Case Study

A 10-year-old girl with a history of poorly controlled asthma presents to the emergency department with severe shortness of breath and audible inspiratory and expiratory wheezing. She is pale, refuses to lie down, and appears extremely frightened. Her pulse is 120 bpm and respirations 32/min. Her mother states that the girl has just recovered from a mild case of flu and had seemed comfortable until this afternoon. The girl uses an inhaler (albuterol) but "only when really needed" because her parents are afraid that she will become too dependent on medication. She administered 2 puffs from her inhaler just before coming to the hospital, but "the inhaler doesn't seem to have helped." What emergency measures are indicated? How should her long-term management be altered?

Introduction Epidemiology of Asthma Symptom of Asthma Classification of Asthma Pathogenesis of Asthma Drugs used for Asthma Basic Pharmacology of Bronchodilators Sympathomimetic b-agonists Methylxanthine Drugs Antimuscarinic Agents Basic Pharmacology of Anti-inflammatory Agents Corticosteroids Cromolyn & Nedocromil Leukotriene inhibitors Other Drugs in the Treatment of Asthma Emergency Asthma Situations

Introduction
Epidemiology of Asthma

Symptom of Asthma
The clinical hallmarks of Asthma Coughing, Shortness of breath, Chest tightness, Wheezing The Symptom of Asthma Smooth muscle contraction Vascular congestion Bronchial wall edema Thick, tenacious secretion

Classification of Asthma (NIH Guidelines)

Type Symptoms Exacerbations Nighttime symptoms Mild Intermittent < 2x/week Brief Mild Persistent >2x/week may affect activity > 2x/month Moderate Persistent Daily Severe Persistent Continuous

Affect activity Frequent, FEV1 2x/week, may last days > 1x/week frequent

< 2x/month

FEV1 PEF FEV1 /FVC

FEV1>80%; PEF >50% Normal

FEV1=80%; PEF >50% Normal

FEV1=60-80% FEV1=60%; PEF 33-50% PEF <30% 1 sec Time <5% >5%

1-second Forced Expiratory Volume (FEV1); Normal peak flows (PEF) Forced vital capacity (FVC)
Data for above table and treatment algorithm adapted from NIH publication No. 97-04053 Practical Guide for the Diagnosis and Management of Asthma, October 1997

Pathogenesis of Asthma

Pathogenesis of Asthma
Allergens (IgE):pollens; mites; Animal dander; Cockroaches Drugs: b-antagonist; NASAD; Sulfites; Benzalkonium chloride Respiratory Infection: Respiratory syncytial virus (RSV) Rhinovirus.. Air pollution: Fog; Smoke; Ozone; Nitrogen dioxide; Sulfur dioxide Cold air Emotional: Stress; Laughter; Anxiety Exercise: dry, cold weather especially

N engl j med 2006,355;21

Basic Pharmacology of Bronchodilators

Basic Pharmacology of Bronchodilators

Drugs used for Asthma

Bronchodilators I. Sympathomimetic b-agonists Albuterol (Ventolin) Bitolterol (Tomalate) Ephedrine Epinephrine Formoterol Isoetherine (Bronkosol) Isoproterenol (Isuprel) Metaproterenol (Alupent) Pirbuterol (Maxair) Salmeterol (Serevent) Terbutaline (Brethine) II. Methylxanthines Aminophylline Theophylline Oxtriphylline III. Antimuscarinic Agents Ipratropium (Atrovent)

Anti-inflammatory agents I. Corticosteroid (Aerosol) Beclomethasone (Banceril) Dexamethasone (Decadron) Flunisolide (AeroBid) Fluticasone (Flovent) Triamcinolone acetonide Methylprednisolone Prednisone (Deltasone)
II. Mast cell stabilizer Cromolyn sodium(Intal) Nedocromil (Tilade) III. Lipo-oxygenase inhibitor Zileuton (Zyflo) IV. Leukotriene Antagonists Zafirlukast (Accolate) Montelukast (Singulair)

Bronchodilators
I. Sympathomimetic b-agonists
Epinephrine, ephedrine, isoproterenol Epinephrine: effective, rapidly; SC or inhaled Ephedrine: 2000 y Isoproterenol: potent Albuterol, terbutaline, metaproterenol pirbuterol, & bitolterol Effective Inhaled or, oral administration Long duration of action. Salmeterol & formoterol. Long-acting b2-selective agonists

