Asthma Part 1 PDF

## Drugs used in Bronchial Asthma - **Normal** airway - **During Asthma Symptoms** - Inflamed and thickened airway wall - Tightened muscles constrict airway - Thickened airway wall - Mucus **Figure 3. Effect of acute asthma attack on the lung. The combination of muscle constriction...

## Drugs used in Bronchial Asthma - **Normal** airway - **During Asthma Symptoms** - Inflamed and thickened airway wall - Tightened muscles constrict airway - Thickened airway wall - Mucus **Figure 3. Effect of acute asthma attack on the lung. The combination of muscle constriction, increased wall thickness due to inflammation, and increased mucus results in a narrowed airway, which limits air flow. Adapted from NHLBI & Wikipedia Commons.** ## Definition of Asthma Asthma, irrespective of the severity, is a chronic inflammatory disorder of the airways. ### Airway inflammation is associated with: - Airway hyperresponsiveness - Airflow limitation - Respiratory symptoms. ## Definition - Episodic and reversible bronchoconstriction - With bronchioles being the most susceptible respiratory segment - Result of - Inflammation - Bronchial smooth muscle hypertrophy and hyperactivity - Mucus plugging ## Bronchial Asthma - Derived from a Greek word meaning difficulty in breathing. - It is the most common chronic disabling disease of childhood, but it affects all age groups - **CLINICAL FEATURES:** Recurrent, episodic bouts of coughing, shortness of breath, chest tightness, and wheezing. ## Bronchial Asthma - Asthma as an inflammatory illness - Accounting 5000 deaths/ year in USA - Asthma is common disorder and it is characterized by airway inflammation and hyperresponsiveness to stimuli that produce bronchoconstriction. These stimuli include cold air, exercise, a wide variety of allergens and emotional stress. - **Extrinsic asthma:** It is mostly episodic, less prone to status asthmaticus. - **Intrinsic asthma:** It tends to be perennial, status asthmaticus is more common. ## Hygiene Hypothesis | Th1 differentiation stimuli: | Lack of Th1 differentiation stimuli: | | :---------------------------------------- | :--------------------------------------------------- | | Older siblings | Only child | | Early daycare exposure | Widespread use of ABX | | Rural environment | Urban environment with allergen sensitization: | | Childhood infections | Dust mites | | Microbial exposure | Cockroaches | - **Th1 No Allergies** Cell-mediated protective immunity - **"Still Th2" Allergies Asthma** Antibody-mediated immunity ## Asthma Diagnosis & Treatment - **Classifying Asthma Severity** | | Intermittent | Mild | Moderate | Severe | | :-------- | :-------------- | :---------- | :------------ | :----------- | | Symptoms | ≤2 days/week | ≤2 days/week | Daily | Throughout the day | | | | but not daily | | | | Night | ≤2 days/month | 3-4 times/month | >1 time/week | Often 7 times/week | | | | | but not nightly | | | Awakenings | | | | | | | ≤2 days/week | >2 days/week | Daily | Several times per day | | | | but not daily | | | | Use of SABAs | | | | | | | (not for EIB) | | | | | | None | Minor limitation | Some limitation | Extremely limited | | Interference w/ | | | | | | Normal activity | | | | | | | FEV₁>80% predicted | FEV1≥80% predicted | FEV₁=60-80% predicted | FEV₁<60% predicted | | Lung Function | FEV1/FVC normal | FEV1/FVC normal | FEV1/FVC reduced 5% | FEV1/FVC reduced >5% | | | Step 1 | Step 2 | Step 3 | Steps 4 - 6 | | Recommend | | | | | | Step for Initiating | | | | | | Treatment | | | | | **Figure 1. Classifying asthma severity and initiating treatment in youths > 12 years of age & adults. The diagnosis of asthma severity is based upon the frequency of asthma flare-ups (e.g. need for use of short-acting beta-2 agonists), interference with normal daily activities, and lung function. The recommended steps for treating asthma based upon the severity of symptoms are summarized in figure 2. ΕΙΒ: Exercise induced bronchoconstriction; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; SABA: short-acting beta-2 agonists. (Adapted from National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma. NIH Publication no. 08-4051, 2007.