CLINICAL PHARMACY IN CLINICAL PHARMACY IN PULMONOLOGY PULMONOLOGY

IntroductionIntroduction

Symptom of respiratory system:Symptom of respiratory system:

nono sputumsputum---antitussives---antitussives CoughCough

sputumsputum --- expectorants --- expectorants

AsthmaAsthma ----- antiasthmatic drugs ----- antiasthmatic drugs

Bronchial asthmaBronchial asthmaBronchial asthmaBronchial asthma is a disease is a disease

caused by increased responsiveness of the caused by increased responsiveness of the tracheobronchial tree to various stimuli. tracheobronchial tree to various stimuli. The result is paroxysmal constriction of the The result is paroxysmal constriction of the bronchial airways. Bronchial asthma is the bronchial airways. Bronchial asthma is the more correct name for the common form more correct name for the common form of asthma. The term 'bronchial' is used to of asthma. The term 'bronchial' is used to differentiate it from 'cardiac' asthma, differentiate it from 'cardiac' asthma, which is a separate condition that is which is a separate condition that is causedcaused by heart failure. Although the two by heart failure. Although the two types of asthma have similar symptoms, types of asthma have similar symptoms, including wheezing (a whistling sound in including wheezing (a whistling sound in the chest) and shortness of breath, they the chest) and shortness of breath, they have quite different causes. have quite different causes.

Bronchial asthmaBronchial asthma (cont’d) (cont’d)Bronchial Bronchial asthmaasthma is a disease of the is a disease of the

lungs in which an obstructive ventilation lungs in which an obstructive ventilation disturbance of the respiratory passages disturbance of the respiratory passages evokes a feeling of shortness of breath. The evokes a feeling of shortness of breath. The cause is a sharply elevated resistance to cause is a sharply elevated resistance to airflow in the airways. Despite its most airflow in the airways. Despite its most strenuous efforts, the respiratory strenuous efforts, the respiratory musculature is unable to provide sufficient musculature is unable to provide sufficient gas exchange. The result is a characteristic gas exchange. The result is a characteristic asthma attack, with spasms of the bronchial asthma attack, with spasms of the bronchial musculature, edematous swelling of the musculature, edematous swelling of the bronchial wall and increased mucus bronchial wall and increased mucus secretion. secretion.

AsthmaAsthma

Pathophysiology:Pathophysiology: Asthma is a disease characterized by Asthma is a disease characterized by

airway inflammation and episodic, airway inflammation and episodic, reversible bronchospasmreversible bronchospasm

Two characteristic features:Two characteristic features:1)1) Inflammatory changes in the airway;Inflammatory changes in the airway;

2)2) Bronchial hyperreactivity to stimuli.Bronchial hyperreactivity to stimuli.

Important mediators: histamine, LTCImportant mediators: histamine, LTC44, , LTDLTD44, etc., etc.

Bronchial asthmaBronchial asthma Symptoms can occur spontaneously or can be Symptoms can occur spontaneously or can be

triggered by respiratory infections, exercise, cold air, triggered by respiratory infections, exercise, cold air, tobacco smoke or other pollutants, stress or anxiety, tobacco smoke or other pollutants, stress or anxiety, or by food allergies or drug allergies. The muscles of or by food allergies or drug allergies. The muscles of the bronchial tree become tight and the lining of the the bronchial tree become tight and the lining of the air passages become swollen, reducing airflow and air passages become swollen, reducing airflow and producing the wheezing sound. Mucus production is producing the wheezing sound. Mucus production is increased. increased.

Typically, the individual usually breathes relatively Typically, the individual usually breathes relatively normally, and will have periodic attacks of wheezing. normally, and will have periodic attacks of wheezing. Asthma attacks can last minutes to days, and can Asthma attacks can last minutes to days, and can become dangerous if the airflow becomes severely become dangerous if the airflow becomes severely restricted. Asthma affects 1 in 20 of the overall restricted. Asthma affects 1 in 20 of the overall population, but the incidence is 1 in 10 in children. population, but the incidence is 1 in 10 in children. Asthma can develop at any age, but some children Asthma can develop at any age, but some children seem to outgrow the illness. Risk factors include self seem to outgrow the illness. Risk factors include self or family history of eczema, allergies or family history or family history of eczema, allergies or family history of asthma. Bronchial asthma causes cough, shortness of asthma. Bronchial asthma causes cough, shortness of breath, and wheezing. Bronchial asthma is an of breath, and wheezing. Bronchial asthma is an allergic condition, in which the airways (bronchi) are allergic condition, in which the airways (bronchi) are hyper-reactive and constrict abnormally when exposed hyper-reactive and constrict abnormally when exposed to allergens, cold or exercise.to allergens, cold or exercise.

Bronchial asthmaBronchial asthma Treatment is aimed at avoiding known Treatment is aimed at avoiding known

allergens and controlling symptoms through allergens and controlling symptoms through medication. A variety of medications for medication. A variety of medications for treatment of asthma are available. People treatment of asthma are available. People with mild asthma (infrequent attacks) may with mild asthma (infrequent attacks) may use inhalers on an as-needed basis. Persons use inhalers on an as-needed basis. Persons with significant asthma (symptoms occur at with significant asthma (symptoms occur at least every week) should be treated with least every week) should be treated with anti-inflammatory medications, preferably anti-inflammatory medications, preferably inhaled corticosteroids, and then with inhaled corticosteroids, and then with bronchodilators such as inhaled Alupent or bronchodilators such as inhaled Alupent or Vanceril. Acute severe asthma may require Vanceril. Acute severe asthma may require hospitalization, oxygen, and intravenous hospitalization, oxygen, and intravenous medications. medications.

