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CLINICAL PHARMACY IN PULMONOLOGY Introduction Symptom of respiratory system: no sputum---antitussives Cough sputum --- expectorants Asthma ----- antiasthmatic drugs Bronchial asthma Bronchial asthma is a disease caused by increased responsiveness of the tracheobronchial tree to various stimuli. The result is paroxysmal constriction of the bronchial airways. Bronchial asthma is the more correct name for the common form of asthma. The term 'bronchial' is used to differentiate it from 'cardiac' asthma, which is a separate condition that is caused by heart failure. Although the two types of asthma have similar symptoms, including wheezing (a whistling sound in the chest) and shortness of breath, they have quite different causes. Bronchial asthma (cont’d) Bronchial asthma is a disease of the lungs in which an obstructive ventilation disturbance of the respiratory passages evokes a feeling of shortness of breath. The cause is a sharply elevated resistance to airflow in the airways. Despite its most strenuous efforts, the respiratory musculature is unable to provide sufficient gas exchange. The result is a characteristic asthma attack, with spasms of the bronchial musculature, edematous swelling of the bronchial wall and increased mucus secretion. Asthma Pathophysiology: Asthma is a disease characterized by airway inflammation and episodic, reversible bronchospasm Two characteristic features: 1) 2) Inflammatory changes in the airway; Bronchial hyperreactivity to stimuli. Important mediators: histamine, LTC4, LTD4, etc. Bronchial asthma Symptoms can occur spontaneously or can be triggered by respiratory infections, exercise, cold air, tobacco smoke or other pollutants, stress or anxiety, or by food allergies or drug allergies. The muscles of the bronchial tree become tight and the lining of the air passages become swollen, reducing airflow and producing the wheezing sound. Mucus production is increased. Typically, the individual usually breathes relatively normally, and will have periodic attacks of wheezing. Asthma attacks can last minutes to days, and can become dangerous if the airflow becomes severely restricted. Asthma affects 1 in 20 of the overall population, but the incidence is 1 in 10 in children. Asthma can develop at any age, but some children seem to outgrow the illness. Risk factors include self or family history of eczema, allergies or family history of asthma. Bronchial asthma causes cough, shortness of breath, and wheezing. Bronchial asthma is an allergic condition, in which the airways (bronchi) are hyper-reactive and constrict abnormally when exposed to allergens, cold or exercise. Bronchial asthma Treatment is aimed at avoiding known allergens and controlling symptoms through medication. A variety of medications for treatment of asthma are available. People with mild asthma (infrequent attacks) may use inhalers on an asneeded basis. Persons with significant asthma (symptoms occur at least every week) should be treated with anti-inflammatory medications, preferably inhaled corticosteroids, and then with bronchodilators such as inhaled Alupent or Vanceril. Acute severe asthma may require hospitalization, oxygen, and intravenous medications. Antiasthmatic Drugs Bronchodilators I. 1. 2. 3. β receptor agonists Theophylline Muscarinic antagonists Anti-inflammatory agents II. 1. 2. Steroids Anti-leukotriene agents Anti-allergic agents III. 1. 2. Stabilizer of inflammatory cell membrane H1 receptor blocker Beta Adrenoceptor Agonists Adrenaline: α,β agonist Ephedrine: α,β agonist Isoprenaline:β1 ,β2 agonist β2-selective agonists Salbutamol: Terbutaline : Clenbuterol: Formoterol: Salmeterol: Bambuterol: intermediateacting long-acting BRONCHODILATORS Sympathomimetics The sympathomimetics, also called beta agonists or adrenergic agents, can be thought of as rescue medications because they provide rapid relief of labored breathing during an asthma episode. Derivatives of adrenaline, or epinephrine, they are chemically altered to maximize this natural compound’s airway muscle relaxing effect while minimizing the heart, muscle, and nervous system side effects of the parent compound. All of the currently available beta agonists are superior to both adrenaline and ephedrine for duration of action and less-pronounced side effects. These potent , when inhaled, provide rapid relief of bronchial obstruction. Duration of action varies from four to six hours. An exception is salmeterol (Serevent®) which works for up to twelve hours but has a slower onset of action of about an hour. These agents are excellent for the prevention of wheezing triggered by exercise or cold air if taken before the activity or exposure. A number of products are