PHARMACOTHERAPY OF RESPIRATORY DISEASES

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.

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. Bronchial asthma causes cough, shortness of breath, and wheezing. Bronchial asthma is an allergic condition, in which the airways (bronchi) are hyperreactive 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 as-needed 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 DrugsI. Bronchodilators

1. β receptor agonists2. Theophylline3. Muscarinic antagonists

II. Anti-inflammatory agents1. Steroids2. Anti-leukotriene agents

III. Anti-allergic agents1. Stabilizer of inflammatory cell membrane

2. 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:

intermediate-intermediate-actingacting

long-actinglong-acting

BRONCHODILATORS. sympathomimetic

• 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.

•  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.  

SALBUTAMOL

• Adverse Reactions of β2 agonists:

1) Skeletal muscle tremor

2) Cardiac effect: tachycardia, arrhymias

3) Metabolism disturbance: ketone bodies↑, acidosis,

[K+]↓

Theophylline• Methylxanthine derivatives.• Mechanism of Action:

1. Inhibit phosphodiesterase (PDE);2. Block adenosine receptors;3. Increase endogenous catecholamine (CA)

releasing;4. Interfere with receptor-operated Ca2+ channels →

[Ca2+]i↓;5. Anti-inflammatory action

• Clinical Use:

1. Asthma: maintenance treatment

2. Chronic obstructive pulmonary disease (COPD)3. 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.

Anticholinergic Drugs• Atrovent® should be

inhaled 4 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.

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.

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.

• Common agents:

I. zafirlukast and montelukast: LTD4-receptor

antagonists

II. zileuton: 5-lipoxygenase inhibitor

Leukotriene Antagonists• 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.

Leukotriene Antagonists• 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.

Glucocorticoids (GCs)

• Mechanism of Action:1. Broad anti-inflammatory efficacy

① Block the synthesis of arachidonic acid by phospholipase A2.

② Reduce bronchial reactivity.

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

Corticosteroids

• With the recognition that airway inflammation is present even in patients with mild asthma, therapy with inhaled glucocorticoids is now recommended at a much earlier stage

• Routes of administration:• Systemic administration: including oral and injection. More severe

toxicity.• Inhalation:

• Common inhalant GCs:• Fluticasone propionate , Beclomethasone dipropionate ,

Budesonide , Triamcinolone acetonide , Flunisolide The goal of all inhaled corticosteroids to (1) produce long-lasting

therapeutic effects at the pulmonary target site, (2) minimize oral bioavailability, and (3) minimize systemic side effects by rapid clearance of absorbed drug.

Corticosteroids

Local Side Effects

• Inhaled glucocorticoids have oropharyngeal side effects whose rate of appearance depends on the dose, the frequency of administration, and the delivery system used:

Dysphonia (hoarseness) Oropharyngeal CandidiasisCough and throat irritation

Step-wise approach to the treatment of asthma LTRA, leukotriene receptor antagonist; SR, slow release. The dose of

inhaled corticosteroids refers to beclomethasone dipropionate

Bronchitis• Inflammation of the mucous membrane of the bronchial tubes

Classification:• 1) asthmatic bronchitis, bronchitis which causes or aggravates

bronchospasm.2) 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.

• 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.

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

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.

Symptoms•Pneumonia manifests itself in the form of high fever, cough and chills. It is accompanied by rapid breathing and a certain amount of wheezing. The patient often complains of chest pain. Some patients also feel extremely 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.

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

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.