Mechanism Stimulate b-adrenergic receptors Inhibit mast cells degranulation Pharmacological Effects Inhibit microvascular leakage Increase mucociliary transport Affecting the mucous secretions Increasing ciliary activity Toxicities Cardiac arrhythmias, Hypoxemia acutely, Tachyphylaxis, tolerance

b-agoists

II. Methylxanthine Drugs

1. Chemistry: Theophylline: 1,3-dimethylxanthine Theobromine: 37 dimethylxanthine Caffeine: 1,3,7-trimethylxanthine From tea, coffee, cocoa 2. Pharmacokinetics: BBB 3. Mechanism of action: (1) Inhibit phosphodiesterase (PDE4)
Cilomilast; roflumilast

(2) Inhibit the receptors of adenosine. (3) Activate the Ryanodine receptor (4) Increases in CD4 and CD8 lymphocytes (5) Anti-inflammatory action

Cilomilast

roflumilast

 PDE cAMP 100/100030_1201-51

A. Cromolyn sodium B. Theophylline C. Salbutamol D. Ipratropium

Pharmacodynamics:
CNS: increased alertness; reduced fatigue; nervousness; insomnia, medullary stimulation, convulsions. CVS: chronotropic; Inotropic low doses:catecholamine release ; presynaptic adenosine receptors high doses:cAMP (PDE4); Ca influx GI: secretion of gastric acid & enzymes Kedney: weak diuretics Smooth Muscle Effects: Bronchodilation Clinical Used: most effective xanthine bronchodilator Relieves airway obstruction; reduces symptoms severity in acute asthma long-term control of asthma alone or with GCSs.

 theophylline 100030_3103
A. B. C. D. cAMP cADP cATP

Caffeine 9802-107100-38
A. B. C. D.

III. Antimuscarinic Agents

Nature source:Datura stramonium for asthma in India atropine Man drake

Mechanism of Action: inhibition of the muscarinic receptors .

Clinical Use of Muscarinic Antagonists: Atropine sulfate: aerosol Ipratropium bromide a more selective 4 ammonium high doses in air route poorly absorbed into the circulation does not readily enter CNS Tiotropium COPD. 24-hour duration

 100130-1304-33
A. propranolol B. carbachol C. acetylcholine D. ipratropium

Datura stramonium for asthma in India atropine

Mechanism of Action: inhibition of the muscarinic receptors . Clinical Use of Muscarinic Antagonists: Atropine sulfate: aerosol Ipratropium bromide a more selective 4 ammonium high doses in air route poorly absorbed into the circulation does not readily enter CNS Tiotropium, COPD. 24-hour duration

 -blocker bioavailability 40%

098/002000c02-56

A. Atropine B. Scopolamine C. Glucocorticoid D. Ipratropium

Anti-inflammatory Agents

I. Corticosteroids
Mechanism of Action: Phosphlipase A2 inhibitor Pharmacological effects Anti-inflammatory activity (1) Block leukotriene synthesis (2) Inhibit cytokine production (3) Reduction of mucosal oedema (4) Adhesion protein activation Immunosuppressive activity Reverse b2-receptor down-regulation

CLINICAL USES Asthma Chronic bronchitis COPD Rhinitis

SIDE EFFECTS
Metabolic effects, Growth suppression, Fluid retention, osteoporosis, Increase susceptibility to infection, Cataract, GI symptoms, Adrenal suppression

Aerosol corticosteroid
Beclomethasone (Banceril) Fluticasone (Flovent) Dexamethasone (Decadron) Triamcinolone acetonide (Azmacort) Flunisolide (AeroBid)

Oral corticosteroids

Methylprednisolone (Solu-Medrol) Prednisone (Deltasone)

 9901-303200-78
A. Prednisolone B. Aspirin C. Tetracycline D. Streptomycin

 9901-103100-27
A. Albuterol B. Budesonide C. Cromolyn sodium D. Theophylline

II. Cromolyn & Nedocromil

Mechanism of Action: inhibit mast cells degranulation little inhibitory from basophils. alteration delayed chloride channels. inhibition antigen challenge inhibition inflammatory response Clinical Use blocks the Bronchoconstriction by antigen inhalation by exercise by aspirin by allergen before unavoidable exposure to an allergen. rhinoconjunctivitis hay fever

Adverse/Side effects:
Throat irritation, Cough, Wheezing, Mouth dryness, Chest tightness , Reversible dermatitis, myositis, gastroenteritis Can be prevented by inhaling a b2adrenoceptor agonist. Serious adverse effects are rare. Reversible dermatitis, myositis, gastroenteritis, pulmonary infiltration with eosinophilia and anaphylaxis

III. 5-lipoxygenase inhibitor

Zileuton
montelukast

IV. Leukotriene inhibitors

Zafirlukast, Montelukast
Selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slowreacting substance of anaphylaxis (SRSA). Indication: For the prophylaxis and chronic treatment of asthma. airway edema, smooth muscle constriction, Altered inflammatory process.