available. Individuals may prefer one agent to another for reasons of taste, cost, or personal preference. Generic agents are now available for albuterol. Users of generic substitutes should be aware of the potential problem of dosage variability. Side effects are mild affecting less than 10% of users. They include rapid heart rate, palpitations, restlessness, anxiety, and muscle tremors. Some children may become "revved up" especially when the oral form is given or sometimes after receiving an aerosol treatment from a nebulizer. Maxair® is thought to cause less heart stimulation while metaproterenol may cause a little more. There is considerable individual variation. • Salmeterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing. • Salmeterol inhalation is used to prevent asthma attacks. It will not treat an asthma attack that has already begun. Salmeterol inhalation is also used to treat chronic obstructive pulmonary disease (COPD) including emphysema and chronic bronchitis. • Salmeterol inhalation may also be used for conditions other than those listed in this medication guide. Adverse Reactions of β2 agonists: 1) Skeletal muscle tremor 2) Cardiac effect: tachycardia, arrhymias 3) Metabolism disturbance: ketone bodies↑, acidosis, [K+]o↓ BRONCHODILATORS Theophylline This drug is so similar to caffeine that they share the same chemical formula. Their three-dimensional structures are slightly different. As small changes in molecular shape often result in major changes in function, theophylline is 100 times as potent a bronchodilator as caffeine. That means you would have to drink several pots of coffee or several six-packs of cola to get the same beneficial effect of a theophylline tablet. Upset stomach, nausea, rapid or irregular heartbeat, insomnia, hyperactive behavior, and headaches are all adverse effects that caffeine and theophylline share. Theophylline has a narrow therapeutic range meaning that such adverse effects occur commonly The belief that theophylline hinders learning is unfounded. In fact, most tests demonstrate enhanced school performance in children taking theophylline. Like caffeine, theophylline is a diuretic. Many patients taking this agent note increased urine production and may awaken at night to answer nature’s call. No longer the mainstay of therapy as it was a decade ago, theophylline still has a role to play in the treatment of asthma. Once a day dosing makes it useful in treating nocturnal asthma (asthma occurring during sleep). It serves an ancillary role in severe cases of asthma. There are also a few patients who respond better to theophylline than to inhaled corticosteroids. Some studies suggest that theophylline may have a mild anti-inflammatory effect but this is far from established. Both theophylline and caffeine are rapidly absorbed from the gastrointestinal tract. Modern theophylline products use specially-formulated tablets or capsules which delay absorption to produce relatively constant blood levels of theophylline throughout the day and night with once daily (Theo24® , Unidor®, Uniphyll®) or twice daily (Slobid® , Theodur®) use. Theophylline Methylxanthine derivatives. Mechanism of Action: 1. 2. 3. 4. 5. Inhibit phosphdiesterase (PDE); Block adenosine receptors; Increase endogenous catecholamine (CA) releasing; Interfere with receptor-operated Ca2+ channels → [Ca2+]i↓; Anti-inflammatory action Clinical Use: 1. 2. 3. Asthma: maintenance treatment Chronic obstructive pulmonary disease (COPD) Central sleep apnea (CSA) Adverse Reactions: Narrow margin of safety. Toxic effects are related to its plasma concentrations. Gastrointestinal distress, tremor, and insomnia. Cardiac arrhythmias, convulsions → lethal. Muscarinic Antagonists There are M1, M2, M3 receptor subtype in the airway. Selectively blocking M1, M3 receptor is resulted in bronchodilating effect. Ipratropium bromide binds to all M-R subtypes (M1, M2 and M3 ), and inhibits acetylcholine-mediated bronchospasm. BRONCHODILATORS Anticholinergic Drugs In the treatment of asthma, anticholinergic drugs are both old and new. One hundred years ago, atropine, the parent drug of this class, was smoked as a cigarette for asthma. Its usefulness was limited by unacceptable side effects of rapid heart rate, hot skin, and dry mucous membranes. Excessive doses could even provoke delusions and irrational behavior. Ipratropium (Atrovent®) preserves the bronchodilator effects while eliminating these adverse effects. Atrovent® is not as potent as the sympathomimetics and is not considered a first choice medication. It has an additive effect when beta agonists are insufficient for symptom relief. It can serve as an acceptable alternate when sympathomimetics aren’t tolerated. Atrovent® should be inhaled four