. 2. Objectives of drug therapy usually involve relief of symptoms rather than curing the disease. 3. One of the major respiratory diseases is asthma. See Figure 1.

Figure 1. Summary of the actions of pharmacologic agents on phases of the disease process.

Figure 2. Inflammatory mediators of asthma. B. Aerosol delivery of drugs has the advantage of delivering drug to intended site of action thus reducing systemic side effects. Basic types of inhalers: 1. Metered dose - However, more than 50% of patients do not use proper metered dose inhaler technique. 2. Nebulizer - Newer delivery approaches include inhalation activated "turbuinhalers." Other new technology includes the "Spiros" inhaler which is a cassette delivery system that is breath-activated and designed to deliver a consistent dose independent of patients ability to inhale forcefully.

Figure 3.

II.

Bronchodilators
A. Sympathetic stimulants Beta adrenergic stimulation increases the formation of cAMP producing dilation of bronchioles and reduced airway resistance, making breathing easier. These drugs have no major anti-inflammatory effects and do not prevent the late-phase response or decrease the bronchiolar hyperresponsiveness in the asthmatic. They are frequently administered by inhalation using pressurized aerosol or dry powder breath activated metered- dose inhalers (MDI). Some agents are also administered orally or parenterally. B. Beta receptors are divided into two groups. 1. Beta-1: effects on heart and lipolysis 2. Beta-2: bronchodilation, vasodilation, and muscle glycogenolysis C. Non-selective beta receptor stimulants (stimulate beta-1 and beta-2) The non-selective agonists have the major disadvantage of stimulating cardiac beta receptors which may produce dangerous arrhythmias. Some also produce adverse effects due to alpha activation. CNS stimulation and a fall in arterial O 2 tension are among other problems. These older agents have been largely replaced by more specific drugs. 1. Epinephrine (OTC Primatene Mist) 2. Isoproterenol (Isuprel) 3. Ephedrine (Primatene tablets, Marax, Quadrinal, etc.) D. Semi-selective beta receptor stimulants Predominantly beta-2, with some beta-1 activity.

1. Metaproterenol (Alupent, Metaprel) 2. Isoetharine (Bronokometer, Bronkosol) E. Selective beta receptor stimulants (predominantly beta-2) Produce bronchodilation without major cardiac stimulation or reduction in arterial 0 2 tension. Tremors are a frequent adverse effect. 1. 2. 3. 4. 5. Albuterol (Ventolin, Proventil) Terbutaline (Bricanyl, Brethine, Brethaire) Bitolterol (Tornalate) Pirbuterol (Maxair) Salmeterol (Serevent) -- slow onset, longer-acting

F. Anticholinergics - ipratropium (Atrovent) Parasympathetic activation is associated with bronchoconstriction and increased secretion. Muscarinic receptor blocker given by inhalation allows sympathetic effect (bronchodilation) to be more prominent. There is no anti-inflammatory effect or decrease in hyperresponsiveness. Ipratropium is particularly useful in treating chronic bronchitis and emphysema. Bronchodilation with anticholinergics is less

dramatic than with 2 agonists. May be useful to combine muscarinic antagonist with 2 agonist. Also, psychogenic asthma can be prevented with ipratropium. G. Methylxanthine bronchodilators The methylxanthines appear to act by inhibiting phosphodiesterase and by blocking adenosine receptors, the latter mechanism probably being more important for bronchodilation. They can also prevent edema, but do not prevent the late-phase reaction or reduce hyperresponsiveness. They are less potent bronchodilators than sympathetic agonists and are of limited usefulness for treatment of acute asthmatic symptoms. Used chronically to decrease incidence of bronchoconstriction. Also used to stimulate respiration in apnea of prematurity. Methylxanthines (primarily theophylline) are available in several dosage forms including oral solutions, sustained-release preparations, etc. 1. Theophylline (Theo-Dur, Uniphyl) a. Pharmacokinetics i. ii. Oral administration, sustained release preparation is given 1 or 2 times daily Clearance affected by many factors: 1. 2. 3. Age Smoking Diseases

b. Adverse effects i. ii. iii. GI distress CNS stimulation Cardiac stimulation and vasodilation

c. Drug interactions i. ii. Decreased theophylline clearance caused by some fluoroquinolines, cimetidine, erythromycin Increased theophylline clearance caused by phenytoin

2. Aminophylline (theophylline-ethylenediamine)

III.