Antiasthmatic DrugsAntiasthmatic Drugs

I.I. BronchodilatorsBronchodilators1.1. β receptor agonistsβ receptor agonists2.2. TheophyllineTheophylline3.3. Muscarinic antagonistsMuscarinic antagonists

II.II. Anti-inflammatory agentsAnti-inflammatory agents1.1. SteroidsSteroids2.2. Anti-leukotriene agentsAnti-leukotriene agents

III.III. Anti-allergic agentsAnti-allergic agents1.1. Stabilizer of inflammatory cell membraneStabilizer of inflammatory cell membrane

2.2. HH11 receptor blocker receptor blocker

Beta Adrenoceptor AgonistsBeta Adrenoceptor Agonists Adrenaline: α,β agonistAdrenaline: α,β agonist Ephedrine: α,β agonistEphedrine: α,β agonist IsoprenalineIsoprenaline ：： ββ11 ,β ,β22 agonist agonist ββ22-selective agonists-selective agonists

Salbutamol:Salbutamol: Terbutaline : Terbutaline : Clenbuterol:Clenbuterol: Formoterol:Formoterol: Salmeterol:Salmeterol: Bambuterol:Bambuterol:

intermediate-acting

long-actinglong-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 βAdverse Reactions of β22 agonists: agonists:

1)1) Skeletal muscle tremorSkeletal muscle tremor

2)2) Cardiac effectCardiac effect: tachycardia, arrhymias: tachycardia, arrhymias

3)3) Metabolism disturbanceMetabolism disturbance: ketone : ketone

bodies↑, acidosis, [Kbodies↑, acidosis, [K++]]oo↓ ↓

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.

TheophyllineTheophylline

Methylxanthine derivatives.Methylxanthine derivatives. Mechanism of ActionMechanism of Action::

1.1. Inhibit phosphdiesterase (PDE);Inhibit phosphdiesterase (PDE);2.2. Block adenosine receptors;Block adenosine receptors;3.3. Increase endogenous catecholamine Increase endogenous catecholamine

(CA) releasing;(CA) releasing;4.4. Interfere with receptor-operated CaInterfere with receptor-operated Ca2+2+

channels → [Cachannels → [Ca2+2+]]ii↓;↓;5.5. Anti-inflammatory actionAnti-inflammatory action

Clinical UseClinical Use::1.1. Asthma: Asthma: maintenance treatmentmaintenance treatment

2.2. Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD)(COPD)

3.3. Central sleep apnea (CSA)Central sleep apnea (CSA) Adverse ReactionsAdverse Reactions::

Narrow margin of safety. Toxic effects are related Narrow margin of safety. Toxic effects are related to its plasma concentrations.to its plasma concentrations.

Gastrointestinal distress, tremor, and insomnia. Gastrointestinal distress, tremor, and insomnia. Cardiac arrhythmias, convulsions → lethal.Cardiac arrhythmias, convulsions → lethal.

Muscarinic AntagonistsMuscarinic Antagonists

There are MThere are M11, M, M22, M, M33 receptor subtype receptor subtype in the airway. in the airway.

Selectively blocking MSelectively blocking M11, M, M3 3 receptor is receptor is resulted in bronchodilating effect.resulted in bronchodilating effect.

Ipratropium bromideIpratropium bromide binds to all M-R binds to all M-R subtypes (Msubtypes (M11, M, M22 and M and M33 ), and inhibits ), and inhibits acetylcholine-mediated acetylcholine-mediated bronchospasm. 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. Stabilizer of mass cell membrane: decrease

the release of mediators from mast cells.

2. Inhibit the function of sensory nerve ending and neurogenic inflammation in airway.

3. Decrease bronchial hyperreactivity.

Ketotifen

H1 receptor blocker.

Prevent and inverse down-regulation of β2-receptor.

Leukotriene AntagonistsLeukotriene Antagonists When mast cells become activated, they release a host of When mast cells become activated, they release a host of

preformed chemical mediators which initiate an asthma attack preformed chemical mediators which initiate an asthma attack consisting of increasing cough, wheeze, and difficulty breathing. consisting of increasing cough, wheeze, and difficulty breathing. The job of the mast cells is not complete with this act. Mast The job of the mast cells is not complete with this act. Mast cells begin to produce a different mixture of chemical cells begin to produce a different mixture of chemical messengers even more potent than the first. This mix includes messengers even more potent than the first. This mix includes prostaglandins, thromboxanes, and leukotrienes. These prostaglandins, thromboxanes, and leukotrienes. These biochemical messengers intensify and prolong the asthma biochemical messengers intensify and prolong the asthma episode. Leukotrienes are responsible for the intensification of episode. Leukotrienes are responsible for the intensification of the asthma episode, called the the asthma episode, called the late phaselate phase, which often begins , which often begins six to twelve hours after the onset of wheezing.six to twelve hours after the onset of wheezing.