times daily for maximum effectiveness. It's available in multidose inhaler form and in unit dose ampoules for nebulizer use. The only common side effect is dry mouth. Combivent® is a convenient, combination product composed of albuterol and ipratropium. Anticholinergic Drugs Anti-inflammatory Agents Asthma medications may be divided into two broad categories, bronchodilators and anti-inflammatory agents. Within each category are several subclasses and variety of products. While bronchodilators relieve the symptoms of coughing and wheezing, the anti-inflammatory agents treat the underlying cause of asthma. The asthmatic state involves fundamental changes in the way the bronchi regulate their internal diameter. When the cells lining the inner surface of the bronchial tubes are injured, forces designed to control airway size become unbalanced. Bronchoconstriction (airway narrowing) becomes predominant. Anti-inflammatory agents act at several points in this process. Cromolyn and nedocromil stabilize mast cells and nerve endings preventing initiation of the inflammatory process. Leukotriene antagonists block the production of leukotrienes, a potent mast cell messenger chemical, or block the transmission of their message to receptor cells. Corticosteroids stabilize blood vessels reducing vascular leakiness. They also restore sensitivity of receptor cells to beta-agonists and down-regulate the production and release of inflammatory chemicals. This results in decreased numbers of eosinophils in the airway walls. Corticosteroids have considerably greater anti-inflammatory activity than any of the other drugs. The result is a gradual resolution of the asthmatic condition. Since these drugs do not relax bronchial muscle, they don’t provide the immediate relief characteristic of bronchodilators. With regular and continued use of anti-inflammatory agents however, the need for bronchodilators is gradually reduced. Inhaled corticosteroids may trigger cough during an acute asthma attack. Oral prednisone may be substituted at such times. Anti-allergic Agents Madiators release inhibitors. No bronchodialator action but can prevent bronchoconstriction caused by a challenge with antigen to which the patient is allergic. The Cromones: Cromolyn & Nedocromil These agents act primarily to stabilize mast cells. They have an extraordinary safety record but high cost and the need for frequent dosing (four times daily for cromolyn, three times for nedocromil) limit their use. Cromolyn may require administration for up to a month before its protective effect is fully noted. Nedocromil is usually helpful within a few days. Neither drug is as potent as the inhaled corticosteroids. Another limiting factor of nedocromil (Tilade®) is its unpleasant aftertaste. Rinsing the mouth with water helps. Both drugs are good preventers of exercise-induced asthma when taken before activity. Because of their safety record, they are the drugs of first choice for children. Both are available as multidose inhalers. Cromolyn (Intal®) is approved for children as young as two years and is available in unit dose ampoules for nebulizer use. Disodium Cromoglycate (SCG) Mechanism of Action: 1. 2. 3. Stabilizer of mass cell membrane: decrease the release of mediators from mast cells. Inhibit the function of sensory nerve ending and neurogenic inflammation in airway. Decrease bronchial hyperreactivity. Ketotifen H1 receptor blocker. Prevent and inverse down-regulation of β2- receptor. Leukotriene Antagonists When mast cells become activated, they release a host of preformed chemical mediators which initiate an asthma attack consisting of increasing cough, wheeze, and difficulty breathing. The job of the mast cells is not complete with this act. Mast cells begin to produce a different mixture of chemical messengers even more potent than the first. This mix includes prostaglandins, thromboxanes, and leukotrienes. These biochemical messengers intensify and prolong the asthma episode. Leukotrienes are responsible for the intensification of the asthma episode, called the late phase, which often begins six to twelve hours after the onset of wheezing. A new class of anti-inflammatory drug, the leukotriene antagonists, consists of two subclasses, the leutins and the lukasts. Leutin-type drugs block the creation of leukotrienes. Lukast-type drugs attach to receptors for leukotrienes on cells thus blocking attachment and consequently preventing the effect of these potent asthma accelerators. Available agents in the United States include the leutin, zileutin (Zyflo®), and the lukasts zafirlukast (Accolate®) and montelukast (Singulair®). These agents are about as effective as the cromones and about half as effective as moderate doses of inhaled