Mast Cell Stabilizers for Asthma Prophylaxis

These agents are not bronchodilators. They stabilize the mast cell membrane and thus reduce the frequency and severity of attacks by inhibiting release of mediators of inflammation and bronchoconstriction. Also some evidence they suppress action of chemotactic peptides on neutrophils. They are used prophylactically in management of asthma and have emerged as a first- line agent in the prophylactic treatment of mild to moderate asthma in children. A. Cromolyn sodium (Intal)

1. Administered as a powder (Spinhaler), metered-dose inhaler, and nebulized solution 2. Also used as a nasal spray (Nasalcrom) in the management of allergic rhinitis B. Nedocromil (Tilade) 1. Newer agent similar to cromolyn 2. Administered by metered dose inhaler for asthma prophylaxis

IV.

Corticosteroids
The corticosteroids have potent anti-inflammatory effects which inhibit the synthesis or release of mediators, prevent the late-phase reaction and reduce hyperresponsiveness. They are highly effective in the treatment of chronic respiratory disease, but oral administration has traditionally been associated with serious systemic adverse effects and pituitary/adrenal suppression. The preparations listed below are administered by inhalation and have a much higher therapeutic index. They are particularly useful as prophylactic agents. In addition to their value in the management of asthma, products containing these steroids (designated below by an *) are available as nasal sprays for the treatment of rhinitis. Systemic (parenteral/oral) use of steroids (e.g., methylprednisolone, prednisone) is sometimes necessary in the management of severe asthmatic states. A. B. C. D. E. Beclomethasone (Beclovent, Vanceril, Beconase*) Flunisolide (AeroBid, Nasalide*) Triamcinolone (Azmacort, Nasacort*) Budesonide (Pulmicort, Rhinocort*) Fluticasone (Flovent, Flonase*)

Potential adverse effects associated with inhaled steroids include hypothalamic/ pituitary/adrenal suppression, bone resorption, effects on carbohydrate and lipid metabolism, cataracts, thinning of skin, purpura, dysphonia, candidiasis and growth retardation. However the incidence of these effects with inhaled steroids is very low or of no significant risk unless prolonged, high doses are employed. It has been suggested that the small risk of adverse effects at even high doses of inhaled steroids is outweighed by the risks of not adequately controlling severe asthma.

Figure 4. Inflammation, nuclear factor - kB and glucocorticoids.

V.

Inhibitors of Leukotriene Effects

Leukotrienes, derived from arachidonic acid through the action of 5-lipoxygenase, are one of the groups of mediators of asthmatic attacks. They cause bronchoconstriction, increased vascular permeability, increased chemotaxis of WBCs and increased mucous secretion. Agents are available which inhibit the formation or block the action of these compounds. Some individuals respond very well to these agents while others appear nonresponsive. These agents are used for allergic or exercise-induced asthma prophylaxis. Generally used along with other prophylactic agents. They are not used for acute treatment of asthmatic attacks. A. Inhibit 5-lipoxygenase and thus blockade of leukotriene synthesis: e.g., zileuton (Zyflo) B. Block leukotriene receptors (especially LTD4), little or no toxicity C. Zafirlukast (Accolate), twice daily D. Montelukast (Singlulair), once daily, metabolite eliminated via bile, also decreases peripheral eosinophils by 15%

VI.

Mucolytic Agents
These agents are used to reduce the viscosity of pulmonary secretions and facilitate their removal. However their effectiveness is not great unless applied directly to the mucous plug. A. N-acetylcysteine (Mucomyst, also the antidote for acetaminophen poisoning) B. Iodinated glycerol (Organidin)

VII.

Antitussives
Cough is a protective reflex and should not be suppressed indiscriminately. Cough may be nonproductive or productive of sputum, this often being the sequence in disease. When nonproductive, suppression of cough may be restful; when productive, suppression is still beneficial, but must be intermittent in order to allow periodic drainage of the sputum. When therapy is indicated, there are two types of preparations used to relieve cough.