A new class of anti-inflammatory drug, the leukotriene A new class of anti-inflammatory drug, the leukotriene antagonists, consists of two subclasses, the antagonists, consists of two subclasses, the leutinsleutins and the and the lukastslukasts. Leutin-type drugs block the creation of leukotrienes. . Leutin-type drugs block the creation of leukotrienes. Lukast-type drugs attach to receptors for leukotrienes on cells Lukast-type drugs attach to receptors for leukotrienes on cells thus blocking attachment and consequently preventing the thus blocking attachment and consequently preventing the effect of these potent asthma accelerators. Available agents in effect of these potent asthma accelerators. Available agents in the United States include the leutin, zileutin (Zyflo®), and the the United States include the leutin, zileutin (Zyflo®), and the lukasts zafirlukast (Accolate®) and montelukast (Singulair®). lukasts zafirlukast (Accolate®) and montelukast (Singulair®). These agents are about as effective as the cromones and about These agents are about as effective as the cromones and about half as effective as moderate doses of inhaled corticosteroids in half as effective as moderate doses of inhaled corticosteroids in controlling the symptoms of asthma.controlling the symptoms of asthma.

Montelukast may be taken once daily while zafirlukast must be Montelukast may be taken once daily while zafirlukast must be taken twice a day. Moreover, administration of zafirlukast with taken twice a day. Moreover, administration of zafirlukast with food may affect its absorption from the gastrointestinal tract. food may affect its absorption from the gastrointestinal tract. Initially, zileutin must be taken four times a day. This may be 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 decreased to three or even two times a day after a period of demonstrated effectiveness. demonstrated effectiveness.

For this class of medication, minor side-effects have been For this class of medication, minor side-effects have been reported infrequently; major ones rarely. Both zileutin and reported infrequently; major ones rarely. Both zileutin and zafirlukast may cause mild, reversible injury to the liver. Patients zafirlukast may cause mild, reversible injury to the liver. Patients taking these medications should have liver function tests prior to taking these medications should have liver function tests prior to initiating therapy and periodically thereafter. They should not be initiating therapy and periodically thereafter. They should not be used in the presence of preexisting liver disease. used in the presence of preexisting liver disease. Churge-Strauss Churge-Strauss SyndromeSyndrome has been reported in some patients with severe has been reported in some patients with severe asthma requiring daily oral corticosteroids whose chronic asthma requiring daily oral corticosteroids whose chronic symptoms initially responded to zafirlukast and, in a few cases, to symptoms initially responded to zafirlukast and, in a few cases, to montelukast. Churge-Strauss Syndrome is a complex of symptoms montelukast. Churge-Strauss Syndrome is a complex of symptoms that occur only in patients with severe asthma. When present, that occur only in patients with severe asthma. When present, patients experience increasing symptoms of asthma as well as patients experience increasing symptoms of asthma as well as skin rash, bruising, and injury to internal organs that may include skin rash, bruising, and injury to internal organs that may include the kidney, liver, and heart. Because the treatment of this the kidney, liver, and heart. Because the treatment of this disorder is oral prednisone and its appearance in patients using disorder is oral prednisone and its appearance in patients using lukasts is associated with intentionally reduced dosages of lukasts is associated with intentionally reduced dosages of prednisone, it remains unclear whether the leukotriene prednisone, it remains unclear whether the leukotriene antagonists cause Churge-Strauss or that the disorder, already antagonists cause Churge-Strauss or that the disorder, already present, is "unmasked" by reduction in daily prednisone use. present, is "unmasked" by reduction in daily prednisone use. Although the answer remains elusive, the former explanation Although the answer remains elusive, the former explanation seems the more plausable given the number of new cases of seems the more plausable given the number of new cases of Churge-Strauss reported with Accolate® use. Prior to the Churge-Strauss reported with Accolate® use. Prior to the introduction of the lukasts for the treatment of asthma this was a introduction of the lukasts for the treatment of asthma this was a very rare disorder.very rare disorder.

Of the three agents, montelukast is by far the most convenient to 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 use as it is administered once daily and can be taken with food or on an empty stomach. Zafirlukast taken twice daily should be on an empty stomach. Zafirlukast taken twice daily should be taken at least one hour before or two hours after meals. Zileutin taken at least one hour before or two hours after meals. Zileutin may be taken without regard to stomach contents but the need to may be taken without regard to stomach contents but the need to dose four times a day makes compliance difficult. Singulair® is dose four times a day makes compliance difficult. Singulair® is approved for adults and children six years of age or older. approved for adults and children six years of age or older. Accolate® and Zyflo® are not approved for children under twelve Accolate® and Zyflo® are not approved for children under twelve years of age. years of age.

Anti-leukotriene agentsAnti-leukotriene agents

Cysteinyl leukotrienes is a important Cysteinyl leukotrienes is a important inflammatory mediator:inflammatory mediator: BronchoconstrictionBronchoconstriction, , increased bronchial increased bronchial

reactivityreactivity, , mucosal edemamucosal edema, , mucus mucus hypersecretionhypersecretion, etc., etc.

Leukotrienes resulte from the action Leukotrienes resulte from the action of 5-lipoxygenase on arachidonic of 5-lipoxygenase on arachidonic acid. acid.

Common agents:Common agents:

I.I. zafirlukastzafirlukast and and montelukastmontelukast: :

LTDLTD44-receptor antagonists-receptor antagonists

II.II. zileutonzileuton: 5-lipoxygenase inhibitor: 5-lipoxygenase inhibitor

Glucocorticoids (GCs)Glucocorticoids (GCs)

Mechanism of ActionMechanism of Action::1.1. Broad anti-inflammatory efficacyBroad anti-inflammatory efficacy

①① Block the synthesis of arachidonic acid by Block the synthesis of arachidonic acid by phospholipase Aphospholipase A22..