corticosteroids in controlling the symptoms of asthma. Montelukast may be taken once daily while zafirlukast must be taken twice a day. Moreover, administration of zafirlukast with food may affect its absorption from the gastrointestinal tract. Initially, zileutin must be taken four times a day. This may be decreased to three or even two times a day after a period of demonstrated effectiveness. For this class of medication, minor side-effects have been reported infrequently; major ones rarely. Both zileutin and zafirlukast may cause mild, reversible injury to the liver. Patients taking these medications should have liver function tests prior to initiating therapy and periodically thereafter. They should not be used in the presence of preexisting liver disease. Churge-Strauss Syndrome has been reported in some patients with severe asthma requiring daily oral corticosteroids whose chronic symptoms initially responded to zafirlukast and, in a few cases, to montelukast. Churge-Strauss Syndrome is a complex of symptoms that occur only in patients with severe asthma. When present, patients experience increasing symptoms of asthma as well as skin rash, bruising, and injury to internal organs that may include the kidney, liver, and heart. Because the treatment of this disorder is oral prednisone and its appearance in patients using lukasts is associated with intentionally reduced dosages of prednisone, it remains unclear whether the leukotriene antagonists cause Churge-Strauss or that the disorder, already present, is "unmasked" by reduction in daily prednisone use. Although the answer remains elusive, the former explanation seems the more plausable given the number of new cases of Churge-Strauss reported with Accolate® use. Prior to the introduction of the lukasts for the treatment of asthma this was a very rare disorder. Of the three agents, montelukast is by far the most convenient to use as it is administered once daily and can be taken with food or on an empty stomach. Zafirlukast taken twice daily should be taken at least one hour before or two hours after meals. Zileutin may be taken without regard to stomach contents but the need to dose four times a day makes compliance difficult. Singulair® is approved for adults and children six years of age or older. Accolate® and Zyflo® are not approved for children under twelve years of age. Anti-leukotriene agents Cysteinyl leukotrienes is a important inflammatory mediator: Bronchoconstriction, increased bronchial reactivity, mucosal edema, mucus hypersecretion, etc. Leukotrienes resulte from the action of 5lipoxygenase on arachidonic acid. Common agents: I. zafirlukast and montelukast: LTD4- receptor antagonists II. zileuton: 5-lipoxygenase inhibitor Glucocorticoids (GCs) Mechanism of Action: 1. Broad anti-inflammatory efficacy ① ② 2. Block the synthesis of arachidonic acid by phospholipase A2. Reduce bronchial reactivity. Increase the responsiveness of βadrenoceptors in the airway. Corticosteroids Routes of administration: Systemic administration: including oral and injection. More severe toxicity. Inhalation: Common inhalant GCs: FP, BDP, BUD, TAA, FNS Corticosteroids Continued use of inhaled corticosteroids reduces bronchial hyperreactivity. This means that for many patients asthma symptoms will disappear as will the need to use additional asthma medications. Use of these medications in children with asthma has been found to restore or preserve normal lung growth. Children with moderate asthma who don’t receive inhaled corticosteroids may reach adulthood with significantly smaller lungs. In adults with asthma, use of inhaled corticosteroids reduces the rate of lung tissue loss over time. A variety of agents are available for use. All are effective on a twice-daily routine. Azmacort® comes with its own built-in spacer but its small volume is not optimal. Aerobid® has a taste that some users find unpleasant. A menthol form, Aerobid-M® tastes better. Budesonide (Pulmicort®) is marketed as a multidose, dry powder inhaler that provides precision dosing without a Freon® propellant. Step-wise approach to the treatment of asthma according to recent guidelines. LTRA, leukotriene receptor antagonist; SR, slow release. The dose of inhaled corticosteroids refers to beclomethasone dipropionate Bronchitis 1) Inflammation of the mucous membrane of the bronchial tubes 2) asthmatic bronchitis, bronchitis which causes or aggravates bronchospasm. 3) chronic bronchitis, a condition of the bronchial tree characterized by cough, hypersecretion of mucus, and expectoration of sputum over a long period of time, associated with frequent bronchial infection; usually due to inhalation, over a prolonged period, of air contaminated by dust or by noxious gases of combustion. 