** ## Asthma Diagnosis - **Labs** - **ABG** - May initially show respiratory alkalosis - If CO2 is normal, respiratory failure may be imminent - Elevated CO2 (respiratory acidosis) are ominous signs and patient likely requires intubation - **Pulmonary function tests** - Peak flows are diminished - Obstructive pattern may be seen when symptomatic (↓ FEV1/FVC) - Improvement with bronchodilator administration - High airway resistance - **Methacholine challenge** - Provacative measure of hyperactivity in a well patient - Functions as a muscarinic cholinergic agonist - Reduction of FEV1 by > 20% is diagnostic of asthma - **Skin testing** - May result in hypersensitivity response to allergen when presented into skin (really diagnoses atopy, not asthma) - **Histological changes** - Terminal bronchioles - Mucus plugs - **Curschmann's spirals** - Presence of trapped epithelial cells killed by eosinophil produced major basic protein - **Charcot-Leyden crystals** - Aggregated eosinophils - Increased mucus-producing cells - Bronchi - **Thickened basement membrane** - Unique to asthma - Hypertrophy of submucosal glands and smooth muscle - Also seen in other lung disorders including chronic bronchitis - Increased immune cell presence ## Pubmed.gov **Ethn Health, 2009 Oct,14(5):527-52. doi: 10.1080/13557850902954195.** **Racial and ethnic differences in adult asthma prevalence, problems, and medical care.** **Gorman BK¹. Chu M.** **RESULTS: Asthma prevalence is lowest among Asian and Hispanic adults, and highest among black and Native American adults.** ## Chronic obstructive pulmonary diseases (COPD) - Includes chronic bronchitis and emphysema - **Chronic bronchitis:** Cough associated with inflammation of the bronchioles - **Emphysema:** Permanent destruction and enlargement of the airspaces distal to the bronchioles - COPD results airway obstruction, dyspnea, ↓ blood O₂ concentrations and ↑ blood CO₂ concentrations. - Risk factor of COPD: Smoking and old age - Treatment: Bronchodilators and long time oxygen therapy. Antibiotics can be used to treat acute exacerbations caused by bacterial infections. ## Classification - **Types** - **Extrinsic** - Typically seen in children with a genetic predisposition - **Type I hypersensitivity to an inhaled (external) allergen** - Proceeds by specific stages - Sensitization - CD4 TH2 cells produce cytokines (IL-4 and IL-5) when initially stimulated by an allergen. - IL-4 induces antibody isotype switch to IgE - IL-5 induces eosinophil activation - Early activation - Mast cells are activated by cross-linking of IgE and release immune activating substances (histamine, leukotrienes, and acetylcholine) when allergen is presented again. - Histamine results in bronchoconstriction, chemotaxis for immune cells, and mucus production - Acetylcholine results in bronchoconstriction (parasympathetic mediated) - Leukotrienes C4, D4, and E4 induce bronchoconstriction - Late activation - Eosinophils are activated - Recruited by eotaxin - Produce major basic protein, which causes further constriction/damage in the airways - **Non-allergen mediated** - Induced by - Infection - Viral URI (RSV, rhinovirus, and parainfluenza virus) - Behavioral - Exertion and stress - Chemical - Drug sensitivity (NSAIDs and aspirin) - Ozone-produced free-radicals - **Intrinsic** - **Status asthmaticus** - Life-threatening asthma attack that does not respond to standard treatments ## Presentation - **Symptoms** - Wheezing - Cough - Mucus production - Note: a child who is becoming sleepy and less responsive is most likely failing, retaining CO2 (case intro) and needs intubation. - **Physical exam** - Tachycardia - Tachypnea with use of accessory muscles - Result of reduced I/E ratio - Pulsus paradoxus - Result of increased lung volume and vascular resistance - **Auscultation** - Prolonged expiratory wheezes (sometimes inspiratory) - High pitched sibilant rhonchi - Dyspnea - Persistent cough with hyperinflation of the lungs ## Asthma Pathophysiology - **Allergens, Sensitizers, Viruses, Air pollutants?