②② Reduce bronchial reactivity.Reduce bronchial reactivity.

2.2. Increase the responsiveness of β-Increase the responsiveness of β-adrenoceptors in the airway.adrenoceptors in the airway.

Corticosteroids

Routes of administrationRoutes of administration:: Systemic administrationSystemic administration: including oral : including oral

and injection. More severe toxicity.and injection. More severe toxicity. InhalationInhalation: :

Common inhalant GCsCommon inhalant GCs:: FP, BDP, BUD, TAA, FNSFP, 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

BronchitisBronchitis 1) 1) Inflammation of the mucous membrane of the Inflammation of the mucous membrane of the

bronchial tubesbronchial tubes2) 2) asthmatic bronchitisasthmatic bronchitis, bronchitis which causes or , bronchitis which causes or aggravates bronchospasm.aggravates bronchospasm.3) 3) chronic bronchitischronic bronchitis, a condition of the bronchial , a condition of the bronchial tree characterized by cough, hypersecretion of tree characterized by cough, hypersecretion of mucus, and expectoration of sputum over a long mucus, and expectoration of sputum over a long period of time, associated with frequent bronchial period of time, associated with frequent bronchial infection; usually due to inhalation, over a infection; usually due to inhalation, over a prolonged period, of air contaminated by dust or by prolonged period, of air contaminated by dust or by noxious gases of combustion.noxious gases of combustion.4) 4) Acute bronchitisAcute bronchitis is usually a short, severe illness is usually a short, severe illness that may show up along with a cold or follow other that may show up along with a cold or follow other viral infections such as measles or whooping cough.viral infections such as measles or whooping cough.

PathologyPathology The top left illustration The top left illustration

shows the normal shows the normal pulmonary tree, while the pulmonary tree, while the lower right illustration at lower right illustration at the bottom shows what the bottom shows what happens during an attack happens during an attack of bronchitis. The of bronchitis. The inflammation of the inflammation of the bronchi and bronchial bronchi and bronchial tubes produces a buildup tubes produces a buildup of mucus. The thickened of mucus. The thickened mucus forms a plug that mucus forms a plug that can block bronchial tubes, can block bronchial tubes, the passages that carry air the passages that carry air from the trachea from the trachea (windpipe) to the alveoli (windpipe) to the alveoli (air sacs) of the lungs. (air sacs) of the lungs. This This results in the difficult results in the difficult breathing characteristic of breathing characteristic of bronchitisbronchitis

BronchitisBronchitis

BronchitisBronchitis.. Treatment Treatment

Routine antibiotic treatment of Routine antibiotic treatment of uncomplicated acute bronchitis is uncomplicated acute bronchitis is not recommended, regardless of not recommended, regardless of duration of cough. If duration of cough. If pertussispertussis infection is suspected (an unusual infection is suspected (an unusual circumstance), a diagnostic test circumstance), a diagnostic test should be performed and should be performed and antimicrobial therapy initiatedantimicrobial therapy initiated

BronchitisBronchitis

Difference Between Difference Between Pneumonia and BronchitisPneumonia and Bronchitis

Both bronchitis and pneumonia are Both bronchitis and pneumonia are serious diseases affecting the lower serious diseases affecting the lower respiratory tract. They can lead to a respiratory tract. They can lead to a lot of discomforts and, if left lot of discomforts and, if left untreated, may cause other serious untreated, may cause other serious conditions. There are a number of conditions. There are a number of differences between the two. differences between the two.

SymptomsSymptoms

Pneumonia manifests itself Pneumonia manifests itself in the form of high fever, in the form of high fever, cough and chills. It is cough and chills. It is accompanied by rapid accompanied by rapid breathing and a certain breathing and a certain amount of wheezing. The amount of wheezing. The patient often complains of patient often complains of chest pain. Some patients chest pain. Some patients also feel extremely also feel extremely exhausted and nauseous. exhausted and nauseous. The symptoms of viral The symptoms of viral pneumonia often resemble pneumonia often resemble those of ordinary those of ordinary fluflu. There . There are chills and high fever. It are chills and high fever. It is often accompanied by is often accompanied by chattering teeth. It may also chattering teeth. It may also produce sputum that is produce sputum that is green, yellow or rust green, yellow or rust colored. Pneumonia colored. Pneumonia becomes apparent when the becomes apparent when the patient experiences a patient experiences a shortness of breath.shortness of breath.

Bronchitis Bronchitis manifests itself as a manifests itself as a cough with cough with headache, chills and headache, chills and a slight fever. A a slight fever. A patient may also patient may also experience a experience a shortness of breath. shortness of breath.

ReasonsReasons Pneumonia and bronchitis Pneumonia and bronchitis

are caused by are caused by different different factorsfactors. Bronchitis occurs . Bronchitis occurs when there is an when there is an inflammation of the inflammation of the bronchial tubes. It may be bronchial tubes. It may be caused by a number of caused by a number of factors, including a factors, including a bacterial or viral bacterial or viral infection.infection. It is also caused It is also caused by irritation originating by irritation originating from from pollutionpollution and and smokesmoke. . Bronchitis may be chronic Bronchitis may be chronic or acute in nature. or acute in nature. Chronic bronchitis occurs Chronic bronchitis occurs over a period of time. over a period of time. Acute bronchitis may last Acute bronchitis may last for a few days. However, it for a few days. However, it is usually cured with the is usually cured with the help of antibiotics. help of antibiotics.