4) Acute bronchitis is usually a short, severe illness that may show up along with a cold or follow other viral infections such as measles or whooping cough. Pathology The top left illustration shows the normal pulmonary tree, while the lower right illustration at the bottom shows what happens during an attack of bronchitis. The inflammation of the bronchi and bronchial tubes produces a buildup of mucus. The thickened mucus forms a plug that can block bronchial tubes, the passages that carry air from the trachea (windpipe) to the alveoli (air sacs) of the lungs. This results in the difficult breathing characteristic of bronchitis Bronchitis Bronchitis. Treatment Routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough. If pertussis infection is suspected (an unusual circumstance), a diagnostic test should be performed and antimicrobial therapy initiated Bronchitis Difference Between Pneumonia and Bronchitis Both bronchitis and pneumonia are serious diseases affecting the lower respiratory tract. They can lead to a lot of discomforts and, if left untreated, may cause other serious conditions. There are a number of differences between the two. Symptoms Pneumonia manifests itself in the Bronchitis manifests itself form of high fever, cough and as a cough with headache, chills. It is accompanied by rapid breathing and a certain amount of chills and a slight fever. A wheezing. The patient often patient may also complains of chest pain. Some experience a shortness of patients also feel extremely breath. exhausted and nauseous. The symptoms of viral pneumonia often resemble those of ordinary flu. There are chills and high fever. It is often accompanied by chattering teeth. It may also produce sputum that is green, yellow or rust colored. Pneumonia becomes apparent when the patient experiences a shortness of breath. Reasons Pneumonia and bronchitis are caused by different factors. Bronchitis occurs when there is an inflammation of the bronchial tubes. It may be caused by a number of factors, including a bacterial or viral infection. It is also caused by irritation originating from pollution and smoke. Bronchitis may be chronic or acute in nature. Chronic bronchitis occurs over a period of time. Acute bronchitis may last for a few days. However, it is usually cured with the help of antibiotics. Pneumonia is caused by an infection of the lungs. It may be caused by bacteria, fungi or by a virus. It usually affects people over the age of 65, or people who have had their immune systems compromised. Differences in treatment The treatment for bronchitis is relatively simple. Once identified the reasons for the infection, a course of antibiotics will be administered. Patient will be advised rest and will need to avoid pollution and smoke. Pneumonia is more of a serious affliction. If the patient have been diagnosed with this disease, will be prescribed a strong antiviral or antibiotics. If the condition worsens, the patient may be hospitalized anywhere between one and three days, depending on the seriousness of condition. Medications: Dozens of antibiotics are available for treating pneumonia, but selecting the best drug is sometimes difficult. Patients with pneumonia need an antibiotic that is effective against the organism causing the disease. When the organism is unknown, "empiric therapy" is given, meaning the doctor chooses which antibiotic is likely to work based on factors such as the patient's age, health, and severity of the illness. In determining the appropriate antibiotic, the physician must first answer a number of questions: How severe is the pneumonia? Mild-to-moderate cases can be treated at home with oral antibiotics. Severe pneumonia usually needs intravenous antibiotics administered in the hospital. If the organism causing the pneumonia is not known, was the disorder community- or hospital-acquired? Different organisms are usually involved in each setting, and the physician can use this information to guess the most likely organism causing the pneumonia. If the organism is known, is it typical or atypical? Community-acquired pneumonias, for example, are usually caused by the typical bacteria Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, which were previously treated with related antibiotics. These antibiotics do not treat organisms such as legionella, mycoplasma, or chlamydia. These organisms are generally treated with a macrolide or possibly a newer quinolone. Does the patient have an impaired immune system? Antibiotics used to treat such patients may differ from those used in patients with healthy immune systems. Antibiotic Treatments for Community-Acquired Pneumonia Joint guidelines issued in 2007 by the Infectious Disease Society of America and the American