** - **NFLAMMATION** 'Chronic eosinophilic bronchitis' - **AIRWAY HYPERRESPONSIVENESS** - **TRIGGERS:** Allergens, Exercise, Cold air, SO2, Particulates - **SYMPTOMS:** Cough, Wheeze, Chest tightness Dyspnea **Source: Peter J. Barnes, MD** ## Bronchial asthma - **Etiology** **TABLE 248-1 RISK FACTORS AND TRIGGERS INVOLVED IN ASTHMA** | Endogenous Factors | Environmental Factors | | :----------------------------------------- | :------------------------------------------ | | Genetic predisposition | Indoor allergens | | Atopy | Outdoor allergens | | Airway hyperresponsiveness | Occupational sensitizers | | Gender | Passive smoking | | Ethnicity? | Respiratory infections | | | Obesity? | | | Early viral infections? | | Triggers | | :----------------------------------------- | | Allergens | | Upper respiratory tract viral infections | | Exercise and hyperventilation | | Cold air | | Sulfur dioxide | | Drugs (B blockers, aspirin) | | Stress | | Irritants (household sprays, paint fumes) | ## Pathophysiology of asthma - **IgE, Allergen, Sensory nerve activation and plasticity, Mast cells/basophils, Macrophages/dendritic cells, Cytokine chemokines, Th2 cells, Eosinophils** - **Inflammation (B, I, cr, t, al)** - **Inflammatory mediators:** Leukotrienes, Prostaglandins, Purines, Histamine, Proteases, PAF, Protons, etc. - **Mucous hypersecretion gland hyperplasia, Mucous plugs, Epithelial shedding Sub-epithelial fibrosis, Plasma leakage, edema, Vasodilation, angiogenesis, Parasympathetic nerve activation and plasticity** - **Bronchoconstriction (B, I, m, t) bronchial hyperreactivity** **Susceptible person → Stimulus triggers → Release of substance form mast cells, eosinophils, basophils, neutrophils and macrophages (release of histamine, adenosine, bradykinin and major basic protein) → Response to asthmatic stimuli-release of lipid mediators derived form arachidonic acid, such as leukotrienes and prostaglandins → Inflammation of airway, edema and desquamation of bronchial epithelium and hypertrophy of bronchial smooth muscle → Airway obstruction** ## Asthma definition - In susceptible individuals, inflammatory symptoms are usually associated with widespread but **variable** airflow obstruction and an increase in airway response to a variety of stimuli. - Obstruction is often **reversible**, either spontaneously or with treatment. ## Asthma Pathophysiology - **Symptoms** - **Airflow obstruction** - **Bronchial hyperresponsiveness** - **Airway inflammation** **The tip of the iceberg** ## Pathology - **Normal Airway: Lumen, Mucosa, Epithelium, Smooth Muscle** - **Asthmatic Airway:** Epithelial damage, Mucus secretion, Mucosal inflammation and edema, Smooth muscle contraction ## Patho-physiology - **Allergen (e.g. pollen)** - **Dendritic Cell** - **CD4+ T-cell (T2 helper cell)** - **IL-4, IL-5, IL-13 Plasma Cell** - **IgE Mast Cell** - **IL-5 Eosinophil** - **Histamine, Leukotrienes, Prostaglandin D2** - **Cytokines, Leukotrienes** ## Inflammatory mediators in asthma | Inflammatory cells | Mediators | Effects | | :------------------- | :------------------ | :----------------------------- | | Mast cells | Histamine | Bronchospasm | | Eosinophils | Leukotrienes | Plasma exudation | | TH2 cells | Prostanoids | Mucus secretion | | Basophils | PAF | | | Neutrophils | Kinins | | | Platelets | Adenosine | | | | Endothelins | AHR | | Structural cells | Nitric oxide | Structural changes | | | Cytokines | | | | Chemokines | | | | Growth factors | | | Epithelial cells | | | | Sm muscle cells | | | | Endothelial cells | | | | Fibroblast | | | | Nerves | | | ## Inflammatory mediators in asthma - **Nerves:** Acetylcholine, Neurokinin A, Substance P - **Inflammatory and Immune Cells:** Histamine, Cysteinyl leukotrienes, Cytokines, Cysteinyl leukotrienes, Leukotriene B4, Cationic proteins, Reactive O₂ metabolites - **Bronchoconstriction, Microvascular leakage, Mucus secretion** - **Inflammatory cell infiltration and activation** - **Epithelial damage** ## Inflammation in asthma patients can be present during symptom-free periods: - Symptoms resolve quickly. Inflammation, however, as measured by airway hyperresponsiveness, takes far longer time. - As chronic inflammation causes an increase in airway hyperresponsiveness, if the inflammation is not controlled, symptoms are likely to reoccur. ## Can asthma be cured? - Asthma is an eminently controllable illness. Indeed, for most sufferers, control is so effective that it amounts to a virtual cure. But asthma is not curable - Asthma is a long-term disease that has no cure. The goal of asthma treatment is to control the disease. ## Underlying principles of management - **Before initiating drug treatment check** - Compliance with existing treatment - Inhaler technique - Eliminate trigger factors ## Controlling Indoor Allergens Indoor environmental exposure to allergens (e.g. dust mites, mold, rodent, cockroach and pet allergens) & pollutants (e.g. nitrogen dioxide from gas stoves & second hand smoke) are major contributors to asthma morbidity, especially in children. **Environmental control strategies** that include eradication of the allergen source, the use of HEPA air purifiers, and allegen-proof mattress & pillow covers can be as effective as asthma controller medications for reducing asthma symptoms and flare-ups (Matsui et al, 2016). ## Aim of management - Aim of asthma management is to control the disease - **Complete Control is defined as** 1. No daytime symptoms 2. No night-time awakening due to asthma 3. No need for rescue medication 4. No asthma attacks 5. No limitations on activity including exercise 6. Normal lung function (in practical terms FEVI and/or PEF>80% predicted or best) 7. Minimal side effects from medication. ## Asthma is a two component disease - **Smooth muscle dysfunction:** Bronchoconstriction, Bronchial hyper-reactivity, Hyperplasia, Inflammatory-mediator release - **Airway inflammation/remodelling:** Inflammatory cell infiltration/activation, Mucosal oedema, Cellular proliferation, Epithelial damage, Basement-membrane thickening **Symptoms\exacerbations** ## Stepwise Approach for Managing Asthma in Adults - **Intermittent Asthma** - **Persistent Asthma: Daily Medication** | | | | | | | | | :-------- | :----------- | :----------- | :----------- | :----------- | :----------- | :----------- | | | Intermittent | mild persistent | moderate persistent | severe persistent | severe persistent | severe persistent | | | Step 1 | Step 2 | Step 3 | Step 4 | Step 5 | Step 6 | | Preferred | SABA (prn) | Low dose ICS | Low dose | Medium dose | High dose | High dose | | | | | ICS + LABA | ICS + LABA | ICS + LABA | ICS + LABA + oral | | | | | OR | | | corticosteroid | | Alternative | Cromolyn, * | Low-dose ICS | Medium-dose ICS | Medium-dose ICS | | | | | LTRA, | | + either LTRA, | + either LTRA, | | | | | or Theophylline | | Theophylline or | Theophylline or | | | | | | | Zileuton | Zileuton | | | | | | | | | AND | AND | | | | | | | Consider | Consider | | | | | | | Omalizumab for | Omalizumab for | | | | | | | patients who have | patients who have | | | | | | | allergies | allergies | | | | | | | | | | | | | | | Step up if needed | Step up if needed | | | | | | | 1ª check adherence | 1ª check adherence | | | | | | | environmental control | environmental control | | | | | | | & comorbid conditions | & comorbid conditions | | | | | | | | | | | | | | | Assess control | Assess control | | | | | | | | | | | | | | | Step down if possible | Step down if possible | | | | | | | & asthma is well controlled | & asthma is well controlled | | | | | | | at least 3 months | at least 3 months | **Severity of Symptoms** **NHLBI Asthma Guidelines 2007** ## Drugs Used In Asthma <start_of_image> - **Bronchodilators** - **B₂ agonists** - SABA - LABA - **Methylxanthines** - Degranulation Inhibitors - Muscarinic antagonists - **Anti-inflammatory agents** - **Leukotriene modifiers** - **Corticosteroids** - ICS - Oral - Antibodies - **Lipoxygenase inhibitors** - **Receptor blockers** - **Oxygen (for low Po2)** - **Inhaled Short acting beta-2 agonists (SABAs) are the preferred drugs of choice for control of acute asthma flare-ups** - **Inhaled Corticosteroids (ICS) are the drugs of first choice for maintenance treatment, reducing the need for frequent use of short acting beta-2 agonists.