Case Study for Undergraduates Bronchial Asthma By, Lokesh Shetty, MPharm firstname.lastname@example.org
An 8-year-old boy is brought to your office because of a chronic cough.His mother says that he coughs frequently throughout the day and willhave symptoms 2 or 3 nights a month as well. This has been a problemon and off for approximately a year, but seems to be worse in the springand fall. He also coughs more when he is riding his bike or playingsoccer. He has been treated twice in the past year for “bronchitis” withantibiotics and cough suppressants but he never seems to clear upcompletely. His examination is normal except for his lungs, which revealexpiratory wheezing. You diagnose him with asthma and prescribe analbuterol inhaler.◆ What is the mechanism of action of the albuterol?◆ What are the most common side effects of the albuterol?◆ What medications can be used to provide long-term control of theasthma symptoms?
Summary: An 8-year-old boy with asthma is prescribed an albuterolinhaler.◆ Mechanism of action of albuterol: B 2-Adrenoceptor agonist inbronchial smooth muscle causes smooth muscle relaxation, inhibits therelease of mediators from mast cells, and stimulates mucociliaryclearance.◆ Most common side effects of albuterol: Skeletal muscle tremor,tachycardia, and cough.◆ Medications for the long-term control of asthma: Inhaledcorticosteroids, long-acting B2-adrenoceptor agonist, cromolyn ornedocromil; second-line agents include oral theophylline, leukotrieneinhibitors, or systemic corticosteroids.
CLINICAL CORRELATION:Asthma It is characterized by acute episodes of Bronchoconstrictioncaused by underlying airway inflammation. A common finding inasthmatics is an increased responsiveness of the bronchi and tracheato exogenous or endogenous stimuli that results in inappropriatecontraction of smooth muscle in the airway, and production of thickviscid mucus and mucosal thickening from edema and cellularinfiltration. Asthma typically occurs with an early-phase response lastingapproximately 1–2 hours that is triggered by autacoids andinflammatory mediators such as histamine, leukotrienes, andprostaglandins. Immunoglobulin E-sensitized (IgE-sensitized) mastcells play a key role in the early-phase response.
The late-phase response that occurs 2–8 hours later is mediated bycytokines from T-helper type 2 (Th2) lymphocytes including granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins 4, 5, 9,and 13. These mediators attract and activate eosinophils and increaseIgE production by B cells. This leads to the chronic Bronchoconstriction,continued mucus production, and cellular infiltration that typify theunderlying inflammation in asthma.Inhaled B2-adrenoceptor agonists (B-agonists) are widely used totreat the acute bronchospastic episodes. They work to relax bronchialsmooth muscle via a cyclic adenosine monophosphate (cAMP)-mediatedreduction in intracellular calcium concentrations, resulting in relaxation.The increase in cAMP also reduces the release of mediators from mastcells in the airways.
Frequent use of these agents can result in a tachyphylaxis(Rapidly decreasing response to a drug following initialdoses.). Patients who require frequent dosing with inhaled â-agonists should also be treated with medications to reduce thefrequency of bronchospastic events. These include inhaledcorticosteroids, long-acting â-agonists, cromolyn or nedocromil, andoral methylxanthines, corticosteroids, or leukotriene modifiers.Inhaled B-agonists commonly cause tremor, tachycardia, andcough.
Objectives1. Understand the medications used in the treatment ofasthma, their mechanisms of action, and adverse effects.2. Know the difference between short-acting symptomatictreatments and long-acting preventive therapies.3. List the mediators of airway inflammation involved inasthma.
Classes of drugs used to treat asthma:Approaches:1. Prevention of Ag: Ab reaction: Avoiding Antigen, if Ag is identified2. Mimicking dilator neurotransmitter: Sympathomimetic3. Blockage of constrictor neurotransmitter: anticholinergics4. Antagonism of release mediators: antihistamines, PAF antagonists5. Prevention of release of mediators: Mast cell stabilisers6. Prevention of bronchial hyperactivity: Corticosteroids7. Directly acting bronchodilators : Methylxanthines
Sympathomimetics:Beta 2 Agonist Short acting and long acting type (selective b2)short albuterol, terbutaline, metaproterenol, and pirbuterol The recommendation for quick relief in all patients regardless ofseverity is two to four puffs of a short-acting inhaled b2-agonistone to three times per occurrence. No CVS through beta 1 Activation of b2-receptors causes bronchodilation.Onset of action occurs in minutes and lasts for 4–6 hours.Long Acting : salmeterol and formoterol, have a much longerhalf-life (up to 12 hours). available in metered-dose inhalers agents produces the same relaxation in airway smooth musclesand also appears to decrease the release of mediators from mastcells and lymphocytes.
Glucocorticoids: Systemic: Hyrocortisone, PrednisoloneInhalational : Beclomethosone , fluticasone etc important treatment for mild persistent and more severeasthma They reduce bronchial hyperirritability, mucosal oedema bysuppressing inflammatory response to AG:AB reaction.Glucocorticoids are potent anti-inflammatory agents andreduce the production of inflammatory mediators. They do not cause relaxation of bronchial smooth muscle. SE :oral candidiasis, increased loss of calcium from bone, andrarely, suppression of the hypothalamic-pituitary-adrenalaxis.
Modifier of Leukotriene Biosynthesis and Leukotriene antagonists: Leukotrienes B4, C4, and D4 play an important role in thepathogenesis of asthma. LCB4 is a potent neutrophile chemoattractant LTC4 and LTD4 are involved in bronchoconstriction andoverproduction of airway mucus. These mediators are derived from arachidonic acid via theenzyme 5-lipoxygenase. Zileuton is an inhibitor of 5-lipoxygenase and thereby decreasesthe biosynthesis of leukotrienes Zafirlukast and montelukast are specific, competitive,Cys-LT1 receptor antagonists. The two classes of drugs are equally effective in the treatment ofmild-to-moderate persistent asthma Zileuton has been associated with liver toxicity, and monitoringliver enzymes is recommended.
Methylxanthines: theophylline, theobromine, and caffeine. Methylxanthines act by inhibiting cyclic nucleotidephosphodiesterases, thereby increasing intracellular cAMP andcyclic guanosine monophosphate (cGMP).chromones, cromolyn and nedocromil MOA inhibition of mediator release from mast cells andsuppression of activation of leukocytes. They have no effect on airway smooth muscle tone and areineffective in reversing Bronchospasm They are poorly absorbed into the systemic circulation and havemild adverse effects including throat irritation,cough, and nasal congestion.
Anticholinergics: Muscarinic antagonists can effectively block theBronchoconstriction, and the increase in mucus secretion thatoccurs in response to vagal discharge. Ipratropium bromide is a quaternary ammonium derivative ofatropine that can be administered by inhalation and that is poorlyabsorbed into the systemic circulation. Ipratropium bromide is useful in patients that are unresponsiveor cannot tolerate β2-receptor agonists and in COPD.
monoclonal antibody: IgE binding to mast cells plays an important role in antigen-induced asthma. A newly developed monoclonal antibody (Omalizumab) thattargets circulating IgE and prevents its interaction with mast cells. thus in treatment of asthma. Omalizumab is indicated for adults and children older than 12years with moderate-to-severe persistent asthma.