Thoracic Society (ITSA/ATS) recommend that mild CAP in otherwise healthy patients be treated with oral macrolide antibiotics (azithromycin, clarithromycin, or erythromycin). Many patients with heart disease, kidney disease, diabetes, or other co-existing conditions may still be treated as outpatients. However, they should be given a fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin) or a beta-lactam (preferably high-dose amoxicillin or amoxicillin-clavulanate), plus a macrolide, unless they live in an area with high S. pneumoniae resistance to macrolides. Antibiotic Treatments for Community-Acquired Pneumonia Current recommendations call for 7 - 10 days of treatment for S. pneumoniae and 10 - 14 days for Mycoplasma pneumoniae and Chlamydia pneumoniae. However, some research suggests that patients with mild-to-moderate community-acquired pneumonia may be successfully treated with 7 days or less of antibiotics. The shorter treatment may increase patient tolerance, and improve the likelihood that patients will stick to the treatment regimen. It will also help limit the growing problem of antibiotic resistance. Antibiotic Treatments for Community-Acquired Pneumonia Many cases of community-acquired pneumonia are caused by S. pneumoniae -- Gram-positive bacteria that usually respond to antibiotics known as beta-lactams (which include penicillin), and to macrolides. However, resistant strains of S. pneumoniae are increasingly common. Most resistant strains respond to fluoroquinolines such as levofloxacin (Levaquin), gemifloxacin (Factive), or moxifloxacin (Avelox). Another common cause of community-acquired pneumonia is H. influenzae. In addition, other important causes of CAP, particularly in younger people, are atypical bacteria, which respond to macrolides (erythromycin, clarithromycin, or azithromycin), ketolides, or newer fluoroquinolones. Antibiotic treatment for CAP is determined by a number of factors, including: The patient's history of antibiotic therapy Co-existing diseases (such as COPD, diabetes, and heart failure) Whether the patient is well enough to be treated at home or requires hospitalization or nursing home care. Treatment options can include a single drug, such as levofloxacin or doxycycline, or combination treatment, such as a macrolide administered with a beta-lactam. Antibiotics taken by mouth are generally enough for patients whose CAP is mild enough to be treated at home. Intravenous antibiotics are required for hospitalized patients with CAP. Antibiotic therapy should be given for a minimum of 5 days -longer if the patient still has a fever and more than one sign of continuing severe illness. Treatment of Viral Infections There are not as many choices for treating viral pneumonia. Oseltamivir (Tamiflu) and zanamivir (Relenza) have been the recommended drugs for influenza A or B infections, but many strains of influenza A have become resistant. Their use is only recommended if they are started in the first 48 hours of symptoms. Taken early, these medications may be effective in reducing symptoms and duration of illness. Treatment of Viral Infections Patients with viral pneumonias are at risk for what are called "superinfections," which generally refers to a secondary bacterial infection, usually caused by S. pneumoniae, S. aureus, or H. influenzae. Doctors most commonly recommend treatment with amoxicillin-clavulanate, cefpodoxime, cefprozil, cefuroxime, or a respiratory fluoroquinolone if these secondary infections occur. Patients with pneumonia caused by varicella-zoster and herpes simplex viruses are usually admitted to the hospital and treated with intravenous acyclovir for 7 days. No antiviral drugs have been proven effective in adults with RSV, parainfluenza virus, adenovirus, metapneumovirus, the SARS coronavirus, or hantavirus. Treatment is largely supportive, with patients receiving oxygen and ventilator therapy as needed. Treatment of RSV in Children. Ribavarin is the first treatment approved for RSV pneumonia, although it has only modest benefits. The American Academy of Pediatrics recommends this drug for children who are at high risk for serious complications of RSV. Chronic Bronchitis. The irregular bronchovascular structures Chronic Bronchitis. Chest film and magnified view from right middle/upper lung field. Irregular contours of bronchovascular structures with irregular diameters. A segmental pneumonia of s9 of right lower lobe shows alveolar densities. Lobar pneumonia in the right upper lobe EXPECTORANTS AND ANTITUSSIVES Expectorants, more accurately known as bronchomucotropic agents, are drugs used to assist in the removal of secretions or exudate from the trachea, bronchi, or lungs. They act by liquifying viscid mucus or mucopurulent