** ## Inhaled therapy constitutes the cornerstone of asthma treatment. ## Kinds of Asthma Treatment | Kinds of Asthma Treatment | Most Often Prescribed For | How the Medicine Works | When the Medicine is Administered | | :------------------------ | :-------------------------------------------------------- | :------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | :------------------------------------------------------------------------------------------------------ | | Controller | Regular long-term use, which helps reduce symptoms and can help prevent asthma attacks | Helps to prevent symptoms that can lead to attacks on an ongoing basis; not intended to provide quick relief from sudden symptoms | Used as a maintenance or preventive medicine to avoid asthma symptoms | | Rescue | Short-term use for acute asthma symptoms and attacks | Provides quick relief from sudden symptoms; not intended to provide long-term control of asthma | Used when symptoms occur and during an attack to treat sudden asthma symptoms | ## Medications for Asthma Management - **Relievers** - Inhaled short acting b₂-agonists - Short acting anticholinergics - Methylxanthines - **Controllers** - Inhaled corticosteroids - Inhaled long-acting b₂-agonists - leukotrienes modifiers - Sustained release theophylline - Systemic glucocorticosteroids - Anti-IgE (Omalizumab) ## Structures of isoproterenol and several ẞ2-selective analogs. - **Isoproterenol:** HO-CH-CH2-NH-C-CH3 (CH3)-CH3-OH - **Terbutaline:** HO-CH-CH2-NH-C-CH3 (CH3)-CH3-OH - **Metaproterenol:** HO-CH-CH2-NH-CH2-CH3 (CH3)-CH3-OH - **Albuterol (salbutamol):** CH2OH-HO-CH-CH2-NH-C-CH3 (CH3)-CH3-OH - **Salmeterol:** CH2OH-HO-CH-CH2-NH-CH2-(CH2)4-CH2-O-CH2-(CH2)2-CH2- **FIGURE 20-3 Structures of isoproterenol and several ẞ2-selective analogs.** ## The following medicines act as short-acting bronchodilators: - Inhaled short-acting ẞ2 agonists - Inhaled ipratropium bromide - β₂ agonist tablets or syrup - Theophyllines. - **Inhaled SABA works more quickly and/or with fewer side effects than the alternatives** ## Sympathomimetics - The selective ẞ₂ agonist is the primary bronchodilators used in the treatment of asthma/ acute asthmatic attacks. - **ẞ2 adrenergic receptor agonists stimulates the beta receptor, increasing the cAMP concentration in smooth muscle and causing bronchodilatation.** It also increase the conductance of large Ca2+-sensitive K+ channels in airway smooth muscle, leading to membrane hyperpolarization and relaxation. - The selective ẞ₂ agonist relax the bronchial smooth muscle without affecting cardiac function. In higher doses selective ẞ2 agonist increasing the heard rate by stimulating the cardiac B₁-receptor. **The selective β₂ agonist produce hypertension to patient those receiving digitalis.** - **Types:** - Long-acting ẞ2 adrenergic receptor agonists (Salmeterol; formoterol) - Short-acting β2 adrenergic receptor agonists (albuterol, levalbuterol, metaproterenol, terbutaline, and pirbuterol) ## Mechanism of action **SALBUTAMOL** - **Beta-2 Adrenoceptor attached to Gs coupled receptor** - **Phosphodiesterase** - **AMINOPHYLLINE** Inhibits phosphodiesterase preventing the breakdown of CAMP - **Adenyl Cyclase** - **CAMP** - **ATP** - **AMP** - **Protein Kinase A** - **Decreased intracellular Calcium** - **Inhibition of phosphorylation of myosin** - **Relaxation of airway smooth muscle cells** - **BRONCHODILATION** ## Albuterol - **Trade Name:** Ventolin, Combivent, Proventil Ⓡ - **Drug Class:** Beta-2 Adrenergic Agonist (short acting) - **Mechanism of Action:** - **Selective ẞ2 agonist.** The prime action of beta-adrenergic drugs is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic AMP from ATP. CAMP mediates the cellular responses - **Indications:** - To produce bronchodilation - **Prevention and relief of bronchospasm related to asthma, and/or exercise-induced bronchospasm** - **Contraindications:** - A history of hypersensitivity to albuterol - **Side Effects:** - Manifestations of overdosage may include: - Tremors - Nervousness - Tachycardia (with the potential to worsen angina) - Hypokalemia - Hypo- or hypertension - **Pharmacokinetics:** - **Aerosol and capsule formulations.** Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines or for COMT - Less than 20% of a single albuterol dose is absorbed systemically following nebulizer administration - Albuterol does not "readily" cross the blood brain barrier - Bronchodilation is maximal in ~15 minutes, and persists for 3-4 hours. - **Major drug Interactions:** - Other sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with albuterol - Albuterol should be administered with extreme caution to patients being treated with MAO inhibitors or tricyclic antidepressants, since the action of albuterol on the vascular system may be potentiated - **Pharmwiki Sections:** ANS Pharm & Pulmonary Pharm - **References:** - Galanter JM, Boushey HA (2015): Drugs Used in Asthma (Chapter 20). In: Basic and Clinical Pharmacology. 