Other Drugs in the Treatment of Asthma

Anti-IgE Mab, Anti-CD4 Mab, Anti-IL-5 Mab, Anti-IL-4 biologics, Anti-TNF biologics Omalizumab (Anti-IgE Mab) Binds to IgE receptors (FC-R1 and FC-R2 receptors) Directed against cytokines (IL-4, IL-5, and IL-13) Antagonists of cell adhesion molecules Protease inhibitors, Inhibits the binding of IgE to mast cells. Reduced exacerbations 88%. Shifting CD4 lymphocytes TH 2 to TH 1. Selective inhibition of the subset of TH2.

Nature Reviews Drug Discovery 2004 3, 831-844

Omalizumab

Nature Reviews Drug Discovery 2004 3, 831-844

GINA (Global Initiative for Asthma) guidelines

Mild persistent

Intermittent

Moderate persistent

Severe persistent
Reliever

Short-acting 2 p.r.n
Inhalated Corticosteroids

Long-acting 2
Oral Anti-leukotriene

Controller

Emergency Asthma Situations

Mild attacks b2 agonists (aerosolized)
(20 minutes/three doses)

Epinephrine (SC) Aminophylline (IV)

(soluble salt of theophylline)

Severe attacks 1. Oxygen 2. Albuterol (aerosolized) 3. Prednisone or Methylprednisolone Respiratory failure supervenes 1. General anesthesia 2. intubation 3. mechanical ventilation.

Antigens, drugs, Infections, Pollution

Pathogenesis:

Avoidance

mast cell
Cromolyn & Nedocromil

b-agonists Theophylline Anticholinergics

mediators

Corticosteroid Leukotriene antagonist 5-lipoxygenase inhibitor

early response: brochoconstriction Brochoconstriction symptoms

late response: inflammation Brochial hyperreactivity

Chronic Obstructive Pulmonary Disease (COPD)

COPD: airflow limitation not fully reversible with bronchodilator. COPD: 85% prolonged habitual cigarette smoking, 15% nonsmokers. COPD: older patients, neutrophilic inflammation, poorly responsive even to high-dose inhaled corticosteroid therapy. Relief of acute symptoms, 1. inhalation of a short-acting agonist (albuterol), 2. anticholinergic drug (ipratropium bromide). Persistent symptoms of exertional dyspnea:
1. long-acting bronchodilator, (eg, salmeterol) 2. long-acting anticholinergics (eg, tiotropium) 3. Theophylline improve diaphragm contractile-ventilatory capacity. 4. Continuous nasal oxygen. 5. Routine use of antibiotics

Allergic rhinitis
Allergic rhinitis: a collection of symptoms, mostly in the nose and eyes, which breathe in something allergies Symptoms: Itchy: nose, mouth, eyes, throat, skin, or any area Problems with smell Runny nose Sneezing Tearing eyes

Treatments for allergic rhinitis

ANTIHISTAMINES: cause little or no sleepiness fexofenadine (Allegra), cetirizine (Zyrtec). Azelastine (Astelin) nasal spray CORTICOSTEROIDS Nasal corticosteroid sprays are the most effective DECONGESTANTS Pseudoephedrine; phenylephrine; oxymetazoline (3 days). benzalkonium chloride: worsen symptoms and cause infection. OTHER TREATMENTS The leukotriene inhibitor (Singulair) ALLERGY SHOTS Allergy shots (immunotherapy): regular injections of the allergen, given in increasing doses (each dose is slightly larger than the previous dose) that may help the body adjust to the antigen.

Mucokinetic Agents
Classification Mucolytics Reducing Agents Proteolytic enzymes Deoxyribonuclease Mechanism of Action Examples

Expectorants
Mucoregulators Hydrating Agents Tensioactive Agents Other compounds

Destroy disulfide bonds Hydrolyze peptide bonds Destroys deoxyribonucleic acid fibers Stimulate gastropulmonary reflex Alter the secretory activity of the bronchial mucosa ctivate sialomucin synthesis Correct water and electrolyte disorders in secretions Make secretions less adhesive Modify fibrillate structures(?)

N-acetylcysteine Trypsine Deoxyribonuclease Guaifenesin

Bromhexine

Carbocysteine Ammonium chloride Water Tyloxapol Eprazinone