exudates, i.e., they are decongestants. Therefore, they are used in the treatment of coughs to help expel these exudates and secretions. Antitussives are agents that specifically inhibit or su ppress the act of coughing. They should not be used to suppress productive cough ing. Expectorants and antitussives are most commonly used in the symptomatic treatment of the common cold or bronchitis. ANTITUSSIVES Coughing is the forceful expulsion of air from the lungs. A cough may be productive or nonproductive. With a productive cough, secretions from the lower respiratory tract are expelled. A nonproductive cough is a dry, hacking one that produces no secretions. An antitussive is a drug used to relieve coughing. Many antitussive drugs are combined with another drug, such as an antihistamine or expectorant, and sold as nonprescription cough medicine. Other antitussives, either alone or in combination with other drugs, are available by prescription only. ACTIONS Some antitussives depress the cough center located in the medulla and are called centrally acting drugs. Codeine and dextromethorphan are examples of centrally acting antitussives. Other antitussives are peripherally acting drugs, which act by anesthetizing stretch receptors in the respiratory passages, thereby decreasing coughing. An example of a peripherally acting antitussive is benzonatate (Tessalon), libexin. ANTITUSSIVES (cont’d) USES Antitussives are used to relieve a nonproductive cough.When the cough is productive of sputum, it should be treated by the primary health care provider who, based on a physical examination, may or may not prescribe or recommend an antitussive. ADVERSE REACTIONS Use of codeine may result in respiratory depression, euphoria, lightheadedness, sedation, nausea, vomiting,and hypersensitivity reactions. The more common adverse reactions associated with the antitussives When used as directed, nonprescription cough medicines containing two or more ingredients have few adverse reactions. However, those that contain an antihistamine may cause drowsiness. CONTRAINDICATIONS Antitussives are contraindicated in patients with known hypersensitivity to the drugs. The narcotic antitussives (those with codeine) are contraindicated in premature infants or during labor when delivery of a premature infant is anticipated. Codeine is a Pregnancy Category C drug except in the pregnant woman at term or when taken for extended periods, when it is considered a Pregnancy Category D drug. ANTITUSSIVES Classification: 一. 1. 2. 二. Central antitussives Dependent central antitussives Independent central antitussives Peripheral antitussives Dependent Central Antitussives Opioid alkaloids. Morphine is the most effective drug for the suppression of cough, but have addiction. Mechanism: suppressing of cough center Codeine Selectively suppress cough center in medulla oblongata Potency: Suppression of cough: ≈1/10 of morphine Analgesia: ≈1/7 of morphine Respiratory depression, constipation, tolerance, dependence < that of morphine Pharmacokinetics: Clinical Uses: Well absorbed from oral and injection. 10% converted to morphine through demethylation Dry cough Adverse Reactions: Respiratory suppression in high dose; Tolerance and physical dependence with frequently repeated administration; Suppress secretion of bronchial gland and movement of cilia. Independent Central Antitussives Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability. Classification: 1) 2) 3) 4) 5) -orphan-antitussives : dextromethorphan amido-antitussives: pentoxyverine, clofedanol piperidine-antitussives: cloperastine morpholine-antitussives: promolate, fominoben; others: eprazinone, zipeprol. Dextromethorphan Dextrorotatory stereoisomers of a methylated derivative of levorphanol Clinical Use: Dry cough. Often + Antihistamine drug Pentoxyverine Suppression of cough: ≈1/3 of codeine. Direct suppression of cough center Atropine-like action and local anesthesia action. Cloperastine Derivative of diphenhydramine Suppression of cough center Blocking H1-receptor Peripheral Antitussives Inhibiting receptor, afferent nerve, efferent nerve of cough reflex arc → cough suppression. 1. 2. local anesthesia action: narcotine, benzonatate; Alleviative action: extractum glycyrrhizae liquidum, Syrup Expectorants Mucokinetic drugs Classification: By the mechanism of action: I. 1. 2. Mucus secretagogue drugs: stimulating gastric mucosa → reflex secretion of bronchial gland↑ → dilution of sputum: ammonium chloride. Mucolytic drugs: 1) 2) 3) 4) break acid mucin: bromhexine drug-SH S-S of mucin → Fragmentation: acetylcysteine Enzymolysis: α-chymotrypsin Surfactant: tyloxapol----Fog inhalation By route of administration: II. 1. Oral drugs: 2. Fog inhalation drugs: 1.8%NaCl, 2%~7.5%NaHCO3.