13th Ed. B Katzung, AJ Trevor (Editors); McGraw-Hill. - rxlist.com (Proventil ®) ## Albuterol Sulfate HFA Inhalation Aerosol - **NDC 0093-3174-31** - **Albuterol Sulfate HFA Inhalation Aerosol 200 Metered** - **Albuterol Sulfate HFA Inhalation Aerosol SHAKE WELL BEFORE USE TEVA 3174 PK0358** - **CONTENTS:** Each actuation delivers 108 mcg of albuterol sulfate from the mouthpiece, in propellant, for a total metered dose of 180 mcg/actuation - **WARNINGS:** Do not use more than 2 puffs at a time. If you experience any problems with this product or your asthma persists seek medical advice. See package insert for full prescribing information. ## Levalbuterol - **Trade Name:** Xopenex® - **Drug Class:** Beta-2 Adrenergic Agonist (short acting) - **Mechanism of Action:** - **The R-isomer of albuterol.** - Only the R-isomer activates the ẞ2 receptor. - **Side Effects:** - There is some experimental evidence that the S-isomer may promote inflammation. However, whether the purified R-isomer actually presents significant clinical advantages is unproven (Galanter & Boushey, 2015). - Similar to albuterol - **Pharmacokinetics:** - **Aerosol formulation** - **References:** - Galanter JM, Boushey HA (2015): Drugs Used in Asthma (Chapter 20). In: Basic and Clinical Pharmacology. 13th Ed. B Katzung, AJ Trevor (Editors); McGraw-Hill. - Tripp K, McVicar WK, Nair P et al.: A cumulative dose study of levalbuterol and racemic albuterol administered by hydrofluoroalkane-134a metered-dose inhaler in asthmatic patients. J Allergy Clin Immunol 122:544-549, 2008. - rxlist.com Xopenex ® - **Keywords** ## Pirbuterol - **Trade Name:** Maxair® - **Drug Class:** Beta-2 Adrenergic Agonist (short acting) - **Mechanism of Action & Side Effects:** - Similar to albuterol - **Pharmacokinetics:** - **Aerosol formulation** - **Notes:** - If administered in equi-potent doses, each ẞ2 agonist will produce the same degree of smooth muscle relaxation. There is "generally" no major advantage of one short-acting ẞ2 agonist over another (Corelli, 2005). - **References:** - Galanter JM, Boushey HA (2015): Drugs Used in Asthma (Chapter 20). In: Basic and Clinical Pharmacology. 13th Ed. B Katzung, AJ Trevor (Editors); McGraw-Hill. - Corelli RL (2005): Pulmonary Disorders. Chapter 23. In: Applied Therapeutics. The Clinical Use of Drugs. 8th Edition. Koda-Kimble MA, Young LY, Kradjan WA, Guglielmo BJ, Alldredge BK, Corelli RL (Editors). Lippincott Williams & Wilkins. pp 23-1 to 23-43. - rxlist.com pirbuterol (Maxair®) ## Long Acting Beta2 Agonists ### Salmeterol - **Trade Name:** Serevent Ⓡ - **Drug Class:** Beta-2 Selective Sympathomimetic (long acting) - **Indications:** - Used in combination therapy with corticosteroids for maintenance treatment of asthma & in the prevention of bronchospasm in patients with reversible obstructive airway disease. - They should NOT be used for monotherapy in the treatment of asthma (see Black Box warning). - Beta-2 agonists have no anti-inflammatory action. - **Pharmacokinetics:** - Taken by inhalation. - Takes 10-25 minutes to act, and therefore should not be used to terminate acute bronchoconstriction. - A long acting (12 hrs or more duration of action) beta-2 agonist. - Its long duration results from its high lipid solubility which allows it to anchor or "moor" within the vicinity of the adrenoreceptor. - **Side Effects:** - **BLACK BOX WARNING:** Increased asthmatic related deaths see formoterol - **References:** - Boushey HA (2012): Drugs Used in Asthma (Chapter 20). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors); McGraw-Hill (Access Medicine). - rxlist.com - salmeterol (Serevent Diskus ®) ### Formoterol - **Trade Names:** Foradil, Brovana Ⓡ - **Drug Class:** Beta-2 Selective Sympathomimetic (long acting) - **Indications:** - Used in combination therapy with corticosteroids for maintenance treatment of asthma & in the prevention of bronchospasm in patients with reversible obstructive airway disease. - They should NOT be used for monotherapy in the treatment of asthma (see Black Box warning). - Beta-2 agonists have no anti-inflammatory action. - **Pharmacokinetics:** - Significant improvement in forced expiratory volume (FEV1) occurs within 5 minutes, post dose (Cote et al, 2009) - Formoterol as a faster onset of action compared to salmeterol due to its lower lipophilicity - Formoterol has a ~12 hour duration of action - **Side Effects:** - WARNING: a клиниical trlal suggests that there may be a very smnall (<1%), buиt slgnlflcanиt lncrease ln asthma-related death ln patlеnиts taklng salmeterol vs. placеbo ovеr a 28 wееk course of drug therapy. Posslblе ехрlаnаtlons for thls observation Include: 1. One hypothesis for the increased deaths is that patients may feel better when taking long-acting beta agonists, and as a result take either lower doses of inhaled corticosteroids, or no corticosteroids at all. This could result in an increase of underlying tissue inflammation, putting patients at an increased risk for a fatal asthma attack. 2. A second hypothesis is that chronic (round the clock) exposure of beta-2 receptors to long-acting beta-2 agonists results in the development of desensitization (tolerance) to all beta-2 agonists. The loss of beta-2 effect then results in an inability to reverse inflammation-induced bronchoconstriction, and an increased incidence of severe asthma related bronchoconstriction. - **Black Box Warning: ASTHMA RELATED DEATH** - Long acting beta-2 agonists such as salmeterol may increase the risk of asthma-related death. These medications should ONLY be used as additional therapy for patients not adequately controlled by low to medium dose inhaled corticosteroids. Data from a large placebo-controlled US trial (Salmeterol Multi-center Asthma Research Trial) that compared salmeterol (Serevant) with placebo added to usual therapy found an increased incidence of asthma-related deaths in patients on salmeterol (13 out of 13,176 patients treated for 28 weeks) vs patients on placebo (3 deaths out of 13, 179 patients). - **References:** - Boushey HA (2012): Drugs Used in Asthma (Chapter 20). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors); McGraw-Hill (Access Medicine). - Cote C et al (2009): Faster onset of action of formoterol versus salmeterol in patients with chronic obstructive pulmonary disease: A multicenter, randomized study. Pulm Pharm Therap 22(1):44-49. doi:10.1016/j.pupt.2008.11.010 - rxlist.com - formoterol (Foradil ®) ## Systemic Bronchodilators ### Terbutaline - **Trade Names Brethine, Bricanyl Ⓡ** - **Drug Class:** Beta-2 Adrenergic Agonist - **Mechanism of Action:** same as albuterol - **Indications:** - Prevention or Reversal of bronchospasm in patients with bronchial asthma and reversible bronchospasm associated with bronchitis and emphysema - In some patients the severity of bronchoconstriction can limit the delivery of drugs by inhalation, making systemic drug administration necessary - **Contraindications:** - Hypersensitivity - **Side Effects:** - Similar to those commonly seen with other sympathomimetic agents (e.g. albuterol) - All these reactions are transient in nature and usually do not require treatment - **Pharmacokinetics:** - Typically given by s.c. injection - **Major drug Interactions:** - Same as with albuterol - **References:** - Boushey HA (2012): Drugs Used in Asthma (Chapter 20). In: Basic and Clinical Pharmacology. 12e. B Katzung, SB Masters AJ Trevor (Editors); McGraw-Hill (Access Medicine). - rxlist.com (Terbutaline Sulfate) ## Epinephrine - **Trade Name:** generic, Adrenalin, Epipen ® - **Drug Class:** Catecholamine, Sympathomimetic - **Mechanism of Action:** - Epinephrine stimulates both a1 & a2 and ẞ1 & ẞ2 receptor subtypes on sympathetic effector cells. - When given i.v. it is a very potent vasoconstrictor and cardiac stimulant. - The rise in systolic blood pressure results from a ẞ1 mediated increase in heart rate and ventricular contractility - The rise in diastolic pressure results from stimulation of a1 and 02 receptor mediated vasoconstriction in many vascular beds - Epinephrine also stimulates ẞ2 receptors present in skeletal muscle blood vessels, resulting in their