Pneumonia is caused by Pneumonia is caused by an infection of the an infection of the lungs. It may be caused lungs. It may be caused by by bacteriabacteria, , fungifungi or by a or by a virusvirus. It usually affects . It usually affects people over the age of people over the age of 65, or people who have 65, or people who have had their immune had their immune systems compromised.systems compromised.

Differences in treatmentDifferences in treatment The treatment for bronchitis The treatment for bronchitis

is relatively simple. Once is relatively simple. Once identified the reasons for the identified the reasons for the infection, a course of infection, a course of antibiotics will be antibiotics will be administered. Patient will be administered. Patient will be advised rest and will need to advised rest and will need to avoid pollution and smoke. avoid pollution and smoke.

Pneumonia is more of a Pneumonia is more of a serious affliction. If the serious affliction. If the patient have been diagnosed patient have been diagnosed with this disease, will be with this disease, will be prescribed a strong antiviral prescribed a strong antiviral or antibiotics. If the condition or antibiotics. If the condition worsens, the patient may be worsens, the patient may be hospitalized anywhere hospitalized anywhere between one and three days, between one and three days, depending on the seriousness depending on the seriousness of condition.of condition.

Medications:Medications: Dozens of antibiotics are Dozens of antibiotics are

available for treating available for treating pneumonia, but selecting pneumonia, but selecting the best drug is sometimes the best drug is sometimes difficult. Patients with difficult. Patients with pneumonia need an pneumonia need an antibiotic that is effective antibiotic that is effective against the organism against the organism causing the disease. When causing the disease. When the organism is unknown, the organism is unknown, "empiric therapy""empiric therapy" is given, is given, meaning the doctor meaning the doctor chooses which antibiotic is chooses which antibiotic is likely to work based on likely to work based on factors such as the factors such as the patient's age, health, and patient's age, health, and severity of the illness.severity of the illness.

In determining the appropriate In determining the appropriate antibiotic, the physician must first antibiotic, the physician must first

answer a number of questions:answer a number of questions:

How severe is the pneumonia? Mild-to-How severe is the pneumonia? Mild-to-moderate cases can be treated at home with moderate cases can be treated at home with oral antibiotics. Severe pneumonia usually oral antibiotics. Severe pneumonia usually needs intravenous antibiotics administered in needs intravenous antibiotics administered in the hospital.the hospital.

If the organism causing the pneumonia is not If the organism causing the pneumonia is not known, was the disorder community- or known, was the disorder community- or hospital-acquired? Different organisms are hospital-acquired? Different organisms are usually involved in each setting, and the usually involved in each setting, and the physician can use this information to guess the physician can use this information to guess the most likely organism causing the pneumonia.most likely organism causing the pneumonia.

If the organism is known, is it typical or If the organism is known, is it typical or atypical? atypical? Community-acquired pneumoniasCommunity-acquired pneumonias, , for example, are usually caused by the typical for example, are usually caused by the typical bacteria bacteria Streptococcus pneumoniaeStreptococcus pneumoniae, , Haemophilus influenzaeHaemophilus influenzae, or , or Moraxella Moraxella catarrhaliscatarrhalis, which were previously treated , which were previously treated with related antibiotics. These antibiotics do with related antibiotics. These antibiotics do not treat organisms such as legionella, not treat organisms such as legionella, mycoplasma, or chlamydia. These organisms mycoplasma, or chlamydia. These organisms are generally treated with a macrolide or are generally treated with a macrolide or possibly a newer quinolone.possibly a newer quinolone.

Does the patient have an impaired immune Does the patient have an impaired immune system? Antibiotics used to treat such system? Antibiotics used to treat such patients may differ from those used in patients may differ from those used in patients with healthy immune systems.patients with healthy immune systems.

Antibiotic Treatments for Antibiotic Treatments for Community-Acquired Community-Acquired

PneumoniaPneumonia Joint guidelines issued in 2007 by the Infectious Joint guidelines issued in 2007 by the Infectious

Disease Society of America and the American Disease Society of America and the American Thoracic Society (ITSA/ATS) recommend that Thoracic Society (ITSA/ATS) recommend that mild CAP in otherwise healthy patients be treated mild CAP in otherwise healthy patients be treated with oral macrolide antibiotics (azithromycin, with oral macrolide antibiotics (azithromycin, clarithromycin, or erythromycin).clarithromycin, or erythromycin).

Many patients with heart disease, kidney disease, Many patients with heart disease, kidney disease, diabetes, or other co-existing conditions may still diabetes, or other co-existing conditions may still be treated as outpatients. However, they should be treated as outpatients. However, they should be given a fluoroquinolone (moxifloxacin, be given a fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin) or a beta-lactam gemifloxacin, or levofloxacin) or a beta-lactam (preferably high-dose amoxicillin or amoxicillin-(preferably high-dose amoxicillin or amoxicillin-clavulanate), plus a macrolide, unless they live in clavulanate), plus a macrolide, unless they live in an area with high an area with high S. pneumoniaeS. pneumoniae resistance to resistance to macrolides.macrolides.