Figure 5. Cough suppressants (centrally acting agents). A. Cough suppressants These drugs suppress coughing by raising the threshold of the central coordinating area to tussal impulses and also dull the perception of cough stimuli. 1. Narcotic cough suppressants a. Codeine b. Hydrocodone (Tussionex) 2. Dextromethorphan 3. Benzonatate (Tessalon) B. Expectorants (peripherally acting agents) These agents act by stimulating the outflow of respiratory tract fluid and modifying the viscosity of secretions to facilitate expectoration. Respiratory tract fluid is a natural mucosal demulcent, which protects irritated mucosa below the epiglottis from which cough impulses arise. 1. Indirect stimulation by activation of gastric reflexes a. Guaifenesin (Humibid, many combinations) b. Iodides (NaI, KI and organic iodides) c. Ammonium chloride

2. Direct stimulation of secretory cells- volatile oils a. Eucalyptus b. Terpin hydrate

VIII.

Decongestants
Sympathomimetic amine decongestants act upon subepithelial precapillary sphincters and venous sinuses of vascular smooth muscle. They stimulate alpha-adrenergic receptors to constrict dilated vessels, promoting drainage, resorption of exudate and decreased hyperemia. Nasal airway patency is improved and breathing is easier. Decongestants can be applied topically or administered systemically. They should be employed only for a few days since continued topical use results in rebound congestion. Oral use results in irritability and insomnia as major adverse effects. They must be used with caution in patients with hypertension, cardiac disease, hyperthyroidism and diabetes. Agents include: A. Oral 1. Phenylpropanolamine (generic) 2. Pseudoephedrine (Sudafed) B. Topical 1. Phenylephrine (Neo-synephrine) 2. Naphazoline (Privine) 3. Xylometazoline (Otrivin) 4. Oxymetazoline (Afrin)

IX.

Antihistamines
By blocking histamine H1 receptors, antihistamines provide symptomatic relief of allergic rhinitis. They are somewhat useful in treating other minor upper respiratory disorders. They are generally considered to be not useful in chronic lower respiratory diseases(e.g., asthma). Sedation and anticholinergic effects are the most common side effects of most antihistamines, particularly those in OTC products. Some prescription antihistamines, e.g., loratidine, fexofenadine and astemizole, are much less likely to produce these adverse effects. The pharmacology of the antihistamines is discussed in more detail in the GI and Musculoskeletal courses. Examples Some of the many antihistamines available include: A. Diphenhydramine (Benadryl) - OTC B. Chlorpheniramine (Chlortrimeton) - OTC C. Astemizole (Hismanal) D. Loratidine (Claritin) E. Fexofenadine (Allegra)

X.

Synthetic Pulmonary Surfactant Preparations

Used in the management of respiratory distress syndrome (RDS) in premature infants A. Colfosceril (Exosurf) B. Beractant (Survanta)

XI.

Agent to Treat Cystic Fibrosis

Dornase alfa (Pulmozyme) This is a genetically engineered form of human DNAase enzyme. Administered by inhalation to patients with cystic fibrosis it breaks down thick mucus, improves lung function and reduces infection. Adverse effects include inflammation of the throat, voice alteration and chest pain.

XII.

Learning Resources
Drugs to remember (trade names not required)

n-acetylcysteine (Mucomyst) albuterol (Venotlin, Proventil) beclamethasone (Beclovent, Vanceril, Beconase) butesonide (Pulmicort, Rhinocort) codeine colfosceril (Exosurf) cromolyn (Intal) dextromethorphan diphenhydramine (Benadryl) dornase alfa epinephrine fexofenadine (Allegra) flunisolide (Aerobid, Nasalide) fluticasone (Flovent, Flonase) Table 2.

guaifenesin (Humibid, etc.) hydrocodone (Tussionex) ipratropium (Atrovent) loratidine (Claritin) oxymetazoline (Afrin) phenyl propanolamine phenylephrine pseudoephedrine (Sudafed) salmeterol (Serevent) terbutaline (Brethine, Brethaire) theophylline triamcinolone (Azmacort, Nasacort)