1. CLINICAL PHARMACY IN PULMONOLOGY

2. Introduction Symptom of respiratory system: no sputum---antitussives
Cough
sputum --- expectorants
Asthma antiasthmatic drugs

3. 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.

4. 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.

13. Antiasthmatic Drugs Bronchodilators Anti-inflammatory agents
β receptor agonists
Theophylline
Muscarinic antagonists
Anti-inflammatory agents
Steroids
Anti-leukotriene agents
Anti-allergic agents
Stabilizer of inflammatory cell membrane
H1 receptor blocker

14. Beta Adrenoceptor Agonists
Adrenaline: α,β agonist
Ephedrine: α,β agonist
Isoprenaline：β1 ,β2 agonist
β2-selective agonists
Salbutamol:
Terbutaline :
Clenbuterol:
Formoterol:
Salmeterol:
Bambuterol:
intermediate-
acting
long-acting

16. 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.

17. • Salmeterol is a bronchodilator
•  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.

19. Adverse Reactions of β2 agonists:
Skeletal muscle tremor
Cardiac effect: tachycardia, arrhymias
Metabolism disturbance: ketone bodies↑, acidosis, [K+]o↓

20. 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.

21. Theophylline Methylxanthine derivatives. Mechanism of Action:
Inhibit phosphdiesterase (PDE);
Block adenosine receptors;
Increase endogenous catecholamine (CA) releasing;
Interfere with receptor-operated Ca2+ channels → [Ca2+]i↓;
Anti-inflammatory action

22. Clinical Use: Adverse Reactions: 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.

23. 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.

24. 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.

25. Anticholinergic Drugs

26. 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.

27. 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.

28. 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.

29. Ketotifen H1 receptor blocker.
Prevent and inverse down-regulation of β2-receptor.

31. 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 5-lipoxygenase on arachidonic acid.

32. Common agents: zafirlukast and montelukast: LTD4-receptor antagonists
zileuton: 5-lipoxygenase inhibitor

33. Glucocorticoids (GCs)
Mechanism of Action:
Broad anti-inflammatory efficacy
Block the synthesis of arachidonic acid by phospholipase A2.
Reduce bronchial reactivity.
Increase the responsiveness of β-adrenoceptors in the airway.

34. Corticosteroids

35. Routes of administration:
Systemic administration: including oral and injection. More severe toxicity.
Inhalation:
Common inhalant GCs:
FP, BDP, BUD, TAA, FNS

36. 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.

37. 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