Antibiotic Treatments for Antibiotic Treatments for Community-Acquired Community-Acquired

PneumoniaPneumonia Current recommendations call for 7 - 10 days Current recommendations call for 7 - 10 days

of treatment for of treatment for S. pneumoniaeS. pneumoniae and 10 - 14 and 10 - 14 days for days for Mycoplasma pneumoniaeMycoplasma pneumoniae and and Chlamydia pneumoniaeChlamydia pneumoniae. However, some . However, some research suggests that patients with mild-to-research suggests that patients with mild-to-moderate community-acquired pneumonia may moderate community-acquired pneumonia may be successfully treated with 7 days or less of be successfully treated with 7 days or less of antibiotics. The shorter treatment may antibiotics. The shorter treatment may increase patient tolerance, and improve the increase patient tolerance, and improve the likelihood that patients will stick to the likelihood that patients will stick to the treatment regimen. It will also help limit the treatment regimen. It will also help limit the growing problem of antibiotic resistance.growing problem of antibiotic resistance.

Antibiotic Treatments for Antibiotic Treatments for Community-Acquired Community-Acquired

PneumoniaPneumonia Many cases of community-acquired pneumonia are Many cases of community-acquired pneumonia are

caused by caused by S. pneumoniae --S. pneumoniae -- Gram-positive bacteria that Gram-positive bacteria that usually respond to antibiotics known as beta-lactams usually respond to antibiotics known as beta-lactams (which include penicillin), and to macrolides. However, (which include penicillin), and to macrolides. However, resistant strains of resistant strains of S. pneumoniaeS. pneumoniae are increasingly are increasingly common. Most resistant strains respond to common. Most resistant strains respond to fluoroquinolines such as levofloxacin (Levaquin), fluoroquinolines such as levofloxacin (Levaquin), gemifloxacin (Factive), or moxifloxacin (Avelox). gemifloxacin (Factive), or moxifloxacin (Avelox). Another common cause of community-acquired Another common cause of community-acquired pneumonia is pneumonia is H. influenzaeH. influenzae..

In addition, other important causes of CAP, particularly In addition, other important causes of CAP, particularly in younger people, are atypical bacteria, which in younger people, are atypical bacteria, which respond to macrolides (erythromycin, clarithromycin, respond to macrolides (erythromycin, clarithromycin, or azithromycin), ketolides, or newer fluoroquinolones.or azithromycin), ketolides, or newer fluoroquinolones.

Antibiotic treatment for Antibiotic treatment for CAP is determined by a CAP is determined by a

number of factors, number of factors, including:including: The patient's history of antibiotic therapyThe patient's history of antibiotic therapy

Co-existing diseases (such as COPD, diabetes, and Co-existing diseases (such as COPD, diabetes, and heart failure)heart failure)

Whether the patient is well enough to be treated at Whether the patient is well enough to be treated at home or requires hospitalization or nursing home home or requires hospitalization or nursing home care.care.

Treatment options can include a single drug, such as Treatment options can include a single drug, such as levofloxacin or doxycycline, or combination treatment, levofloxacin or doxycycline, or combination treatment, such as a macrolide administered with a beta-lactam.such as a macrolide administered with a beta-lactam.

Antibiotics taken by mouth are generally enough for Antibiotics taken by mouth are generally enough for patients whose CAP is mild enough to be treated at patients whose CAP is mild enough to be treated at home. Intravenous antibiotics are required for home. Intravenous antibiotics are required for hospitalized patients with CAP. Antibiotic therapy hospitalized patients with CAP. Antibiotic therapy should be given for a minimum of 5 days -- longer if should be given for a minimum of 5 days -- longer if the patient still has a fever and more than one sign of the patient still has a fever and more than one sign of continuing severe illness.continuing severe illness.

Treatment of Viral Treatment of Viral InfectionsInfections

There are not as many choices for treating viral There are not as many choices for treating viral pneumonia. Oseltamivir (Tamiflu) and pneumonia. Oseltamivir (Tamiflu) and zanamivir (Relenza) have been the zanamivir (Relenza) have been the recommended drugs for influenza A or B recommended drugs for influenza A or B infections, but many strains of influenza A have infections, but many strains of influenza A have become resistant. Their use is only become resistant. Their use is only recommended if they are started in the first 48 recommended if they are started in the first 48 hours of symptoms. Taken early, these hours of symptoms. Taken early, these medications may be effective in reducing medications may be effective in reducing symptoms and duration of illness.symptoms and duration of illness.

Treatment of Viral Treatment of Viral InfectionsInfections

Patients with viral pneumonias are at risk for what are called Patients with viral pneumonias are at risk for what are called "superinfections," which generally refers to a secondary bacterial "superinfections," which generally refers to a secondary bacterial infection, usually caused by infection, usually caused by S. pneumoniaeS. pneumoniae, , S. aureusS. aureus, or , or H. H. influenzaeinfluenzae. Doctors most commonly recommend treatment with . Doctors most commonly recommend treatment with amoxicillin-clavulanate, cefpodoxime, cefprozil, cefuroxime, or a amoxicillin-clavulanate, cefpodoxime, cefprozil, cefuroxime, or a respiratory fluoroquinolone if these secondary infections occur.respiratory fluoroquinolone if these secondary infections occur.

Patients with pneumonia caused by varicella-zoster and herpes Patients with pneumonia caused by varicella-zoster and herpes simplex viruses are usually admitted to the hospital and treated simplex viruses are usually admitted to the hospital and treated with intravenous acyclovir for 7 days.with intravenous acyclovir for 7 days.

No antiviral drugs have been proven effective in adults with RSV, No antiviral drugs have been proven effective in adults with RSV, parainfluenza virus, adenovirus, metapneumovirus, the SARS parainfluenza virus, adenovirus, metapneumovirus, the SARS coronavirus, or hantavirus. Treatment is largely supportive, with coronavirus, or hantavirus. Treatment is largely supportive, with patients receiving oxygen and ventilator therapy as needed.patients receiving oxygen and ventilator therapy as needed.

Treatment of RSV in ChildrenTreatment of RSV in Children. Ribavarin is the first treatment . Ribavarin is the first treatment approved for RSV pneumonia, although it has only modest approved for RSV pneumonia, although it has only modest benefits. The American Academy of Pediatrics recommends this benefits. The American Academy of Pediatrics recommends this drug for children who are at high risk for serious complications of drug for children who are at high risk for serious complications of RSV.RSV.

Chronic BronchitisChronic Bronchitis. The . The irregular bronchovascular irregular bronchovascular

structuresstructures

Chronic BronchitisChronic Bronchitis. Chest film and magnified . Chest film and magnified view from right middle/upper lung field. view from right middle/upper lung field. Irregular contours of bronchovascular Irregular contours of bronchovascular structures with irregular diameters.structures with irregular diameters.

A segmental pneumoniaA segmental pneumonia of of s9 of right lower lobe shows s9 of right lower lobe shows

alveolar densities.alveolar densities.

LobarLobar pneumoniapneumoniain the right upper lobein the right upper lobe

EXPECTORANTS   AND   ANTITUSSIVESEXPECTORANTS   AND   ANTITUSSIVES Expectorants,  more  accurately  known  as Expectorants,  more  accurately  known  as

 bron- chomucotropic agents, are drugs used to  bron- chomucotropic agents, are drugs used to assist in the  removal  of  secretions  or  exudate assist in the  removal  of  secretions  or  exudate  from  the trachea, bronchi, or lungs. They act by  from  the trachea, bronchi, or lungs. They act by liquifying viscid mucus or mucopurulent liquifying viscid mucus or mucopurulent exudates, i.e., they are  decongestants. exudates, i.e., they are  decongestants.  Therefore,  they  are  used  in  the treatment of  Therefore,  they  are  used  in  the treatment of coughs to help expel these exudates and coughs to help expel these exudates and  secretions.   secretions.  Antitussives  are  agents  that  specifically  inhibit Antitussives  are  agents  that  specifically  inhibit  or  suppress  the  act  of  coughing.  They should  or  suppress  the  act  of  coughing.  They should not be used to suppress productive cough ing. not be used to suppress productive cough ing. Expectorants and antitussives are most Expectorants and antitussives are most commonly used in the symptomatic treatment of commonly used in the symptomatic treatment of the common   cold   or   bronchitis.   the common   cold   or   bronchitis.   

ANTITUSSIVESANTITUSSIVES Coughing is the forceful expulsion of air from the lungs. Coughing is the forceful expulsion of air from the lungs.

A cough may be productive or nonproductive. With a A cough may be productive or nonproductive. With a productive cough, secretions from the lowerproductive cough, secretions from the lowerrespiratory tract are expelled. A nonproductive cough is respiratory tract are expelled. A nonproductive cough is a dry, hacking one that produces no secretions. An a dry, hacking one that produces no secretions. An antitussive is a drug used to relieve coughing. Many antitussive is a drug used to relieve coughing. Many antitussive drugs are combined with another drug, such antitussive drugs are combined with another drug, such as an antihistamine or expectorant, and sold as as an antihistamine or expectorant, and sold as nonprescription cough medicine. Other antitussives, nonprescription cough medicine. Other antitussives, either alone or in combination with other drugs, are either alone or in combination with other drugs, are available by prescription only.available by prescription only.

ACTIONSACTIONSSome antitussives depress the cough center located in Some antitussives depress the cough center located in the medulla and are called centrally acting drugs. the medulla and are called centrally acting drugs. CodeineCodeine and and dextromethorphandextromethorphan are examples of are examples of centrally actingcentrally acting anti- anti-tussives. Other antitussives are tussives. Other antitussives are peripherally actingperipherally acting drugs, which act by anesthetizing stretch receptors in drugs, which act by anesthetizing stretch receptors in the respiratory passages, thereby decreasing coughing. the respiratory passages, thereby decreasing coughing. An example ofAn example ofa peripherally acting antitussive is a peripherally acting antitussive is benzonatatebenzonatate (Tessalon)(Tessalon), , libexinlibexin. .

ANTITUSSIVESANTITUSSIVES (cont’d) (cont’d)USESUSES

Antitussives are used to relieve a nonproductive cough.When Antitussives are used to relieve a nonproductive cough.When the cough is productive of sputum, it should be treated by the the cough is productive of sputum, it should be treated by the primary health care provider who, based on a physical primary health care provider who, based on a physical examination, may or may not prescribe or recommend an examination, may or may not prescribe or recommend an antitussive.antitussive.

ADVERSE REACTIONSADVERSE REACTIONSUse of codeine may result in respiratory depression,Use of codeine may result in respiratory depression, euphoria, euphoria, light-headedness, sedation, nausea, vomiting,and light-headedness, sedation, nausea, vomiting,and hypersensitivity reactions. The more common adverse hypersensitivity reactions. The more common adverse reactions associated with the antitussives When used as reactions associated with the antitussives When used as directed, nonprescription cough medicines containing two or directed, nonprescription cough medicines containing two or more ingredients have few adverse reactions. However, those more ingredients have few adverse reactions. However, those that contain an antihistamine may cause drowsiness.that contain an antihistamine may cause drowsiness.

CONTRAINDICATIONSCONTRAINDICATIONSAntitussives are contraindicated in patients with known Antitussives are contraindicated in patients with known hypersensitivity to the drugs. The narcotic antitussives (those hypersensitivity to the drugs. The narcotic antitussives (those with codeine) are contraindicated in premature infants or with codeine) are contraindicated in premature infants or during labor when delivery of a premature infant is anticipated. during labor when delivery of a premature infant is anticipated. Codeine is a Pregnancy Category C drug except in the pregnant Codeine is a Pregnancy Category C drug except in the pregnant woman at termwoman at termor when taken for extended periods, when it is considered a or when taken for extended periods, when it is considered a Pregnancy Category D drug. Pregnancy Category D drug.

ANTITUSSIVESANTITUSSIVES

ClassificationClassification::一．一． Central antitussivesCentral antitussives

1.1. DependentDependent central antitussivescentral antitussives

2.2. Independent central antitussivesIndependent central antitussives

二．二． Peripheral antitussivesPeripheral antitussives

DependentDependent Central Central AntitussivesAntitussives

Opioid alkaloidsOpioid alkaloids.. Morphine is the most effective drug Morphine is the most effective drug

for the suppression of cough, but for the suppression of cough, but have addiction.have addiction.

MechanismMechanism: suppressing of cough : suppressing of cough centercenter

CodeineCodeine

Selectively suppress cough center in Selectively suppress cough center in medulla oblongatamedulla oblongata

PotencyPotency: : Suppression of cough: ≈1/10 of morphineSuppression of cough: ≈1/10 of morphine Analgesia: ≈1/7 of morphineAnalgesia: ≈1/7 of morphine Respiratory depression, constipation, Respiratory depression, constipation,

tolerance, dependence tolerance, dependence ＜ ＜ that of that of morphinemorphine

PharmacokineticsPharmacokinetics:: Well absorbed from oral and injection.Well absorbed from oral and injection. 10% converted to morphine through 10% converted to morphine through

demethylation demethylation Clinical UsesClinical Uses::

Dry coughDry cough Adverse ReactionsAdverse Reactions::

Respiratory suppression in high dose;Respiratory suppression in high dose; Tolerance and physical dependence with Tolerance and physical dependence with

frequently repeated administration;frequently repeated administration; Suppress secretion of bronchial gland and Suppress secretion of bronchial gland and

movement of cilia.movement of cilia.

Independent Central Independent Central AntitussivesAntitussives

Stereoisomers of opioid molecules that are Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction devoid of analgesic effects and addiction liability.liability.

ClassificationClassification::1)1) -orphan-orphan--antitussivesantitussives : dextromethorphan : dextromethorphan2)2) amido-antitussivesamido-antitussives: pentoxyverine, clofedanol: pentoxyverine, clofedanol3)3) piperidine-antitussivespiperidine-antitussives: cloperastine: cloperastine4)4) morpholine-antitussivesmorpholine-antitussives: promolate, fominoben;: promolate, fominoben;5)5) othersothers: eprazinone, zipeprol.: eprazinone, zipeprol.

DextromethorphanDextromethorphan

Dextrorotatory stereoisomers of a Dextrorotatory stereoisomers of a methylated derivative of levorphanolmethylated derivative of levorphanol

Clinical UseClinical Use:: Dry cough. Often + Antihistamine drugDry cough. Often + Antihistamine drug

PentoxyverinePentoxyverine

Suppression of cough: ≈1/3 of Suppression of cough: ≈1/3 of codeine.codeine.

Direct suppression of cough center Direct suppression of cough center Atropine-like action and local Atropine-like action and local

anesthesia action.anesthesia action.

CloperastineCloperastine

Derivative of diphenhydramineDerivative of diphenhydramine Suppression of cough centerSuppression of cough center Blocking HBlocking H11-receptor-receptor

Peripheral AntitussivesPeripheral Antitussives

Inhibiting receptor, afferent nerve, Inhibiting receptor, afferent nerve, efferent nerveefferent nerve of cough reflex arc → of cough reflex arc → cough suppression.cough suppression.

1.1. local anesthesia actionlocal anesthesia action: narcotine, : narcotine, benzonatate;benzonatate;

2.2. Alleviative actionAlleviative action: extractum : extractum glycyrrhizae liquidum, Syrupglycyrrhizae liquidum, Syrup

ExpectorantsExpectorants Mucokinetic drugsMucokinetic drugs ClassificationClassification::I.I. By the mechanism of action:By the mechanism of action:

1.1. Mucus secretagogue drugsMucus secretagogue drugs: stimulating : stimulating gastric mucosa → reflex secretion of gastric mucosa → reflex secretion of bronchial gland↑ → dilution of sputum: bronchial gland↑ → dilution of sputum: ammonium chlorideammonium chloride. .

2.2. Mucolytic drugsMucolytic drugs::1)1) break acid mucin: break acid mucin: bromhexinebromhexine2)2) drug-SH S-S of mucin → Fragmentation: drug-SH S-S of mucin → Fragmentation:

acetylcysteineacetylcysteine3)3) Enzymolysis: Enzymolysis: α-chymotrypsinα-chymotrypsin4)4) Surfactant: Surfactant: tyloxapoltyloxapol--------Fog inhalationFog inhalation

II.II. By route of administrationBy route of administration ：：

1.1. Oral drugsOral drugs::

2.2. Fog inhalation drugsFog inhalation drugs: 1.8%NaCl, : 1.8%NaCl,

2%~7.5%NaHCO2%~7.5%NaHCO33..